This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Poitout, V. Articles by Robertson, R. P. Search for Related Content PubMed PubMed Citation Articles by Poitout, V. Articles by Robertson, R. P.

Minireview: Secondary ß-Cell Failure in Type 2 Diabetes—A Convergence of Glucotoxicity and Lipotoxicity

Pacific Northwest Research Institute (V.P., R.P.R.), Seattle, Washington 98122; and Departments of Medicine (V.P., R.P.R.) and Pharmacology (R.P.R.), University of Washington, Seattle, Washington 98195

Address all correspondence and requests for reprints to: Vincent Poitout, D.V.M., Ph.D., Pacific Northwest Research Institute, 720 Broadway, Seattle, Washington 98122. E-mail: vpoitout{at}pnri.org

	Abstract

Top Abstract Introduction Glucotoxicity Lipotoxicity Glucolipotoxicity: Glucose and... Conclusion References

 
Chronic hyperglycemia and hyperlipidemia can exert deleterious effects on ß-cell function, respectively referred to as glucotoxicity and lipotoxicity. Over time, both contribute to the progressive deterioration of glucose homeostasis characteristic of type 2 diabetes. The mechanisms of glucotoxicity involve several transcription factors and are, at least in part, mediated by generation of chronic oxidative stress. Lipotoxicity is probably mediated by accumulation of a cytosolic signal derived from the fatty acid esterification pathway. Our view that hyperglycemia is a prerequisite for lipotoxicity is supported by several recent studies performed in our laboratories. First, prolonged in vitro exposure of isolated islets to fatty acids decreases insulin gene expression in the presence of high glucose concentrations only, and glucose is rate-limiting for the incorporation of fatty acids into neutral lipids. Second, normalization of blood glucose in Zucker diabetic fatty rats prevents accumulation of triglycerides and impairment of insulin gene expression in islets, whereas normalization of plasma lipid levels is without effect. Third, high-fat feeding in Goto-Kakizaki rats significantly impairs glucose-induced insulin secretion in vitro, whereas a similar diet has no effect in normoglycemic animals. We propose that chronic hyperglycemia, independent of hyperlipidemia, is toxic for ß-cell function, whereas chronic hyperlipidemia is deleterious only in the context of concomitant hyperglycemia.

	Introduction

Top Abstract Introduction Glucotoxicity Lipotoxicity Glucolipotoxicity: Glucose and... Conclusion References

 
TYPE 2 DIABETES mellitus is a heterogeneous syndrome of polygenic origin and involves both defective insulin secretion and peripheral insulin resistance. ß-Cell dysfunction is a sine qua non for the development of the disease, but the nature of the primary ß-cell defect is still elusive. Once diabetes is established, chronic hyperglycemia and hyperlipidemia can exert deleterious effects on ß-cell function, respectively referred to as glucotoxicity and lipotoxicity. Over time, both of these phenomena contribute to the progressive deterioration of glucose homeostasis characteristic of this disease. The purpose of this minireview is to present recent advances in the understanding of the interrelationships between glucotoxicity and lipotoxicity, and to propose the hypothesis that lipotoxicity occurs only in the presence of hyperglycemia, whereas glucotoxicity occurs independently of hyperlipidemia.

	Glucotoxicity

Top Abstract Introduction Glucotoxicity Lipotoxicity Glucolipotoxicity: Glucose and... Conclusion References

 
Glucotoxicity, ß-cell exhaustion, and glucose desensitization
Considerable evidence has been reported suggesting that chronic hyperglycemia impairs glucose-induced insulin secretion and insulin gene expression (reviewed in Ref. 1). Adverse effects of chronic hyperglycemia on ß-cell function encompass three distinct phenomena: glucose desensitization, ß-cell exhaustion, and glucotoxicity. Glucose desensitization refers to the rapid and reversible refractoriness of the ß-cell exocytotic machinery that occurs after a short exposure to elevated glucose ¹ and is a physiological adaptive mechanism that occurs even when insulin secretion is inhibited, thus differentiating it from ß-cell exhaustion (2). ß-Cell exhaustion refers to depletion of the readily releasable pool of intracellular insulin following prolonged exposure to a secretagogue (3, 4). In contrast, the term glucotoxicity describes the slow and progressively irreversible effects of chronic hyperglycemia on pancreatic ß-cell function, which occur after prolonged exposure to elevated glucose. The fact that these associated ß-cell defects are reversible up until a certain point in time and become irreversible thereafter suggests a continuum between ß-cell exhaustion and glucotoxicity, the latter becoming predominant after prolonged exposure (5, 6). In addition to inducing functional changes, chronic hyperglycemia can also decrease ß-cell mass by inducing apoptosis (7, 8).

