The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes

REVIEW

Mary-Elizabeth Patti and Silvia Corvera

Research Division, Joslin Diabetes Center (M.-E.P.), and Harvard Medical School (M.-E.P.), Boston, Massachusetts 02215; and Program in Molecular Medicine (S.C.), University of Massachusetts Medical School, Worcester, Massachusetts 01605 Downloaded from https://academic.oup.com/edrv/article/31/3/364/2354793 by guest on 23 September 2021

The pathophysiology of type 2 diabetes mellitus (DM) is varied and complex. However, the association of DM with obesity and inactivity indicates an important, and potentially pathogenic, link between fuel and energy homeostasis and the emergence of metabolic disease. Given the central role for mitochondria in fuel utilization and energy production, disordered mitochondrial function at the cellular level can impact whole-body metabolic homeostasis. Thus, the hypothesis that defective or insufficient mitochondrial function might play a potentially pathogenic role in mediating risk of type 2 DM has emerged in recent years. Here, we summarize current literature on risk factors for diabetes pathogenesis, on the specific role(s) of mitochondria in tissues involved in its pathophysiology, and on evidence pointing to alterations in mitochondrial function in these tissues that could contribute to the development of DM. We also review literature on metabolic phenotypes of existing animal models of impaired mitochondrial function. We conclude that, whereas the association between impaired mitochondrial function and DM is strong, a causal pathogenic relationship remains uncertain. How- ever, we hypothesize that genetically determined and/or inactivity-mediated alterations in mitochondrial oxidative activity may directly impact adaptive responses to overnutrition, causing an imbalance between oxidative activity and nutrient load. This imbalance may lead in turn to chronic accumulation of lipid oxidative metabolites that can mediate insulin resistance and secretory dysfunction. More refined experimental strategies that accurately mimic potential reductions in mitochondrial functional capacity in humans at risk for diabetes will be required to determine the potential pathogenic role in human insulin resistance and type 2 DM. (Endocrine Reviews 31: 364–395, 2010)

I. Type 2 Diabetes Pathogenesis I. Type 2 Diabetes Pathogenesis A. Risk factors associated with type 2 diabetes II. General Overview of Mitochondrial Biology ype 2 diabetes mellitus (DM) in the United States and A. The dynamic morphology of mitochondria B. Mechanisms that control mitochondrial density and T around the world has reached epidemic proportions. capacity At present, 17.9 million people in the United States have III. Role of Mitochondria in Tissue-Specific Contexts been diagnosed with diabetes, with an additional 5.7 mil- A. Muscle lion undiagnosed (1). Together, this encompasses 8% of B. Adipose tissue C. Liver the population, and thus, diabetes is a major public health D. Pancreatic ␤-cells issue. In addition, current data indicate that 57 million IV. Experimental Strategies to Explore the Relationship be- Americans suffer from prediabetes (defined as fasting tween Mitochondrial Function and DM blood glucose between 100 and 125 mg/dl) (1). Diabetes A. PGC-1 ␣ and ␤ overexpression disproportionately affects specific ethnic populations, B. PGC-1 knockout models C. Other mitochondrial function defects with risk increased 1.8-fold in African-Americans, 1.7- V. Conclusions fold in Mexican-Americans, and 2.2-fold in Native Amer-

ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: BMI, Body mass index; CoA, coenzyme A; COX, cytochrome oxidase; CPT1, Printed in U.S.A. carnitine palmitoylotransferase 1; DM, diabetes mellitus; ERR, estrogen-related receptor;

Copyright © 2010 by The Endocrine Society ETC, electron transport chain; FADH2, reduced flavin adenine dinucleotide; MIDD, mater- doi: 10.1210/er.2009-0027 Received July 2, 2009. Accepted December 24, 2009. nally inherited diabetes and deafness; mtDNA, mitochondrial DNA; NADH, reduced nic- First Published Online February 15, 2010 otinamide adenine dinucleotide; NASH, nonalcoholic steatohepatitis; NMR, nuclear magnetic resonance; NRF, nuclear respiratory factor; OXPHOS, oxidative phosphorylation; PGC, PPAR␥ coactivator; PPAR, peroxisome proliferator-activated receptor; ROS, reactive oxygen species; RQ, respiratory quotient; TCA, tricarboxylic acid; UCP, uncoupling protein.

364 edrv.endojournals.org Endocrine Reviews, June 2010, 31(3):364–395 Endocrine Reviews, June 2010, 31(3):364–395 edrv.endojournals.org 365 icans. In addition to the major health consequences to glucose disposal during the hyperinsulinemic euglycemic individuals, including higher risk of death, heart disease, clamp or by iv glucose tolerance testing, is common in stroke, kidney disease, blindness, amputations, neuropa- high-risk individuals years before the onset of type 2 DM thy, and pregnancy-related complications, diabetes and its (27–29). However, insulin resistance is not predictive of complications result in a total cost of $174 billion in the diabetes in individuals without a family history of diabe- United States (2). By far, the largest proportion is derived tes, indicating that additional unidentified factors are nec- from type 2 DM, which accounts for more than 90% of essary for disease progression (30). diabetes. Unfortunately, the incidence of diabetes has Multiple mechanisms have recently emerged as poten- more than doubled in the past 25 yr, with 1.6 million new tial causes of insulin resistance and/or diabetes progres- cases diagnosed in adults in 2007 (2) and a projected in- sion, among them impaired mitochondrial capacity crease of 165% from 2000 to 2050 (4). and/or function; altered insulin signaling due to cellular Downloaded from https://academic.oup.com/edrv/article/31/3/364/2354793 by guest on 23 September 2021 Intimately linked with the rise in diabetes prevalence is lipid accumulation, proinflammatory signals, and endo- the burgeoning epidemic of obesity around the world, par- plasmic reticulum stress; and reduced incretin-dependent ticularly in developed societies (5). In 2004, 17% of chil- and -independent ␤-cell insulin secretion. In this review, dren in the United States between ages 2 and 19 yr were we will focus on a critical assessment of the evidence link- overweight, and 32% of adults over age 20 were obese (6). ing mitochondrial function to diabetes pathogenesis, at Both obesity and related inactivity are likely to contribute both a cellular and whole-body level. to the pathogenesis of diabetes because the incidence of diabetes can be reduced by modest weight loss and exercise (7–9). In light of these findings, an important public health II. General Overview of Mitochondrial Biology goal should be to understand the complex pathophysiology of diabetes and to identify and target specific mech- Mitochondria are double-membrane organelles that serve anisms to prevent DM in at-risk individuals. multiple essential cellular functions (Fig. 1) mediated by thousands of mitochondrial-specific proteins encoded by A. Risk factors associated with type 2 diabetes both the nuclear and mitochondrial genomes (31, 32). Multiple physiological abnormalities can be found in Although mitochondria are most often recognized for individuals with established type 2 DM, defined on the their role in generating the majority of cellular ATP via basis of elevations in fasting and/or postprandial glucose oxidative phosphorylation (OXPHOS), other essential (2). These include insulin resistance in muscle and adipose metabolic functions include the generation by the tricar- tissue, ␤-cell dysfunction leading to impaired insulin se- boxylic acid (TCA) cycle of numerous metabolites that cretion, increased hepatic glucose production, abnormal function in cytosolic pathways, oxidative catabolism of secretion and regulation of incretin hormones, and altered amino acids, ketogenesis, ornithine cycle activity (“urea balance of central nervous system pathways controlling cycle”), the generation of reactive oxygen species (ROS) food intake and energy expenditure. Given this diverse with important signaling functions (33, 34), the control of constellation of abnormalities in multiple tissues and the cytoplasmic calcium (35, 36), and the synthesis of all cel- secondary consequences of established hyperglycemia and lular Fe/S clusters, protein cofactors essential for cellular hyperlipidemia, it is difficult to identify the primary events functions such as protein translation and DNA repair (37). that lead to the development of diabetes. To address this The rate-limiting first step in steroidogenesis also occurs in key clinical and scientific question, it is important not only mitochondria, thus linking mitochondrial function to to determine abnormalities associated with established endocrine homeostasis (38–41). This multiplicity of disease, but also to identify underlying metabolic char- organelle functions explains the variability in patho- acteristics preceding the onset of disease in at-risk physiology, severity, and age of onset of the increasing individuals. number of diseases recognized to arise from primary or Risk factors for the development of and/or progression secondary alterations in specific mitochondrial path- of type 2 DM include: 1) genetics (10–16), exemplified by ways (37, 42–44). the high risk of type 2 DM in particular ethnic groups (17) and the high concordance rates in monozygotic twin pairs A. The dynamic morphology of mitochondria (18); and 2) both prenatal and postnatal environmental In the thin sections observed by electron microscopy factors, including suboptimal intrauterine environment and shown in most textbooks, mitochondria appear (19, 20), low birth weight (19, 21), obesity (22, 23), in- as discrete, small, bean-shaped, double-membrane or- activity (24), gestational diabetes (25), and advancing age ganelles. However, more recent studies based on light mi- (26). Several longitudinal studies have indicated that in- croscopy in live cells have revealed that mitochondria exist sulin resistance, measured as reduced insulin-stimulated as a reticulum that is in continuous communication 366 Patti and Corvera Mitochondria and Type 2 DM Endocrine Reviews, June 2010, 31(3):364–395 Downloaded from https://academic.oup.com/edrv/article/31/3/364/2354793 by guest on 23 September 2021

FIG. 1. Basic structural and functional features of the mitochondrial reticulum (illustrated from left to right). The mitochondrial reticulum is composed of an inner and outer membrane, between which lies the intermembrane space, and a matrix contained within the inner membrane. The surface of the inner membrane is folded into cristae. The organization and distribution of the mitochondrial reticulum is controlled by interactions with cytoskeletal elements such as microtubules. The matrix contains the enzymatic machinery for fatty acid ␤ oxidation, which generates acetyl-CoA from acyl chains, and reducing equivalents in the form of NADH and FADH2 in the process. Acetyl-CoA fuels the TCA cycle, which also produces NADH and FADH2. These donate electrons to the ETC, leading to the generation of a proton gradient across the inner mitochondrial membrane. Dissipation of this gradient through the mitochondrial ATPase generates ATP. Delay of electron transport by the ETC results in the production of ROS, which can activate UCPs that dissipate the proton gradient without producing ATP. The electrochemical gradient also causes cytoplasmic Caϩϩ to enter the matrix, buffering cytoplasmic Caϩϩ levels and promoting TCA cycle flux. Mitochondria are also crucial in the generation of iron-sulfur clusters that form the prosthetic group of numerous proteins involved in multiple cellular pathways. The mitochondrial reticulum undergoes continuous fusion and fission reactions that involve both the inner and outer mitochondrial membranes, allowing redistribution of matrix content, such as mtDNA, within the reticulum. The proteins that compose all mitochondrial machineries are encoded both by mtDNA and by nuclear DNA. The master transcription factor operating on mtDNA is TFAM, which is encoded in the nuclear genome. The expression of mitochondrial genes in the nucleus is driven by numerous transcription factors, which are in turn controlled by specific coactivators and corepressors that respond to cellular energy demands. through dynamic fusion and fission events, moving ac- gene products. The ETC transports electrons from donors tively to different regions of the cell through interactions (NADH at complex I, FADH2 at complex II) to a final with the cytoskeleton (Fig. 2). The mitochondrial reticu- acceptor, molecular oxygen, forming H2O at complex IV. lum is composed of an outer and an inner membrane, The transport of electrons is accompanied by release of between which is the intermembrane space, and a matrix large amounts of free energy, most of which is harnessed limited by the inner membrane (Fig. 1). The area of the for the translocation of protons from the matrix to the inner membrane can be greater than that of the outer mem- intermembrane space; the remainder is dissipated as heat brane due to the presence of cristae, inner membrane in- (Fig. 3). The energy contained in the proton electrochem- vaginations that contain all the transmembrane proteins ical gradient generated by the ETC is then coupled to ATP of the electron transport chain (ETC) as well as the mito- production as protons flow back into the matrix through chondrial ATPase (45–47). The mitochondrial matrix the mitochondrial ATPase. Thus, OXPHOS results from contains the components of the TCA cycle and of the ␤-ox- electron transport, the generation of a proton gradient, idation pathway, which provide reduced nicotinamide ad- and subsequent proton flux coupled to the mitochondrial enine dinucleotide (NADH) and reduced flavin adenine ATPase. Each of these steps can vary in efficiency; for dinucleotide (FADH2) to the ETC. example, the exact stoichiometry between electron flow The ETC is composed of four large multisubunit com- and proton pumping, or between proton pumping and plexes (complexes I to IV) with more than 85 individual ATP synthesis varies depending on the probability of loss Endocrine Reviews, June 2010, 31(3):364–395 edrv.endojournals.org 367 Downloaded from https://academic.oup.com/edrv/article/31/3/364/2354793 by guest on 23 September 2021

