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ABSTRACT: Pancreatic β-cell dysfunction is central in diabetes. The diabetic milieu may impair proinsulin folding, leading to β-cell endoplasmic reticulum (ER) stress and apoptosis, and thus a worsening of the diabetes. Autophagy is crucial for the well-being of the β-cell; however, the impact of stimulating autophagy on β-cell adaptation to ER stress is unknown. We studied the crosstalk between ER stress and autophagy in a rodent model of diabetes, called Akita, in which proinsulin gene mutation leads to protein misfolding and β-cell demise. We found that proinsulin misfolding stimulates autophagy and, in symmetry, inhibition of autophagy induces β-cell stress and apoptosis. Under conditions of excessive proinsulin misfolding, stimulation of autophagy by inhibiting MTORC1 alleviates stress and prevents apoptosis. Moreover, treatment of diabetic Akita mice with the MTORC1 inhibitor rapamycin improves diabetes and prevents β-cell apoptosis. Thus, autophagy is a central adaptive mechanism in β-cell stress. Stimulation of autophagy may become a novel therapeutic strategy in diabetes.
Autophagy 02/2013; 9(4). · 7.45 Impact Factor
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ABSTRACT: Accumulation of misfolded proinsulin in the β-cell leads to dysfunction induced by endoplasmic reticulum (ER) stress, with diabetes as a consequence. Autophagy helps cellular adaptation to stress via clearance of misfolded proteins and damaged organelles. We studied the effects of proinsulin misfolding on autophagy and the impact of stimulating autophagy on diabetes progression in Akita mice, which carry a mutation in proinsulin, leading to its severe misfolding. Treatment of female diabetic Akita mice with rapamycin improved diabetes, increased pancreatic insulin content, and prevented β-cell apoptosis. In vitro, autophagic flux was increased in Akita β-cells. Treatment with rapamycin further stimulated autophagy, evidenced by increased autophagosome formation and enhancement of autophagosome-lysosome fusion. This was associated with attenuation of cellular stress and apoptosis. The mammalian target of rapamycin (mTOR) kinase inhibitor Torin1 mimicked the rapamycin effects on autophagy and stress, indicating that the beneficial effects of rapamycin are indeed mediated via inhibition of mTOR. Finally, inhibition of autophagy exacerbated stress and abolished the anti-ER stress effects of rapamycin. In conclusion, rapamycin reduces ER stress induced by accumulation of misfolded proinsulin, thereby improving diabetes and preventing β-cell apoptosis. The beneficial effects of rapamycin in this context strictly depend on autophagy; therefore, stimulating autophagy may become a therapeutic approach for diabetes.
Diabetes 12/2012; · 8.29 Impact Factor
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Diabetes Obesity and Metabolism 10/2012; 14 Suppl 3:iv-viii. · 3.38 Impact Factor
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ABSTRACT: Insulin deficiency is the underlying cause of hyperglycemia in type 2 diabetes. The gerbil Psammomys obesus (P. obesus) is a naturally insulin resistant rodent with tendency to develop diet-induced hyperglycemia associated with obesity. P. obesus does not exhibit hyperglycemia in its natural desert habitat, feeding on low caloric vegetation. However, when fed regular laboratory chow containing higher caloric density, the animals develop moderate obesity and hyperglycemia. Diabetes development and progression is very fast in P. obesus. The animals reach the irreversible hypoinsulinemic stage of the disease, in which a marked reduction of β-cell mass is apparent, within 4-6 weeks of high caloric diet. The present review describes the P. obesus of the Hebrew University colony, with emphasis on its use for the study of β-cell dysfunction in type 2 diabetes.
Methods in molecular biology (Clifton, N.J.) 01/2012; 933:89-102.
