Genes and pathophysiology of type 2 diabetes: more than just the Randle cycle all over again Alan R. Shuldiner, John C. McLenithan J Clin Invest. 2004;114(10):1414-1417. https://doi.org/10.1172/JCI23586. Commentary The Randle cycle, which has been invoked to explain the reciprocal relationship between fatty acid oxidation and glucose oxidation, has long been implicated as a potential mechanism for hyperglycemia and type 2 diabetes mellitus (T2DM). Now genetic, functional genomic, and transgenic approaches have identified PPARγ coactivators (PGC-1α and PGC-1β) as key regulators of mitochondrial number and function. They regulate adaptive thermogenesis as well as glucose and fat oxidation in muscle and fat tissue, gluconeogenesis in liver, and even glucose-regulated insulin secretion in β cells. PGC- 1α and PGC-1β mRNA levels and the mitochondrial genes they regulate are decreased in muscle of people with prediabetes and T2DM. A new report indicates that PGC-1α and PGC-1β mRNA levels decrease with age in individuals with a genetic variant in PGC-1α, and these decreases correlate with alterations in whole-body glucose and fatty acid oxidation. These findings provide insights into how aging modifies genetic susceptibility to alterations in oxidative phosphorylation and T2DM. Find the latest version: https://jci.me/23586/pdf commentaries Address correspondence to: William M. 114:1475–1483. doi:10.1172/JCI200422562. Role of hemodynamic factors in glomerular barrier 5. Daniels, B.S., Hauser, E.B., Deen, W.M., and Hostet- function. Kidney Int. 9:36–45. Deen, Department of Chemical Engineer- ter, T.H. 1992. Glomerular basement membrane: 12. Maynard, S.E., et al. 2003. Excess placental soluble ing and Division of Biological Engineering, in vitro studies of water and protein permeability. fms-like tyrosine kinase 1 (sFlt1) may contrib- Massachusetts Institute of Technology, 77 Am. J. Physiol. 262:F919–F926. ute to endothelial dysfunction, hypertension, Massachusetts Avenue, Room 66-572, Cam- 6. Edwards, A., Deen, W.M., and Daniels, B.S. 1997. and proteinuria in preeclampsia. J. Clin. Invest. Hindered transport of macromolecules in isolated 111:649–658. doi:10.1172/JCI200317189. bridge, Massachusetts 02139, USA. Phone: glomeruli. I. Diffusion across intact and cell-free 13. Rostgaard, I., and Qvortrup, K. 1997. Electron (617) 253-4535; Fax: (617) 253-2072; capillaries. Biophys. J. 72:204–213. microscopic demonstration of filamentous molec- E-mail: [email protected]. 7. Bolton, G.R., Deen, W.M., and Daniels, B.S. 1998. ular sieve plugs in capillary fenestrae. Microvasc. Res. Assessment of the charge-selectivity of glomerular 53:1–13. 1. Rodewald, R., and Karnovsky, M.J. 1974. Porous basement membrane using ficoll sulfate. Am. J. 14. Henry, C.B., and Duling, B.R. 1999. 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Intrarenal handling glomerular size selectivity in healthy and nephrotic 10. Drumond, M.C., and Deen, W.M. 1994. Structural of proteins in rats using fractional micropuncture humans. Am. J. Physiol. 273:F430–F437. determinants of glomerular hydraulic permeabil- technique. Am. J. Physiol. 263:F601–F606. 4. Wartiovaara, J., et al. 2004. Nephrin strands con- ity. Am. J. Physiol. 26:F1–F12. 17. Ruotsalainen, V., et al. 1999. Nephrin is specifically tribute to a porous slit diaphragm scaffold as 11. Ryan, G.B., and Karnovsky, M.J. 1976. Distribu- located at the slit diaphragm of glomerular podo- revealed by electron tomography. J. Clin. Invest. tion of endogenous albumin in the rat glomerulus: cytes. Proc. Natl. Acad. Sci. U. S. A. 96:7962–7967. Genes and pathophysiology of type 2 diabetes: more than just the Randle cycle all over again Alan R. Shuldiner and John C. McLenithan Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland, USA. Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, Maryland, USA. The Randle cycle, which has been invoked to explain the reciprocal relation- neous and polygenic nature of the condi- ship between fatty acid oxidation and glucose oxidation, has long been impli- tion and due to our limited understand- cated as a potential mechanism for hyperglycemia and type 2 diabetes mel- ing of its underlying pathophysiology. In litus (T2DM). Now genetic, functional genomic, and transgenic approaches the past decade, new and powerful tools have identified PPARγ coactivators (PGC-1α and PGC-1β) as key regulators of for probing the molecular, genetic, and mitochondrial number and function. They regulate adaptive thermogenesis pathophysiological basis of glucose and as well as glucose and fat