FIG. 2. Visualization of the dynamic nature of the mitochondrial reticulum in a cultured muscle cell. C2C12 mouse myoblasts were FIG. 3. Coupled and uncoupled respiration. Electrons derived from stained with MitoTracker green and imaged in culture at 37 C. Images reduced donors NADH and FADH2 are transported within the ETC to of a segment of the cell captured at 30-sec intervals are shown on the molecular oxygen, producing water. The flow of electrons within the left. The comparison between successive frames reveals scission events ETC is coupled to translocation of protons due to the large amount of (arrowheads), branching events (V), and fusion events (brackets) free energy released during electron transport. The remainder of this occurring at 30-sec intervals. free energy is released as heat. The proton gradient thus produced is dissipated through the mitochondrial ATPase, and the consequent decrease in free energy drives ATP synthesis. This process is known as of electrons from the ETC before reaching complex IV OXPHOS, or coupled respiration. Under circumstances where NADH and on non-ATPase-coupled proton leak through the and FADH2 are available, but movement of electrons down the respiratory chain is slow, some of those electrons will be released from inner mitochondrial membrane [e.g., via uncoupling the respiratory chain and reduce molecular oxygen, forming the Ϫ proteins (UCPs)]. superoxide anion O2 , hydrogen peroxide, and the hydroxyl radical The high electronegative potential generated by the OHϪ. These are the main ROS formed at steady state. Accumulation of proton gradient also drives the rapid entry of Caϩϩ into ROS activates UCPs, which dissipate the proton gradient without producing ATP, resulting in uncoupled respiration. the mitochondrial matrix, buffering its concentration in ϩϩ the cytoplasm. In the mitochondrial matrix, Ca can generated in the mitochondrial matrix, to be shared within stimulate flux through the Krebs cycle by stimulating the entire mitochondrial reticulum. Although the molec- ϩϩ dehydrogenase activities (36). The exit of Ca from ular machinery of mitochondrial fusion and fission has the matrix is driven by electroneutral exchange with been elucidated (48), it has only recently been established ϩ ϩ Na or H . that mitochondrial fusion and fission also contribute mul- The ETC is also a potent source of ROS. Loss of elec- tiple other mitochondrial functions, including the control trons from the ETC can result in reduction of oxygen to of cellular calcium handling, ROS production, and ener- Ϫ form O2 , which can be dismutated to H2O2 and subse- getic output (49–51). Moreover, human diseases arising Ϫ quently converted to the hydroxyl radical, OH . These from mutations in conserved elements of the mitochon- three products constitute the major ROS formed during drial fusion machinery have been identified, such as respiration. As the name implies, these species are highly Charcot-Marie-Tooth type 2A caused by mutations in reactive, and acute, very high elevations, or more chronic mitofusin 2, and autosomal dominant optic atrophy, elevations can be extremely damaging to the cell. ROS caused by mutations in optic atrophy 1 (49). A role for generation is more likely to occur when the proton gra- mitochondrial fusion machinery in metabolic control has dient is large and electron carriers are highly reduced, e.g., also been suggested by the findings that mitofusin 2 levels when ADP is rate-limiting for ATP production or when are controlled during muscle development and are reduced availability of O2 is limiting. Uncoupling proteins are con- in both obesity and type 2 DM in parallel with insulin sidered to be natural regulators of this process, responding resistance (52). to and controlling ROS production by mitigating the formation of a large proton gradient. B. Mechanisms that control mitochondrial density The mitochondrial matrix also contains the circular and capacity mitochondrial DNA (mtDNA) molecule, which encodes The term mitochondrial biogenesis is often used to de- for 37 genes (13 of which are subunits of the ETC). Trans- scribe the generation of more mitochondria in response to lation of these proteins occurs within the mitochondrial increased energy demands, or the multiplication of mito- matrix, utilizing mtDNA-encoded rRNA and tRNA. chondria necessary for cell growth and division. However, Mitochondrial fission and fusion allow the transcrip- the copy number of specific mitochondrial proteins and tional products of mtDNA, as well as multiple metabolites the functional capacity of each distinct mitochondrial 368 Patti and Corvera Mitochondria and Type 2 DM Endocrine Reviews, June 2010, 31(3):364–395 pathway may be very variable between different tissues required for mitochondrial biogenesis during develop- and between different physiological conditions. Thus, the ment (59), they are necessary for the expression of the full term mitochondrial biogenesis can be ambiguous because complement of proteins of mitochondrial OXPHOS and multiple parameters, including mtDNA copy number, fatty acid ␤-oxidation pathways in muscle and brown ad- mitochondrial density, levels of specific mitochondrial ipose tissue (59–69). Moreover, PGC-1␣ and PGC-1␤ are proteins, and mitochondrial functional output may vary crucial for the rapid bursts in mitochondrial proliferation independently of each other. For example, the prolifera- that accompany perinatal heart and brown adipose tissue tion of mitochondria occurring to sustain hyperplastic development (59). These data support the concept that growth is probably very different from that occurring to mitochondrial adaptation to specific energy needs is support hypertrophic growth in any given tissue, and the mediated by PGC-1␣ and PGC-1␤; by contrast, mito- regulatory mechanisms controlling these adaptive changes chondrial expansion during cell proliferation is more Downloaded from https://academic.oup.com/edrv/article/31/3/364/2354793 by guest on 23 September 2021 are likely to be distinct. likely to depend on serum-responsive coactivators such as PPRC (70). 1. Transcriptional control mechanisms The role of corepressors in the transcriptional control Although we know very little about specific mecha- of energy metabolism genes is less extensively studied. nisms that control different modalities of mitochondrial However, evidence in cultured cells and in mouse models biogenesis, it is clear that these mechanisms require co- points to a critical role of the corepressor RIP140 in con- ordination between the nuclear and mitochondrial ge- trolling important aspects of mitochondrial energy me- nomes. Transcription of the mitochondrial genome is tabolism in both adipose tissue and muscle (71–75). under the control of a single transcription factor, Tfam, RIP140 suppresses UCP1 through interaction with spe- which is encoded by the nuclear genome. In turn, Tfam cific enhancer elements and also suppresses expression of expression is regulated by the transcription factors NRF genes involved in ␤-oxidation and respiratory chain as- (nuclear respiratory factor)-1 and NRF-2, which spe- sembly. RIP140 also interacts directly with many of the cifically activate numerous nuclear-encoded genes in- transcription factors coactivated by PGC-1␣ (76). The volved in mitochondrial respiration (53, 54). Thus, mechanisms that control the balance between PGC-1 co- through NRF-stimulated expression of Tfam, the tran- activators and RIP140 and other corepressors are not clear scription of the mitochondrial genome is stimulated in but are likely to represent key regulatory mechanisms of coordination with that of nuclear-encoded mitochondrial energetic adaptation. genes. The expression of many other mitochondrial genes is controlled by additional nuclear transcription factors, including peroxisome proliferator-activated 2. Posttranscriptional control mechanisms receptor (PPAR) ␣, PPAR␦, estrogen-related receptor The expansion of the mitochondrial reticulum requires (ERR) ␣/␥, and Sp1, which can induce expression of not only the expression of genes encoding mitochondrial mitochondrial genes in a tissue-dependent and physio- proteins but also the import of these into the mitochon- logical context-dependent manner (55). drial space (77–80) and the coordinated expansion of mi- A high level of transcriptional coordination is required tochondrial membranes. Mitochondrial inner and outer to ensure coupling of mitochondrial activity to other met- membranes have distinct lipid compositions that differ abolic activities within the cell and to mediate appropriate from that of other membrane-bound organelles and from parallel changes in all components of multiprotein com- the plasma membrane. Specific features of mitochondrial plexes. This coordination is accomplished through the ac- membranes are their relative lack of cholesterol and the tion of transcriptional coactivators and corepressors. The high content of cardiolipin, which is unique to mitochon- best studied coactivators of mitochondrial gene transcrip- drial membranes and essential for the proper assembly and tion are members of the PPAR␥ coactivator (PGC) family, function of the respiratory chain (81–83). Mitochondrial including PGC-1␣, PGC-1␤ (56, 57), and PPRC, a related lipids are most likely synthesized in the endoplasmic serum-responsive coactivator (58). These respond to cel- reticulum (the primary site of lipid biosynthesis in eu- lular energy-requiring conditions such as cell growth, hyp- karyotic cells) and transferred to mitochondria via as- oxia, glucose deprivation, and exercise (55) to activate yet unidentified mechanisms. However, recent work transcription factors promoting mitochondrial remodel- has identified mechanisms regulating the synthesis of ing and/or biogenesis, thus restoring cellular energetics. cardiolipin and phosphatidylethanolamine in mito- For example, PCG-1␣ is highly expressed in muscle, liver, chondria inner membranes via the action of mitochon- and brown fat, and expression is further increased in these drial prohibitins (84). In addition, cardiolipin synthesis tissues in response to exercise, fasting, and cold exposure, requires the mitochondrial translocator assembly and respectively. Although PGC-1␣ and -␤ do not appear to be maintenance protein Tam41, revealing a mechanism for Endocrine Reviews, June 2010, 31(3):364–395 edrv.endojournals.org 369 the coordination of protein import and mitochondrial sition to carbohydrate oxidation (increased RQ) during membrane lipid assembly (85). the fed state. Availability of fuels, particularly lipids, and The area and composition of the mitochondrial inner capacity to oxidize them within mitochondria are also and outer membranes must be tailored to accommodate critical for sustained exercise. Thus, mitochondrial func- the specific components of mitochondria from different tional capacity is likely to directly affect muscle metabolic cells and tissues, which are each likely to have optimal lipid function and, because of its large contribution to total composition and density. This essential requirement for body mass, to have a significant impact on whole-body specific lipid composition is underscored by the morpho- metabolism. This possibility is supported by the findings logical and functional alterations in mitochondria seen in of increased mitochondrial content in skeletal muscle in an Barth syndrome, a disorder arising from mutations in a individual with hypermetabolism and resistance to weight lipid acyltransferase, tafazzin (41, 86). The resulting al- gain (Luft syndrome) (90). Downloaded from https://academic.oup.com/edrv/article/31/3/364/2354793 by guest on 23 September 2021 terations in cardiolipin structure cause profound changes in the assembly and distribution of respiratory chain com- 2. Potential mechanisms by which impaired muscle ponents within mitochondrial cristae (84, 87, 88). Inter- mitochondrial oxidative function could result in estingly, lymphoblasts from patients with Barth syndrome insulin resistance can produce ATP at normal levels but display an expanded Skeletal muscle is the largest insulin-sensitive organ mitochondrial reticulum (89). These observations under- in humans, accounting for more than 80% of insulin- score the existence of mechanisms that can compensate in stimulated glucose disposal. Thus, insulin resistance in part for specific mitochondrial deficiencies. this tissue has a major impact on whole-body glucose Given the complex and dynamic structure of mitochon- homeostasis. Indeed, multiple metabolic defects have dria and the diversity and physiological importance of been observed in muscle from insulin-resistant but nor- their multiple functions, assessing the role of mitochon- moglycemic subjects at high risk for diabetes develop- dria in human pathology requires a comprehensive char- ment, including: 1) reduced insulin-stimulated glycogen acterization not only of mitochondrial structure and synthesis (27, 91, 92); 2) alterations in insulin signal abundance, but also of the pathways that compensate transduction (93); and 3) increased muscle lipid accu- for suboptimal mitochondrial capacity and functional mulation (94). Although it remains unclear whether any output—which may then modify disease severity and of these defects play a causal role in insulin resistance, progression. In the following sections, we will critically intramyocellular lipid excess strongly correlates with analyze the findings that have suggested a role for mi- the severity of insulin resistance, even after correction tochondrial function in the establishment of diabetes for the degree of obesity (94), and has been observed in risk and the gaps in our knowledge that must be filled muscles of multiple fiber types (95). Moreover, lipid to determine the merits of this hypothesis. excess has been linked experimentally to induction of insulin resistance (96) and alterations in insulin signal transduction (97–99). III. Role of Mitochondria in Thus, one possible mechanism by which impaired mi- Tissue-Specific Contexts tochondrial function might contribute to insulin resistance is via altered metabolism of fatty acids. Increased A. Muscle tissue lipid load, as with obesity, and/or sustained inac- 1. Role of mitochondria in muscle tivity, may lead to the accumulation of fatty acyl coenzyme Mitochondria are particularly important for skeletal A (CoA), diacylglycerols, ceramides, products of incom- muscle function, given the high oxidative demands im- plete oxidation, and ROS, all of which have been linked posed on this tissue by intermittent contraction. Mito- experimentally to reduced insulin signaling and action chondria play a critical role in ensuring adequate levels of (96–102). Additional mechanisms potentially linking im- ATP needed for contraction by the muscle sarcomere. This paired mitochondrial oxidative function to insulin re- high-level requirement for ATP by sarcomeres has likely sistance include: 1) reduced ATP synthesis for energy- contributed to the distinct subsarcolemmal and sarco- requiring functions such as insulin-stimulated glucose mere-associated populations of mitochondria in muscle. uptake; 2) abnormalities in calcium homeostasis (neces- Moreover, muscle cells must maintain metabolic flexibil- sary for exercise-induced glucose uptake) (103–105); and ity, defined as the ability to rapidly modulate substrate 3) reduced ATP production during exercise (106), poten- oxidation as a function of ambient hormonal and ener- tially contributing to reduced aerobic capacity, muscle getic conditions. For example, healthy muscle tissue pre- fatigue, and decreased voluntary exercise over time— dominantly oxidizes lipid in the fasting state, as evidenced further feeding a vicious cycle of inactivity-fueled insulin by low respiratory quotient (RQ), with subsequent tran- resistance. 370 Patti and Corvera Mitochondria and Type 2 DM Endocrine Reviews, June 2010, 31(3):364–395

