SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. The Importance of Prenatal Factors in β-Cell Regulation
  4. Glucotoxicity and Lipotoxicity
  5. Role of the β-Cell Mass
  6. Therapeutic Perspectives
  7. Conclusions
  8. References

The regulation of blood glucose levels involves a finely tuned relationship between insulin sensitivity, hepatic glucose output, and production of insulin. The cardiometabolic syndrome includes in its definition criteria a disturbance of normal glucose tolerance and implies development of both insulin resistance and β-cell dysfunction. There is now abundant evidence pointing toward a central role of dysregulation of the β-cell function and mass in the development of impaired glucose tolerance. Mechanisms implicated in β-cell dysfunction include genetic abnormalities, prenatal and early postnatal insults, and environmental events along with obesity, dyslipidemia-lipotoxicity, glucotoxicity, oxidative stress, chronic low-grade inflammation, amyloid deposition, and activation of the local renin—angiotensin system. Novel therapeutic characteristics of known medications such as metformin, thiazolidinediones, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and novel medications such as exendin-4 promise encouraging possibilities to battle against the cardiometabolic syndrome and the future development of cardiovascular disease.

The cardiometabolic syndrome (CMS) is one of the fastest growing conditions in industrialized countries.1 The concept of the CMS recognizes the fact that cardiovascular disease risk factors cluster and have the ability to predict cardiovascular disease, stroke, type 2 diabetes mellitus (T2DM), and chronic kidney disease. The abundant experimental data that have enriched the concept of the syndrome over the past years have identified insulin resistance and compensatory hyperinsulinemia as key players in the development of CMS. Hence, it is not surprising that some of the most important definition criteria systems directly address insulin resistance/hyperglycemia measurements (the European Group for the Study of Insulin Resistance, World Health Organization), while other systems only include the existence of hyperglycemia, a marker of noncompensated insulin resistance (International Diabetes Federation, National Cholesterol Education Program/Adult Treatment Panel III).

The endocrine pancreas has long been neglected when evaluating the CMS, but if we accept that the CMS is a strong predictor of T2DM1 and a condition in which insulin secretion is impaired, several events must affect β-cell function before overt hyperglycemia occurs.2 Indeed, a delicate balance between insulin sensitivity and pancreatic secretion of insulin, as well as the production of glucose in the liver regulates blood glucose concentrations (Figure 1).3

image

Figure 1. The interactive balance between production of glucose in the liver, insulin sensitivity, and β-cell ability to produce insulin determines glucose tolerance.

The hyperbolic equation (insulin secretion × insulin sensitivity = constant) implies that if insulin sensitivity is reduced, then the β cell must significantly increase insulin output to maintain euglycemia.4 While evaluation of insulin sensitivity is currently standardized, the development of consistent measurement of insulin secretion is an emerging field, and current methods include the acute insulin response to intravenous glucose (AIRg) or nonglucose challenge (e.g., arginine) during the hyperglycemic hyperinsulinemic clamp study (AIRmax), the ratio of proinsulin to insulin, and the AIR during the frequently sampled IV glucose tolerance test.4

Insulin resistance and β-cell dysfunction can coexist and result in decreased glucose tolerance/hyperglycemia. The relative importance of each of these factors remains to be fully elucidated, but β-cell dysfunction is critical for the development of hyperglycemia.5 Even though absolute insulin levels are increased in the initial stages of T2DM, their β-cell mass is unable to produce normoglycemia, which suggests an early impaired secretory capability. In rodent models, single defects in the insulin action pathway induce hyperinsulinemia and β-cell hyperplasia instead of diabetes,6 and overt hyperglycemia develops only after significant insulin secretion deficiency.7 Indeed, the appearance of clinical T2DM is related more to major β-cell dysfunction than to reductions in insulin sensitivity.8 Caucasian patients with impaired glucose tolerance have insulin secretory dysfunction when compared with those with normal glucose tolerance.3 Also, evidence of insulin secretory dysfunction has been noted in individuals with impaired fasting glucose, glucose intolerance, and T2DM. Insulin sensitivity was more significantly reduced in advanced stages of carbohydrate intolerance and T2DM.3

Mechanisms that account for β-cell dysfunction in CMS and T2DM appear to be multifactorial in origin (Figure 2). The importance of genetic factors has been demonstrated in first-degree relatives of T2DM patients, in whom there is impaired ability of the pancreas to produce insulin when stimulated with glucose. These findings have been reproduced in identical twins of T2DM patients and in Japanese-American populations who exhibited features of the CMS, in which a polymorphism related to reduced β-cell function was identified.