Mechanisms of glucotoxicity
Impairment of insulin gene expression after prolonged exposure to elevated glucose levels is associated with diminished activity of two major ß-cell transcription factors, pancreatic-duodenum homeobox-1 (9, 10) and the activator of the rat insulin promoter element 3b1 (11, 12). Increased expression of the insulin gene transcriptional repressor CCAAT/enhancer-binding protein ß (13, 14) and of the proto-oncogene c-myc (15) have also been reported. The latter has been postulated to reflect a loss of differentiation of ß-cells exposed to elevated glucose, which could explain, in part, defective ß-cell function (15). The biochemical mechanisms of glucotoxicity have been proposed to involve generation of chronic oxidative stress (16, 17, 18, 19). In the insulin-secreting HIT-T15 cell, generation of reactive oxygen species in the presence of a reducing sugar (17) or chronic exposure to elevated glucose (18) leads to decreased transcription of the insulin gene, an effect prevented by the antioxidants aminoguanidine and N-acetyl-cysteine (NAC). Chronic exposure of isolated islets to elevated glucose levels in vitro leads to accumulation of advanced glycation end-products, impaired ß-cell function, and apoptosis, all of which can be prevented by aminoguanidine and NAC (16, 20). Finally, treatment of Zucker diabetic fatty (ZDF) rats with aminoguanidine or NAC normalizes plasma glucose levels and restores insulin secretion, insulin content, and insulin mRNA levels (18). These findings firmly support the hypothesis that glucotoxicity is mediated, at least in part, by chronic oxidative stress.

	Lipotoxicity

Top Abstract Introduction Glucotoxicity Lipotoxicity Glucolipotoxicity: Glucose and... Conclusion References

 
Chronically elevated fatty acids affect ß-cell function
Similar to the paradoxically deleterious effects of chronic hyperglycemia, fatty acids (FA), which are essential ß-cell fuels in the normal state, become toxic when chronically present in excessive levels. Prolonged exposure of pancreatic ß-cells to FA increases basal insulin release but inhibits glucose-induced insulin secretion (reviewed in Ref. 21). In addition, FA inhibit insulin gene expression in the presence of elevated glucose levels (22, 23, 24), in part via negative regulation of the transcription factor pancreatic-duodenum homeobox-1 (22). Finally, excessive FA induce ß-cell death by apoptosis both in vitro (25, 26) and in ZDF rat islets (7, 27).

Mechanisms of lipotoxicity
One central question in understanding the mechanisms of FA effects is whether they are due to increased FA oxidation and a resulting decrease in glucose oxidation, or to generation of a cytosolic signal via esterification of FA. We favor the view that one or several intermediate metabolites generated in the FA esterification pathway mediate deleterious effects of chronically elevated FA, mostly because prolonged exposure to FA is associated with profound alterations in lipid metabolism and minimal changes in glucose metabolism (28). The biochemical basis for this hypothesis was first proposed by Prentki and Corkey (29) and has been recently reviewed in detail (30). According to this model, the simultaneous presence of elevated glucose and FA results in accumulation of cytosolic citrate, the precursor of malonyl-CoA, which in turn inhibits carnitine-palmitoyl-tranferase-1, the enzyme responsible for transport of FA into the mitochondrion. Sustained inhibition of carnitine-palmitoyl-tranferase-1 results in cytosolic accumulation long-chain fatty acyl CoAs (LC-CoA), which are proposed to mediate the deleterious effects of chronically elevated FA (29). This model proposes that the glucose concentration plays a critical role in the effects of FA. Whether LC-CoA accumulation directly affects ß-cell function, or whether it serves as a precursor for other active molecules such as diacylglycerols or phospholipids is not known. Similarly, the nature of the effectors downstream of lipid metabolite accumulation is unknown, although several candidates have been proposed, including the ATP-sensitive potassium channel, PKC, uncoupling protein-2 (UCP-2), direct effects on the exocytotic machinery, or modulation of gene expression (reviewed in Ref. 30).

	Glucolipotoxicity: Glucose and FA Synergistically Harm the ß-Cell

Top Abstract Introduction Glucotoxicity Lipotoxicity Glucolipotoxicity: Glucose and... Conclusion References

 
The "malonyl-CoA/LC-CoA hypothesis" proposed as a biochemical basis for lipotoxicity implies that the effects of FA are greatly influenced by the concomitant glucose concentration. If this hypothesis is correct, in the presence of physiological glucose concentrations elevated FA should be readily oxidized in the mitochondrion and should not harm the ß-cell. In contrast, under circumstances where both FA and glucose are elevated, accumulation of metabolites derived from fatty acid esterification would inhibit glucose-induced insulin secretion and insulin gene expression. Recent studies performed in our laboratories support this hypothesis.

