Lipids and Glucose in Type 2 Diabetes What Is the Cause and Effect?

Reviews/Commentaries/ADA Statements REVIEW ARTICLE

Lipids and Glucose in Type 2 Diabetes What is the cause and effect?

1 GUENTHER BODEN, MD viving times of famine would be increased 2 MARKKU LAAKSO, MD if they could maximize energy storage (as fat) during times of surplus food availability. The stored fat could then be used during periods of starvation. istorically, type 2 diabetes was con- If this had happened, our understanding Adipocytes take up and store FFAs. sidered to revolve around a glu- of the pathogenesis of type 2 diabetes may The two main types of adipose tissue are H cose-insulin axis. The foundations have developed along a different route subcutaneous and visceral adipose tissue. for this thinking were probably laid down and led us more quickly to our current About 80% of body fat is located in the by two momentous discoveries in diabe- awareness that obesity, or more accu- subcutaneous adipose tissue, and ϳ10% tes research. According to popular leg- rately, the products of excess adipose tis- is located in visceral adipose tissue (7). end, Oskar Minkowski noticed that urine sue, precede the perturbations of glucose The remainder is in various other loca- from his pancreatectomized dogs at- metabolism. tions, such as perirenal and peritoneal ad- tracted an inordinate number of flies. He It is now apparent that elevation of ipose tissue (7). is then alleged to have tasted the urine plasma free fatty acids (FFAs) plays a piv- The body uses its fat reserves during and noted its sweetness. From this ob- otal role in the development of type 2 di- periods of low energy intake, when FFAs servation came the supposition that the abetes by causing insulin resistance. Type are being released for other tissues to be pancreas produced a substance that con- 2 diabetes develops because pancreatic used as fuel. However, if plasma FFA lev- trolled sugar concentration, and diabetes ␤-cells eventually fail to produce enough els are elevated for more than a few hours, occurred in the absence of this substance. insulin to compensate for the ongoing in- they will cause insulin resistance (8). In The second landmark was the discovery sulin resistance. There is a tight associa- certain conditions, the FFA-induced in- by Frederick Banting that insulin was the tion between type 2 diabetes and sulin resistance has the beneficial effect of active element from the pancreas. As a dyslipidemia. The latter is characterized preserving carbohydrate for use by vital consequence of these two discoveries, the by raised small, dense LDL levels, ele- tissues, such as the central nervous sys- concept that the glucose-insulin relation- vated levels of triglycerides, and low lev- tem. This is the case during starvation and ship was the central element of fuel me- els of HDL. Individually, the latter two during the second half of pregnancy, tabolism gained a firm hold. Diabetes has factors increase the risk of cardiovascular when the insulin resistance of the mother since been considered to be a disorder disease, and the combination of the two is preserves glucose for the growing fetus. primarily associated with abnormal glu- a risk factor for cardiovascular heart dis- cose metabolism. This notion is given cre- ease that is at least as strong as a high level PATHOLOGICAL dence by the considerable amount of data of LDL cholesterol (2). Some (3,4) but not CONSEQUENCES OF FAT indicating that the chronic elevation of all (5) studies have demonstrated that ACCUMULATION plasma glucose causes many of the micro- increased levels of small, dense LDL are In contrast to its beneficial effects during vascular complications of diabetes. associated with an elevated risk of cardio- periods of starvation and gestation, dur- In 1992, McGarry (1) asked what vascular disease. ing prolonged periods of energy excess, would have happened if Minkowski had the FFA-induced insulin resistance be- lacked a sense of taste but had a good EVOLUTIONARY comes counterproductive because there is nose. If that had been the case, he may RATIONALE FOR FAT no need for preservation of carbohydrate have smelled