3. Evidence for reduced muscle mitochondrial oxidative particularly in subsarcolemmal fractions (114). Interest- function in DM ingly, this fraction is also characterized by even greater An important early clue suggesting that muscle mito- reductions in OXPHOS activity (114). chondrial oxidative dysfunction may be associated with Nuclear magnetic resonance (NMR) spectroscopy has insulin resistance in humans was the series of observations also been used to assess mitochondrial function in vivo, by Simoneau and Kelley that obesity is associated with with studies finding similar reductions in oxidative func- reductions in citrate synthase, malate dehydrogenase, car- tion in both insulin resistance and type 2 DM. For exam- nitine palmitoylotransferase 1 (CPT1), and cytochrome ple, rates of mitochondrial OXPHOS in offspring of type oxidase (COX) activity in the fasting state (107, 108) and 2 diabetic subjects, as assessed by 31P spectroscopy, are with parallel increases in activity of the glycolytic enzymes reduced by 30% in the fasting state (117), and TCA cycle 13 hexokinase and phosphofructokinase (109). Moreover, flux, modeled using rates of 4- C-glutamate enrichment Downloaded from https://academic.oup.com/edrv/article/31/3/364/2354793 by guest on 23 September 2021 oxidative activity (e.g., citrate synthase, acyl CoA dehy- during infusion of 13C-acetate, is reduced by 30% (118). drogenase) is a robust correlate of insulin sensitivity, even The magnitude of these changes is strikingly similar to the better than either im triglycerides or long-chain fatty acyl 38% lower muscle mitochondrial density, assessed by CoA (110). Furthermore, leg balance studies demon- electron microscopy, in this same population—again sug- strated that obesity-linked insulin resistance and diabetes gesting that decreased mitochondrial density might be an are both associated with reduced fasting lipid oxidation, important factor in reduced oxidative capacity in individ- as indicated by higher RQ, as well as inability to suppress uals with a family history of diabetes. lipid oxidation and switch to carbohydrate oxidation in Alterations in intrinsic function of mitochondria have response to meals/insulin stimulation (111), a state termed also been identified in isolated mitochondria from humans “metabolic inflexibility” (112). Impaired flexibility also with insulin resistance and DM. Mogensen et al. (119) correlates with intramyocellular accumulation of lipids observed decreases in maximal ADP-stimulated respira- (107), and 24-h RQ can predict subsequent weight gain tion (state 3, malate and pyruvate as substrates) in (110, 113). Together, these data suggest that an intrinsic mitochondria isolated from obese subjects with DM as defect in multiple components of oxidative metabolism, or compared with obesity alone; these differences persisted altered regulation, may contribute to the development of even after normalization to citrate synthase activity. Thus, both obesity and insulin resistance. these data suggest that in addition to decreased mitochon- The diminished capacity for appropriate regulation of drial density, there is an additional intrinsic defect(s) in oxidative metabolism observed in the above studies could TCA, OXPHOS, membrane potential, or adenine nucle- be linked to reduced mitochondrial function due to: 1) otide transporters in mitochondria of individuals with es- abnormal mitochondrial density and/or in vivo function; tablished diabetes. and/or 2) intrinsic defects in oxidative metabolism of lip- Such underlying functional defects may be subtle at ids or other substrates. Multiple studies suggest that hu- baseline but may be unmasked during acute energetic man insulin resistance is indeed accompanied by impaired stress. For example, short-term exercise normally in- in vivo mitochondrial oxidative function—in turn linked, creases ATP synthesis rates. However, this adaptive re- at least in part, to reduced mitochondrial density. Ritov et sponse is completely mitigated/abolished in nonobese al. (114) demonstrated that the enzymatic activity of first-degree relatives of type 2 diabetics—despite normal OXPHOS complex I, as assessed by the activity of rote- basal ATP synthesis rates (106). Similarly, insulin-stimu- none-sensitive NADH:O2 oxidoreductase, was reduced lated ATP synthesis is reduced by more than 90% in nono- by about 40% in skeletal muscle biopsy samples from bese first-degree relatives of type 2 diabetics (120), more individuals with type 2 DM and by 20% in obese individ- than would be expected from the 30% decrease in mito- uals. Similarly, Boushel et al. (115) found modest reduc- chondrial density and oxidative function observed in the tions in ADP and succinate-stimulated oxygen consump- same population. Because these short-term experimental tion in permeabilized muscle fibers from obese individuals protocols (several hours in duration at most) would not be with type 2 DM. In each of these studies, differences in expected to alter mitochondrial density, DNA content, or oxidative capacity did not remain after normalization for number, these data strongly suggest that inability to ap- mitochondrial mass by citrate synthase activity or mtDNA propriately modulate oxidative function in response to the content, respectively, suggesting that reduced mitochon- prevailing energetic environment is a signature of insulin drial mass might be a major contributor. This possibility resistance and diabetes risk. is consistent with electron microscopy demonstrating di- Analysis of global gene expression patterns has also minished mitochondrial size in obesity and diabetes (116), demonstrated a 20–30% reduction in mRNA expression Endocrine Reviews, June 2010, 31(3):364–395 edrv.endojournals.org 371 levels for multiple nuclear-encoded genes of the OXPHOS DNA content, potentially mediated by chronic fatty acid pathway in humans with type 2 DM (121–123). Impor- activation of PPAR nuclear receptors (130–132). Simi- tantly, similar reductions in OXPHOS gene expression larly, relatively short-term reductions in serum fatty acids have been observed in some, but not all, populations of and intracellular fatty acyl CoA levels mediated by acipi- insulin-resistant, but completely normoglycemic, individ- mox treatment in healthy humans are associated with uals (122, 124).1 These differences may reflect popula- reduced expression of nuclear-encoded mitochondrial ox- tion-specific differences in obesity, physical fitness, or idative genes—in parallel with enhanced insulin sensitivity ethnicity. Interestingly, a recent study of Asian Indian (294). Together, these seemingly disparate data suggest subjects found no correlation between changes in that genetic background (127), age at dietary intervention, OXPHOS gene expression and insulin resistance (125). In specific dietary lipid composition, and duration of diet these individuals, expression of OXPHOS and TCA cycle may be important variables to consider when analyzing Downloaded from https://academic.oup.com/edrv/article/31/3/364/2354793 by guest on 23 September 2021 genes, mtDNA content, and ATP production rates were the interaction between OXPHOS gene expression and actually higher in both nondiabetic and diabetic individ- diet. Moreover, alterations in OXPHOS gene expression uals compared with Northern European controls, despite may be a secondary response to an underlying primary lower overall insulin sensitivity. However, circulating trig- defect in oxidative metabolism, reflecting attempts to lycerides were significantly elevated in both nondiabetic compensate for reductions in mitochondrial capacity (in- and diabetic individuals of Asian Indian origin (125). creased OXPHOS expression), or the deleterious effects of These results also raise the question of whether levels of lipid overload and accumulation on transcription of OXPHOS gene expression and function must be consid- OXPHOS genes (decreased OXPHOS expression), or a ered relative to the oxidative fuel load in an individual. For mixture of both. Additionally, because OXPHOS gene example, high OXPHOS expression in the population expression is coordinately regulated, patterns of differen- mentioned above may still be inadequate for appropriate tial OXPHOS expression may be more readily detectable and complete oxidation of a chronic high load of circu- in disease states, yet not necessarily mirror other aspects of lating lipids, whereas lower OXPHOS levels may be mitochondrial oxidative capacity. sufficient under conditions of a low circulating lipid Reduced physical fitness is associated with reduced load (see Fig. 5). muscle OXPHOS gene expression. In humans, maximal Such data also highlight the importance of considering oxygen uptake is robustly correlated with OXPHOS gene additional aspects of oxidative mitochondrial function be- expression (133). Similarly, in rats bred for low aerobic yond OXPHOS expression or capacity. For example, pri- capacity over multiple generations, expression of several mary myotubes isolated from obese humans with type 2 OXPHOS genes is markedly reduced, even in the absence DM display reduced basal lipid oxidation and insulin- stimulated glucose oxidation with no differences in of obesity (134). Conversely, OXPHOS expression can be OXPHOS gene expression (126). Thus, defects in lipid increased with exercise training (133, 135), a potent in- oxidation in DM can be significant contributors to disor- sulin sensitizer. dered oxidative metabolism even in the absence of detect- Genetic and epigenetic modifications may also con- able alterations in OXPHOS gene expression or function. tribute to reduced expression of OXPHOS genes in type 2 DM. For example, expression of COX7A1, a complex 4. Factors affecting OXPHOS gene expression in muscle IV gene down-regulated in type 2 DM, is heritable (50– Several conditions associated with susceptibility to in- 72% heritability, as assessed by analysis in monozy- sulin resistance, including obesity, lipid accumulation, gotic and dizygotic twins), indicating a strong genetic and aging, have all been associated with reduced nuclear- or shared familial environmental contribution (136). encoded OXPHOS gene expression. Reduced OXPHOS Similar patterns are observed for the complex I gene gene expression has been observed in response to genetic NDUFB6 (137) and the ATP synthase component and nutritional obesity (127), short-term high-fat feeding ATP5O (138). Indeed, expression of nuclear-encoded (even in humans) (128), lipid infusion (129), and lipid OXPHOS genes is significantly more concordant be- loading of myotubes (127). However, these responses are tween monozygotic twins than expected and is the top- not observed in all studies of high-fat feeding; in fact, some ranking gene set for concordance in pathway analysis of studies demonstrate that high-fat feeding is associated global gene expression. Mediators of mitochondrial with increased numbers of mitochondrial protein and biogenesis, including ERR␣, may contribute to the 1 Patti ME, Liu M, Zin W, Lerin C, Dreyfuss J, Vokes M, Schroeder J, Tatro E, Park P, Kohane I, Kasif S, Goldfine AB, submitted. Transcriptome analysis reveals parallel dysregulation of oxidative metabolism and inflammation in muscle and adipose tissue with progression of insulin resistance in humans. 372 Patti and Corvera Mitochondria and Type 2 DM Endocrine Reviews, June 2010, 31(3):364–395 strong heritability of OXPHOS components.2 Interest- 124, 137). In turn, PGC-1␣ expression may also be re- ingly, epigenetic mechanisms may also contribute to duced as a consequence of promoter methylation (146) or these patterns because reduced expression parallels in- caused by insulin itself (145), obesity (126), and sustained creased DNA methylation of both the COX7A1 pro- lipid exposure (126). For example, saturated fatty acids moter (136) and NDUFB6 (137, 139). reduce PGC-1␣ promoter transcriptional activity and ex- Aging is also linked to impaired oxidative function pression in cultured myotubes, in parallel with reduced