In vitro studies
First, we asked whether prolonged exposure of isolated islets to palmitate differentially affects insulin gene expression in the presence of low vs. high glucose concentrations (23). We showed that a 72-h culture in the presence of palmitate does not affect insulin content or insulin mRNA levels at low glucose, but these both significantly decrease in the presence of high glucose. Second, we sought to determine whether prolonged culture of islets with palmitate is associated with glucose-dependent incorporation of FA into neutral lipids (31). We found that glucose and palmitate have additive effects on FA metabolism upon prolonged exposure: glucose increases overall cellular lipid synthesis, whereas palmitate specifically directs lipid partitioning toward neutral lipid synthesis. As a result, palmitate-induced accumulation of intracellular triglycerides (TG) only occurs in the presence of high glucose. The glucose-dependent accumulation of neutral lipids was inversely correlated to insulin mRNA levels.

In vivo studies
To differentiate between hyperlipidemia and hyperglycemia as secondary metabolic forces leading to TG accumulation and defective insulin gene expression in ZDF rat islets, we treated ZDF animals between 6 and 12 wk of age with either the lipid-lowering drug bezafibrate or the blood glucose-lowering agent phlorizin (32). Neither treatment had an effect on body weight. As expected, phlorizin treatment prevented the rise in blood glucose levels between 6 and 12 wk without affecting lipid levels, whereas bezafibrate prevented the rise in plasma TG without affecting glucose levels. Islet TG content was decreased by phlorizin treatment, but not by bezafibrate treatment, suggesting that islet TG accumulation in this model requires hyperglycemia. Phlorizin, but not bezafibrate, prevented the decrease in insulin mRNA levels between 6 and 12 wk of age. Thus, we concluded from these studies that antecedent hyperglycemia, not hyperlipidemia, is associated with increased islet TG content and decreased insulin gene mRNA levels in ZDF rats. To determine whether hyperlipidemia induced by high-fat feeding differentially affects ß-cell function in normoglycemic vs. hyperglycemic rats, we administered a high-fat diet for 6 wk to either Goto-Kakizaki (GK) or age-matched Wistar rats (33). Six weeks of high-fat feeding did not affect glucose-stimulated insulin release in islets from Wistar rats but decreased the maximal response to glucose in islets from GK rats by approximately 50%. Administration of insulin during the 6 wk of diet normalized both blood glucose and plasma FA levels and completely prevented the decrease in GSIS in islets from high-fat-fed GK animals. The mechanisms of high-fat diet-induced impairment of insulin secretion did not seem to involve intraislet TG accumulation, because we were not able to detect any differences in TG levels in islets between either Wistar or GK rats fed a regular or high-fat diet. We observed, however, an increase in the expression of UCP-2 in islets from high-fat-fed GK rats, which was prevented by insulin treatment.

These results clearly support the hypothesis that hyperglycemia is required for lipotoxicity to occur. They are consistent with the clinical observation that the majority of hyperlipidemic individuals are not diabetic. That ß-cell function is usually normal in patients with disorders of lipid metabolism suggests that obesity or dyslipidemia are not sufficient to cause ß-cell dysfunction.

	Conclusion

Top Abstract Introduction Glucotoxicity Lipotoxicity Glucolipotoxicity: Glucose and... Conclusion References

 
ß-Cell failure in type 2 diabetes is an evolving process, which, regardless of the nature of the initial defect, gradually worsens over time. Chronically elevated blood glucose levels adversely affect insulin secretion. The mechanisms of glucotoxicity involve defective insulin gene expression and are at least partly mediated by chronic oxidative stress. Presented here is the view that chronically elevated FA levels do not harm the ß-cell as long as blood glucose levels are normal, but profoundly affect ß-cell function in the presence of concomitant hyperglycemia. Thus, glucotoxicity and lipotoxicity are closely interrelated, in the sense that lipotoxicity does not exist without chronic hyperglycemia. Furthermore, the effects of glucose on lipid metabolism are so profound that lipotoxicity can be viewed as one mechanism of glucotoxicity. Generation of reactive oxygen species may be an alternative mechanism of both glucotoxicity and lipotoxicity. Exposure of islets to palmitate induces generation of reactive oxygen species (34), and treatment of islets with metformin, which has antioxidant properties, protects from deleterious effects of FA (35). It is therefore conceivable that glucotoxicity and lipotoxicity interdependently converge toward the generation of damaging effectors on ß-cell function.

	Footnotes

 
Studies performed in our laboratories were supported by grants from the American Diabetes Association (to V.P.) and the National Institutes of Health (R-01-DK-58096 to V.P. and R-01-DK-38325 to R.P.R).