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ABSTRACT: We have recently generated lipophilic D-xylose derivatives that increase the rate of glucose uptake in cultured skeletal muscle cells in an AMP-activated protein kinase (AMPK)-dependent manner. The derivative 2,4:3,5-dibenzylidene-D-xylose-diethyl dithioacetal (EH-36) stimulated the rate of glucose transport by increasing the abundance of glucose transporter-4 in the plasma membrane of cultured myotubes. The present study aimed at investigating potential antihyperglycaemic effects of EH-36 in animal models of diabetes. Two animal models were treated subcutaneously with EH-36: streptozotocin-induced diabetes in C57BL/6 mice (a model of insulin-deficient type 1 diabetes), and spontaneously diabetic KKAy mice (Kuo Kondo rats carrying the A(y) yellow obese gene; insulin-resistant type 2 diabetes). The in vivo biodistribution of glucose in control and treated mice was followed with the glucose analogue 2-deoxy-2-[(18) F]-D-glucose; the rate of glucose uptake in excised soleus muscles was measured with [(3) H]-2-deoxy-D-glucose. Pharmacokinetic parameters were determined by non-compartmental analysis of the in vivo data. The effective blood EH-36 concentration in treated animals was 2 μM. It reduced significantly the blood glucose levels in both types of diabetic mice and also corrected the typical compensatory hyperinsulinaemia of KKAy mice. EH-36 markedly increased glucose transport in vivo into skeletal muscle and heart, but not to adipose tissue. This stimulatory effect was mediated by Thr(172) -phosphorylation in AMPK. Biochemical tests in treated animals and acute toxicological examinations showed that EH-36 was well tolerated and not toxic to the mice. These findings indicate that EH-36 is a promising prototype molecule for the development of novel antidiabetic drugs.
Journal of Cellular and Molecular Medicine 05/2011; 16(3):594-604. · 4.13 Impact Factor
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ABSTRACT: Thioredoxin-interacting protein (TXNIP) regulates critical biological processes including inflammation, stress and apoptosis. TXNIP is upregulated by glucose and is a critical mediator of hyperglycemia-induced beta-cell apoptosis in diabetes. In contrast, the saturated long-chain fatty acid palmitate, although toxic to the beta-cell, inhibits TXNIP expression. The mechanisms involved in the opposing effects of glucose and fatty acids on TXNIP expression are unknown. We found that both palmitate and oleate inhibited TXNIP in a rat beta-cell line and islets. Palmitate inhibition of TXNIP was independent of fatty acid beta-oxidation or esterification. AMP-activated protein kinase (AMPK) has an important role in cellular energy sensing and control of metabolic homeostasis; therefore we investigated its involvement in nutrient regulation of TXNIP. As expected, glucose inhibited whereas palmitate stimulated AMPK. Pharmacologic activators of AMPK mimicked fatty acids by inhibiting TXNIP. AMPK knockdown increased TXNIP expression in presence of high glucose with and without palmitate, indicating that nutrient (glucose and fatty acids) effects on TXNIP are mediated in part via modulation of AMPK activity. TXNIP is transcriptionally regulated by carbohydrate response element-binding protein (ChREBP). Palmitate inhibited glucose-stimulated ChREBP nuclear entry and recruitment to the Txnip promoter, thereby inhibiting Txnip transcription. We conclude that AMPK is an important regulator of Txnip transcription via modulation of ChREBP activity. The divergent effects of glucose and fatty acids on TXNIP expression result in part from their opposing effects on AMPK activity. In light of the important role of TXNIP in beta-cell apoptosis, its inhibition by fatty acids can be regarded as an adaptive/protective response to glucolipotoxicity. The finding that AMPK mediates nutrient regulation of TXNIP may have important implications for the pathophysiology and treatment of diabetes.
PLoS ONE 01/2011; 6(12):e28804. · 4.09 Impact Factor
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Diabetes Obesity and Metabolism 11/2009; 11 Suppl 4:iv-ix. · 3.38 Impact Factor
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ABSTRACT: Palmitate is a potent inducer of endoplasmic reticulum (ER) stress in beta-cells. In type 2 diabetes, glucose amplifies fatty-acid toxicity for pancreatic beta-cells, leading to beta-cell dysfunction and death. Why glucose exacerbates beta-cell lipotoxicity is largely unknown. Glucose stimulates mTORC1, an important nutrient sensor involved in the regulation of cellular stress. Our study tested the hypothesis that glucose augments lipotoxicity by stimulating mTORC1 leading to increased beta-cell ER stress.