acetone, and this may have ACCUMULATION for use by vital tissues. Under these con- led him to the conclusion that removal of According to the thrifty gene hypothesis ditions, glucose levels remain normal the pancreas affects fatty acid metabolism. (6), the probability of an individual sur- only as long as the basal and postprandial ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● secretion of insulin by the pancreas is From the 1Division of Endocrinology/Diabetes/Metabolism and the General Clinical Research Center, Tem- 2 sufficient to compensate for the insulin ple University Hospital, Philadelphia, Pennsylvania; and the Department of Medicine, University of Kuopio, resistance. Kuopio, Finland. Address correspondence and reprint requests to G. Boden, MD, Temple University Hospital, 3401 N. Broad St., Philadelphia, PA 19140. E-mail: [email protected]. INDUCTION OF INSULIN Received for publication 27 May 2004 and accepted in revised form 10 June 2004. G.B. and M.L. have received honoraria from AstraZeneca Pharmaceuticals. RESISTANCE BY FFAS Abbreviations: DAG, diacylglycerol; FFA, free fatty acid; IL, interleukin; IRS, insulin receptor substrate; The mechanisms by which elevated FFA NF, nuclear factor; NHANES III, Third National Health and Nutrition Examination Survey; PKC, protein levels result in insulin resistance have kinase C; PPAR, peroxisome proliferator–activated receptor; TNF, tumor necrosis factor; TZD, thiazo- been determined in skeletal muscle, lidinedione. A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion where most insulin-stimulated glucose factors for many substances. uptake occurs. Formerly, it was believed © 2004 by the American Diabetes Association. that FFA production from overloaded fat

DIABETES CARE, VOLUME 27, NUMBER 9, SEPTEMBER 2004 2253 Lipids, glucose, and type 2 diabetes

Figure 1—Potential mechanism of FFA on insulin resistance and atherogenesis in human muscle. The key initiating event is an increase in plasma FFA followed by increased uptake of FFA into muscle. This leads to intramyocellular accumulation of fatty acyl-CoA and DAG and activation of PKC (the ␤ II and ␦ isoforms). It is assumed that activation of PKC interrupts insulin signaling by serine phosphorylation of IRS-1, resulting in a decrease in tyrosine phosphorylation of IRS-1. At the same time, activation of PKC also leads to production of inflammatory and proatherogenic proteins through activation of the I␬B-␣/NF-␬B pathway. The broken lines indicate that activation of PKC by reactive oxygen species (ROS) and activation of the I␬B-␣/NF-␬B pathway by ROS has not been demonstrated in human muscle but only in bovine aortic smooth muscle and endothelial cells (ref. 84). PI, phosphatidylinositol. cells disrupted glucose homeostasis via However, it is probably not the accumu- can cause insulin resistance is by increas- the Randle glucose–fatty acid cycle. First lation of fat in muscle cells that causes ing oxidative stress (26). Reactive oxygen described by Randle et al. (9) in 1963, the insulin resistance but rather the accumu- species can activate PKC and the NF-␬B hypothesis was that glucose uptake is relation of other metabolites, including di- pathway (Fig. 1) and thereby contribute duced when tissue energy needs are being acylglycerol (DAG), that occur at the same to insulin resistance (17,27). met by FFA oxidation. The oxidation of time (17). FFAs also affect the functioning of in- FFAs was thought to result in decreased DAG, which is an intermediate of tri- sulin in the liver and thus contribute to glucose oxidation and an increase in in- glyceride metabolism, is a potent activa- hepatic overproduction of glucose and to tracellular citrate levels, which would tor of protein kinase C (PKC) (18). In elevated circulating blood glucose levels decrease glycolysis and glucose uptake. In healthy volunteers, along with the rise in (28). The main role of insulin in the liver is vivo and in vitro studies have only par- intramyocellular levels of DAG, there was control of glucose production. The mecha- tially confirmed Randle’s hypothesis (8, a concomitant increase in PKC activity nism by which insulin acutely (within 1–2 10–12). For instance, insulin-stimulated (17). PKC is an enzyme that can phos- h) suppresses hepatic glucose production is glucose uptake has been found to proceed phorylate serine and threonine residues by inhibiting glycogenolysis (29). FFAs normally for several hours after maximal on both the insulin receptor (19,20) and produce insulin resistance in the liver by inhibition of carbohydrate oxidation by insulin receptor substrate (IRS)-1 (20, inhibiting the acute insulin suppression of fatty acids (8,11–13). 