Endocrinology Vol. 145, No. 8 3563-3565
Copyright © 2004 by The Endocrine Society
ß-Cell Lipotoxicity: Burning Fat into Heat?
Vincent Poitout
Principal Scientist, Pacific Northwest Research Institute, Seattle, Washington 98122 and Affiliate Assistant Professor, Department of Medicine, University of Washington, Seattle, Washington 98195
Address all correspondence and requests for reprints to: Vincent Poitout, Pacific Northwest Research Institute, 720 Broadway, Seattle, Washington 98122. E-mail: vpoitout{at}pnri.org.
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Introduction
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The metabolic syndrome associates central adiposity, insulin resistance, hypertension, and dyslipidemia, and represents a high-risk factor for cardiovascular disease and type 2 diabetes. The lipotoxicity hypothesis proposes that ectopic accumulation of fat in nonadipose tissue is a central pathogenic process in the metabolic syndrome and plays a major role in muscle and liver insulin resistance, diabetic cardiomyopathy, and pancreatic ß-cell dysfunction (1). Whereas most individuals are capable of compensating for insulin resistance by increasing insulin secretion and thus maintain normal glucose levels, patients predisposed to developing type 2 diabetes fail to adequately compensate, resulting in ß-cell failure and chronic hyperglycemia. Once ß-cell failure has occurred, the convergent effects of chronic hyperglycemia and hyperlipidemia adversely affect ß-cell function (2), leading to the inexorable deterioration of insulin secretion observed during the course of type 2 diabetes (3). A number of in vivo and in vitro studies have shown that under conditions of elevated glucose levels (i.e. above the normoglycemic level of 
5.6 mM), prolonged exposure to pathological levels of fatty acids results in accumulation of triglycerides in ß-cells and impairment of insulin secretion, insulin gene expression, and cell viability (reviewed in Ref. 4). However, the mechanisms whereby fat accumulation in ß-cells impairs insulin secretion are poorly understood. A report in this issue of Endocrinology (5) provides new evidence for a link between lipogenesis and the expression of uncoupling protein-2 (UCP-2), shedding new light onto the mechanisms of lipotoxicity in the ß-cell.
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AMP-activated protein kinase (AMPK) as a fuel sensor
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Accumulation of triglycerides in ß-cells has been observed in a number of lipotoxic models, as exemplified by the massive increase in islet fat content that precedes the development of diabetes in Zucker Diabetic Fatty rats (6). In isolated islets, triglyceride accumulation after exposure to exogenous fatty acids only occurs when glucose concentrations are elevated (7). This permissive effect of glucose is due to its influence on lipid metabolism. When glucose concentrations are normal, excessive fatty acids are readily oxidized in the mitochondria. In contrast, when glucose concentration increases, fatty acid partitioning is switched to lipogenesis, a switch that entails coordinated changes in metabolic signaling (8) and gene expression (9). Increasing evidence suggests that the enzyme AMPK acts as a metabolic sensor that detects changes in the cellular energy state and directs the ß-cell into a storage mode in the face of nutrient oversupply (10), similar to its role in muscle and liver (11). Glucose negatively regulates AMPK activity in ß-cells (12), and AMPK inhibition at high glucose levels results in increased malonyl-coenzyme A (CoA) levels, diminution of fatty acid oxidation, and stimulation of lipogenesis (10). Importantly, agents that activate AMPK, such as 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), leptin, metformin, and troglitazone, prevent lipotoxicity in several experimental models (reviewed in Ref. 10).
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Sterol regulatory element binding protein-1c (SREBP1c) as an effector of lipotoxicity
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The transcription factor SREBP1c transactivates genes involved in fatty acid synthesis (13). Glucose regulates SREBP1c gene transcription (14), and overexpression of a constitutively active form of SREBP1c in INS-1 cells (5, 15) and isolated islets (16) results in triglyceride accumulation and impairs insulin secretion. Furthermore, activation of AMPK with AICAR decreases triglyceride content, increases fatty acid oxidation, and rescues insulin secretion in SREBP1c-overexpressing INS-1 cells (5), suggesting that SREBP1c is a target of AMPK in ß-cells, as has been shown in hepatocytes (17). Prevention of fatty acid-induced ß-cell death by AICAR in INS-1 cells was also recently reported by El-Assaad et al. (18). Overall, these observations suggest that AMPK serves as a metabolic sensor and SREBP1c as an effector in the metabolic switch occurring in ß-cells when both glucose and fatty acids are elevated, leading to increased lipogenesis and triglyceride accumulation (Fig. 1
). How, then, does triglyceride accumulation impair insulin secretion? A series of recent reports convincingly establishes a role for UCP-2 as a downstream target.