We found that glucose amplifies palmitate-induced ER stress by increasing IRE1alpha protein levels and activating the JNK pathway, leading to increased beta-cell apoptosis. Moreover, glucose increased mTORC1 activity and its inhibition by rapamycin decreased beta-cell apoptosis under conditions of glucolipotoxicity. Inhibition of mTORC1 by rapamycin did not affect proinsulin and total protein synthesis in beta-cells incubated at high glucose with palmitate. However, it decreased IRE1alpha expression and signaling and inhibited JNK pathway activation. In TSC2-deficient mouse embryonic fibroblasts, in which mTORC1 is constitutively active, mTORC1 regulated the stimulation of JNK by ER stressors, but not in response to anisomycin, which activates JNK independent of ER stress. Finally, we found that JNK inhibition decreased beta-cell apoptosis under conditions of glucolipotoxicity.
Collectively, our findings suggest that mTORC1 mediates glucose amplification of lipotoxicity, acting through activation of ER stress and JNK. Thus, mTORC1 is an important transducer of ER stress in beta-cell glucolipotoxicity. Moreover, in stressed beta-cells mTORC1 inhibition decreases IRE1alpha protein expression and JNK activity without affecting ER protein load, suggesting that mTORC1 regulates the beta-cell stress response to glucose and fatty acids by modulating the synthesis and activity of specific proteins involved in the execution of the ER stress response. This novel paradigm may have important implications for understanding beta-cell failure in type 2 diabetes.
PLoS ONE 02/2009; 4(3):e4954. · 4.09 Impact Factor
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Arie Gruzman,
Ofer Shamni,
Moriya Ben Yakir,
Daphna Sandovski,
Anna Elgart,
Evgenia Alpert,
Guy Cohen,
Amnon Hoffman,
Yehoshua Katzhendler, Erol Cerasi,
Shlomo Sasson
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ABSTRACT: Type 2 diabetes mellitus has reached epidemic proportions; therefore, the search for novel antihyperglycemic drugs is intense. We have discovered that D-xylose increases the rate of glucose transport in a non-insulin-dependent manner in rat and human myotubes in vitro. Due to the unfavorable pharmacokinetic properties of D-xylose we aimed at synthesizing active derivatives with improved parameters. Quantitative structure-activity relationship analysis identified critical hydroxyl groups in D-xylose. These data were used to synthesize various hydrophobic derivatives of D-xylose of which compound 19 the was most potent compound in stimulating the rate of hexose transport by increasing the abundance of glucose transporter-4 in the plasma membrane of myotubes. This effect resulted from the activation of AMP-activated protein kinase without recruiting the insulin transduction mechanism. These results show that lipophilic D-xylose derivatives may serve as prototype molecules for the development of novel antihyperglycemic drugs for the treatment of diabetes.
Journal of Medicinal Chemistry 01/2009; 51(24):8096-108. · 4.80 Impact Factor
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Diabetes Obesity and Metabolism 11/2008; 10 Suppl 4:1-4. · 3.38 Impact Factor
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Merav Fraenkel,
Mali Ketzinel-Gilad,
Yafa Ariav,
Orit Pappo,
Melis Karaca,
Julien Castel,
Marie-France Berthault,
Christophe Magnan, Erol Cerasi,
Nurit Kaiser,
Gil Leibowitz
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ABSTRACT: Mammalian target of rapamycin (mTOR) and its downstream target S6 kinase 1 (S6K1) mediate nutrient-induced insulin resistance by downregulating insulin receptor substrate proteins with subsequent reduced Akt phosphorylation. Therefore, mTOR/S6K1 inhibition could become a therapeutic strategy in insulin-resistant states, including type 2 diabetes. We tested this hypothesis in the Psammomys obesus (P. obesus) model of nutrition-dependent type 2 diabetes, using the mTOR inhibitor rapamycin.
Normoglycemic and diabetic P. obesus were treated with 0.2 mg x kg(-1) x day(-1) i.p. rapamycin or vehicle, and the effects on insulin signaling in muscle, liver and islets, and on different metabolic parameters were analyzed.
Unexpectedly, rapamycin worsened hyperglycemia in diabetic P. obesus without affecting glycemia in normoglycemic controls. There was a 10-fold increase of serum insulin in diabetic P. obesus compared with controls; rapamycin completely abolished this increase. This was accompanied by weight loss and a robust increase of serum lipids and ketone bodies. Rapamycin decreased muscle insulin sensitivity paralleled by increased glycogen synthase kinase 3beta activity. In diabetic animals, rapamycin reduced beta-cell mass by 50% through increased apoptosis. Rapamycin increased the stress-responsive c-Jun NH(2)-terminal kinase pathway in muscle and islets, which could account for its effect on insulin resistance and beta-cell apoptosis. Moreover, glucose-stimulated insulin secretion and biosynthesis were impaired in islets treated with rapamycin.