image

Figure 2. Beta-cell dysfunction in the cardiometabolic syndrome (CMS) is determined by a complex interrelating cascade of pathophysiologic events that include a genetic predisposition and environmental influences. In genetically predisposed individuals, prenatal and postnatal factors contribute synergistically to affect the normal β-cell function and induce increased apoptosis, leading to impaired insulin secretion ability and impaired glucose and lipids homeostasis, typical of CMS and type 2 diabetes mellitus. PDX-1=pancreatic-duodenum homeobox-1; C/EBP=CCAT/enhancer-binding protein; IL=interleukin; TNF=tumor necrosis factor; FA=fatty acids; LDL=low-density lipoprotein; VLDL=very LDL; ROS=reactive oxygen species; RAS=renin—angiotensin system.

The Importance of Prenatal Factors in β-Cell Regulation

  1. Top of page
  2. Abstract
  3. The Importance of Prenatal Factors in β-Cell Regulation
  4. Glucotoxicity and Lipotoxicity
  5. Role of the β-Cell Mass
  6. Therapeutic Perspectives
  7. Conclusions
  8. References

Using different rodent models, it has been shown that deleterious prenatal and early postnatal stimuli, including decreased uteroplacental perfusion and nutrient restriction can cause irreversible pancreatic developmental abnormalities. During adult life, these are translated into decreased β-cell mass and insulin-producing ability. Mechanisms proposed to explain the pancreatic developmental alterations include decreased functional stem cells and growth factor expression (insulin-like growth factor-II is highly relevant), impairment of nutrient-stimulated insulin secretion, and alterations in pancreatic nerve innervation.11 Mitochondrial dysfunction and increased reactive oxygen species (ROS) production in rat islets have been implicated in the development of adult-onset diabetes after intrauterine growth restriction (IUGR).12

Human studies are scant, but one small trial showed that IUGR causes reduction of fetal endocrine pancreatic tissue and insulin-producing β cells.13 In a young Caucasian population of nondiabetic men (aged 19 years) with low birth weights, reduced insulin secretion/sensitivity was reported.14 However, others have reported that the main persistent defect in adults born with IUGR is insulin resistance.15

Malnutrition causes pancreatic alterations in rats. High-carbohydrate milk formula given in the early postnatal period causes long-lasting hyper-insulinemia and adult-onset obesity.16 Interestingly, the previously described metabolic defects could also have chronic effects in the offspring,15 suggesting that environmental insults may somehow modify gene expression. Candidate mechanisms are epigenetic modifications involving DNA methylation patterns.17 Collectively, the above considerations suggest a genetic background for the rapid expansion of the CMS and that prenatal insults, more common in developing countries,18 shape the metabolic profile of the individual.

Glucotoxicity and Lipotoxicity

  1. Top of page
  2. Abstract
  3. The Importance of Prenatal Factors in β-Cell Regulation
  4. Glucotoxicity and Lipotoxicity
  5. Role of the β-Cell Mass
  6. Therapeutic Perspectives
  7. Conclusions
  8. References

The reciprocal interaction of fatty acid (FA) and glucose oxidation is well characterized, and it has been established that chronic hyperglycemia (glucotoxicity) and hyperlipidemia (lipotoxicity), as found in the CMS, can impair β-cell function. The responses of the β cells in conditions of high-circulating levels of glucose are a continuum. Glucotoxicity refers to prolonged and potentially irreversible impairment of glucose-induced insulin secretion in β cells in conditions of chronic hyperglycemia. This is opposed to insulin desensitization, which refers to transient blockade of the insulin secretion and β-cell exhaustion, produced by depletion of intracellular reserves of insulin. These adaptations occur during acute and prolonged hyperglycemia and are reversible.