Abbreviations: FA, Fatty acids; GK, Goto-Kakizaki; LC-CoA, long-chain fatty acyl CoAs; NAC, N-acetyl-cysteine; TG, triglycerides; UCP-2, uncoupling protein-2; ZDF, Zucker diabetic fatty.

¹ "Elevated glucose" refers to concentrations above the physiological plasma levels of 5.6 mM, such as those measured in type 2 diabetic patients.

Received August 28, 2001.

Accepted for publication October 12, 2001.

	References

Top Abstract Introduction Glucotoxicity Lipotoxicity Glucolipotoxicity: Glucose and... Conclusion References

 

1. Robertson RP, Harmon JS, Tanaka Y, Sacchi G, Tran POT, Gleason CE, Poitout V 2000 Glucose toxicity of the ß-cell: cellular and molecular mechanisms. In: Le Roith D, Taylor S, Olefsky JM, eds. Diabetes mellitus. A fundamental and clinical text. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 125–132
2. Kilpatrick ED, Robertson RP 1998 Differentiation between glucose-induced desensitization of insulin secretion and ß-cell exhaustion in the HIT-T15 cell line. Diabetes 47:606–611[Abstract]
3. Sako Y, Grill VE 1990 Coupling of ß-cell desensitization by hyperglycemia to excessive stimulation and circulating insulin in glucose-infused rats. Diabetes 39:1580–1583[Abstract]
4. Leahy JL, Bumbalo LM, Chen C 1994 Diazoxide causes recovery of ß-cell glucose responsiveness in 90% pancreatectomized diabetic rats. Diabetes 43:173–179[Abstract]
5. Moran A, Zhang H-J, Olson LK, Harmon JS, Poitout V, Robertson RP 1997 Differentiation of glucose toxicity from ß-cell exhaustion during the evolution of defective insulin gene expression in the pancreatic islet cell line, HIT-T15. J Clin Invest 99:534–539[Medline]
6. Gleason CE, Gonzalez M, Harmon JS, Robertson RP 2000 Determinants of glucose toxicity and its reversibility in the pancreatic islet ß-cell line, HIT-T15. Am J Physiol Endocrinol Metab 279:E997–E1002
7. Pick A, Clark J, Kubstrup C, Levisetti M, Pugh W, Bonner-Weir S, Polonsky K 1998 Role of apoptosis in failure of ß-cell mass compensation for insulin resistance and ß-cell defects in the male Zucker diabetes fatty rat. Diabetes 47:358–364[Abstract]
8. Donath MY, Gross DJ, Cerasi E, Kaiser N 1999 Hyperglycemia-induced ß-cell apoptosis in pancreatic islets of Psammomys obesus during development of diabetes. Diabetes 48:738–744[Abstract]
9. Olson LK, Redmon JB, Towle HC, Robertson RP 1993 Chronic exposure of HIT cells to high glucose concentrations paradoxically decreases insulin gene transcription and alters binding of insulin gene regulatory protein. J Clin Invest 92:514–519
10. Olson LK, Sharma A, Peshavaria M, Wright CVE, Towle HC, Robertson RP, Stein R 1995 Reduction of insulin gene transcription in HIT-T15 cells chronically exposed to a supraphysiologic glucose concentration is associated with loss of STF-1 transcription factor expression. Proc Natl Acad Sci USA 92:9127–9131[Abstract/Free Full Text]
11. Sharma A, Olson LK, Robertson RP, Stein R 1995 The reduction of insulin gene transcription in HIT-T15 ß cells chronically exposed to high glucose concentration is associated with the loss of RIPE3b1 and STF-1 transcription factor expression. Mol Endocrinol 9:1127–1134[Abstract]
12. Poitout V, Olson LK, Robertson RP 1996 Chronic exposure of ßTC-6 cells to supraphysiologic concentrations of glucose decreases binding of the RIPE-3b1 insulin gene transcription activator. J Clin Invest 97:1041–1046[Medline]
13. Lu M, Seufert J, Habener JF 1997 Pancreatic ß-cell-specific repression of insulin gene transcription by CCAAT/Enhancer-binding protein ß. Inhibitory interactions with basic helix-loop-helix transcription factor E47. J Biol Chem 272:28349–28359[Abstract/Free Full Text]
14. Seufert J, Weir GC, Habener JF 1998 Differential expression of the insulin gene transcriptional repressor CCAAT/enhancer-binding protein beta and transactivator islet duodenum homeobox-1 in rat pancreatic ß cells during the development of diabetes mellitus. J Clin Invest 101:2528–2539[Medline]
15. Jonas JC, Sharma A, Hasenkamp W, Ilkova H, Patane G, Laybutt R, Bonner-Weir S, Weir GC 1999 Chronic hyperglycemia triggers loss of pancreatic ß cell differentiation in an animal model of diabetes. J Biol Chem 274:14112–14121[Abstract/Free Full Text]
16. Tajiri Y, Moller C, Grill V 1997 Long term effects of aminoguanidine on insulin release and biosynthesis: evidence that the formation of advanced glycosylation end products inhibits ß-cell function. Endocrinology 138:273–280[Abstract/Free Full Text]