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FIG. 1. Potential mechanisms of lipotoxicity in pancreatic ß-cells. A, Under physiological circumstances, glucose metabolism results in an increase in the cellular ATP/ADP ratio, which triggers insulin secretion. This pathway is amplified by the generation of signals derived from cytosolic long-chain CoA esters (LC-CoA). Acute exposure to exogenous fatty acids potentiates glucose-induced insulin secretion, probably via the provision of LC-CoA. B, In contrast, chronic and simultaneous elevations of glucose and fatty acids result in decreased AMPK activity, which in turn stimulates SREBP1c and promotes lipogenesis and triglyceride accumulation. Hydrolysis of triglycerides, stimulated by glucose, further increases intracellular fatty acids that, through SREBP1c, stimulate UCP-2 expression. Fatty acids also stimulate PPAR expression, which then contributes to the increase in UCP-2 expression. UCP-2-induced mitochondrial uncoupling lowers ATP production from glucose metabolism, thereby impairing glucose-induced insulin secretion.
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UCP-2 as a downstream mediator of lipotoxicity
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UCP-2 is a ubiquitously expressed mitochondrial carrier capable of uncoupling the respiratory chain from ATP synthesis, although its biological functions are not clearly understood. Recent evidence suggests that UCP-2 modulates insulin secretion and plays a role in lipotoxicity. First, increasing UCP-2 expression in ß-cells impairs insulin secretion (19, 20). Second, UCP-2 knockout animals have increased circulating insulin levels and are protected from genetic (21) or nutritional (22) diabetes. Third, UCP-2 expression is increased in islets after high-fat feeding in rodents (20, 23) or exposure to fatty acids in vitro (24, 25). Fourth, oleic acid activates the UCP-2 promoter in INS-1 cells, an effect mediated directly by SREBP1c (26) and indirectly by peroxisome proliferator-activated receptor- (PPAR) (27). Finally, islets isolated from UCP-2 knockout animals are protected from lipotoxicity (22). These observations suggest that fatty acids activate the expression of UCP-2 in ß-cells, resulting in mitochondrial uncoupling. Because glucose-induced insulin secretion depends upon ATP generation from glucose metabolism, such uncoupling is predicted to impair insulin secretion.
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The connection between triglycerides and UCP-2
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It appears, therefore, that triglyceride accumulation on the one hand, and UCP-2 overexpression on the other hand, are potential mechanisms of lipotoxicity in ß-cells. The study of Yamashita et al. (5) suggests that both mechanisms may be related. Indeed, overexpression of SREBP1c increased UCP-2 protein levels and decreased the ATP/ADP ratio. Furthermore, knocking down UCP-2 expression by RNA silencing partially restored glucose-induced insulin release without affecting triglyceride content in SREBP1c overexpressing islets. Similarly, Patanè et al. (25) have shown that the expression of PPAR is increased in islets exposed to fatty acids, and that a PPAR antagonist prevents the increase in UCP2 expression and rescues insulin secretion. These data suggest that triglyceride stores might serve as a pool of endogenously released fatty acids, which in turn stimulate UCP-2 overexpression. Consistent with this model is the observation that islets overexpressing hormone-sensitive lipase, which is induced by glucose in ß-cells (28), have increased UCP-2 expression and are lipotoxic (29). In addition to their direct activation of the UCP-2 promoter (26), fatty acids may also induce UCP-2 expression via the production of reactive oxygen species (30). Altogether, these observations suggest a sequence of events leading to lipotoxicity whereby the simultaneous elevation of glucose and fatty acids is sensed by AMPK as a state of fuel oversupply, resulting in activation of SREBP1c and PPAR, increased lipogenesis, accumulation of triglycerides, secondary release of endogenous fatty acids from triglyceride stores, stimulation of UCP2 expression, mitochondrial uncoupling, and inhibition of glucose-induced insulin secretion (Fig. 1
). Although this model has not been validated in all its aspects, it provides a testable hypothesis to elucidate the mechanisms of lipotoxicity in the ß-cell and to identify potential targets for pharmacological interventions to prevent the deterioration of insulin secretion in type 2 diabetes.
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Acknowledgments
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The author apologizes to the many investigators who have contributed to this field and could not be cited due to space limitations.