Glucotoxicity appears to be mediated through mechanisms that include reduced activity of key β-cell transcription factors such as the pancreatic-duodenum homeobox-1 and RIPE 3b1, while there is a reciprocal increase in the expression of transcriptional repressors of the insulin gene, such as CCAT/enhancer-binding protein β.19 Pancreatic-duodenum homeobox-1 also exhibits mitochondrial actions related to insulin secretion, which has drawn attention to mitochondrial dysfunction as a factor involved in both β-cell dysfunction/loss and insulin resistance.20

Oxidative stress has been implicated in glucotoxicity, because reduced transcription of genes involved in insulin production has been associated with hyperglycemia-mediated generation of advanced glycation end-products and ROS.21 In vitro, these effects can be prevented to some extent by antioxidants.22 Indeed, chronic hyperglycemia drives ROS-producing biochemical pathways, which include glucose oxidation through anaerobic glycolysis, glucosamine generation, protein glycosylation/oxidation through Schiff reactions, and glucose auto-oxidation.23 The overproduction of ROS eventually overcomes endogenous antioxidant systems such as catalase, copper/zinc and manganese superoxide dismutase, and glutathione peroxidase, which have been found to be scarce in the endocrine pancreas22,23 compared with other tissues, therefore placing this organ in a particularly vulnerable condition for oxidative stress.

Similar to glucotoxicity, lipotoxicity has deleterious effects on the endocrine pancreas. Chronically elevated levels of FA in plasma and in the pancreatic islets impair β-cell function and glucose-stimulated secretion of insulin. It has been documented that elevated FA can inhibit insulin gene expression and the transcription factor islet duodenum homeobox-1 under hyperglycemic conditions.24 Chronically impaired FA metabolism in prolonged hyperlipidemia results in inhibition of the carnitine palmitoyl transferase 1, the limiting enzyme that regulates entry of FA inside the mitochondria for subsequent β oxidation. In conditions of hyperglycemia, this leads to cytosolic accumulation of long-chain fatty acyls coenzyme A, which, in turn, has been associated with impaired β-cell function.25 Mediators of this interaction could include modulation of gene expression, protein kinase C, the adenosine triphosphate-sensitive potassium channel, and uncoupling protein-2. Oxidative stress also appears to play a key role, as FA inside pancreas islets lead to increased ROS generation.26 This effect appears to be reversed by metformin, an agent with antioxidant effects.27 T2DM patients display markers of chronic oxidative stress significantly above those of non-diabetic persons, while their levels of glutathione are reduced.28

Interestingly, experimental evidence indicates that toxic effects of lipids require coexistence of hyperglycemia. In vitro, FA do not affect cultured β-cell insulin production during euglycemia but, as hyperglycemia develops, the synthesis significantly declines.29 In Zucker diabetic fat rats, control of hyperglycemia without affecting circulating lipids reduces triglyceride accumulation in pancreatic islets and preserves insulin production. On the contrary, reduction in circulating lipids without glycemic control does not produce the same effects; leading some authors to the hypothesis that chronic hyperglycemia is required for development of lipotoxicity.30,31

Role of the β-Cell Mass

  1. Top of page
  2. Abstract
  3. The Importance of Prenatal Factors in β-Cell Regulation
  4. Glucotoxicity and Lipotoxicity
  5. Role of the β-Cell Mass
  6. Therapeutic Perspectives
  7. Conclusions
  8. References

Regulation of the β-cell mass involves a precise balance between replication and apoptosis. A reduction in the β-cell mass has been postulated to have a causal relationship on the development of glucose intolerance and T2DM, which adds to defects in insulin secretion (Figure 3). In most rodent models and humans, short-term hyperglycemia has been related to an expansion of the β-cell mass. However, in conditions of chronic hyperglycemia, there is a decrease in the proliferative ability of pancreatic (3 cells in humans and in the Psammomys obesus model, whose pancreas exhibits behavior comparable to the human pancreas. A recent autopsy-based study found an increased β-cell mass in obese nondiabetic patients, mainly accounted for by neogenesis-mediated proliferation, while in obese individuals with glucose intolerance (features of the CMS), the β-cell mass was reduced by approximately 40%. Moreover, in the lean T2DM subjects, the reduction was estimated at 41% and in obese and T2DM patients it reached roughly 63%.34 Apoptosis, the main mechanism responsible, was found to be increased by 10- and three-fold in lean and obese T2DM patients, respectively. Importantly, neogenesis rates did not show significant differences between the groups studied, leading to the conclusion that the loss of β cells was mediated by increased apoptosis and not by reduced neogenesis.