17. Matsuoka TA, Kajimoto Y, Watada H, Kaneto H, Kishimoto M, Umayahara Y, Fujitani Y, Kamada T, Kawamori R, Yamakasi Y 1997 Glycation-dependent, reactive oxygen species mediated suppression of the insulin gene promoter activity in HIT cells. J Clin Invest 99:144–150[Medline]
18. Tanaka Y, Gleason CE, Tran POT, Harmon JS, Robertson RP 1999 Prevention of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by antioxidants. Proc Natl Acad Sci USA 96:10857–10862[Abstract/Free Full Text]
19. Ihara Y, Toyokuni S, Uchida K, Odaka H, Tanaka T, Ikeda H, Hiai H, Seino Y, Yamada Y 1999 Hyperglycemia causes oxidative stress in pancreatic beta-cells of GK rats, a model of type 2 diabetes. Diabetes 48:927–932[Abstract]
20. Kaneto H, Fujii J, Myint T, Miyazawa N, Islam KN, Kawasaki Y, Suzuki K, Makamura M, Tatsumi H, Yamasaki Y, Taniguchi N 1996 Reducing sugars trigger oxidative modification and apoptosis in pancreatic ß-cells by provoking oxidative stress through the glycation reaction. Biochem J 320(Pt. 3): 855–863
21. McGarry JD, Dobbins RL 1999 Fatty acids, lipotoxicity and insulin secretion. Diabetologia 42:128–138[CrossRef][Medline]
22. Gremlich S, Bonny C, Waeber G, Thorens B 1997 Fatty acids decrease IDX-1 expression in rat pancreatic islets and reduce GLUT2, glucokinase, insulin, and somatostatin levels. J Biol Chem 272:30261–30269[Abstract/Free Full Text]
23. Jacqueminet S, Briaud I, Rouault C, Reach G, Poitout V 2000 Inhibition of insulin gene expression by long-term exposure of pancreatic ß-cells to palmitate is dependent upon the presence of a stimulatory glucose concentration. Metabolism 49:532–536[CrossRef][Medline]
24. Ritz-Laser B, Meda P, Constant I, Klages N, Charollais A, Morales A, Magnan C, Ktorza A, Philippe J 1999 Glucose-induced preproinsulin gene expression is inhibited by the free-fatty acid palmitate. Endocrinology 140: 4005–4014
25. Maedler K, Spinas GA, Dyntar D, Moritz W, Kaiser N, Donath MY 2001 Distinct effects of saturated and monounsaturated fatty acids on ß-cell turnover and function. Diabetes 50:69–76[Abstract/Free Full Text]
26. Cnop M, Hannaert JC, Hoorens A, Eizirik DL, Pipeleers DG 2001 Inverse relationship between cytotoxicity of free fatty acids in pancreatic islet cells and cellular triglyceride accumulation. Diabetes 50:1771–1777[Abstract/Free Full Text]
27. Shimabukuro M, Higa M, Zhou YT, Wang MY, Newgard CB, Unger RH 1998 Lipoapoptosis in ß-cells of obese prediabetic fa/fa rats. Role of serine palmitoyltransferase overexpression. J Biol Chem 273:32487–32490[Abstract/Free Full Text]
28. Segall L, Lameloise N, Assimacopoulos-Jeannet F, Roche E, Corkey P, Thumelin S, Corkey BE, Prentki M 1999 Lipid rather than glucose metabolism is implicated in altered insulin secretion caused by oleate in INS-1 cells. Am J Physiol 277:E521–E528
29. Prentki M, Corkey BE 1996 Are the ß-cell signaling molecules malonyl-CoA and cytosolic long-chain acyl-CoA implicated in multiple tissue defects of obesity and NIDDM? Diabetes 45:273–283[Abstract]
30. Prentki M, Roduit R, Lameloise N, Corkey BE, Assimacopoulos-Jeannet F 2001 Glucotoxicity, lipotoxicity and pancreatic ß-cell failure: a role for malonyl-CoA, PPAR and altered lipid partitioning. Can J Diabetes Care 25:36–46
31. 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]
32. Harmon JS, Gleason CE, Tanaka Y, Poitout V, Robertson RP 2001 Antecedent hyperglycemia, not hyperllipidemia, is associated with increased islet triacylglycerol content and decreased insulin gene mRNA level in Zucker diabetic fatty rats. Diabetes, 50:2481–2486[Abstract/Free Full Text]
33. Briaud I, Kelpe CL, Johnson LM, Tran POT, Poitout V, Differential effects of hyperlipidemia on insulin secretion in islets of Langerhans from hyperglycemic vs. normoglycemic rats. Diabetes, in press
34. Carlsson C, Borg LA, Welsh N 1999 Sodium palmitate induces partial mitochondrial uncoupling and reactive oxygen species in rat pancreatic islets in vitro. Endocrinology 140:3422–3428[Abstract/Free Full Text]
35. Patane G, Piro S, Rabuazzo AM, Anello M, Vigneri R, Purrello F 2000 Metformin restores insulin secretion altered by chronic exposure to free fatty acids or high glucose: a direct metformin effect on pancreatic ß-cells. Diabetes 49:735–740[Abstract]