21). The latter two molecules are impor- glycogenolysis (30). Insulin also promotes It is now thought that FFAs induce tant for insulin signaling. Serine phos- hepatic uptake of FFAs and production of insulin resistance in human muscle at the phorylation of IRS-1 can lead to its de- intracellular triglycerides. Thus, insulin re- level of insulin-stimulated glucose trans- struction and to insulin resistance (22). sistance in the liver may contribute to ele- port or phosphorylation by impairing the A change in intracellular DAG levels vated plasma FFA levels. insulin-signaling pathway (Fig. 1) is also accompanied by activation of the An increase in visceral fat could also (13,14). In a study of nondiabetic men nuclear factor (NF)-␬B pathway (Fig. 1) cause insulin resistance by mechanisms and women, insulin resistance developed (17). NF-␬B has been linked to fatty acid– that do not directly involve FFAs (Fig. 1). 2–4 h after an acute elevation in plasma induced impairment of insulin action in Adipose tissue is a source of inflammatory FFA concentration and took a similar rodents (23,24). NF-␬B is also increas- mediators, such as tumor necrosis factor amount of time to disappear after plasma ingly recognized as playing a crucial role (TNF)-␣ (31) and interleukin (IL)-6 (32) FFA levels had returned to normal (8,15). in the pathogenesis of coronary artery dis- and peptides that include resistin (33), This delay indicates that FFAs have an in- ease (25). Thus, the activation of NF-␬B leptin (34), and adiponectin (35). So far, direct effect, a contention that is sup- may also help to explain the increased however, the physiological relevance of ported by the observation that acute prevalence of vascular disease in obese these adipokines for the development of increases in plasma FFAs increased tri- patientswithtype2diabetes.Consequent- insulin resistance in humans has not been glyceride content in muscle cells of hu- ly, lowering FFA concentrations may pre- established. man volunteers (16). This rise in vent activation of the NF-␬B pathway and intramyocellular triglyceride concentra- have benefits beyond increasing insulin ADIPONECTIN AND tion occurred several hours after the ele- sensitivity and improving regulation of INSULIN RESISTANCE vation of FFAs and coincided with the glucose levels. Of all the adipokines mentioned, adi- development of insulin resistance (16). Another mechanism by which FFAs ponectin is most likely to affect insulin

2254 DIABETES CARE, VOLUME 27, NUMBER 9, SEPTEMBER 2004 Boden and Laakso sensitivity. Adiponectin is produced ex- basis of this new definition, the actual nicotinic acid analogs are drugs that lower clusively in adipocytes. It stimulates fatty proportion of overweight people with im- plasma FFA levels. Their usefulness is acid oxidation, decreases plasma triglyc- paired glucose metabolism will be higher limited, however, because the initial low- erides, and improves glucose metabolism than the estimates from published sur- ering of plasma FFA levels by nicotinic by increasing insulin sensitivity (36). Adi- veys (including NHANES III) that used acid is invariably followed by a sharp FFA ponectin levels are negatively correlated the older definition. rebound (51) that increases insulin resis- with the development of insulin resis- Recently, it has become clearer why tance, at least temporarily. There has tance in rhesus monkeys (37). The plasma many obese, insulin-resistant people will therefore been considerable interest in levels of adiponectin in Caucasians and never develop diabetes. In obese people drugs that activate the peroxisome prolif- Pima Indians are negatively correlated with