image

Figure 3. This image portrays a single islet (one of approximately one million and 100 nm in diameter) within the pancreas. The f> cells occur centrally in a tightly packed and morula-like configuration (Figure 4) and are the predominant cell type of the islet (approximately 60%). The f> cells are responsible for the synthesis of insulin and amylin islet hormones. The f> cells are capable of remodeling (β-cell plasticity) and are subject to expansion or involution as depicted, which may result in hyperinsulinemia or hypoinsulinemia, depending on their surrounding environmental milieu. The a cells (glucagon-producing) and 6 cells (somatostatin-producing) are usually located at the periphery of the islet, while the pancreatic polypeptide cells are more scattered throughout the islet. The afferent arteriole and the efferent venules depict a core-to-mantel microcirculation along the insular-acinar pathway. T2DM=type 2 diabetes mellitus; ECM=extracellular matrix

The failure of the human pancreas to adapt to conditions of increased metabolic requirements, such as the CMS, is related to a deleterious effect of altered carbohydrate metabolism. Significant increases in circulating glucose levels can lead to excess production of interleukin 1β (IL-1β) in the islets, which have the ability to up-regulate the expression of Fas, a known mediator of apoptosis.35 Fas up-regulation mediated by hyperglycemia has been documented in vitro and in vivo and can be activated upon reduction in the expression of the caspase-8 inhibitor FLIP, which may trigger apoptotic pathways.36 It has been suggested that glucose-mediated Fas up-regulation also contributes to impairment of insulin secretion.36

Obesity, one of the main characteristics of the CMS, is well known to be associated with impaired glucose and lipid metabolism as well as dysfunctional adipose tissue, a source of different adipokines such as leptin, TNF-α and IL-6,37 which could potentially cause β-cell dysfunction. Leptin, originally known to be implicated in the regulation of appetite and adipose tissue mass, also exhibits proinflammatory cytokine-like activity and induces β-cell apoptosis in vitro by activating IL-1β while decreasing production of IL-1 receptor antagonist.38 Longstanding high levels of saturated FA, contrary to unsaturated FA, which have the opposite action, can impair β-cell function. Experimental evidence suggests that low-density lipoproteins and very low-density lipoproteins exert pro-apoptotic actions, while high-density lipoproteins appear to be protective.39

Importantly, all elements of the renin—angiotensin system have been identified in the pancreas. The role of a local endocrine renin—angiotensin system was discussed by Drs. Hayden, Stump, and Sowers in the introductory article of this Journal.40

Finally, some regulators of insulin sensitivity affect both generation of insulin resistance and decreased β-cell mass and/or function. The nuclear factor ?B, which has been implicated in the chronic low-grade inflammation and insulin resistance present in obesity, has been related to β-cell dysfunction/apoptosis through increased IL-1β, an effect that is reversible by anti-inflammatory agents such as salicylate and thiazolidinediones.41 Beta cells are under intense secretory demand, especially in conditions of impaired glucose tolerance (Figure 4). Impairment of normal protein folding in the endoplasmic reticulum as part of the endoplasmic reticulum stress can redirect β cells to apoptosis and has also been implicated in the development of insulin resistance.42,43

image

Figure 4. This image demonstrates the necessary tight connections between two β cells (adherens junctions), which are necessary for maintaining normal first-phase insulin secretion. Also noted are the multiple insulin secretory granules (arrows).

Therapeutic Perspectives

  1. Top of page
  2. Abstract
  3. The Importance of Prenatal Factors in β-Cell Regulation
  4. Glucotoxicity and Lipotoxicity
  5. Role of the β-Cell Mass
  6. Therapeutic Perspectives
  7. Conclusions
  8. References

There are emerging data showing that some therapeutic strategies can lessen the rate of β-cell attrition. The Diabetes Prevention Program study44 demonstrated the importance of intensive lifestyle modification and, to a positive but lesser extent, the importance of metformin as compared with placebo in the prevention of T2DM. Thiazolidinediones have also shown promising results. Buchanan and associates45 found in a double-blinded trial of high-risk Hispanic women treated with troglitazone vs. placebo for 30 months, that the thiazolidinedione preserved β-cell function.

Matsui and associates demonstrated that peroxisome proliferator-activated receptor γ stimulation protects islets from lipotoxicity by regulating triglyceride partitioning in white adipose tissue and that pioglitazone can restore impaired insulin secretion under conditions of islet fat accumulation. Also, a recent in vitro study showed that in human islets, activation of a peroxisome proliferator-activated receptor y agonist by rosiglitazone inhibits islet cell apoptosis secondary to deposition of islet amyloid polypeptide through activation of the phosphatidylinositol 3'-kinase-Akt signaling cascade.