This article has been cited by other articles:

				M. Prentki and S. R. M. Madiraju Glycerolipid Metabolism and Signaling in Health and Disease Endocr. Rev., October 1, 2008; 29(6): 647 - 676. [Abstract] [Full Text] [PDF]

				X. Huang, D. J. Moore, R. J. Ketchum, C. S. Nunemaker, B. Kovatchev, A. L. McCall, and K. L. Brayman Resolving the Conundrum of Islet Transplantation by Linking Metabolic Dysregulation, Inflammation, and Immune Regulation Endocr. Rev., August 1, 2008; 29(5): 603 - 630. [Abstract] [Full Text] [PDF]

				S. Numazawa, H. Sakaguchi, R. Aoki, T. Taira, and T. Yoshida Regulation of the susceptibility to oxidative stress by cysteine availability in pancreatic {beta}-cells Am J Physiol Cell Physiol, August 1, 2008; 295(2): C468 - C474. [Abstract] [Full Text] [PDF]

				D. J. Chess and W. C. Stanley Role of diet and fuel overabundance in the development and progression of heart failure Cardiovasc Res, July 15, 2008; 79(2): 269 - 278. [Abstract] [Full Text] [PDF]

				V. Poitout and R. P. Robertson Glucolipotoxicity: Fuel Excess and {beta}-Cell Dysfunction Endocr. Rev., May 1, 2008; 29(3): 351 - 366. [Abstract] [Full Text] [PDF]

				J. Chen, G. Saxena, I. N. Mungrue, A. J. Lusis, and A. Shalev Thioredoxin-Interacting Protein: A Critical Link Between Glucose Toxicity and {beta}-Cell Apoptosis Diabetes, April 1, 2008; 57(4): 938 - 944. [Abstract] [Full Text] [PDF]

				F. Allagnat, F. Alonso, D. Martin, A. Abderrahmani, G. Waeber, and J.-A. Haefliger ICER-1{gamma} Overexpression Drives Palmitate-mediated Connexin36 Down-regulation in Insulin-secreting Cells J. Biol. Chem., February 29, 2008; 283(9): 5226 - 5234. [Abstract] [Full Text] [PDF]

				E. Ortega, J. Koska, N. Pannacciulli, J. C Bunt, and J. Krakoff Free triiodothyronine plasma concentrations are positively associated with insulin secretion in euthyroid individuals Eur. J. Endocrinol., February 1, 2008; 158(2): 217 - 221. [Abstract] [Full Text] [PDF]

				D. L. Eizirik, A. K. Cardozo, and M. Cnop The Role for Endoplasmic Reticulum Stress in Diabetes Mellitus Endocr. Rev., February 1, 2008; 29(1): 42 - 61. [Abstract] [Full Text] [PDF]

				S. Weksler-Zangen, I. Raz, S. Lenzen, A. Jorns, S. Ehrenfeld, G. Amir, A. Oprescu, Y. Yagil, C. Yagil, D. H. Zangen, et al. Impaired Glucose-Stimulated Insulin Secretion Is Coupled With Exocrine Pancreatic Lesions in the Cohen Diabetic Rat Diabetes, February 1, 2008; 57(2): 279 - 287. [Abstract] [Full Text] [PDF]

				D. K. Hagman, M. G. Latour, S. K. Chakrabarti, G. Fontes, J. Amyot, C. Tremblay, M. Semache, J. A. Lausier, V. Roskens, R. G. Mirmira, et al. Cyclical and Alternating Infusions of Glucose and Intralipid in Rats Inhibit Insulin Gene Expression and Pdx-1 Binding in Islets Diabetes, February 1, 2008; 57(2): 424 - 431. [Abstract] [Full Text] [PDF]

				M. Y. Donath, D. M. Schumann, M. Faulenbach, H. Ellingsgaard, A. Perren, and J. A. Ehses Islet Inflammation in Type 2 Diabetes: From metabolic stress to therapy Diabetes Care, February 1, 2008; 31(Supplement_2): S161 - S164. [Abstract] [Full Text] [PDF]