(140) in parallel with reductions in OXPHOS gene ex- OXPHOS expression and O2 consumption (127). PGC-1 pression, including COX7A1, NDUFB6, and ATP50 activity can also be modulated at the level of translation (136–138). It is unclear at this time whether this is a direct and by posttranscriptional changes, including inhibitory effect of aging per se or related to reduced physical fitness, GCN5-mediated acetylation (147) and stimulatory sirtuin 1 mediated deacetylation (148). These multiple modes of increased tissue lipid accumulation, or other factors ac- Downloaded from https://academic.oup.com/edrv/article/31/3/364/2354793 by guest on 23 September 2021 companying typical patterns of aging. Genetic polymor- PGC-1␣ regulation are likely to have evolved from the phisms may also influence age-dependent reductions in need to adapt mitochondrial energy metabolism in re- expression (137). sponse to increasingly diverse inputs. A key question is whether the changes in OXPHOS In summary, insulin resistance has been associated with gene expression observed in type 2 DM are secondary alterations in skeletal muscle mitochondrial oxidative features of the diabetes metabolic environment such as function and its transcriptional regulatory pathways. hyperglycemia or insulin resistance. Reductions in However, several lines of evidence suggest that this may OXPHOS gene expression in patients with established not be a causal relationship in all situations. First, oxida- type 2 DM can be partially normalized by insulin treat- tive dysfunction is not observed in all insulin resistant in- ment (123). Expression of multiple OXPHOS genes is also dividuals (125). Second, oxidative activity is determined markedly reduced in mice made insulin deficient by treat- by the need to generate energy to meet cellular demands, ment with the ␤-cell toxin streptozotocin, and can be e.g., contraction and ion transport; thus oxidative capac- normalized by insulin (141). Similarly, withdrawal of ity is not likely to be limiting in the resting state in muscle insulin in individuals with type 1 diabetes reduces muscle (3). Rather, alterations in relative utilization of substrates, OXPHOS gene expression and ATP production rates an imbalance between fuel load and cellular energy re- (142). Short-term experimental induction of acute hyper- quirements, and/or differential thresholds for generation glycemia in humans does not fully mirror this pattern of of or resolution of oxidative stress in this setting may contribute to differential susceptibility to insulin resistance in gene expression (143), suggesting that the response to in- muscle. These concepts are examined more fully in the sulin deficiency is not completely due to resultant hyper- conclusion (Section V). glycemia. Moreover, experimental insulin therapy does not modulate mitochondrial respiration (144), so mechanisms linking insulin action with OXPHOS gene expres- B. Adipose tissue sion remain unclear. 1. Roles of mitochondria in adipose tissue Changes in the levels of OXPHOS and other oxidative The role of adipose tissue mitochondria is most appar- genes must occur in response to cellular energetic and met- ent in brown adipose tissue, where flux through the ETC abolic needs, and in a coordinated manner that ensures the generates heat in the process of thermogenesis, a poten- stoichiometric assembly of the products of distinct genes tially important mechanism regulating systemic metab- into functional complexes. As in other tissues, the coor- olism even in adult humans (149–152). In this tissue, dination of OXPHOS gene expression in muscle is medi- electron transport is greatly accelerated due to tissue-spe- ated in part by the action of coactivators and corepressors. cific expression of the mitochondrial UCP1. UCP1 hinders PGC-1␣ has been recognized as an important coactivator the establishment of, or dissipates, a proton gradient of in skeletal muscle, contributing to fiber type determina- sufficient magnitude to sustain the synthetic activity of the tion, glucose uptake, and oxidative capacity (see Section mitochondrial ATPase (150, 153–155), thus driving con- IV. A). Moreover, alterations in muscle PGC-1␣ and -␤ tinuous accelerated electron transport. UCP1-mediated mRNA expression are observed in humans with insulin uncoupling alone, however, cannot fully account for the resistance—being reduced by nearly 50% in muscle from large thermogenic capacity of brown adipocytes in the individuals with diabetes (122, 145) and in some popula- absence of mechanisms that ensure continuous substrate tions of normoglycemic insulin-resistant humans (121, delivery to the ETC. Thus, brown adipocyte mitochondria 2 Stender-Petersen KL, Poulsen P, Butte A, Jensen CB, Yee J, Leykin I, Vaag A, Pedersen O, Patti ME, manuscript under review. Gene expression analysis in monozygotic twins reveals heritable contributions to PGC-1/ERR pathways. Endocrine Reviews, June 2010, 31(3):364–395 edrv.endojournals.org 373 also contain high levels of CPT1b, which is critical for the (168), and regional differences in metabolic activity can be entry of fatty acids into the mitochondria for ␤-oxidation. linked to varying mitochondria densities (169). Higher ␤-Oxidation, in turn, generates large amounts of reducing mitochondrial density and even UCP1 can be induced in equivalents for the ETC. response to pharmacological or genetic alterations of White adipocytes have been described to contain low white adipocytes (170–177), suggesting that white adi- levels of mitochondria, which is indeed the case when pose tissue could potentially be induced to acquire more compared with brown adipocytes or muscle. However, oxidative metabolic phenotypes, promoting increased fuel mitochondrial density increases dramatically, and mi- consumption and thus energy expenditure. Whether re- tochondrial remodeling occurs during white adipocyte spiratory chain uncoupling mediated through the induc- differentiation (156–158), suggesting that mitochondrial tion of UCP1 in white adipocytes alone could reduce free functions are required to support the multiple biological fatty acid release, or whether an additional increase in Downloaded from https://academic.oup.com/edrv/article/31/3/364/2354793 by guest on 23 September 2021 roles of mature white adipocytes. Interestingly, a recent mitochondrial oxidative capacity would be required, is compendium of mitochondrial proteins from 14 different debated (178–182). mouse tissues indicates that white adipocyte mitochondria Gain-of-function studies in mice where ectopic expres- contain a more diverse protein repertoire than mitochon- sion of UCPs mitigate diet-induced obesity support the dria from heart, skeletal muscle, or brain (31). Thus, white notion that uncoupling could be sufficient (183, 184). adipocyte mitochondria appear to be equipped for a However, UCP1 expression in adipocytes driven by the broader array of functions compared with mitochondria aP2 promoter failed to significantly raise resting metabolic in tissues that must sustain rapid bursts of energy-requir- rate (185). Moreover, in cultured adipocytes, ectopic ex- ing processes. Among the mitochondrial functions that pression of UCP1 impairs fatty acid synthesis (186, 187). may be relevant for white adipose tissue function are the These results suggest that, in the absence of mechanisms to anaplerotic generation of metabolic intermediates for ensure continuously elevated fuel oxidation, such as those fatty acid synthesis and esterification (159), the mainte- present in brown fat, uncoupling of white adipose tissue nance of a robust pathway for the folding and secretion of mitochondria may decrease ATP levels and impair ana- high abundance circulating proteins such as adiponectin bolic flux (183). (160), and interactions between mitochondrial function In addition to effects on fuel utilization, decreased mi- and components of the insulin signaling pathway (161). tochondrial capacity in adipocytes may also alter adipocyte insulin sensitivity and/or function due to the high 2. Potential mechanisms by which impaired adipose tissue energetic requirements for fatty acid storage, adipokine mitochondrial oxidative capacity could result in secretion (160), insulin signaling (161), and glucose up- insulin resistance take. Interestingly, in cultured adipocytes, impairment of The large capacity of brown adipose tissue mitochon- respiratory chain function through depletion of Tfam dur- dria to oxidize fatty acids results in a measurable impact ing adipocyte differentiation results in impaired insulin- on whole-body metabolism; increased brown adipose tis- stimulated glucose transport (161); data in animal models sue abundance correlates negatively with fuel storage and are necessary to determine the physiological relevance of weight gain in rodents, and vice versa (162). The role of this finding. brown adipose tissue in human metabolism has typically been thought to be minor. However, recent work has led 3. Evidence for reduced adipose tissue mitochondrial to reconsideration of this notion, noting that humans pos- capacity in DM sess adipose tissue depots that are cold-sensitive and hy- White adipocyte mitochondrial content is decreased in permetabolic, as assessed by their very high uptake of both rodent and human obesity (177, 188–191) and cor- labeled glucose (152, 163). Such depots appear to be less relates with insulin resistance that accompanies obesity. In active as a function of aging and/or obesity (151, 164– humans, white adipocyte mtDNA copy number is in- 167). Thus, impaired mitochondrial capacity in brown versely correlated with age and BMI and directly corre- adipose tissue might be functionally linked to impaired lated with basal and insulin-induced lipogenesis (192). thermogenesis and energy expenditure, and thus increased Thus, reduced mtDNA content could reduce adipocyte susceptibility to obesity-linked insulin resistance. capacity for lipid storage, promoting ectopic lipid accu- The relevance of white adipocyte mitochondria to mulation in peripheral tissues such as muscle and liver. In whole-body metabolism and metabolic disease may de- parallel, expression of nuclear-encoded OXPHOS genes is pend on the extent to which mitochondrial respiratory down-regulated in visceral adipose tissue of humans with capacity and/or the total mass of white adipose tissue type 2 DM (193). Administration of thiazolidinediones would be sufficient to impact circulating free fatty acid induces changes in mitochondrial content and remodeling levels. White adipocytes display a high degree of plasticity in white adipocytes concomitantly with an improvement 374 Patti and Corvera Mitochondria and Type 2 DM Endocrine Reviews, June 2010, 31(3):364–395 in insulin sensitivity (170, 173, 177, 190, 194–198). Mi- mitochondrial density are not known but could be medi- tochondrial levels in white adipocytes are also increased in ated by decreased expression of PGC-1␣, as observed in response to adrenergic stimulation, ␤-3 agonists, and CB1 obese humans (206). blockade in mice (195, 199, 200), again in parallel with enhanced insulin sensitivity. C. Liver Whether changes in mitochondrial density are a cause The liver plays a central, unique role in carbohydrate, or consequence of changes in insulin sensitivity is unclear. protein, and fat metabolism. It is critical for maintaining However, some evidence suggests that lack of insulin sig- glucose homeostasis (1) during fuel availability, via stor- naling does not reduce mitochondrial capacity in adipose age of glucose as glycogen or conversion to lipid for export tissue. For example, mice with adipose tissue-specific ab- and storage in adipose tissue, and (2) in the fasting state, lation of the insulin receptor (FIRKO mice) display high via catabolism of glycogen, synthesis of glucose from Downloaded from https://academic.oup.com/edrv/article/31/3/364/2354793 by guest on 23 September 2021 levels of mitochondrial genes involved in fatty acid oxi- noncarbohydrate sources such as amino acids (gluconeo- dation and OXPHOS over the lifespan of the animals genesis), and ketogenesis. In turn, these responses are reg- (201). Thus, mechanisms that induce and maintain active ulated by the key hormones insulin and glucagon, which mitochondria in adipocytes can bypass defects in insulin modulate signaling pathways and gene expression, lead- signaling, and indeed, insulin signaling may repress mito- ing to inhibition or stimulation of glucose production, chondrial gene expression and/or function. respectively. 4. Factors affecting mitochondrial OXPHOS expression and Recent human data have highlighted the importance of function in adipose tissue disordered hepatic metabolism, including inappropriately The genetic program leading to brown adipose tissue increased hepatic glucose production, hyperlipidemia, development, and potentially to the high abundance of and lipid accumulation, in both obesity and type 2 DM mitochondria, is initiated by the zinc-finger protein (207). Similarly, rodent data also support an important PRDM16 (202–204). Current reports support the hypoth- role for the liver in diabetes pathogenesis. For example, esis that brown adipocytes and myocytes share a common liver-specific insulin receptor knockout (LIRKO) mice de- cellular lineage, potentially explaining their similarity velop insulin resistance, glucose intolerance, impaired in- with regard to containing mitochondria specialized in fuel sulin suppression of hepatic glucose production, and oxidation. In addition, the transcriptional coactivators altered patterns of hepatic gene expression (208). Inter- PGC-1␣ and -1␤ (56) play a critical role in the expansion estingly, these mice are also dyslipidemic and susceptible of the mitochondrial reticulum and in the induction of to atherosclerosis (209). UCP1 and the brown adipose tissue thermogenic program during the perinatal period (59). 1. Role of mitochondria in liver Adipocyte mitochondrial density and OXPHOS activ- Given the diverse array of unique metabolic functions ity can be regulated in response to factors that affect lipid centered in the liver, it is not surprising that ultrastructure metabolism. For example, Toh et al. (176) and Nishino, et and function of hepatic mitochondria are distinct from al. (205) find that mice deficient in Fsp27, a lipid droplet that of muscle. Electron microscopy demonstrates that protein that promotes lipid storage in white and brown mitochondrial area is 44% lower in liver than in heart adipocytes, have increased whole-body energy expendi- (210) with smaller size, fewer cristae, and lower matrix ture, resistance to diet-induced obesity, and enhanced in- density. Protein expression of multiple OXPHOS compo- sulin sensitivity. This apparent paradoxical result (high nents and Tfam (expressed per milligram of protein) and insulin sensitivity despite deficiency in lipid storage), ap- citrate synthase activity are also lower in liver (e.g., 7% pears to be due to the increased mitochondrial density and that of cardiac muscle) (211). Similarly, patterns of gene activity in white adipocytes, which are brown-like in their expression are distinct in liver (32). Functionally, isolated increased capacity to oxidize large quantities of fatty ac- hepatic mitochondria have relative reductions in ids. Nitric oxide production by the endothelial nitric oxide OXPHOS proteins, respiratory chain cytochromes, and synthase has also been linked to enhanced adipose tissue maximal activity of complexes III and IV (211). Despite mitochondrial biogenesis and prevention of high-fat diet- lower OXPHOS capacity, state 3 respiration and respira- induced obesity (200). Conversely, both genetic and diet- tory control ratio are equivalent in liver and muscle, in- induced obesity result in decreased mitochondrial density dicating differences in relative substrate concentrations and OXPHOS activity in adipose tissue (127, 177, and lower “excess capacity” in liver. Recent application of 189–191), potentially contributing to adipose tissue dys- 31P NMR to the liver in humans demonstrates that rates of function and exacerbation of insulin resistance. The mech- ATP synthesis are 3-fold higher in liver than in muscle anisms whereby obesity results in a reduction in adipose (212). By contrast, the content of mtDNA, expressed ei- Endocrine Reviews, June 2010, 31(3):364–395 edrv.endojournals.org 375 ther per gram of tissue or per mitochondrion, is actually hepatic insulin resistance. Transgenic mice expressing li- higher in liver than in other tissues. Together, these data poprotein lipase in the liver have a 2-fold increase in he- again emphasize differences in protocols assessing mi- patic triglyceride content