oxidation in muscle and fat tissue, gluconeogenesis energy homeostasis have provided key in liver, and even glucose-regulated insulin secretion in β cells. PGC-1α and insights into the molecular basis of dia- PGC-1β mRNA levels and the mitochondrial genes they regulate are decreased betes. Some of these insights have proven in muscle of people with prediabetes and T2DM. A new report indicates that quite surprising based upon the current PGC-1α and PGC-1β mRNA levels decrease with age in individuals with a state of knowledge, while others have been genetic variant in PGC-1α, and these decreases correlate with alterations in logical extensions of the state of the field. whole-body glucose and fatty acid oxidation (see the related article beginning on page 1518). These findings provide insights into how aging modifies genet- Genetics of diabetes: ic susceptibility to alterations in oxidative phosphorylation and T2DM. what we do know Simply put, diabetes occurs as a result of Type 2 diabetes mellitus (T2DM), consid- and other industrialized countries. Obesity an absolute or relative deficiency of insu- ered a rare disease no more than 100 years and advancing age are potent risk factors lin. The former occurs in autoimmune ago, is now an epidemic in the United States for T2DM, pointing to lifestyle changes forms of diabetes, e.g., type 1 diabetes mel- of the 20th century that are responsible litus, or latent autoimmune diabetes in Nonstandard abbreviations used: HNF, hepatocyte for the current epidemic. However, despite adults, in which progressive destruction of nuclear factor; IPF-1, insulin promoter factor-1; MIDD, our diabetogenic environment, some indi- insulin-secreting cells leads to an abso- maternally inherited diabetes and deafness; OXPHOS, β oxidative phosphorylation; PGC, PPARγ coactivator; viduals develop diabetes and others do lute deficiency of insulin. Relative insulin T2DM, type 2 diabetes mellitus; VO2max, total body not. Multiple studies provide evidence that deficiency is far more pervasive and in its aerobic capacity. genetic factors are important contributors most common form, T2DM, is caused by Conflict of interest: Alan R. Shuldiner serves as a to the large inter-individual variation in insulin resistance (most often due to obe- consultant for Amgen, Pfizer, Inc., and Serono, Inc. He receives research support from Merck & Co., Inc. diabetes susceptibility (1, 2). Identification sity) coupled with progressive failure of Citation for this article: J. Clin. Invest. 114:1414–1417 of T2DM susceptibility genes has proven the β cell to secrete sufficient insulin to (2004). doi:10.1172/JCI200423586. challenging, in part due to the heteroge- compensate for the increased insulin resis- 1414 The Journal of Clinical Investigation http://www.jci.org Volume 114 Number 10 November 2004 commentaries betes syndromes. Although relatively rare, these syndromes have provided important insights into the molecular and cellular basis of glucose homeostasis. For exam- ple, some forms of autosomal dominant T2DM are due to defects in transcription factors necessary for normal β cell growth and differentiation (e.g., hepatocyte nuclear factors [HNFs], β2/neuroD, insu- lin promoter factor-1 [IPF-1]) (4), while others are due to mutations in molecules involved in glucose-regulated insulin secretion (e.g., glucokinase or the regula- tory subunit of the ATP-sensitive potas- sium channel) (4, 5). MIDD, caused by mutations in mitochondrial DNA, is asso- ciated with defective insulin secretion and also some element of insulin resistance (6). Although the specific mechanisms where- by mitochondrial DNA mutations lead to MIDD have not been fully elucidated, this rare syndrome points to mitochondrial function as a key factor in glucose homeo- stasis that may be relevant to the more common forms of T2DM (also see below). Other monogenic diabetes syndromes are associated with insulin resistance. For example, autosomal recessive forms of extreme insulin resistance are due to muta- tions in the insulin receptor gene (7). Genet- ic syndromes of lipodystrophy are typically associated with insulin resistance and dia- betes. Dunnigan-type autosomal dominant familial partial lipoatrophic diabetes is due to mutations in the nuclear envelope pro- tein lamin A/C (encoded by LMNA) (8) and dominant negative mutations in PPARγ (encoded by PPARG) (9). The mechanism whereby mutations in LMNA lead to this syndrome is unknown but may be due to Figure 1 disruption in nuclear function and result- Schematic of the pleiotropic effects of PGC-1α and PGC-1β.