Rapamycin induces fulminant diabetes by increasing insulin resistance and reducing beta-cell function and mass. These findings emphasize the essential role of mTOR/S6K1 in orchestrating beta-cell adaptation to hyperglycemia in type 2 diabetes. It is likely that treatments based on mTOR inhibition will cause exacerbation of diabetes.
Diabetes 05/2008; 57(4):945-57. · 8.29 Impact Factor
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ABSTRACT: Endocrine cells produce large amounts of one or more peptides. The post-translational control of selective production of a single protein is often unknown. We used 3 unrelated approaches to diminish PKCepsilon in rat islets to evaluate its role in preferential glucose-mediated insulin production. Transfection with siRNA (siR-PKCepsilon) or expression of inactive PKCepsilon (PKCepsilon-KD) resulted in a significant reduction in insulin response to glucose (16.7 mmol/l). Glucose stimulation resulted in concentration of PKCepsilon in the perinuclear region, an area known to be rich in ER-Golgi systems, associated with insulin-containing structures. ss'COP1 (RACK2) is the anchoring protein for PKCepsilon. Glucose-stimulated proinsulin production was diminished by 50% in islets expressing PKCepsilon-KD, and 60% in islets expressing RACK2 binding protein (epsilonV1-2); total protein biosynthesis was not affected. In islets expressing epsilonV1-2, a chase period following glucose stimulus resulted in a reduced proinsulin conversion to mature insulin. We propose that PKCepsilon plays a specific role in mediating the glucose-signal into insulin production: binding to ss'COP1 localizes the activated enzyme to the RER where it modulates the shuttling of proinsulin to the TGN. Subsequently the enzyme may be involved in anterograde trafficking of the prohormone or in its processing within the TGN.
Biochimica et Biophysica Acta 05/2008; 1783(10):1929-34. · 4.66 Impact Factor
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Diabetes Obesity and Metabolism 12/2007; 9 Suppl 2:1-4. · 3.38 Impact Factor
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ABSTRACT: The most common form of diabetes, type 2 diabetes (T2D) is a major Public Health issue which is receiving a great deal of attention both in industrial and public research, in order to develop new and more effective drugs. The hyperglycaemia of T2D is the result of two interdependent defects : decreased biological efficacy of insulin in target tissues (insulin resistance), and a decreased capacity for beta cells to secrete insulin in response to glucose. Furthermore, hyperglycaemia evolves with time and even with rigorous treatment there is a progressive deterioration of glucose homeostasis. Seventy five percent of DT2 patients are obese and show a perturbed lipid profile. beta-cell plasticity is a unique property of these cells to adapt their number and volume (beta-cell mass) and their function to the increased secretory demand linked to insulin resistance. This is well documented in physiological (pregnancy) as well in pathophysiological conditions (obesity, acromegaly). Although the lack of reliable techniques makes it very difficult to document it in humans, this property is likely altered in DT2, mainly as a consequence of the prolonged exposure of islet cells to high plasma levels of glucose and free fatty acids (gluco-lipotoxicity). The mechanisms by which hyperglycaemia and hyperlipidemia exert their deleterious effects on the beta-cell include the generation of Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS) and Advanced Glycosylation End Products (AGE). Altogether the prevailing clinical and experimental data urge us to consider that the pathophysiology of DT2 lies, at least in part, the inability of beta-cells to adapt their functional mass to the prevailing insulin demand. This re-evaluation of the pathophysiology of DT2 stimulates the research of new therapeutic approaches aimed at maintaining and/or restoring the functional beta-cell mass by targeting the mechanisms responsible for its decrease.