Finally, an intriguing possibility among the new pharmacologic therapies is exendin-4. This peptide has 50% homology with glucagon-like peptide 1, an incretin released from the gastrointestinal L cells in response to nutrient ingestion. Both peptides augment β-cell function by enhancing insulin secretion stimulated by glucose, improving first-phase insulin secretion and stimulating cell growth and neogenesis. , Exendin-4 treatment of cultured β cells can prevent apoptosis and necrosis induced by cytokines. This effect requires the activation of protein kinase B. As noted earlier, IUGR can impair β-cell mass and function. Treatment with exendin-4 in the neonatal period of rats exposed to uteroplacental insufficiency prevents the progressive reduction of β-cell mass, an effect possibly mediated by normalization of the expression of pancreatic-duodenum homeobox-1.50 Tus, this new class of medication holds promise for the maintenance of insulin-producing β cells.

Conclusions

  1. Top of page
  2. Abstract
  3. The Importance of Prenatal Factors in β-Cell Regulation
  4. Glucotoxicity and Lipotoxicity
  5. Role of the β-Cell Mass
  6. Therapeutic Perspectives
  7. Conclusions
  8. References

While β-cell dysfunction and insulin resistance have both been implicated in the pathogenesis of the CMS, alterations in glucose tolerance require impairment in the insulin-secretion ability of the endocrine pancreas. Mechanisms implicated in the hyperglycemia of the CMS and T2DM include alterations in the regulation of the mechanisms that lead to production of insulin in β cells (Figure 4), as well as in the regulation of the β-cell mass (Figure 3). The numerous abnormalities typical of the CMS, including obesity, hyperglycemia, dyslipidemia, oxidative stress, renin—angiotensin system activation, and production of inflammatory mediators in a dysfunctional adipose tissue, provide a metabolic milieu for the impairment of insulin secretion and enhanced apoptosis of β cells, events that contribute to the development of T2DM in the long-term (Figure 2 and Figure 3). The discovery of the intricate details of the regulation of the endocrine function and β-cell mass, such as the expression of transcriptional activators and repressors of the insulin gene, should provide new insights into the prevention of T2DM, one of the most daunting causes of cardiovascular disease.

Acknowledgment: The authors wish to acknowledge the Electron Microscopy Core Facility at the University of Missouri-Columbia, Columbia, MO, and Cheryl A. Jensen, electron microscopy specialist, for excellent help with preparation of transmission electron micrographs.