and are insulin resistant (219). tochondrial abundance, capacity, and function and At a cellular level, incubation of hepatocytes with satu- highlight tissue diversity of mitochondrial structure and rated long-chain fatty acids induces insulin resistance by function, which may contribute to tissue-specific disease reducing insulin-stimulated tyrosine phosphorylation of susceptibility. the insulin receptor and its downstream substrates (220, 221). These effects in the liver appear to be mediated via 2. Potential mechanisms by which impaired hepatic reduced expression of the insulin receptor (221). Although mitochondrial function could influence hepatic insulin these effects could be mediated by accumulation of fatty sensitivity acyl CoA, diacylglycerols, and ceramides (as in muscle; Downloaded from https://academic.oup.com/edrv/article/31/3/364/2354793 by guest on 23 September 2021 Impairments in mitochondrial number and/or oxida- Section III.A), it is intriguing that effects of fatty acids in tive function could potentially affect multiple cellular liver cells can be prevented by inhibition of CPT1, indi- functions within hepatocytes, both directly (e.g., reduced cating a critical role for mitochondrial oxidation in induc- ATP generation, alterations in oxidative stress, reduced ing lipid-mediated insulin resistance, perhaps via products capacity for fatty acid oxidation) and indirectly, via effects of incomplete oxidation and/or generation of ROS (220). on energy-requiring processes, including gluconeogenesis, Fatty acids can also alter expression and/or function of key synthesis of urea, bile acids, cholesterol, and proteins, and regulatory transcription factors in the liver (e.g., PGC-1␤, detoxification. Because accumulation of lipid within PPAR␣, hepatic nuclear factor 4␣) (127, 222–224) or hepatocytes is a key marker of insulin resistance in humans posttranscriptional regulation of mRNA stability (225). (207) and a major contributor to nonalcoholic fatty liver Fatty acid-induced reductions in insulin receptor number disease, nonalcoholic steatohepatitis (NASH), and cirrho- and function in the liver (211) may also reduce hepatic sis, we will first consider relationships between hepatic insulin clearance (226), causing systemic hyperinsulin- lipid metabolism and insulin resistance, and in Section emia, itself a contributor to both insulin resistance and III.C.3 will review evidence linking DM and hepatic ste- reduced mitochondrial function (214, 227, 228). atosis to alterations in fatty acid metabolism or more A second possibility is that hepatic insulin resistance global mitochondrial dysfunction. itself contributes to alterations in mitochondrial oxidative Hepatic lipid accumulation may result when adipose capacity. Indeed, a recent paper demonstrated that mice lipid storage capacity is exceeded, as in obesity or adi- with hepatic insulin resistance due to deletions of the pocyte dysfunction (e.g., lipodystrophy) (213). Alter- major insulin receptor substrates (IRS-1 and IRS-2) have natively, lipid accumulation may reflect an additional impaired mitochondrial function and biogenesis, as dem- imbalance between de novo hepatic lipogenesis and mi- onstrated by reduced NADH oxidation, reduced ATP tochondrial oxidative metabolism. Although the relative production rates, reduced numbers of mitochondria per roles of each of these possibilities is incompletely understood, cell, reduced fatty acid oxidation, and increased hepatic hepatic lipid accumulation is associated with obesity in hu- triglyceride accumulation (229). Mitochondrial dysfunc- mans, particularly central (abdominal) in location (214, tion was reversed by deletion of Foxo1. These data indi- 215), and in parallel with low adiponectin levels (216). cate that normal insulin signaling, which inhibits Foxo1, Interestingly, hepatic lipid accumulation is also a robust is required for maintenance of normal mitochondrial func- predictor of not only hepatic, but also muscle and adipose tion in this model. It remains unclear whether additional insulin sensitivity [better than intraabdominal fat, body components of the in vivo environment, such as glucose mass index (BMI), or other obesity measures] (217, 218). intolerance and hyperinsulinemia, contribute to mito- Conversely, modest weight loss (about 8 kg) normalizes chondrial dysfunction in these mice. However, more intrahepatic lipid in subjects with type 2 DM, in parallel broadly, these data indicate that hepatic insulin resistance with normalization of hepatic insulin sensitivity, even in can cause mitochondrial dysfunction, at least in mice. the absence of changes in intramyocellular lipid accumulation or circulating adipocytokines (215). 3. Evidence for impaired liver mitochondrial function Although these data highlight an intimate relationship in diabetes and NASH between obesity, intrahepatic lipid metabolism, and insu- Although human liver studies have been limited due to lin sensitivity in humans, mechanisms responsible for lack of tissue biopsy samples from otherwise healthy in- these links remain unclear. One possibility is that excessive dividuals, two groups have examined hepatic gene expres- hepatic lipid accumulation may play a central, pathogenic sion related to mitochondrial function in both obesity and role in insulin resistance. Support for this hypothesis type 2 DM (230–232). In the first (232), severe obesity comes from experimental lipid loading, which can induce (mean BMI 52 kg/m2) was associated with reduced ex- 376 Patti and Corvera Mitochondria and Type 2 DM Endocrine Reviews, June 2010, 31(3):364–395 pression of seven of 25 genes encoding OXPHOS genes; of ␤-oxidation genes (230, 236). Similarly, circulating expression of these genes was inversely correlated with ␤-hydroxybutyrate levels are increased in NASH (235). hepatic lipid accumulation and paralleled by reduced ex- Together, these data suggest excessive, but incomplete, pression of PGC-1␣ and genes known to be regulated by fatty acid oxidation, potentially limited by reduced thyroid hormone. Similar patterns were observed in obese availability of NADϩ and FAD. Byproducts of incom- subjects with established type 2 DM. Interestingly, replete fatty acid oxidation could act in concert with ad- duced expression of OXPHOS genes (e.g., COX7C, ipose tissue-derived inflammatory signals (e.g., TNF␣), ATP5C1) was also observed in mice fed a high-fat diet and and altered expression and activation of proinflamma- normalized by acute therapy with thyroid hormone T3— tory (e.g., IL-1R family) and profibrotic genes (e.g., suggesting that functional hepatic thyroid hormone resis- TGFB1, FGFR2), to increase production of ROS and ultimately contribute to the development of NASH and tance could contribute to reduced expression of mitochon- Downloaded from https://academic.oup.com/edrv/article/31/3/364/2354793 by guest on 23 September 2021 drial oxidative genes in this context (232). cirrhosis (235). In contrast, studies in Japanese individuals with estab- In summary, available data indicate that hepatic lipid lished DM and modest obesity (BMI 27 kg/m2) observed accumulation and insulin resistance are intimately linked a modestly increased expression of multiple genes within with mitochondrial oxidative dysfunction. We hypothe- all complexes of OXPHOS complexes, in parallel with size that modest obesity may be associated with compen- BMI and insulin resistance (measured by homeostasis satory up-regulation of OXPHOS gene expression in model assessment of insulin resistance, HOMA-IR) (231). response to sustained lipid load and/or functional defects Up-regulation of these OXPHOS genes was also positively in complete fatty acid oxidation. Up-regulation of ␤ associated with expression of several genes linked to mi- PGC-1 in this context may contribute to increased glu- tochondrial biogenesis (e.g., PGC-1␤, ERR␣, NRF, thy- coneogenesis and hyperlipidemia, in part via coactivation roid hormone receptor) and both ROS generation (e.g., of sterol regulatory element binding transcription factor 1, NADPH oxidase) and attenuation (e.g., glutathione per- as observed in high-fat diet-fed mice (223). With aging, oxidase). Thus, increased ROS related to increased fatty chronic ROS exposure, and/or the development of insulin acid oxidation and/or hyperglycemia might contribute to resistance related to obesity or sustained lipid accumula- up-regulation of OXPHOS gene expression in coexisting tion, OXPHOS expression may fall. Although this may be obesity and type 2 DM. Although these two data sets ap- an appropriate response, limiting oxidative stress, it may pear to be discordant (i.e., obesity-linked down-regulation also contribute to a vicious cycle of further impairments in of mitochondrial oxidative gene expression in the first, oxidative capacity, increased lipid accumulation, and and up-regulation in the second), several differences in the progressive insulin resistance. To test this hypothesis, lon- study population may account for these findings: 1) much gitudinal measurements of gene expression, oxidative greater degree of adiposity and hepatic steatosis in the function, and lipid accumulation in humans with progressive obesity and evolution of insulin resistance would be first; 2) differences in ethnicity (Caucasian-Americans vs. required—but are unlikely to be performed due to the in- Japanese); and 3) differences in insulin sensitivity and gly- vasive nature of serial liver biopsies in humans. cemia (insulin sensitive vs. resistant comparison in the first study, coexisting DM in the second). Studies of individuals with NASH provide additional D. Pancreatic ␤-cells opportunities to identify potential interactions between 1. Roles of mitochondria in ␤-cells hepatic lipid accumulation, insulin resistance, and mito- Mitochondrial capacity is central to the key function of chondrial function in humans. Indeed, enzymatic activity the pancreatic ␤-cell—regulated insulin secretion. Both of complexes I-V is reduced in liver extracts from patients rapid (first phase) and more prolonged (second phase) with NASH and is inversely correlated with BMI and insulin secretion (237) are dependent on glucose metab- HOMA-IR (233, 234). Moreover, NASH is characterized olism and mitochondrial oxidative capacity; glucose ox- by prominent abnormalities in mitochondrial ultrastruc- idation increases the ATP/ADP ratio, inhibiting plasma ture, with increased size, loss of cristae, and paracrystal- membrane K-ATP channels and allowing voltage-gated line inclusion bodies similar to those observed in some calcium channels to open. Increased cytoplasmic calcium mitochondrial myopathies (235). Although these data then triggers exocytosis of plasma-membrane docked in- cannot address whether such changes are indeed patho- sulin granules (first phase). Subsequent recruitment of genic, it is interesting that reduced OXPHOS activity in granules to the plasma membrane (second phase) appears this setting is accompanied by increased tissue long-chain to depend on mitochondrial metabolites produced by acylcarnitines and reduced short-chain acylcarnitines, de- anaplerosis (238). Mitochondrial metabolism is also re- spite normal CPT1 activity and increased expression quired for the transient, controlled production of ROS, Endocrine Reviews, June 2010, 31(3):364–395 edrv.endojournals.org 377 which is required for the mitochondrial signaling path- produced by the activity of the ETC. Low levels of ROS are ways that trigger granule exocytosis (239, 240). necessary for insulin secretion, but chronic, high mitochondrial ROS production can have a deleterious effect on ␤ 2. Evidence for reduced ␤-cell mitochondrial capacity in DM -cell function (254–256). Thus, the activation of UCP2 ␤ Given the crucial role of mitochondrial ATP genera- protects the -cell from the deleterious effects of excess tion, anaplerosis, and ROS production in insulin secre- ROS (257) by dissipating the proton gradient and decreas- tion, mitochondrial dysfunction in ␤-cells would be ing ROS production in a controlled negative feedback expected to reduce insulin secretion and thus promote the manner (Fig. 4). However, it also leads to decreased ATP development of DM. Consistent with this possibility, production, which impairs insulin secretion. Thus, UCPs ␤-cell specific deletion of Tfam reduces insulin secretory must uncouple respiration sufficiently to mitigate toxic levels of ROS, but not enough to decrease ATP and ROS capacity and ␤-cell mass, yielding so-called mitochondrial Downloaded from https://academic.oup.com/edrv/article/31/3/364/2354793 by guest on 23 September 2021 DM (241). Moreover, Tfam has recently been shown to be below the levels necessary for insulin secretion. This del- ␤ directly downstream of PDX1, a key transcription factor icate balance in which UCP2 is desirable for -cell pro- for ␤-cell development (242). tection, but undesirable for glycemic control, probably In humans, the key role of ␤-cell mitochondria is ex- underlies the discrepancy in results between two reports emplified by the development of diabetes in families on the phenotype of UCP2 knockout mice. In a mixed harboring mutations in mtDNA. Of these, the best stud- background, UCP2 knockout improves glycemic control ied is the 3243AϾG mutation in the mtDNA-encoded in ob/ob mice (258), whereas in a pure C57BL6/J back- ␤ tRNALeu, UUR gene, which is associated with maternally ground, UCP2 knockout accelerates -cell failure and di- inherited diabetes and deafness (MIDD) (243, 244). An- abetes (259). other example is mutation 14577 TϾC, a missense sub- The levels and activity of UCP2 and the rate of ROS stitution in the NADH dehydrogenase 6 gene (245). In this production are both increased by high-fat diet and hy- case, mitochondrial respiratory chain complex I activity perphagia, possibly through the actions of nonesterified fatty acids and their ceramide derivatives (260). It is likely and O2 consumption rates are decreased by 65 and 62%, respectively, in hybrid cell lines derived from probands. that decreased ATP production due to unbalanced acti- Interestingly, mitochondrial diabetes only develops vation of UCPs by direct actions of fatty acids and their upon aging, with an average age of onset between 35 and derivatives, in addition to excessive ROS, could underlie ␤ 40 yr for MIDD and 48 yr for 14577 TϾC. This contrasts the accumulation of -cell damage that precedes type 2 with the early childhood onset of diabetes in syndromes DM (Fig. 4). such as maturity-onset diabetes of the young 2 (MODY2), in which a mutation in glucokinase, the first step of glycolysis, results in attenuated glucose-stimulated ATP generation and insulin secretion. These data suggest that mitochondrial diabetes is more likely to result from a gradual deterioration of ␤-cell function, rather than from an acute functional impairment due to insufficient ATP production (246). One of the mechanisms by which mtDNA mutations might lead to a gradual deterioration in ␤-cell function, and not to an acute failure of insulin secretion due to decreased ATP levels, could be the stress imposed by an increase in metabolic flux to compensate for inefficiencies in FIG. 4. Hypothesized mechanism by which free fatty acid (FFA) excess the ETC. Consistent with this view, clonal cytosolic hybrid impairs insulin secretion. A, As described above, the activity of the ETC cells harboring mitochondria derived from MIDD pa- leads to the synthesis of ATP and the generation of a small amount of ␤ tients exhibit impaired calcium handling and elevated ROS. In the -cell, both ATP and ROS are signals that trigger insulin secretion. Excessive accumulation of ROS is mitigated normally by the ROS under metabolic stress (247, 248). Chronically in- activation of UCP2, which dissipates the proton gradient, decreasing creased ROS production could also induce ␤-cell death both ATP and ROS production. The presence of this normal negative and result in gradual onset of diabetes (249–253). feedback loop suggests that the control of excessive ROS generation is imperative in the ␤-cell, even if it occurs at the expense of decreasing ATP synthesis. B, In the presence of excess FFA, this normal feedback 3. Factors affecting mitochondrial function in ␤-cells loop is compromised by a direct activation of UCP2 by FFA, as well as ␤ an effect of FFA to increase the amount of UCP2. Thus, uncoupling Mitochondrial function in -cells is highly regulated by occurs to an excessive degree, compromising ATP synthesis enough to the levels and activities of UCPs, in turn regulated by ROS impair insulin secretion and ␤-cell fitness. 378 Patti and Corvera Mitochondria and Type 2 DM Endocrine Reviews, June 2010, 31(3):364–395