Medecine sciences: M/S 11/2007; 23(10):885-94. · 0.64 Impact Factor
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ABSTRACT: Succinate stimulates insulin secretion and proinsulin biosynthesis. We studied the effects of reduced nicotinamide adenine dinucleotide phosphate (NADPH)-modulating pathways on glucose- and succinate-stimulated insulin secretion and proinsulin biosynthesis in the rat and the insulin-resistant Psammomys obesus. Disruption of the anaplerotic pyruvate/malate shuttle by phenylacetic acid inhibited glucose- and succinate-stimulated insulin secretion and succinate-stimulated proinsulin biosynthesis in both species. In contrast, phenylacetic acid failed to inhibit glucose-stimulated proinsulin biosynthesis in P. obesus islets. Inhibition of the NADPH-consuming enzyme neuronal nitric oxide synthase (nNOS) with l-N(G)-nitro-l-arginine methyl ester or with N(G)-monomethyl-l-arginine(G) doubled succinate-stimulated insulin secretion in rat islets, suggesting that succinate- and nNOS-derived signals interact to regulate insulin secretion. In contrast, nNOS inhibition had no effect on succinate-stimulated proinsulin biosynthesis in both species. In P. obesus islets, insulin secretion was not stimulated by succinate in the absence of glucose, whereas proinsulin biosynthesis was increased 5-fold. Conversely, under stimulating glucose levels, succinate doubled insulin secretion, indicating glucose-dependence. Pyruvate ester and inhibition of nNOS partially mimicked the permissive effect of glucose on succinate-stimulated insulin secretion, suggesting that anaplerosis-derived signals render the beta-cells responsive to succinate. We conclude that beta-cell anaplerosis via pyruvate carboxylase is important for glucose- and succinate-stimulated insulin secretion and for succinate-stimulated proinsulin biosynthesis. In P. obesus, pyruvate/malate shuttle dependent and independent pathways that regulate proinsulin biosynthesis coexist; the latter can maintain fuel stimulated biosynthetic activity when the succinate-dependent pathway is inhibited. nNOS signaling is a negative regulator of insulin secretion, but not of proinsulin biosynthesis.
Endocrinology 12/2006; 147(11):5110-8. · 4.46 Impact Factor
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ABSTRACT: Glucose metabolism affects most major signal pathways in pancreatic beta-cells. Multiple protein kinases, including protein kinase C (PKC) isoenzymes, are involved in these effects; however, their role is poorly defined. Moreover, the dynamics of kinase isoenzyme activation in reference to the biphasic insulin secretion is unknown. In perfused pancreas of Wistar rats, PKCalpha staining was strongly associated with insulin staining, jointly accumulating in the vicinity of the plasma membrane during early first-phase insulin response. The signal declined before the onset of second phase and reappeared during second-phase insulin release as foci, only weekly associated with insulin staining; this signal persisted for at least 15 min after glucose stimulation. In the GK rat, glucose had minimal effect on beta-cell PKCalpha. In control beta-cells, PKCdelta stained as granulated foci with partial association with insulin staining; however, no glucose-dependent translocation was observed. In the GK rat, only minimal staining for PKCdelta was observed, increasing exclusively during early first-phase secretion. In Wistar beta-cells, PKCepsilon concentrated near the nucleus, strongly associated with insulin staining, with dynamics resembling that of biphasic insulin response, but persisting for 15 min after cessation of stimulation. In GK rats, PKCepsilon staining lacked glucose-dependent changes or association with insulin. PKCzeta exhibited bimodal dynamics in control beta-cells: during early first phase, accumulation near the cell membrane was observed, dispersing thereafter. This was followed by a gradual accumulation near the nucleus; 15 min after glucose stimulus, clear PKCzeta staining was observed within the nucleus. In the GK rat, a similar response was only occasionally observed. In control beta-cells, glucose stimulation led to a transient recruitment of PKCtheta, associated with first-phase insulin release, not seen in GK beta-cell. Data from this and related studies support a role for PKCalpha in glucose-induced insulin granule recruitment for exocytosis; a role for PKCepsilon in activation of insulin granules for exocytosis and/or in the glucose-generated time-dependent potentiation signal for insulin release; and a dual function for PKCzeta in initiating insulin release and in a regulatory role in the transcriptional machinery. Furthermore, diminished levels and/or activation of PKCalpha, PKCepsilon, PKCtheta, and PKCzeta could be part of the defective signals downstream to glucose metabolism responsible for the deranged insulin secretion in the GK rat.
