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Copyright of Diabetes & Metabolism is the property of Masson Editeur and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract: GLP-1 and GIP are incretins known to affect beta-cell function and turnover. However, information on the direct actions of these hormones on human islet cells is limited. We tested the effects of acute (45min) or prolonged (2days) exposure to GLP-1 or GIP, alone or in combination, on the function and some molecular features of human islets isolated from non-diabetic and type 2 diabetic multiorgan donors. Acutely, both GLP-1 and, more markedly so, GIP, significantly potentiated glucose-stimulated insulin release, with no apparent synergic action. Some of these effects were observed with type 2 diabetic islets as well. Following prolonged exposure to the incretins, improved insulin secretion was observed, and transcription of insulin, PDX-1 and Bcl-2 was increased in both non-diabetic and diabetic islets, with the combination of GLP-1 and GIP showing more significant effects. Although it is still unclear at what extent these beta-cell direct actions of individual or combined incretins occur in-vivo in humans, nevertheless the results of the present study suggest that enhancing the exposure of pancreatic islets to circulating levels of both incretins may be useful for therapeutical purposes. [ABSTRACT FROM AUTHOR]

Copyright of Diabetes & Metabolism is the property of Masson Editeur and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Peroxisome proliferator-activated receptors (PPARs) are a subgroup of the superfamily of nuclear receptors, with three distinct main types: α, β and γ (subdivided into γ1 and γ2). Recently, the presence of PPARγ has been reported in human islets. Whether other PPAR types can be found in human islets, how islet PPARγ mRNA expression is regulated by the metabolic milieu, their role in insulin secretion, and the effects of a PPARγ agonist are not known. In this study, human pancreatic islets were prepared by collagenase digestion and density gradient purification from nonobese adult donors. The presence of PPAR mRNAs was assessed by RT-PCR, and the effect was evaluated of exposure for up to 24 h to either 22.2 mmol/1 glucose and/or 0.25, 0.5, or 1.0 mmol/1 long-chain fatty acid mixture (oleate to palmitate, 2:1). PPARβ and, to a greater extent, total PPARγ and PPARγ2 mRNAs were expressed in human islets, whereas PPARα mRNA was not detected. Compared with human adipose tissue, PPARγ mRNA was expressed at lower levels in the islets, and PPARβ at similar levels. The expression of PPARγ2 mRNA was not affected by exposure to 22.2 mmol/1 glucose, whereas it decreased markedly and time dependently after exposure to progressively higher free fatty acids (FFA). This latter effect was not affected by the concomitant presence of high glucose. Exposure to FFA caused inhibition of insulin mRNA expression, glucose-stimulated insulin release, and reduction of islet insulin content. The PPARγ agonists rosiglitazone and 15-deoxy-Δ-12,14prostaglandin J2 prevented the cytostatic effect of FFA as well as the FFA-induced changes of PPAR and insulin mRNA expression. In conclusion, this study shows that PPARγ mRNA is expressed in human pancreatic islets, with predominance of PPARγ2; exposure to FFA downregulates PPARγ2 and insulin mRNA expression and inhibits glucose-stimulated insulin secretion; exposure to PPARγ agonists can prevent these effects. [ABSTRACT FROM AUTHOR]

The type II transmembrane glycoprotein CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase) has been proposed as a mediator of insulin secretion from pancreatic beta-cells and as a candidate for autoimmune reactions in type 2 diabetes. We evaluated the presence of anti-CD38 autoantibodies in Caucasian patients with diabetes and investigated the effect of these antibodies on insulin secretion from isolated human pancreatic islets. The presence of anti-CD38 autoantibodies was evaluated by using Western blot analysis in 236 patients with type 2 diabetes (mean age 63 years), in 160 patients with type 1 diabetes (mean age 38 years), and in 159 nondiabetic subjects. Anti-CD38 autoantibody titers at least 3 SD above the mean value of the control group were found in 9.7% of type 2 diabetic patients and in 13.1% of type 1 diabetic patients (chi2 = 15.9, P = 0.0003 vs. 1.3% of control subjects). No significant differences were observed in sex distribution, current age, age at diabetes onset, BMI, fasting serum glucose, or glycemic control between anti-CD38+ and anti-CD38-diabetic patients in either the type 2 or type 1 diabetic groups. The effect of 23 anti-CD38- and 13 anti-CD38+ sera on insulin secretion at low (3.3 mmol/l) or high (16.7 mmol/l) medium glucose concentrations was evaluated in isolated human pancreatic islets. Data are medians (interquartile range). The anti-CD38+ sera potentiated insulin release both at low [95 (64) vs. 23 (12) microU/ml of control incubations, respectively, P < 0.0001] and high [271 (336) vs. a control of 55 (37) microU/ml, respectively, P = 0.001] medium glucose concentrations, whereas the anti-CD38- sera did not. Furthermore, in the pooled data from all 36 tested sera, insulin levels in the islet incubation medium were directly related to the anti-CD38 antibody titer. We conclude that autoantibodies to CD38 are associated with both type 1 and type 2 diabetes in Caucasian subjects. These autoantibodies exert a stimulatory effect on insulin secretion by cultured human islets. The role of this autoimmune reaction in the pathogenesis of diabetes remains to be elucidated. [ABSTRACT FROM AUTHOR]