normal pancreatic ␤-cells, FFAs are erator–activated receptors (PPARs), with percent body fat and plasma insulin potent insulin secretagogues and can which are nuclear transcription factors levels and are positively correlated with compensate for the insulin resistance that that regulate the expression of numerous insulin-mediated glucose uptake (35,38). they produce. Acute elevations of plasma genes involved in lipid and carbohydrate In addition, plasma levels of adiponectin FFAs have long been known to stimulate metabolism, inflammation, and vascular are lower in individuals with type 2 dia- insulin secretion (42). More importantly, tone. betes than in age- and body mass– prolonged elevations of plasma FFAs matched individuals without diabetes (2–4 days) have been shown to potentiate PPAR-␥ (35). Thus, the impaired release of adipo- glucose-stimulated insulin secretion in Thiazolidinediones (TZDs), in contrast to nectin that occurs in obesity may contrib- healthy volunteers (43–45). Moreover, nicotinic acid analogs, lower plasma FFA ute to insulin resistance and development when chronic elevated plasma FFA levels levels without a rebound phenomenon of type 2 diabetes. were lowered in obese diabetic and non- (52–54). The binding affinity between The mechanism leading to decreased diabetic subjects, insulin secretion rates TZDs and PPAR-␥ correlates well with adiponectin levels in obesity (39) is not decreased by 30–50% (46), indicating their insulin-sensitizing activity. There- clear. Adiponectin is inhibited by insulin that the elevated plasma FFAs had sup- fore, it is generally accepted that TZDs and TNF-␣. Therefore, hyperinsulinemia ported 30–50% of basal insulin secretion. exert their action through PPAR-␥ caused by obesity-induced insulin resis- In contrast, in first-degree relatives of (55,56). PPAR-␥ is expressed at highest tance, together with enhanced TNF-␣ patients with type 2 diabetes (i.e., in indi- concentrations in adipose tissue and at expression, may contribute to reduced viduals who are genetically predisposed much lower concentrations in liver and adiponectin secretion. It has also been to develop diabetes), FFAs are unable to muscle (57,58), suggesting that the pri- suggested that visceral adipose tissue may fully compensate with adequately in- mary action of TZDs is on adipose tissue. produce an as yet unidentified substance creased insulin secretion for the insulin In support, it has been shown that TZDs that destabilizes adiponectin mRNA (40). resistance that they produce (45,47). This play an important role in adipocyte devel- defect in FFA-stimulated insulin secre- opment (59) and that they lower plasma FFAs AND INSULIN tion can also be demonstrated in patients levels of FFAs (Fig. 2) (52–54). In addi- SECRETION with impaired glucose tolerance (47,48) tion, TZDs have been postulated to im- Insulin resistance in the liver results in and in patients with overt type 2 diabetes prove insulin sensitivity by redistributing overproduction of glucose, whereas insu- (46). These observations suggest that the fat from visceral to subcutaneous adipose lin resistance in skeletal muscle produces obese individuals who develop type 2 di- tissue (60,61) and by increasing blood underutilization of glucose. Because FFAs abetes have a genetic predisposition to levels of adiponectin (62,63). can induce insulin resistance in both liver pancreatic ␤-cell failure. This hypothesis The available TZDs (pioglitazone and and muscle, all overweight or obese peo- is supported by the fact that these individ- rosiglitazone) have a generally good safety ple, who are likely to have elevated uals have a defect in both FFA and glu- and tolerability profile. They have been plasma FFA levels, might be expected to cose-stimulated insulin secretion (49) associated with increased development of have elevated glucose levels. This, how- and by in vitro studies showing that basal edema, which can exacerbate or lead to ever, is not the case because only approx- insulin secretion from normal Wistar rat congestive heart failure (64,65) in high- imately half of overweight individuals islets increased when cultured for 7 days risk patients with