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Footnotes
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Work performed in the author’s laboratory was supported by the National Institutes of Health, the American Heart Association, and a Thomas R. Lee Career Development Award from the American Diabetes Association.
Abbreviations: AICAR, 5-Aminoimidazole-4-carboxamide ribonucleoside; AMPK, AMP-activated protein kinase; CoA, coenzyme A; PPAR, peroxisome proliferator-activated receptor; SREBP1c, sterol regulatory element binding protein-1c; UCP-2, uncoupling protein-2.
Received April 14, 2004.
Accepted for publication April 21, 2004.
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References
|
|---|
- Unger RH 2003 Minireview: weapons of lean body mass destruction: the role of ectopic lipids in the metabolic syndrome. Endocrinology 144:5159–5165[CrossRef][Medline]
- Poitout V, Robertson RP 2002 Minireview: secondary ß-cell failure in type 2 diabetes—a convergence of glucotoxicity and lipotoxicity. Endocrinology 143:339–242[Abstract/Free Full Text]
- 1995 U. K. prospective diabetes study 16. Overview of 6 years’ therapy of type II diabetes: a progressive disease. U. K. Prospective Diabetes Study Group. Diabetes 44:1249–1258
- McGarry JD, Dobbins RL 1999 Fatty acids, lipotoxicity and insulin secretion. Diabetologia 42:128–138[CrossRef][Medline]
- Yamashita T, Eto K, Okazaki Y, Yamashita S, Yamauchi T, Sekine N, Nagai R, Noda M, Kadowaki T 2004 Role of uncoupling protein-2 up-regulation and triglyceride accumulation in impaired glucose-stimulated insulin secretion in a ß-cell lipotoxicity model overexpressing sterol regulatory element-binding protein-1c. Endocrinology 145:3566–3577[Abstract/Free Full Text]
- Unger RH 1997 How obesity causes diabetes in Zucker diabetic fatty rats. Trends Endocrinol Metab 8:276–282[CrossRef][Medline]
- Briaud I, Harmon JS, Kelpe CL, Segu VB, Poitout V 2001 Lipotoxicity of the pancreatic ß-cell is associated with glucose-dependent esterification of fatty acids into neutral lipids. Diabetes 50:315–321[Abstract/Free Full Text]
- Prentki M 1996 New insights into pancreatic ß-cell metabolic signaling in insulin secretion. Eur J Endocrinol 134:272–286[Abstract/Free Full Text]
- Roche E, Farfari S, Witters LA, Assimacopoulos-Jeannet F, Thumelin S, Brun T, Corkey BE, Saha AK, Prentki M 1998 Long-term exposure of ß-INS cells to high glucose concentrations increases anaplerosis, lipogenesis, and lipogenic gene expression. Diabetes 47:1086–1094[Abstract]
- Ruderman N, Prentki M 2004 AMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome. Nat Rev Drug Discov 3:340–351[CrossRef][Medline]
- Hardie DG 2003 Minireview: the AMP-activated protein kinase cascade: the key sensor of cellular energy status. Endocrinology 144:5179–5183[CrossRef][Medline]
- Salt IP, Johnson G, Ashcroft SJ, Hardie DG 1998 AMP-activated protein kinase is activated by low glucose in cell lines derived from pancreatic ß-cells, and may regulate insulin release. Biochem J 335:533–539
- Foufelle F, Ferre P 2002 New perspectives in the regulation of hepatic glycolytic and lipogenic genes by insulin and glucose: a role for the transcription factor sterol regulatory element binding protein-1c. Biochem J 366:377–391[CrossRef][Medline]
- Hasty AH, Shimano H, Yahagi N, Amemiya-Kudo M, Perrey S, Yoshikawa T, Osuga J, Okazaki H, Tamura Y, Iizuka Y, Shionoiri F, Ohashi K, Harada K, Gotoda T, Nagai R, Ishibashi S, Yamada N 2000 Sterol regulatory element-binding protein-1 is regulated by glucose at the transcriptional level. J Biol Chem 275:31069–31077[Abstract/Free Full Text]
- Wang H, Maechler P, Antinozzi PA, Herrero L, Hagenfeldt-Johansson KA, Bjorklund A, Wollheim CB 2003 The transcription factor SREBP-1c is instrumental in the development of ß-cell dysfunction. J Biol Chem 278:16622–16629[Abstract/Free Full Text]