We describe a method to consistently prepare human islets for transplantation. By combining a simple collagenase digestion method and a density gradient purification system, we were able to obtain successful isolations (≥200,000 islet equivalents, ≥50% purity) in 69% of processed glands. No reagent of animal source was used. Isolated islets were morphologically well maintained and functionally competent, with sterility confirmed in 97% of cases. Two patients were transplanted with islets prepared by this method; graft function was demonstrated for a few months. Improved simplicity and consistency, together with adequate quality of the preparations, are the main features of this isolation method. [Copyright &y& Elsevier]

Abstract: Background and aims: Islet transplantation is an attractive approach to treat type 1 diabetic patients. However, suboptimal islet engraftment still represents an unsolved problem. It has been shown that human islets release monocyte chemoattractant protein-1 (MCP-1), one of the most powerful macrophage chemokines, which may impair the fate of the transplant. The aim of this study was to evaluate the presence and role of MCP-1 in isolated human islets, including genotyping for a common polymorphism. Methods: Pancreatic islets were isolated by enzymatic digestion and gradient purification from 41 nondiabetic multiorgan donors. We measured MCP-1 mRNA expression by quantitative real- time reverse-transcriptase polymerization chain reaction, analyzed the MCP-1 single nucleotide polymorphism, −2518 G/A (SNP, rs 1024611) and evaluated glucose-stimulated insulin release (IR; μU/islet/min). Results: MCP-1 mRNA expression was found in all studied batches of islets. Overall, IR was significantly higher at 16.7 mmol/L than 3.3 mmol/L glucose. We observed a significant negative correlation between MCP-1 mRNA expression and stimulation index (SI). We found that MCP-1 mRNA expression was significantly higher in CC and CT compared with TT genotype groups. Finally, SI was significant lower in the CC with respect to the TT genotype group. Conclusions: These data show that MCP-1 gene expression regulated by the −2518 G/A polymorphism, is correlated with glucose-stimulated insulin release. The study of MCP-1 expression and genotype on isolated islets before transplantation may be useful to understand the inflammatory response after infusion of human islets into patients with type 1 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Abstract: Background and Aims: Pancreatic islet transplantation has become one of the potential treatments for type 1 diabetes. We evaluated functional and viability parameters of isolated islets in relation to donors clinical characteristics and preparation variables. Methods: Islets were isolated from 70 nondiabetic multiorgan donors of overall age of 62.5 ± 15.9 years. There were 41 men and 29 women. Their mean body mass index (BMI) was 25.62 ± 3.09 kg/m2. We evaluated the islet number (IEQ/g pancreatic tissue) insulin release (IR; μU/islet/min) in response to 3.3 (g) or 16.7 (G) mmol/L glucose; calcium flux concentration (CFC); and islet cell viability. Results: IEQ was 5249 ± 1505, with 73.7 ± 14.96% viable islet cells. IR was 0.03 ± 0.01 at g and 0.11 ± 0.06 at G (stimulation index [S] = 3.24 ± 1.96). CFC was 1.95 ± 1.03 ΔRFU. We observed positive correlations between viable cells and IR at g (R 2 = 0.260; P = .013), IR at G (R 2 = 0.165; P = .013), and CFC (R 2 = 0.175; P = .047). A positive correlation was documented between BMI and g (R 2 = 0.245; P = .016) and negative correlations between age with SI (R 2 = 0.188; P = .052) and cold ischemia time with IEQ (R 2 = 0.865; P = .0061). Conclusions: These results showed that quality control of isolated human pancreatic islets allowed assessment of beta-cell function and survival before transplantation, revealing several important variables. [ABSTRACT FROM AUTHOR]