preexisting vascular have abnormal glucose levels; in the Third in 2 mmol/l FFAs but decreased in islets disease (66,67). The highest incidences of National Health and Nutrition Examina- from Zucker fatty rats who are predis- edema and congestive heart failure were tion Survey (NHANES III), 23% of over- posed to develop diabetes (50). seen when TZDs were used in combina- weight or obese (BMI Ն25 kg/m2) tion with insulin (65,68,69). Alongside individuals had impaired fasting glucose PEROXISOME improvements in glycemia and in some (fasting glucose concentration of 110– PROLIFERATOR–ACTIVATED lipid parameters, e.g., HDL, clinical trials 125 mg/dl) or impaired glucose tolerance RECEPTORS: A TARGET FOR have also reported dose-dependent (2-h glucose concentration of 140–199 THERAPEUTIC weight gain compared with placebo and mg/dl), and 23% had diabetes (41). INTERVENTION small decreases in hemoglobin and he- NHANES III was conducted using a lower Prolonged exposure to elevated FFA lev- matocrit after treatment with TZDs (70,71). limit of fasting glucose of 110 mg/dl to els is central to the development of insulin define impaired fasting glucose, but the resistance and type 2 diabetes, making PPAR-␣ American Diabetes Association has since modulation of these levels an attractive FFAs are natural ligands for PPAR-␣, defined the cutoff as 100 mg/dl. On the therapeutic strategy. Nicotinic acid and which is preferentially expressed in tis-

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Figure 2—Potential contributions of PPAR-␣ and PPAR-␥ to improvements in insulin sensitivity. sues where fatty acids are oxidized such as sitivity. Specific PPAR-␣ agonism can proach may offer an attractive option for the liver, muscle, kidney, and heart. Acti- lower lipid levels in rats and improve in- therapeutic intervention. Ongoing stud- vation of PPAR-␣ stimulates the expres- sulin sensitivity (76,77), whereas studies ies are examining the efficacy and safety of sion of genes involved in fatty acid and of fibrates in humans have either reported these new agents. lipoprotein oxidation in the liver and improved (78,79) or unimproved (80,81) muscle (72,73). PPAR-␣ activators, such insulin sensitivity. SUMMARY as fibrates, decrease plasma FFA and tri- From an initial perception that a disorder glyceride concentrations by stimulating Dual PPAR-␣/␥ activation of glucose metabolism was the primary several metabolic pathways (Fig. 2). Fi- PPAR-␥ exerts its beneficial effect by low- event in the pathogenesis of type 2 diabe- brates increase fatty acid uptake and oxi- ering plasma FFA levels, increasing tes, there is now a growing appreciation dation by increasing the expression of plasma adiponectin levels, and redistrib- that chronic elevation of FFA levels is an lipoprotein lipase in the liver and by de- uting fat from visceral to subcutaneous early event that contributes to the devel- creasing apolipoprotein C-III concentra- depots, and PPAR-␣ activation lowers opment of this disease. FFAs induce insu- tions. Apolipoprotein C-III is a protein plasma FFA levels through increased fat lin resistance, which increases with FFA that inhibits triglyceride hydrolysis by li- oxidation. Therefore, dual PPAR-␣/␥ ago- levels, and this can be a beneficial adap- poprotein lipase, and its downregulation nism may have advantages over selective tive response during starvation and preg- by fibrates results in reduced triglyceride PPAR subtype activation (82,83). Specif- nancy. However, insulin resistance can and VLDL production by the liver (74). ically, dual PPAR-␣/␥ agonism may lower become counterproductive when there is Simultaneously, these agents enhance in- plasma FFAs more than either PPAR-␣ or an excess of energy intake associated with travascular triglyceride metabolism (75). PPAR-␥ alone (Fig. 2). Given the central physical inactivity. The extra fuel is stored The lowering of FFAs through increased role of FFAs in the development of insulin in visceral and subcutaneous fat depots. oxidation may well improve insulin sen- resistance and type 2 diabetes, this ap- As fat accumulates, there is an ongoing

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