References

  1. Top of page
  2. Abstract
  3. The Importance of Prenatal Factors in β-Cell Regulation
  4. Glucotoxicity and Lipotoxicity
  5. Role of the β-Cell Mass
  6. Therapeutic Perspectives
  7. Conclusions
  8. References
  • 1
    Wannamethee SG, Shaper AG, Lennon L, et al. Metabolic syndrome vs Framingham Risk Score for prediction of coronary heart disease, stroke, and type 2 diabetes mellitus. Arch Intern Med. 2005;165:26442650.
  • 2
    Van Haeften TW, Pimenta W, Mitrakou A, et al. Disturbances in beta-cell function in impaired fasting glycemia. Diabetes. 2002;51: S265S270.
  • 3
    Porte D Jr. Mechanisms for hyperglycemia in the metabolic syndrome. The key role of beta-cell dysfunction. Ann N Y Acad Sci. 1999;892:7383.
  • 4
    Ahren B, Pacini G. Islet adaptation to insulin resistance: mechanism and implications for intervention. Diabetes Obes Metab. 2005;7:28.
  • 5
    Hanley AJ, Wagenknecht LE, D'Agostino RB Jr, et al. Identification of subjects with insulin resistance and beta-cell dysfunction using alternative definitions of the metabolic syndrome. Diabetes. 2003;52:27402747.
  • 6
    Porte D Jr, Khan SE. The key role of islet dysfunction in type II diabetes mellitus. Clin Invest Med. 1995;18:247254.
  • 7
    Bruning JC, Winnay S, Bonner-Weir SI, et al. Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles. Cell. 1997;88:561572.
  • 8
    Therauchi Y, Sakura H, Yasuda K, et al. Pancreatic beta-cell-specific targeted disruption of glucokinase gene. Diabetes mellitus due to defective insulin secretion to glucose. J Biol Chem. 1995;270:3025330256.
  • 9
    Vaag A, Heriksen JE, Madsbad S, et al. Insulin secretion, insulin action, and hepatic glucose production in identical twins discordant for non-insulin-dependent diabetes mellitus. J Clin Invest. 1995;95:690698.
  • 10
    Stone LM, Kahn SE, Fujimoto WY. et al. A variation at position −30 of the beta-cell glucokinase gene promoter is associated with reduced beta-cell function in middle-aged Japanese-American men. Diabetes. 1996;45:422428.
  • 11
    McMillen IC, Robinson JS. Developmental origins of the metabolic syndrome: prediction, plasticity and programming. Physiol Rev. 2005;85:571633.
  • 12
    Simmons RA, Suponitsky-Kroyter I, Selak MA. Progressive accumulation of mitochondrial DNA mutations and decline in mitochondrial function lead to beta-cell failure. J Biol Chem. 2005;280:2878528791.
  • 13
    Van Assche FA, De Prins F, Aerts L, et al. The endocrine pancreas in small-for-dates infants. Br J Obstet Gynaecol. 1977;84:751753.
  • 14
    Jensen CB, Storgaard H, Dela F. et al. Early differential defects of insulin secretion and action in 19-year-old caucasian men who had low birth weight. Diabetes. 2002;51:12711280.
  • 15
    Beringue F, Blondeau B, Castellotti MC. et al. Endocrine pancreas development in growth-retarded human fetuses. Diabetes. 2002;51:385391.
  • 16
    Srinivasan M, Laychock SG, Hill Dj, et al. Neonatal nutrition: metabolic programming of pancreatic islets and obesity. Exp Biol Med (Maywood). 2003;228:1523.
  • 17
    Ashdown-Lambert JR. A review of low birth weight: predictors, precursors and morbidity outcomes. J R Soc Health. 2005;125:7683.
  • 18
    Shuldiner AR, McLenithan JC. Genes and pathophysiology of type 2 diabetes: more than just the Randle cycle all over. J Clin Invest. 2004;114:14141417.
  • 19
    Seufert J, Weir GC, Habener JF. Differential expression of the insulin gene transcriptional repressor CCAAT/enhancer-binding protein beta and transactivator islet duodenum homeobox-1 in rat pancreatic beta cells during the development of diabetes mellitus. J Clin Invest. 1998;101:25282539.
  • 20
    Lowell BB, Shulman GI. Mitochondrial dysfunction and type 2 diabetes. Science. 2005;307:384387.
  • 21
    Tajiri Y, Moller C, Grill V. Long-term effects of aminoguanidine on insulin release and biosynthesis: evidence that the formation of advanced glycosilation end products inhibits B-cell function. Endocrinolog y. 1997;138:273280.
  • 22
    Tanaka Y, Gleason CE, Tran PO. et al. Prevention of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by antioxidants. Proc Natl Acad Sci U S A. 1999;96:1085710862.
  • 23
    Robertson RP, Harmon J, Tran PO, et al. Glucose toxicity in beta-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection. Diabetes. 2003;52:581587.
  • 24
    Gremlich S, Bonny C, Waeber G, et al. Fatty acids decrease IDX-1 expression in rat pancreatic islets and reduce GLUT2, glucokinase, insulin and somatostatin levels. J Biol Chem. 1997;272:3026130269.
  • 25
    Lameloise N, Muzzin P, Prentki M. et al. Uncoupling protein 2: a possible link between fatty acid excess and impaired glucose-induced insulin secretion? Diabetes. 2001;50:803809.