Diabetes 04/2006; 55(3):590-9. · 8.29 Impact Factor
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Diabetes 01/2006; 54 Suppl 2:S1-3. · 8.29 Impact Factor
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ABSTRACT: Type 2 diabetes is characterized by insulin resistance and progressive beta-cell failure. Deficient insulin secretion, with increased proportions of insulin precursor molecules, is a common feature of type 2 diabetes; this could result from inappropriate beta-cell function and/or reduced beta-cell mass. Most studies using tissues from diabetic patients are retrospective, providing only limited information on the relative contribution of beta-cell dysfunction versus decreased beta-cell mass to the "beta-cell failure" of type 2 diabetes. The gerbil Psammomys obesus is a good model to address questions related to the role of insulin resistance and beta-cell failure in nutritionally induced diabetes. Upon a change from its natural low-calorie diet to the calorie-rich laboratory food, P. obesus develops moderate obesity associated with postprandial hyperglycemia. Continued dietary load, superimposed on its innate insulin resistance, results in depletion of pancreatic insulin stores, with increased proportions of insulin precursor molecules in the pancreas and the blood. Inadequate response of the preproinsulin gene to the increased insulin needs is an important cause of diabetes progression. Changes in beta-cell mass do not correlate with pancreatic insulin stores and are unlikely to play a role in disease initiation and progression. The major culprit is the inappropriate insulin production with depletion of insulin stores as a consequence. Similar mechanisms could operate during the evolution of type 2 diabetes in humans.
Diabetes 01/2006; 54 Suppl 2:S137-44. · 8.29 Impact Factor
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ABSTRACT: S 21403 (mitiglinide) is a new drug for type 2 diabetes mellitus (T2DM). Its action on insulin release and biosynthesis was investigated in several experimental systems utilizing pancreas from normal and T2DM animals. At high concentrations (10 microM), S 21403, like classical sulphonylurea, induced insulin release in the absence of glucose. In contrast, at therapeutic (0.1-1.0 microM) concentrations, S 21403 amplified insulin secretion glucose dose-dependently and with similar magnitude in normal and diabetic GK rat islets. In perfused GK rat pancreas, S 21403 induced normal kinetics of insulin secretion including first-phase response. The effect of S 21403 was strongly modulated by physiological factors. Thus, 0.1 microM adrenaline inhibited S 21403-induced insulin release. There was marked synergism between S 21403 and arginine in GK rat islets, combination of the two normalizing insulin secretion. In primary islet cultures from normal rats or prediabetic Psammomys obesus, prolonged exposure to S 21403 did not induce further depletion of insulin stores under normal or 'glucotoxic' conditions. Proinsulin biosynthesis was not affected by 2-h exposure of rat or prediabetic P. obesus islets to 1 microM S 21403. Yet, 24-h exposure of rat islets to S 21403 resulted in 30% increase in proinsulin biosynthesis at 8.3 mM glucose. Amplification by S 21403 of glucose-induced insulin secretion in diabetic GK beta-cells with restoration of first-phase response, a strong synergistic interaction with arginine and marked inhibition by adrenaline, make it a prime candidate for successful oral antidiabetic agent.
British Journal of Pharmacology 12/2005; 146(6):872-81. · 4.41 Impact Factor
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ABSTRACT: Recent studies ascribe a major role to pancreatic beta-cell loss in type 2 diabetes. We investigated the dynamics of beta-cell mass during diabetes evolution in Psammomys obesus, a model for nutrition-dependent type 2 diabetes, focusing on the very early and the advanced stages of the disease. P. obesus fed a high-calorie diet for 26 days developed severe hyperglycemia, beta-cell degranulation, and markedly reduced pancreatic insulin content. Reducing calories for 7 days induced normoglycemia in 90% of the animals, restoring beta-cell granulation and insulin content. To dissociate effects of diet from blood glucose reduction, diabetic animals received phlorizin for 2 days, which normalized glycemia and increased the pancreatic insulin reserve to 50% of control, despite a calorie-rich diet. During diabetes progression, beta-cell mass decreased initially but recovered spontaneously to control levels, despite persistent hyperglycemia. Strikingly, however, beta-cell mass did not correlate with degree of hyperglycemia or pancreatic insulin content. We conclude that reduced insulin reserve is the main cause of diabetes progression, whereas irreversible beta-cell mass reduction is a late event in P. obesus. The rapid recovery of the pancreas by phlorizin-induced normoglycemia implies a causal relationship between hyperglycemia and islet dysfunction. Similar mechanisms could be operative during the evolution of type 2 diabetes in humans.
Diabetes 02/2005; 54(1):138-45. · 8.29 Impact Factor