Although the tissues reviewed above are considered and inflammatory signaling. However, these same ani- central to the pathophysiology of DM, other tissues such mals displayed increased liver gluconeogenic enzyme lev- as gut, brain, kidney, neuronal tissues, and endothelium els and impaired insulin suppression of hepatic glucose are also likely to be implicated in a primary or secondary production, thus nullifying the potentially beneficial effect manner in the pathophysiology of DM and /or its com- of modest muscle PGC-1␣ overexpression on whole-body plications. The aspects of mitochondrial function unique glucose homeostasis. to each of these tissues and the consequences of their po- Higher levels of overexpression of PGC-1␣ achieved tential dysfunction in relation to DM pathophysiology are through actin promoter-driven expression in transgenic relatively less explored areas and are thus outside the scope animals display a strikingly different phenotype (263, of this review. 264). In these animals, mitochondrial density and

OXPHOS gene expression are more than double basal Downloaded from https://academic.oup.com/edrv/article/31/3/364/2354793 by guest on 23 September 2021 levels, and large increases in UCP2 gene expression are IV. Experimental Strategies to Explore the also observed. Mitochondrial energetics are impaired, Relationship between Mitochondrial Function with 60% decreases in ATP levels in muscle homogenates and DM and concomitant increases in AMP kinase activation, probably as a compensatory response to decreased mito- Although available data demonstrate links between mitochondrial functionality. Muscle function appears com- chondrial oxidative function and phenotypes linked to in- promised, as evidenced by decreased voluntary exercise, sulin resistance and diabetes, it remains unclear whether muscle atrophy, and decreased insulin sensitivity. these are simply associations or whether oxidative dys- Inducible overexpression of PGC-1␣ in skeletal muscle function can contribute to insulin resistance and diabetes (265) results in increased mitochondrial density and a ro- risk. To address this question, we will examine available bust increase in expression of OXPHOS genes and genes data from experimental models in which OXPHOS necessary for fatty acid oxidation. In these animals, both function has been altered. Such studies have shed light on the basic mechanisms underlying mitochondrial bio- muscle glucose uptake and glycogen deposition were in- genesis and on the consequences of disruption of normal creased. Although low-intensity exercise performance did mitochondrial homeostatic mechanisms on cell and not differ in this model, high-performance exercise was whole-body oxidative metabolism. A summary of these impaired, in parallel with failure to mobilize stored gly- studies is presented in Tables 1 and 2 and is discussed in cogen. Similarly, inducible expression in cardiac muscle Section IV.A and B. can have deleterious effects. When higher levels of PGC-1␣ overexpression are restricted to heart during A. PGC-1 ␣ and ␤ overexpression early life (266), increased neonatal mitochondrial prolif- PGC-1␣ and related coactivators are critical for the eration is observed, but it is accompanied by myofibrillar ␣ regulation of mitochondrial oxidative capacity, as dem- displacement. In adults, PGC-1 induction led to a more onstrated by the approximately 2-fold increases in modest mitochondrial proliferation, which was neverthe- mtDNA and oxygen consumption and a 50% increase less surprisingly accompanied by cardiomyopathy. Thus, in mitochondrial density in myotubes overexpressing whole-body and inducible skeletal muscle- or cardiac-spe- PGC-1␣ (56). To address whether this family plays the cific overexpression of PGC-1␣ can produce deleterious same functional role in vivo, several different models of effects on muscle structure and function. PGC-1␣ transgenic expression have been generated, each When PGC-1␣ overexpression is restricted to skeletal of which differs in tissue selectivity, levels of overexpres- muscle but overexpressed throughout development by the sion achieved, and resulting metabolic phenotype (Ta- use of the creatine kinase gene promoter, very large in- ble 1). The lowest level of PGC-1␣ overexpression was creases in mitochondrial mass, OXPHOS, and fatty acid achieved in rat muscle by means of electroporation (261). oxidation genes are observed (267–269). In this model, This resulted in modest up-regulation of mitochondrial ATP synthesis rate and exercise performance are in- proteins, increased palmitate oxidation, and increased increased, and fatty acid oxidation is also enhanced. De- sulin-stimulated glucose uptake. Similarly, transgenic spite these effects, insulin sensitivity is normal in mice expressing human PGC-1␣ driven by its own pro- PGC-1␣ transgenic mice fed a chow diet and, surpris- moter displayed a modest (30% higher than basal) in- ingly, is reduced during high-fat feeding. Insulin resis- crease in mRNA expression of several OXPHOS genes, tance was paralleled by accumulation of triglycerides fiber type switching, and enhanced muscle insulin sensi- and long-chain acyl CoA (270). tivity (262). Importantly, this modest PGC-1␣ overex- Although PGC-1␤-mediated gene expression and func- pression also was accompanied by decreased levels of ROS tion appear to overlap considerably with that of PGC-1␣, norn eiw,Jn 00 13:6–9 edrv.endojournals.org 31(3):364–395 2010, June Reviews, Endocrine

TABLE 1. Studies of PGC-1␣ transgenic expression models

First author, year Mito density OXPHOS Non-OXPHOS Insulin (Ref.) Model Mito DNA (EM) mRNA/protein mRNA/protein Mito energetics Exercise capacity sensitivity Other Benton, 2008 (261) PGC-1␣ 1 113% 180% 1 COXIV 1 muscle 1 AMP kinase electroporation protein activity Ward, 2009 (262) PCG-1␣ whole-body 130% 1 mRNA 1 muscle Hepatic insulin own promoter resistance Miura, 2003, 2006 PGC-1␣ whole-body 1 200–300% 1 number 150–200% 300% 1 in UCP2 60% 2 ATP levels in 2 voluntary 2 whole-body 1 AMP kinase (263, 264) ␣-actin promoter 1 mRNA mRNA homogenates activity Russell, 2004 (266) PGC-1␣ inducible 1 350% Myofibrillar disorganization heart cardiac failure Wende, 2007 (265) PGC-1␣ inducible 1 150–250% 150% 1 FAO gene No change in low intensity, 1 glucose uptake, skeletal muscle 1 mRNA mRNA 2 performance at high glycogen intensity deposition, decreased glycolysis Lin, 2002 (268); PGC-1␣ MCK 1 166–250% 1 250% in EDL 170–300% 200–400% 1 in 50–60% 1 ATP 1 exercise performance; 2 muscle and No change in AMP Sandri, 2006 promoter 1 mRNA FAO gene mRNA synthesis by NMR 2 fatigue in vitro, whole-body kinase activity (269); Calvo, protection from only in high- 2008 (267); denervation-induced fat diet Choi, 2008 (270) atrophy Arany, 2007 (271) PGC-1␤ MCK 1 200–500% 200–500% 1 FAO 120–130% 1 endurance promoter 1 mRNA and gene mRNA protein Kamei, 2003 (272) PGC1-␤ whole-body 1 whole-body ␤-actin promoter

Mito, Mitochondrial; EM, electron microscopy; MCK, muscle creatine kinase; 2, decrease; 1, increase; EDL, extensor digitorum longus; FAO, fatty acid oxidation.