- Diraison F, Parton L, Ferre P, Foufelle F, Briscoe CP, Leclerc I, Rutter GA 2004 Over-expression of sterol-regulatory-element-binding protein-1c (SREBP1c) in rat pancreatic islets induces lipogenesis and decreases glucose-stimulated insulin release: modulation by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). Biochem J 378:769–778[CrossRef][Medline]
- Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE 2001 Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108:1167–1174[CrossRef][Medline]
- El-Assaad W, Buteau J, Peyot ML, Nolan C, Roduit R, Hardy S, Joly E, Dbaibo G, Rosenberg L, Prentki M 2003 Saturated fatty acids synergize with elevated glucose to cause pancreatic ß-cell death. Endocrinology 144:4154–4163[CrossRef][Medline]
- Chan CB, MacDonald PE, Saleh MC, Johns DC, Marban E, Wheeler MB 1999 Overexpression of uncoupling protein 2 inhibits glucose-stimulated insulin secretion from rat islets. Diabetes 48:1482–1486[Abstract]
- Chan CB, De Leo D, Joseph JW, McQuaid TS, Ha XF, Xu F, Tsushima RG, Pennefather PS, Salapatek AM, Wheeler MB 2001 Increased uncoupling protein-2 levels in ß-cells are associated with impaired glucose-stimulated insulin secretion: mechanism of action. Diabetes 50:1302–1310[Abstract/Free Full Text]
- Zhang C-Y, Baffy G, Perret P, Krauss S, Peroni O, Grujic D, Hagen T, Vidal-Puig A-J, Boss O, Kim Y-B, Zheng XX, Wheeler MB, Shulman GI, Chan CB, Lowell BB 2001 Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, ß-cell dysfunction, and type 2 diabetes. Cell 105:745–755[CrossRef][Medline]
- Joseph JW, Koshkin V, Zhang CY, Wang J, Lowell BB, Chan CB, Wheeler MB 2002 Uncoupling protein 2 knockout mice have enhanced insulin secretory capacity after a high-fat diet. Diabetes 51:3211–3219[Abstract/Free Full Text]
- Briaud I, Kelpe CL, Johnson LM, Tran POT, Poitout V 2002 Differential effects of hyperlipidemia on insulin secretion in islets of Langerhans from hyperglycemic vs. normoglycemic rats. Diabetes 51:662–668[Abstract/Free Full Text]
- Lameloise N, Muzzin P, Prentki M, Assimacopoulos-Jeannet F 2001 Uncoupling protein 2: a possible link between fatty acid excess and impaired glucose-induced insulin secretion? Diabetes 50:803–809[Abstract/Free Full Text]
- Patanè G, Anello M, Piro S, Vigneri R, Purrello F, Rabuazzo AM 2002 Role of ATP production and uncoupling protein-2 in the insulin secretory defect induced by chronic exposure to high glucose or free fatty acids and effects of peroxisome proliferator-activated receptor- inhibition. Diabetes 51:2749–2756[Abstract/Free Full Text]
- Medvedev AV, Robidoux J, Bai X, Cao W, Floering LM, Daniel KW, Collins S 2002 Regulation of the uncoupling protein-2 gene in INS-1 ß-cells by oleic acid. J Biol Chem 277:42639–42644[Abstract/Free Full Text]
- Medvedev AV, Snedden SK, Raimbault S, Ricquier D, Collins S 2001 Transcriptional regulation of the mouse uncoupling protein-2 gene. Double E-box motif is required for peroxisome proliferator-activated receptor--dependent activation. J Biol Chem 276:10817–10823[Abstract/Free Full Text]
- Winzell MS, Svensson H, Arner P, Ahren B, Holm C 2001 The expression of hormone-sensitive lipase in clonal ß-cells and rat islets is induced by long-term exposure to high glucose. Diabetes 50:2225–2230[Abstract/Free Full Text]
- Winzell MS, Svensson H, Enerback S, Ravnskjaer K, Mandrup S, Esser V, Arner P, Alves-Guerra MC, Miroux B, Sundler F, Ahren B, Holm C 2003 Pancreatic ß-cell lipotoxicity induced by overexpression of hormone-sensitive lipase. Diabetes 52:2057–2065[Abstract/Free Full Text]
- Krauss S, Zhang CY, Scorrano L, Dalgaard LT, St-Pierre J, Grey ST, Lowell BB 2003 Superoxide-mediated activation of uncoupling protein 2 causes pancreatic ß cell dysfunction. J Clin Invest 112:1831–1842[CrossRef][Medline]
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Introduction
AMP-activated protein kinase...