				H. Li, P. N. Black, A. Chokshi, A. Sandoval-Alvarez, R. Vatsyayan, W. Sealls, and C. C. DiRusso High-throughput screening for fatty acid uptake inhibitors in humanized yeast identifies atypical antipsychotic drugs that cause dyslipidemias J. Lipid Res., January 1, 2008; 49(1): 230 - 244. [Abstract] [Full Text] [PDF]

				A. I. Oprescu, G. Bikopoulos, A. Naassan, E. M. Allister, C. Tang, E. Park, H. Uchino, G. F. Lewis, I. G. Fantus, M. Rozakis-Adcock, et al. Free Fatty Acid Induced Reduction in Glucose-Stimulated Insulin Secretion: Evidence for a Role of Oxidative Stress In Vitro and In Vivo Diabetes, December 1, 2007; 56(12): 2927 - 2937. [Abstract] [Full Text] [PDF]

				B. G. Topp, L. L. Atkinson, and D. T. Finegood Dynamics of insulin sensitivity, -cell function, and -cell mass during the development of diabetes in fa/fa rats Am J Physiol Endocrinol Metab, December 1, 2007; 293(6): E1730 - E1735. [Abstract] [Full Text] [PDF]

				Y. Lee, M. Ravazzola, B.-H. Park, Y. K. Bashmakov, L. Orci, and R. H. Unger Metabolic Mechanisms of Failure of Intraportally Transplanted Pancreatic {beta}-Cells in Rats: Role of Lipotoxicity and Prevention by Leptin Diabetes, September 1, 2007; 56(9): 2295 - 2301. [Abstract] [Full Text] [PDF]

				R. Bartoov-Shifman, G. Ridner, K. Bahar, N. Rubins, and M. D. Walker Regulation of the Gene Encoding GPR40, a Fatty Acid Receptor Expressed Selectively in Pancreatic beta Cells J. Biol. Chem., August 10, 2007; 282(32): 23561 - 23571. [Abstract] [Full Text] [PDF]

				M. R. Hayden, P. R. Karuparthi, C. M. Manrique, G. Lastra, J. Habibi, and J. R. Sowers A BRIEF COMMUNICATION: Longitudinal Ultrastructure Study of Islet Amyloid in the HIP Rat Model of Type 2 Diabetes Mellitus Experimental Biology and Medicine, June 1, 2007; 232(6): 772 - 779. [Abstract] [Full Text] [PDF]

				T. Rose, S. Efendic, and M. Rupnik Ca2+-Secretion Coupling Is Impaired in Diabetic Goto Kakizaki rats J. Gen. Physiol., June 1, 2007; 129(6): 493 - 508. [Abstract] [Full Text] [PDF]

				S. S. Choe, A H. Choi, J.-W. Lee, K. H. Kim, J.-J. Chung, J. Park, K.-M. Lee, K.-G. Park, I.-K. Lee, and J. B. Kim Chronic Activation of Liver X Receptor Induces {beta}-Cell Apoptosis Through Hyperactivation of Lipogenesis: Liver X Receptor-Mediated Lipotoxicity in Pancreatic {beta}-Cells Diabetes, June 1, 2007; 56(6): 1534 - 1543. [Abstract] [Full Text] [PDF]

				J. B. Flowers, M. E. Rabaglia, K. L. Schueler, M. T. Flowers, H. Lan, M. P. Keller, J. M. Ntambi, and A. D. Attie Loss of Stearoyl-CoA Desaturase-1 Improves Insulin Sensitivity in Lean Mice but Worsens Diabetes in Leptin-Deficient Obese Mice Diabetes, May 1, 2007; 56(5): 1228 - 1239. [Abstract] [Full Text] [PDF]

				S. S. Qader, J. Jimenez-Feltstrom, M. Ekelund, I. Lundquist, and A. Salehi Expression of islet inducible nitric oxide synthase and inhibition of glucose-stimulated insulin release after long-term lipid infusion in the rat is counteracted by PACAP27 Am J Physiol Endocrinol Metab, May 1, 2007; 292(5): E1447 - E1455. [Abstract] [Full Text] [PDF]

				B. L. Wajchenberg {beta}-Cell Failure in Diabetes and Preservation by Clinical Treatment Endocr. Rev., April 1, 2007; 28(2): 187 - 218. [Abstract] [Full Text] [PDF]

				T. T. Goh, T. M. Mason, N. Gupta, A. So, T. K. T. Lam, L. Lam, G. F. Lewis, A. Mari, and A. Giacca Lipid-induced beta-cell dysfunction in vivo in models of progressive beta-cell failure Am J Physiol Endocrinol Metab, February 1, 2007; 292(2): E549 - E560. [Abstract] [Full Text] [PDF]