  • 26
    Carlsson C, Borg LA, Welsh N. Sodium palmitate induces partial mitochondrial uncoupling and reactive oxygen species in rat pancreatic islets in vitro. Endocrinology. 1999;140:34223428.
  • 27
    Patane G, Piro S, Rabuazzo AM. et al. Metformin restores insulin secretion altered by chronic exposure to free fatty acids or high glucose: a direct metformin effect on pancreatic beta cells. Diabetes. 2000;49:735740.
  • 28
    Robertson RP, Harmon J, Tran PO, et al. Beta-cell glucose toxicity, lipotoxicity, and chronic oxidative stress in type 2 diabetes. Diabetes. 2004;53:S119S124.
  • 29
    Jacqueminet S, Briaud I, Rouault C. et al. Inhibition of insulin gene expression by long-term exposure of pancreatic beta cells to palmitate is dependent on the presence of a stimulatory glucose concentration. Metabolism. 2000;49:532536.
  • 30
    Harmon JS, Gleason CE, Tanaka Y. et al. Antecedent hyperglycemia, not hyperlipidemia, is associated with increased islet triacylglycerol content and decresed insulin gene mRNA level in Zucker diabetic fatty rats. Diabetes. 2001;50:24812486.
  • 31
    Donath MY, Gross DJ, Cerasi E. et al. Hyperglycemia-induced beta-cell apoptosis in pancreatic islets of Psammomys obesus during development of diabetes. Diabetes. 1999;48:738744.
  • 32
    Butler AE, Janson J, Bonner-Weir S, et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52:102110.
  • 33
    Maedler K, Sergeev P, Ris F. et al. Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest. 2002;110:851860.
  • 34
    Maedler K, Spinas GA, Lehmann R. et al. Glucose induces beta-cell apoptosis via upregulation of the Fas receptor in human islets. Diabetes. 2001;50:16831690.
  • 35
    Donath MY, Ehses JA, Maedler K, et al. Mechanisms of beta-cell death in type 2 diabetes. Diabetes. 2005;54:S108S113.
  • 36
    Maedler K, Fontana A, Ris F. et al. FLIP switches Fas-mediated glucose signaling in human pancreatic beta cells from apoptosis to cell replication. Proc Natl Acad Sci U S A. 2002;99:82368241.
  • 37
    Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 2004;89:25482556.
  • 38
    Maedler K, Serggev P, Ehses JA. et al. Leptin modulates beta cell expression of IL-1 receptor antagonist and release of IL-1beta in human islets. Proc Natl Acad Sci U S A. 2004;101:81388143.
  • 39
    Roehrich ME, Mooser V, Lenain V. et al. Insulin-secreting beta-cell dysfunction induced by human lipoproteins. J Biol Chem. 2003;278:1836818375.
  • 40
    Hayden MR, Stump CS, Sowers JR. Organ involvement in the cardiometabolic syndrome. J Cardiometabolic Syndr. 2006;1:1624.
  • 41
    Zeender E, Maedler K, Bosco D. et al. Pioglitazone and sodium salicylate protect human beta-cells against apoptosis and impaired function induced by glucose and interleukin-1beta. J Clin Endocrinol Metab. 2004;89:50595066.
  • 42
    Araki E, Oyadomari S, Mori M. Endoplasmic reticulum stress and the development of diabetes mellitus. Intern Med. 2003;42:714.
  • 43
    Ozcan U, Cao Q, Yilmaz E. et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes mellitus. Science. 2004;306:457461.
  • 44
    Kitabchi AE, Temprosa M, Knowler WC. et al., for The Diabetes Prevention Program Research Group. Role of insulin secretion and insulin sensitivity in the evolution of type 2 diabetes in the diabetes prevention program: effects of lifestyle intervention and metformin. Diabetes. 2005;54:24042414.
  • 45
    Buchanan TA, Xiang AH, Peters RK. et al. Preservation of pancreatic β-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes. 2002;51:27962803.
  • 46
    Matsui J, Therauchi Y, Kubota N. et al. Pioglitazone reduces islet triglyceride content and restores impaired glucose-stimulated insulin secretion in heterozygous peroxisome proliferator-activated receptor—gamma-deficient mice on a high-fat diet. Diabetes. 2004;53:28442854.
  • 47
    Lin CY, Gurlo T, Haataja L. et al. Activation of peroxisome proliferator-activated receptor-gamma by rosiglitazone protects human islet cells against human islet amyloid polypeptide toxicity by phosphatidylinostol 3'-kinase-dependent pathway. J Clin Endocrinol Metab. 2005;90:66786686.
  • 48
    Li L, El-Kholy W, Rhodes CJ, et al. Glucagon-like peptide-1 protects beta cells from cytokine-induced apoptosis and necrosis: role of protein kinase B. Diabetologia. 2005;48:13391349.
  • 49
    Hansen PA, Corbett HA. Incretin hormones and insulin sensitivity. Trends Endocrinol Metab. 2005;16:135136.
  • 50
    Stoffers DA, Desai BM, DeLeon DD, et al. Neonatal exendin-4 prevents the development of diabetes in the intrauterine growth retarded rat. Diabetes. 2003;52:734740.