Functional and Molecular Defects of Pancreatic Islets in Human Type 2 Diabetes

Abstract

To shed further light on the primary alterations of insulin secretion in type 2 diabetes and the possible mechanisms involved, we studied several functional and molecular properties of islets isolated from the pancreata of 13 type 2 diabetic and 13 matched nondiabetic cadaveric organ donors. Glucose-stimulated insulin secretion from type 2 diabetic islets was significantly lower than from control islets, whereas arginine-and glibenclamide-stimulated insulin release was less markedly affected. The defects were accompanied by reduced mRNA expression of GLUT1 and -2 and glucokinase and by diminished glucose oxidation. In addition, AMPactivated protein kinase activation was reduced. Furthermore, the expression of insulin was decreased, and that of pancreatic duodenal homeobox-1 (PDX-1) and forkhead box O1 (Foxo-1) was increased. Nitrotyrosine and 8-hydroxy-2-deoxyguanosine concentrations, markers of oxidative stress, were significantly higher in type 2 diabetic than control islets, and they were correlated with the degree of glucose-stimulated insulin release impairment. Accordingly, 24-h exposure to glutathione significantly improved glucose-stimulated insulin release and decreased nitrotyrosine concentration, with partial recovery of insulin mRNA expression. These results provide direct evidence that the defects of insulin secretion in type 2 diabetic islets are associated with multiple islet cell alterations. Most importantly, the current study shows that the functional impairment of type 2 diabetic islets can be, at least in part, reversible. In this regard, it is suggested that reducing islet cell oxidative stress is a potential target of human type 2 diabetes therapy. Diabetes 54:727-735, 2005

The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients

“…Pancreas procurement and islet isolation Pancreases were obtained with the approval of the local Ethics Committee and processed as described [27][28][29]. Thirty-one glands were used.…”

“…For morphological and morphometric studies, as well as for LCM experiments, pancreatic samples were obtained immediately before islet preparation. Islet isolation was performed by enzymatic digestion and density gradient purification [27][28][29]. Handpicked islets were kept at 37°C in a CO 2 incubator for 3-6 days before the experiments were performed, with no difference between non-diabetic and diabetic islets in terms of length of incubation.…”

“…Culture medium consisted of M199 medium, containing 5.5 mmol/l glucose, 10% (vol./vol.) bovine serum and antibiotics [27][28][29]. In a separate series of experiments, islets were cultured for an additional 24 h in the presence of 11.1 mmol/l glucose to assess the impact of increasing glucose concentration on some of the studied parameters.…”

The Zinc Finger Protein ZBTB20 Regulates Transcription of Fructose-1,6-Bisphosphatase 1 and β Cell Function in Mice

“…25,26 This defect is islet intrinsic and relatively glucose specific in the earlier stages of the disease. 27,28 Some factors (eg, hypoxia-inducible factor 1␣ and ARNT/hypoxiainducible factor 1␤) have been shown to contribute to altered function of diabetic ␤ cells. 29,30 Our results suggest that ZBTB20 may be another important player in ␤ cell dysfunction during the pathogenesis of T2DM.…”

Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin

“…Incubation of islets or beta cells in high glucose and NEFA has been shown to cause impaired insulin secretion, which can be improved with antioxidant treatment [46,47]. Increased markers of oxidative stress have also been measured in islets from patients with type 2 diabetes, and improvements were seen when the islets were treated with the antioxidant glutathione [48]. Our own work has shown that islets from the DBA/2 mouse, a strain susceptible to diabetes, hypersecrete insulin in the normal 'non-stressed' state (as discussed earlier) but are susceptible to oxidative stress induced by high glucose, which is associated with impaired insulin secretion [17].…”