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Aims/hypothesis: Type 2 diabetes (T2D) is characterized by a progressive loss of beta-cell function, and the “disappearance” of beta-cells in T2D may also be caused by the process of beta -cell dedifferentiation. Since noradrenergic innervation inhibits insulin secretion and density of noradrenergic fibers is increased in type 2 diabetes mouse models, we aimed to study the relation between islet innervation, dedifferentiation and beta-cell function in humans. Methods: Using immunohistochemistry and electron microscopy, we analyzed pancreata from organ donors and from patients undergoing pancreatic surgery. In the latter, a pre-surgical detailed metabolic characterization by oral glucose tolerance test (OGTT) and hyperglycemic clamp was performed before surgery, thus obtaining in vivo functional parameters of beta-cell function and insulin secretion. Results: The islets of diabetic subjects were 3 times more innervated than controls (0.91 ± 0.21 vs 0.32 ± 0.10, n.fibers/islet; p = 0.01), and directly correlated with the dedifferentiation score (r = 0.39; p = 0.03). In vivo functional parameters of insulin secretion, assessed by hyperglycemic clamp, negatively correlated with the increase in fibers [beta-cell Glucose Sensitivity (r = −0.84; p = 0.01), incremental second-phase insulin secretion (r = −0.84, p = 0.03) and arginine-stimulated insulin secretion (r = −0.76, p = 0.04)]. Moreover, we observed a progressive increase in fibers, paralleling worsening glucose tolerance (from NGT through IGT to T2D). Conclusions/interpretation: Noradrenergic fibers are significantly increased in the islets of diabetic subjects and this positively correlates with beta-cell dedifferentiation score. The correlation between in vivo insulin secretion parameters and the density of pancreatic noradrenergic fibers suggests a significant involvement of these fibers in the pathogenesis of the disease, and indirectly, in the islet dedifferentiation process.

Objective: Changes in bile flow after bariatric surgery may beneficially modulate secretion of insulin and incretins, leading to diabetes remission. However, the exact mechanism(s) involved is still unclear. Here, we propose an alternative method to investigate the relationship between alterations in physiological bile flow and insulin and incretin secretion by studying changes in gutpancreatic function in extrahepatic cholestasis in nondiabetic humans. Methods: To pursue this aim, 58 nondiabetic patients with recent diagnosis of periampullary tumors underwent an oral glucose tolerance test (OGTT), and a subgroup of 16 patients also underwent 4-hour mixed meal tests and hyperinsulinemic-euglycemic clamps. Results: The analysis of the entire cohort revealed a strong inverse correlation between total bilirubin levels and insulinogenic index. When subjects were divided on the basis of bilirubin levels, used as a marker of altered bile flow, subjects with high bilirubin levels displayed inferior glucose control and decreased insulin secretion during the OGTT. Altered bile flow elicited a markedly greater increase in glucagon and glucagon-like peptide 1 (GLP-1) secretion at fasting state, and following the meal, both glucagon and GLP-1 levels remained increased over time. Conversely, Glucose-dependent insulinotropic polypeptide (GIP) levels were comparable at the fasting state, whereas the increase following meal ingestion was significantly blunted with high bilirubin levels. We reveal strong correlations between total bilirubin and glucagon and GLP-1 levels. Conclusions: Our findings suggest that acute extrahepatic cholestasis determines major impairment in enteroendocrine gut-pancreatic secretory function. The altered bile flow may determine a direct deleterious effect on beta-cell function, perhaps mediated by the impairment of incretin hormone function.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the latest therapeutic strategy in the treatment of type 2 diabetes mellitus (T2DM). Using an insulin-independent mechanism (glycosuria), they reduce glucose toxicity and improve insulin sensitivity and Î2-cell function. The promising results obtained in clinical trials show that SGLT2 significantly improves glycemic control and provides greater cardiovascular protection, combined with a reduction in body weight and blood pressure (BP). This review focuses on ertugliflozin, a new, highly selective, and reversible SGLT2 inhibitor. Clinical trials published to date show that ertugliflozin, both as a monotherapy and as an add-on to oral antidiabetic agents, is safe and effective in reducing glycosylated hemoglobin (HbA1c), body weight, and BP in T2DM patients.