Type 2 diabetes is characterized by insulin resistance and inadequate insulin secretion. In the advanced stages of the disease, ␤-cell dysfunction worsens and insulin therapy may be necessary to achieve satisfactory metabolic control. Studies in autopsies found decreased ␤-cell mass in pancreas of people with type 2 diabetes. Apoptosis, a constitutive program of cell death modulated by the Bcl family genes, has been implicated in loss of ␤-cells in animal models of type 2 diabetes. In this study, we compared the effect of 5 days' culture in high glucose concentration (16.7 mmol/l) versus normal glucose levels (5.5 mmol/l) or hyperosmolar control (mannitol 11 mmol/l plus glucose 5 mmol/l) on the survival of human pancreatic islets. Apoptosis, analyzed by flow cytometry and electron and immunofluorescence microscopy, was increased in islets cultured in high glucose (HG5) as compared with normal glucose (NG5) or hyperosmolar control (NG5؉MAN5). We also analyzed by reverse transcriptase-polymerase chain reaction and Western blotting the expression of the Bcl family genes in human islets cultured in normal glucose or high glucose. The antiapoptotic gene Bcl-2 was unaffected by glucose change, whereas Bcl-xl was reduced upon treatment with HG5. On the other hand, proapoptotic genes Bad, Bid, and Bik were overexpressed in the islets maintained in HG5. To define the pancreatic localization of Bcl proteins, we performed confocal immunofluorescence analysis on human pancreas. Bad and Bid were specifically expressed in ␤-cells, and Bid was also expressed, although at low levels, in the exocrine pancreas. Bik and Bcl-xl were expressed in other endocrine islet cells as well as in the exocrine pancreas. These data suggest that in human islets, high glucose may modulate the balance of proapoptotic and antiapoptotic Bcl proteins toward apoptosis, thus favoring ␤-cell death.

OBJECTIVE -Our aim was to evaluate the long-term effects of transplanted islets on diabetic macro-/microangiopathy in type 1 diabetic kidney-transplanted patients.RESEARCH DESIGN AND METHODS -A total of 34 type 1 diabetic kidneytransplanted patients underwent islet transplantation and were divided into two groups: successful islet-kidney transplantation (SI-K; 21 patients, fasting C-peptide serum concentration Ͼ0.5 ng/ml for Ͼ1 year) and unsuccessful islet-kidney transplantation (UI-K; 13 patients, fasting C-peptide serum concentration Ͻ0.5 ng/ml). Patients cumulative survival, cardiovascular death rate, and atherosclerosis progression were compared in the two groups. Skin biopsies, endothelial dependent dilation (EDD), nitric oxide (NO) levels, and atherothrombotic risk factors [von Willebrand factor (vWF) and D-dimer fragment (DDF)] were studied cross-sectionally.RESULTS -The SI-K group showed a significant better patient survival rate (SI-K 100, 100, and 90% vs. UI-K 84, 74, and 51% at 1, 4, and 7 years, respectively, P ϭ 0.04), lower cardiovascular death rate (SI-K 1/21 vs. UI-K 4/13, 2 ϭ 3.9, P ϭ 0.04), and lower intima-media thickness progression than the UI-K group (SI-K group: ⌬1-3 years Ϫ13 Ϯ 30 m vs. UI-K group: ⌬1-3 years 245 Ϯ 20 m, P ϭ 0.03) with decreased signs of endothelial injuring at skin biopsy. Furthermore, the SI-K group showed a higher EDD than the UI-K group (EDD: SI-K 7.8 Ϯ 4.5% vs. UI-K 0.5 Ϯ 2.7%, P ϭ 0.02), higher basal NO (SI-K 42.9 Ϯ 6.5 vs. UI-K 20.2 Ϯ 6.8 mol/l, P ϭ 0.02), and lower levels of vWF (SI-K 138.6 Ϯ 15.3 vs. UI-K 180.6 Ϯ 7.0%, P ϭ 0.02) and DDF (SI-K 0.61 Ϯ 0.22 vs. UI-K 3.07 Ϯ 0.68 g/ml, P Ͻ 0.01). C-peptide-tocreatinine ratio correlated positively with EDD and NO and negatively with vWF and DDF.CONCLUSIONS -Successful islet transplantation improves survival, cardiovascular, and endothelial function in type 1 diabetic kidney-transplanted patients. Diabetes Care 26:1129 -1136, 2003I slet transplantation, particularly after kidney transplantation, is an alternative to pancreas transplantation to restore endogenous insulin secretion (1-7). Islet transplantation is a safe procedure leading to an improvement of glycometabolic control and of protein and lipid metabolism (1,3,6 -8). The benefits of the improvement of glycometabolic control alone on macroangiopathy are unknown (9,10).Patients with type 1 diabetes are at high risk for several cardiovascular disorders, such as coronary artery disease, stroke, peripheral arterial disease, cardiomyopathy, and congestive heart failure (11). These risks are particularly high in patients with uremia and type 1 diabetes, even after kidney transplantation (12). A worsening of carotid lesion has been observed in patients undergoing kidneyalone transplantation (13). High levels of von Willebrand factors (vWF) and Ddimer fragments (DDFs), and impaired endothelial-dependent dilation (EDD) are commonly involved in development of atherosclerosis (14). In particular, endothelium modulates platelet adhesion, macrophage migration, lipid transp...

At least four types of endocrine-like cells have been detected histochemically in the mucosa of the human colon and rectum, i.e. argentaffin cells storing 5-hydroxytryptamine (5HT) and non-argentaffin cells reacting with glucagon, somatostatin and bovine pancreatic peptide (BPP) antibodies. Ultrastructurally, four main types and three rare types of endocrine-like cells have been identified. Among the former cells were: (1) argentaffin EC1 cells, known to store 5HT and substance P, (2) poorly argyrophil L cells, corresponding to the glucagon-immunoreactive cells storing enteroglucagon or glucagon-like immunoreactivity (GLl), (3) inconstantly argyrophil F-like cells, possibly corresponding to BPP-immunoreactive cells, and (4) fairly argyrophil H cells of unknown function. Rare D cells, corresponding to somatostatin cells, N cells, corresponding to neurotensin cells, and P cells, of unknown function, have been also found.

Recent evidence suggests that insulin signaling through the insulin receptor A type (Ex11-), regulates insulin gene transcription. Because chronic hyperglycemia negatively affects insulin receptor function and regulates alternative splicing of the insulin receptor, we inquired whether chronic exposure of pancreatic beta-cells to high glucose results in alterations in insulin signaling due to changes in insulin receptor expression and relative abundance of its spliced isoforms. Our results demonstrate that the insulin receptor is localized in insulin secretory vescicles in human pancreatic beta-cells. Furthermore, we find that alterations in insulin expression and secretion caused by chronic exposure to high glucose are paralleled by decreased insulin receptor expression and increased relative abundance of the Ex11+ isoform in both human islets and RIN beta-cells. PDX-1 and HMGI(Y) transcription factors are down-regulated by high glucose. These changes are associated with defects in insulin signaling involving insulin receptor-associated PI 3-kinase/Akt/PHAS-I pathway in RIN beta-cells. Re-expression in RIN beta-cells chronically exposed to high glucose of the Ex11-, but not the Ex11+, isoform restored insulin mRNA expression. These data suggest that changes in early steps of insulin receptor signaling may play a role in determining beta-cell dysfunction caused by chronic hyperglycemia.

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