				M. C Saleh, M. B Wheeler, and C. B Chan Endogenous islet uncoupling protein-2 expression and loss of glucose homeostasis in ob/ob mice. J. Endocrinol., September 1, 2006; 190(3): 659 - 667. [Abstract] [Full Text] [PDF]

				M. Z. Khaldi, H. Elouil, Y. Guiot, J. C. Henquin, and J. C. Jonas Antioxidants N-acetyl-L-cysteine and manganese(III)tetrakis (4-benzoic acid)porphyrin do not prevent beta-cell dysfunction in rat islets cultured in high glucose for 1 wk Am J Physiol Endocrinol Metab, July 1, 2006; 291(1): E137 - E146. [Abstract] [Full Text] [PDF]

				M. K. Lingohr, I. Briaud, L. M. Dickson, J. F. McCuaig, C. Alarcon, B. L. Wicksteed, and C. J. Rhodes Specific Regulation of IRS-2 Expression by Glucose in Rat Primary Pancreatic Islet beta-Cells J. Biol. Chem., June 9, 2006; 281(23): 15884 - 15892. [Abstract] [Full Text] [PDF]

				L. I. Rachek, N. P. Thornley, V. I. Grishko, S. P. LeDoux, and G. L. Wilson Protection of INS-1 Cells From Free Fatty Acid-Induced Apoptosis by Targeting hOGG1 to Mitochondria. Diabetes, April 1, 2006; 55(4): 1022 - 1028. [Abstract] [Full Text] [PDF]

				V. Poitout, D. Hagman, R. Stein, I. Artner, R. P. Robertson, and J. S. Harmon Regulation of the Insulin Gene by Glucose and Fatty Acids J. Nutr., April 1, 2006; 136(4): 873 - 876. [Abstract] [Full Text] [PDF]

				D. Kawamori, H. Kaneto, Y. Nakatani, T.-a. Matsuoka, M. Matsuhisa, M. Hori, and Y. Yamasaki The Forkhead Transcription Factor Foxo1 Bridges the JNK Pathway and the Transcription Factor PDX-1 through Its Intracellular Translocation J. Biol. Chem., January 13, 2006; 281(2): 1091 - 1098. [Abstract] [Full Text] [PDF]

				M. Y. Donath, J. A. Ehses, K. Maedler, D. M. Schumann, H. Ellingsgaard, E. Eppler, and M. Reinecke Mechanisms of {beta}-Cell Death in Type 2 Diabetes Diabetes, December 1, 2005; 54(suppl_2): S108 - S113. [Abstract] [Full Text] [PDF]

				N. Welsh, M. Cnop, I. Kharroubi, M. Bugliani, R. Lupi, P. Marchetti, and D. L. Eizirik Is There a Role for Locally Produced Interleukin-1 in the Deleterious Effects of High Glucose or the Type 2 Diabetes Milieu to Human Pancreatic Islets? Diabetes, November 1, 2005; 54(11): 3238 - 3244. [Abstract] [Full Text] [PDF]

				D. K. Hagman, L. B. Hays, S. D. Parazzoli, and V. Poitout{paragraph} Palmitate Inhibits Insulin Gene Expression by Altering PDX-1 Nuclear Localization and Reducing MafA Expression in Isolated Rat Islets of Langerhans J. Biol. Chem., September 16, 2005; 280(37): 32413 - 32418. [Abstract] [Full Text] [PDF]

				H. Wang, G. Kouri, and C. B. Wollheim ER stress and SREBP-1 activation are implicated in {beta}-cell glucolipotoxicity J. Cell Sci., September 1, 2005; 118(17): 3905 - 3915. [Abstract] [Full Text] [PDF]

				Y.-F. Zhao, D. J Keating, M. Hernandez, D. D. Feng, Y. Zhu, and C. Chen Long-term inhibition of protein tyrosine kinase impairs electrophysiologic activity and a rapid component of exocytosis in pancreatic {beta}-cells J. Mol. Endocrinol., August 1, 2005; 35(1): 49 - 59. [Abstract] [Full Text] [PDF]

				E. Sobngwi, J.-F. Gautier, J.-P. Kevorkian, J.-M. Villette, J.-P. Riveline, S. Zhang, P. Vexiau, S. M. Leal, C. Vaisse, and F. Mauvais-Jarvis High Prevalence of Glucose-6-Phosphate Dehydrogenase Deficiency without Gene Mutation Suggests a Novel Genetic Mechanism Predisposing to Ketosis-Prone Diabetes J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4446 - 4451. [Abstract] [Full Text] [PDF]

D. Porte J