379 Downloaded from https://academic.oup.com/edrv/article/31/3/364/2354793 by guest on 23 September 2021 September 23 on guest by https://academic.oup.com/edrv/article/31/3/364/2354793 from Downloaded 380 at n ovr iohnraadTp MEdcieRves ue21,31(3):364–395 2010, June Reviews, Endocrine DM 2 Type and Mitochondria Corvera and Patti

TABLE 2. Studies of PGC-1␣ or PGC-1␤ knockout models

First author, Mito Mito density OXPHOS mRNA/ Non-OXPHOS Insulin year (Ref.) Model DNA (EM) protein mRNA/protein Mito energetics Exercise capacity sensitivity Other Lin, 2004 (69); PGC-1␣ whole-body KO Normal 30–60% 2 mRNA; ATP levels 2 20% in 10–50% 2 cardiac 1 whole-body 2 body weight, Arany, 50% 2 CytC heart contractile performance increased 2005 (68) protein AMP kinase activity Leone, 2005 PGC-1␣ whole-body KO 30% 2 40–60% 2 mRNA 10% 2 in state 3 50% 2 fatigue resistance, 1 whole-body Hepatic steatosis (67) respiration abnormal cardiac response to stress Lehman, 2008 PGC-1␣ whole-body KO 2 cristae density Slight 2 mRNA 60% 2 in metabolic 2 cardiac power (61) in heart efficiency Handschin, PGC-1␣ muscle-specific Normal 30–40% 2 mRNA 50% 2 ALAS1 60% 2 grip strength, 1 muscle 2 food 2007 KO endurance, muscle consumption, (63, 64) damage basal and 2 body exercise weight, muscle inflammation, ␤-cell dysfunction Lai, 2008 (62) PGC-1␤ whole-body KO Not changed Modest 2 in state 3 2 running duration (heart) respiration Lelliot, 2006 PGC-1␤ whole-body KO 2 20% 20–40% 2 mRNA 2 state 3 and 4 2 chronotropic response Normal 2 body weight, (66) respiration, to dobutamine hepatic 2 ATP synthesis steatosis on high-fat diet Vianna, 2006 PGC-1␤ whole-body 2 30% 20–30% 2 mRNA Normal 1 hepatic lipid (65) hypomorph levels Sonoda, 2007 PGC-1␤ whole-body Normal 30–40% 2 mRNA Normal Normal Hepatic steatosis (59) hypomorph on high-fat diet Lai, 2008 (62) PGC-1␣ and PGC-1␤ 2 60%, heart Perinatal lethality due to Perinatal muscle-specific KO cardiac failure lethality due to cardiac failure

2, Decrease; 1, increase; KO, knockout; CytC, cytochrome C; ALAS1, 5-aminolevulinate synthase 1. Downloaded from https://academic.oup.com/edrv/article/31/3/364/2354793 by guest on 23 September 2021 September 23 on guest by https://academic.oup.com/edrv/article/31/3/364/2354793 from Downloaded Endocrine Reviews, June 2010, 31(3):364–395 edrv.endojournals.org 381

PGC-1␤ has distinct expression profiles in skeletal muscle, mice have been generated (61, 67–69). These mice con- being expressed in parallel with myosin IIx rather than sistently display 30–60% reductions in OXPHOS gene type I fibers (271). In addition, PGC-1␣ and PGC-1␤ co- expression in muscle, normal to decreased mitochondrial activate different nuclear receptors (272). Muscle-specific density in skeletal muscle, and decreased cristae density in transgenic overexpression of PGC-1␤ results in increased heart. Functionally, decreases in ATP levels, state 3 res- oxidative fiber content and increased expression of piration, and metabolic efficiency are seen, and cardiac OXPHOS and multiple other mitochondrial genes. and skeletal muscle performance is reduced in response to Mice displayed enhanced endurance and oxidative stress. Many of these phenotypes are recapitulated in a work (271). Consistent with these findings, whole-body muscle-specific PGC-1␣ knockout line (63, 64) (Table 2). ␤ transgenic overexpression of PGC-1 resulted in in- In addition, both lines of whole-body PGC-1␣ knockout creased oxidative metabolism, protection from obesity animals display cold sensitivity, likely related to impaired Downloaded from https://academic.oup.com/edrv/article/31/3/364/2354793 by guest on 23 September 2021 induced by high-fat diet or hyperphagia, and enhanced mitochondrial function in brown adipose tissue (67, 69) insulin sensitivity (272). (Table 2). Taken together, these studies suggest that modest Interestingly, muscle is significantly more insulin sen- overexpression of PGC-1␣ (261, 262) and transgenic sitive in both whole-body and muscle-specific PGC-1␣ overexpression of PGC-1␤ (271, 272) increase oxidative null mice. This apparently paradoxical finding—where metabolism and insulin sensitivity. By contrast, high- decreased oxidative function is not paralleled by insulin level overexpression of PGC-1␣ may actually reduce resistance—may be explained by the leanness and hyperinsulin sensitivity via reduced glycolysis and/or glucose activity noted in one of the whole-body knockout lines oxidation (265) or myofibrillar disruption/myopathy, po- (68, 69). In the muscle-specific knockout lines, reduction tentially limiting exercise tolerance. Moreover, high-level expression of PGC-1␣ can induce not only increases in in food intake, body weight, and adiposity (despite de- lipid oxidation genes but also parallel increases in expres- creased physical activity) may also contribute to insulin ␣ sion of genes promoting lipid uptake and synthesis (270). sensitivity (63, 64). Thus, lack of PGC-1 per se does not The net balance of these effects, and thus the net accumu- lead to insulin resistance, despite clear alterations in mus- lation of pathogenic lipid species, is likely to be determined cle and metabolic phenotypes. It is possible that the com- by the metabolic and hormonal milieu. For example, in pensatory mechanisms elicited by the complete lack of cultured myotubes overexpressing PGC-1␣ (273), lipid PGC-1␣, which result in a leaner phenotype, have a par- content is decreased in the serum-starved condition, re- adoxical insulin-sensitizing effect. For example, decreased flecting increased oxidation of lipids; by contrast, in the metabolic efficiency (61), defined as decreased ATP pro- serum-replete state, intracellular fatty acid levels are induced per unit of oxidized fuel and/or oxygen, may lead to creased, likely due to both increased de novo fatty acid enhanced whole-body fuel utilization and thus a leaner, synthesis from glucose and fatty acid synthesis by chain more insulin-sensitive phenotype. Activation of AMP ki- elongation (273). Thus, high-level expression of PGC-1 nase in this setting of reduced ATP production may also may actually cause accumulation of lipids and/or incom- contribute to enhanced insulin sensitivity (274). plete oxidation products, leading to reduced insulin Despite pronounced muscle and brown adipose tissue sensitivity, as observed in PGC-1␣ transgenic mice (267– functional impairments seen in models of PGC-1␣ defi- 269). These results also suggest that inappropriate, non- ciency, mitochondrial density in muscle and brown adi- physiological regulation of PGC-1␣ expression may pre- pose tissue is not notably decreased, indicating the vent appropriate modulation of oxidative metabolism possible compensatory role of PGC-1␤ in mitochondrial with feeding/fasting, or exercise/recovery—the hallmarks biogenesis. PGC-1␤-null mice (59, 62, 65, 66) display phe- of impaired metabolic flexibility observed in human insu- notypes similar to, but not identical to, those of PGC-1␣ lin resistance. knockouts, including reduced expression of OXPHOS B. PGC-1 knockout models genes, reduced ATP synthesis, reduced exercise capacity, Because enhanced insulin sensitivity is seen in some and impaired thermogenesis (59, 62). Insulin sensitivity in models of PGC-1 transgenic overexpression and human these animals is reported to be normal. PGC-1␤-null mice diabetes is associated with reduced PGC-1␣ and PGC-1␤ have more striking hepatic phenotypes, with hepatic in- expression, an important question is whether PGC-1␣ or sulin resistance, even on normal chow, and steatosis with PBC-1␤ deficiencies per se could result in insulin resis- high-fat feeding (59, 65, 66). These data raise the possi- tance. The results from studies of PGC-1␣ or PGC-1␤ bility that reduced expression of PGC1 family genes and knockout models shed some light on this question (Table impaired oxidative function may play a more important, 2). Two independent lines of whole-body PGC-1␣-null and potentially pathogenic role in liver than in muscle. 382 Patti and Corvera Mitochondria and Type 2 DM Endocrine Reviews, June 2010, 31(3):364–395

The existence of compensation for PGC-1␤ deficiency may enhance insulin action, potentially via ATP deficiency by PGC-1␣ and vice versa is evidenced by the phenotype and/or secondary activation of AMP kinase (280). of double PGC-1␣ and PGC-1␤ muscle-specific knockout To address whether reductions in OXPHOS content or mice (62). These animals display normal mitochondrial function may contribute to diabetes-related metabolic biogenesis during development but die early after birth phenotypes, we can also consider phenotypes related to due to failure of perinatal mitochondrial proliferation and genes regulating transcription of mtDNA. The nuclear- consequent cardiac failure (62). encoded mitochondrial transcription factor Tfam is Together, data from knockout mice have provided im- essential for transcription of mtDNA and thus mitochon- portant insights into the complex and multifaceted roles of drial development, as indicated by the embryonic lethality PGC-1␣ and PGC-1␤ as mediators of basal and adaptive of Tfam-null mice (281). Similarly, skeletal and cardiac energy homeostasis. PGC-1␣ and PGC-1␤ are both re- muscle-specific deletion of Tfam causes severe OXPHOS Downloaded from https://academic.oup.com/edrv/article/31/3/364/2354793 by guest on 23 September 2021 quired for the full complement of OXPHOS gene expres- deficits, dilated cardiomyopathy, and death during early sion, the establishment of correct fuel partitioning, and postnatal life (282). Skeletal muscle-specific Tfam defi- optimal metabolic efficiency because whole-body and ciency is accompanied by increased AMP kinase activation tissue-specific knockout of either of these genes leads to and increased glycolysis, indicating that compensatory deranged multiorgan metabolic phenotypes that are more mechanisms to maintain ATP levels are activated in re- evident during energetic stress. In light of these pheno- sponse to impaired mitochondrial energetics (282). In types, it is interesting to consider whether the 40–50% these mice, insulin sensitivity is normal and glucose tol- reduction in both PGC-1␣ and PGC-1␤ expression ob- erance is enhanced, consistent with a need for enhanced served in humans with obesity and type 2 DM in both liver fuel utilization in response to inefficient mitochondrial (232) and muscle (122), potentially mediated by lipid ex- ATP production. Thus, in these experimental models in cess, may contribute to further impairment in oxidative which mitochondrial oxidative capacity is severely re- capacity and a vicious cycle of maladaptive responses dur- stricted, insulin action is enhanced. ing energetic stress. DNA polymerase ␥ is a mtDNA polymerase critical for maintenance of mtDNA. POLG-null mice die during em- C. Other mitochondrial function defects bryogenesis with severe mtDNA depletion (283), whereas PGC-1 family members interact with the family of es- knock-in mutant mice have accelerated aging potentially trogen-related nuclear receptors, or ERRs, to transacti- linked to impaired repair of mtDNA mutations (284). vate transcription of oxidative genes (275) and mitofusins Mice null for the mitochondrial helicase Twinkle have (276). Interestingly, ERR␣-null mice have reduced body weight and are normoglycemic, in parallel with up-regu- impaired respiratory chain activity and muscle atrophy, lation of medium-chain acyl-CoA dehydrogenase and re- but no defect in exercise capacity (285). Thus, these data duced lipogenesis, both of which may contribute to resis- indicate that primary defects in mtDNA, even when pro- tance to diet-induced obesity (277). Although the duced experimentally by ablation of nuclear-encoded physiological effects of the related gene ERR␥ remain genes, do not produce overt metabolic phenotypes. These unclear, it interacts with PGC-1 to regulate expression observations are consistent with those in humans harbor- of ERR␣ (278), and polymorphisms at this locus were ing mutations in mtDNA, where mitochondrial diabetes found to be associated with increased glucose area un- typically manifests as a gradual deterioration of pancreatic ␤ der the curve in a genetic analysis of Old Order Amish -cell function (see Section III.D). subjects (279). Pospisilik et al. (274) used an alternative strategy to test whether experimentally induced respiratory chain V. Conclusions complex deficiency would induce metabolic phenotypes. Tissue-specific ablation of the nuclear-encoded gene, mi- Mitochondrial function in tissues involved in the patho- tochondrial apoptosis-inducing factor (AIF), produced genesis of DM (liver, muscle, adipose tissue, and pancre- modest defects in respiratory chain gene expression and atic ␤-cells) is critical for multiple aspects of cellular function, as expected; however, both muscle- and liver- metabolism. In each of these tissues, mitochondrial oxi- specific null mice had increased insulin sensitivity, reduced dative activity must be appropriate to fully oxidize nutri- fat mass, and improved glucose tolerance. Although de- ent loads, particularly fatty acids. Failure of complete fects in AIF may not precisely replicate respiratory chain oxidation can lead to accumulation of lipid intermediates, defects mediated by other genes, these data mirror to a incomplete fatty acid oxidation products, and ROS, in- large extent those in PGC-1-␣ null mice and again suggest ducing both insulin resistance (muscle, liver, adipose) and that modest defects in mitochondrial oxidative capacity altered secretion (␤-cells). Endocrine Reviews, June 2010, 31(3):364–395 edrv.endojournals.org 383

The sufficiency to fully oxidize fatty acids resides in the mal adaptive responses would be intolerant to moderate- balance between: 1) net mitochondrial oxidative activity, high fuel loads, leading to lipid accumulation, incomplete in turn determined by the need to generate energy to meet oxidation, production of ROS, and acute insulin resis- cellular demands, e.g., contraction and ion transport; tance (Fig. 5B). In turn, such alterations in mitochondrial and 2) fuel availability (determined by food intake, ad- activity could be mediated by genetic factors (family his- iposity, and adipose storage capacity) (Fig. 5A). Balance tory, ethnicity), epigenetic mechanisms, developmental is achieved when oxidative activity equals or exceeds exposures, and aging. With time, insufficient oxidative fuel loads. capacity could be resolved by compensatory mechanisms Under normal homeostatic conditions, both oxidative that increase oxidative capacity (e.g., exercise, mitochon- activity and cellular fuel availability could in principle be drial biogenesis) (Fig. 5C, top right) or decrease fuel load altered to ensure that mitochondrial function is appropri- (weight loss) (Fig. 5C, middle right). Insufficient compen- Downloaded from https://academic.oup.com/edrv/article/31/3/364/2354793 by guest on 23 September 2021 ate for the ambient metabolic environment. For example, sation could result in chronic insulin resistance (Fig. 5C, cellular demand for energy can be increased through ex- bottom right). ercise, and fuel availability can be reduced through weight Two key questions arise from this model: 1) does in- loss and/or reduced food intake. terindividual variation in either baseline or adaptive In this context, interindividual variation in oxidative mitochondrial oxidative responses alter risk for insulin capacity and/or activity, fuel load, or ability to modulate resistance; and 2) does chronic imbalance itself resulting mitochondrial activity (acute response), increase mito- from chronic overnutrition (e.g., ROS damage to mtDNA) chondrial capacity (chronic response), or resolve oxida- impair mitochondrial capacity, leading to further meta- tive stress could determine the set point of metabolic bolic imbalance? With regard to the first question, mild balance. Such differences could become prominent par- deficiencies in mitochondrial activity, and/or an inability ticularly in an obesogenic environment. Thus, individuals to increase activity and capacity in response to cellular with a high oxidative capacity or adaptive responses energy demand, could explain the reduced exercise ability would have high tolerance to large fuel loads. Conversely, seen in individuals with a family history of DM (106). individuals with low oxidative capacity and/or subopti- Over time, this phenotype could contribute to reduced voluntary exercise and increase the likelihood of an imbalance between mitochondrial activity and fatty acid load. Secondly, chronic imbalance in energy metabolism due to overnutrition, obesity, and inactivity could directly contribute to increased cellular and mitochondrial ROS production. In turn, excessive ROS can induce both insulin resistance and mitochondrial dysfunction. For example, a high-fat, high-sucrose diet in the diabetes-prone C57BL6 mouse causes mitochondrial alterations in parallel with enhanced ROS production and impaired insulin sensitivity. Similarly, exposure of muscle cells in vitro to saturated fatty acids or high-fat feeding in mice results in

FIG. 5. Dynamic relationship between oxidative activity and fuel load alterations in mitochondrial structure and insulin resis- leading to development of disease. In this diagram, oxidative capacity tance, both of which are reversed by antioxidants refers to the ability to generate energy in response to varying energy (286–288). Thus, oxidative stress can induce mitochon- requirements, and balance is indicated by oxidative capacity equaling or exceeding fuel loads. A, High oxidative activity can ensue from high- drial dysfunction in parallel with insulin resistance—per- energy requirements (chronic exercise, high metabolic rate). Individuals haps an adaptive response aimed at limiting further oxi- with a high oxidative capacity will have high tolerance to large fuel dative damage. More importantly, resolution of oxidative loads. B, Low oxidative activity can ensue from a lack of energy stress can reverse insulin resistance. These data also sug- requirement (sedentary lifestyle) or inability to generate energy (mitochondrial myopathies, intrauterine exposures, genetics) as seen in gest that defects in resolution of oxidative stress may be the failure of ATP synthesis in DM patients in response to exercise. another mechanism conferring increased risk for both mi- Individuals with low oxidative capacity are intolerant to moderate-high tochondrial dysfunction and insulin resistance. fuel loads that lead to ROS generation, lipid accumulation, incomplete oxidation, and acute insulin resistance. C, Insufficient oxidative The effects of these variables on disease progression can capacity can be resolved by compensatory mechanisms that increase be hypothesized to occur in three stages (Table 3). In the oxidative activity (e.g., exercise, top right) decrease fuel load (weight first stage, mitochondrial activity is adequate relative to loss, middle right), or resolve maladaptive patterns of oxidative stress. Insufficient compensation results in chronic insulin resistance (bottom fuel intake, and normal insulin sensitivity and secretion right). are observed. In a second stage, mitochondrial activity is 384 Patti and Corvera Mitochondria and Type 2 DM Endocrine Reviews, June 2010, 31(3):364–395

TABLE 3. Stages of disease progression

Stage I: healthy Stage II: physiological stress Stage III: failure of insulin sensitive with appropriate compensation compensation Oxidative capacity Normal exercise capacity Inappropriately low relative to load, Further + and activity and activity due to: ● Inactivity ● Reduced fitness ● Genetic susceptibility ● Aging Oxidative load Normal Increased, due to: Sustained _ ● Cellular overnutrition ● Obesity Cellular response Normal ● Initial 1 mitochondrial ● + Nuclear-encoded OXPHOS Downloaded from https://academic.oup.com/edrv/article/31/3/364/2354793 by guest on 23 September 2021 patterns biogenesis, inadequate to gene expression meet metabolic demand ● 1 Incomplete oxidation ● Vicious cycle of suboptimal ● 1 ROS generation oxidative capacity ● 1 Tissue lipid accumulation Physiological Normal insulin sensitivity Insulin resistance ● Progressive insulin resistance consequences and secretion ● Insulin secretory dysfunction ● Type 2 DM

2, Decrease; 1, increase. inadequate relative to oxidative load, leading to the de- are insufficient to answer this question with certainty or to velopment of oxidative stress, insulin resistance, impaired determine whether impaired oxidative capacity can cause insulin secretion, or both. Insulin resistance per se could insulin resistance, or result from insulin resistance. Animal result in further reductions in mitochondrial capacity data are inherently limited by interspecies comparisons. (229, 289), which in the absence of compensation (e.g., Moreover, it is also difficult to fully recapitulate in an decreased food intake) would lead to a third stage, char- animal model the subtle changes in mitochondrial activ- acterized by further imbalance, ␤-cell failure, and progres- ities and capacity and the interactions between mitochon- sion to DM. drial function and relative fuel load that, in humans, can We return to the key question—do variations in oxi- enhance diabetes risk. Nevertheless, results from multiple dative activity underlie the risk for and development of mouse models now indicate that absolute deficiency of the DM in humans? Unfortunately, the current human data PGC-1 family of coactivators or mitochondrial OXPHOS per se does not directly produce insulin resistance. Thus, we interpret the current data to indicate that an individual’s intrinsic mitochondrial oxidative activity may determine the magnitude of chronic cellular dysfunction and influence adaptive responses to chronic fuel excess, as with obesity or inactivity. Moreover, experimental induction of insulin resistance and/or components of the insulin-resistant/diabetes milieu may contribute to reductions in mitochondrial oxidative capacity, further fuel- ing a vicious cycle of diabetes risk (Fig. 6). To fully dissect these possibilities, better animal models, together with prospective longitudinal studies in humans analyzing OXPHOS FIG. 6. Vicious cycle leading to progressively increased risk of DM. An individual’s capacity in different tissues, their variation intrinsic mitochondrial oxidative capacity is determined by numerous factors with aging, weight gain, and fuel load, and their including genetic and ethnic background, intrauterine exposures, and age. Chronic fuel excess, in the setting of suboptimal oxidative activity, results in fatty acid correlation with the development of metabolic accumulation, incomplete oxidation, increased oxidative stress, and ROS generation disease are necessary. The recent emergence of leading to impairment in oxidative capacity, compounding the deleterious effects of metabolomic approaches will likely facilitate fuel excess. With time, mitochondrial damage ensues, further exacerbating the process. Together, these factors contribute to progressively impaired insulin further assessment of mitochondrial function sensitivity, insulin secretion, and heightened risk of DM. in humans, potentially allowing use of clini- Endocrine Reviews, June 2010, 31(3):364–395 edrv.endojournals.org 385 cally accessible blood samples for such longitudinal stud- 2. Centers for Disease Control and Prevention, US Department ies (290–293). A still-unanswered but intriguing question of Health and Human Services 2007 National diabetes fact is whether altered energetics during developmentally sheet. http://www.cdc.gov/diabetes/pubs/factsheet07.htm 3. Holloszy JO 2009 Skeletal muscle “mitochondrial defi- sensitive periods (e.g., intrauterine or early postnatal ciency” does not mediate insulin resistance. Am J Clin Nutr life) could ultimately increase susceptibility to insulin 89:463S–466S resistance. 4. Boyle JP, Honeycutt AA, Narayan KM, Hoerger TJ, Geiss In summary, we hypothesize that mitochondrial oxi- LS, Chen H, Thompson TJ 2001 Projection of diabetes dative activity can be considered as a key determinant burden through 2050: impact of changing demography and disease prevalence in the U.S. Diabetes Care 24: underlying diabetes risk. In isolation, reductions in mito- 1936–1940 chondrial activity mediated by genetic factors (family his- 5. Roglic G, Unwin N, Bennett PH, Mathers C, Tuomilehto tory, ethnicity), epigenetic mechanisms, developmental J, Nag S, Connolly V, King H 2005 The burden of mortality Downloaded from https://academic.oup.com/edrv/article/31/3/364/2354793 by guest on 23 September 2021 exposures, and aging may not be sufficient to induce in- attributable to diabetes: realistic estimates for the year sulin resistance. However, when sustained fuel excess 2000. Diabetes Care 28:2130–2135 (e.g., resulting from overnutrition or impaired fat storage) 6. Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM 2006 Prevalence of overweight and obesity exceeds energetic demands and/or oxidative capacity, in the United States, 1999–2004. JAMA 295:1549–1555 and/or appropriate compensatory mechanisms are insuf- 7. Hu FB, Manson JE, Stampfer MJ, Colditz G, Liu S, ficient (e.g., due to inactivity or failure of mitochondria to Solomon CG, Willett WC 2001 Diet, lifestyle, and the adapt to higher cellular oxidative demands), a vicious cy- risk of type 2 diabetes mellitus in women. N Engl J Med cle of insulin resistance and impaired insulin secretion can 345:790–797 8. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, be initiated (Fig. 6). Resulting lipid accumulation and ox- Lachin JM, Walker EA, Nathan DM 2002 Reduction in the idative stress can alter transcriptional responses and dam- incidence of type 2 diabetes with lifestyle intervention or age mitochondria, further reducing OXPHOS capacity, metformin. 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AJ, Chatterjee VK, O’Rahilly S 1999 Dominant negative mutations in human PPAR␥ associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 402: 880–883 Acknowledgments 11. Fajans SS, Bell GI, Polonsky KS 2001 Molecular mechanisms and clinical pathophysiology of maturity-onset dia- Address all correspondence and requests for reprints to: Mary-Elizabeth betes of the young. N Engl J Med 345:971–980 Patti, Joslin Diabetes Center, One Joslin Place, Room 620, Boston, Mas- 12. Florez JC, Jablonski KA, Bayley N, Pollin TI, de Bakker PI, sachusetts 02215. E-mail: [email protected]; or Shuldiner AR, Knowler WC, Nathan DM, Altshuler D Silvia Corvera, Program in Molecular Medicine, 373 Plantation Street, 2006 TCF7L2 polymorphisms and progression to diabetes Suite 107, Worcester, Massachusetts 01605. E-mail: silvia.corvera@ in the Diabetes Prevention Program. N Engl J Med 355: umassmed.edu. 241–250 The authors gratefully acknowledge research support from National 13. Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Institutes of Health Grants DK062948 (to M.-E.P.), DK080366 (to Manolescu A, Sainz J, Helgason A, Stefansson H, Emilsson S.C.), the Graetz Foundation (to M.-E.P.), LM008748 (to M.-E.P.), V, Helgadottir A, Styrkarsdottir U, Magnusson KP, DK060837 (Diabetes Genome Anatomy Project, to M.-E.P., and S.C.), Walters GB, Palsdottir E, Jonsdottir T, Gudmundsdottir M01 RR001032 (General Clinical Research Center), DK36836 (Diabe- T, Gylfason A, Saemundsdottir J, Wilensky RL, Reilly tes and Endocrinology Research Center, Joslin Diabetes Center), and MP, Rader DJ, Bagger Y, Christiansen C, Gudnason V, DK32520 (Diabetes Endocrinology Research Center, University of Mas- Sigurdsson G, Thorsteinsdottir U, Gulcher JR, Kong A, sachusetts Medical School). Stefansson K 2006 Variant of transcription factor 7-like 2 Disclosure Summary: The authors have nothing to disclose. (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 38:320–323 14. 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