Spotlight on ertugliflozin and its potential in the treatment of type 2 diabetes: Evidence to date

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 \uce\ub2-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

Effects of PCSK9 inhibition on glucose metabolism and β-cell function in humans: a pilot study

BackgroundAnti-PCSK9 monoclonal antibodies are effective in reducing LDL-C and cardiovascular events by neutralizing circulating PCSK9. PCSK9, however, is also expressed in tissues, including the pancreas, and studies on PCSK9 KO mice have shown impaired insulin secretion. Statin treatment is already known to affect insulin secretion. Our aim was to conduct a pilot study to evaluate the effect of anti-PCSK9 mAb on glucose metabolism and β-cell function in humans.MethodsFifteen non-diabetic subjects, candidates for anti-PCSK9 mAb therapy, were enrolled. All underwent OGTT at baseline and after 6 months of therapy. During OGTT, insulin secretion parameters were derived from C-peptide by deconvolution (β cell glucose sensitivity). Surrogate insulin sensitivity indices were also obtained from OGTT (Matsuda).ResultsGlucose levels during OGTT were unchanged after 6 months of anti-PCSK9 mAb treatment, as well as insulin and C-peptide levels. The Matsuda index remained unchanged, while β-cell glucose sensitivity improved post-therapy (before: 85.3 ± 65.4; after: 118.6 ± 70.9 pmol min-1m-2mM-1; p<0.05). Using linear regression, we found a significant correlation between βCGS changes and BMI (p=0.004). Thus, we compared subjects with values above and below the median (27.6 kg/m2) and found that those with higher BMI had a greater increase in βCGS after therapy (before: 85.37 ± 24.73; after: 118.62 ± 26.83 pmol min-1m-2mM-1; p=0.007). There was also a significant correlation between βCGS change and Matsuda index through linear regression (p=0.04), so we analyzed subjects who had values above and below the median (3.8). This subgroup analysis showed a slight though not significant improvement in βCGS in more insulin resistant patients, (before: 131.4 ± 69.8; after: 170.8 ± 92.7 pmol min-1m-2mM-1; p=0.066).ConclusionsOur pilot study demonstrates that six-month treatment with anti-PCSK9 mAb improves β-cell function, and does not alter glucose tolerance. This improvement is more evident in patients with greater insulin-resistance (low Matsuda) and higher BMI

Pancreaticoduodenectomy model demonstrates a fundamental role of dysfunctional β cells in predicting diabetes

Background: The appearance of hyperglycemia is due to insulin resistance, functional deficits in the secretion of insulin and a reduction of β-cell mass. There is a long-standing debate as to the relative contribution of these factors to clinically manifest β-cell dysfunction. The aim of this study was to verify the acute effect of one of these factors, the reduction of β-cell mass, on the subsequent development of hyperglycemia. Methods: To pursue this aim, non-diabetic patients, scheduled for identical pancreaticoduodenectomy surgery, underwent oral glucose tolerance tests (OGTT) and hyperglycemic clamps (HC), followed by arginine stimulation before and after surgery. Based on post-surgery OGTT, subjects were divided into 3 groups depending on glucose tolerance: normal (post-NGT), impaired (post-IGT) or diabetic (post-DM). Results: At baseline, the three groups showed similar fasting glucose and insulin levels, however, examining the various parameters, we found that reduced first phase insulin secretion and reduced glucose sensitivity and rate sensitivity were predictors of eventual post-surgery development of impaired glucose tolerance and diabetes. Conclusion: Despite comparable functional mass and fasting glucose and insulin levels at baseline, and the very same 50% mass reduction, only reduced first phase insulin secretion and glucose sensitivity predicted the appearance of hyperglycemia. These functional alterations could be pivotal to the pathogenesis of type 2 diabetes (T2DM)

Sotagliflozin, the first dual SGLT inhibitor: Current outlook and perspectives 11 Medical and Health Sciences 1103 Clinical Sciences

Sotagliflozin is a dual sodium-glucose co-transporter-2 and 1 (SGLT2/1) inhibitor for the treatment of both type 1 (T1D) and type 2 diabetes (T2D). Sotagliflozin inhibits renal sodium-glucose co-transporter 2 (determining significant excretion of glucose in the urine, in the same way as other, already available SGLT-2 selective inhibitors) and intestinal SGLT-1, delaying glucose absorption and therefore reducing post prandial glucose. Well-designed clinical trials, have shown that sotagliflozin (as monotherapy or add-on therapy to other anti-hyperglycemic agents) improves glycated hemoglobin in adults with T2D, with beneficial effects on bodyweight and blood pressure. Similar results have been obtained in adults with T1D treated with either continuous subcutaneous insulin infusion or multiple daily insulin injections, even after insulin optimization. A still ongoing phase 3 study is currently evaluating the effect of sotagliflozin on cardiovascular outcomes (ClinicalTrials.gov NCT03315143). In this review we illustrate the advantages and disadvantages of dual SGLT 2/1 inhibition, in order to better characterize and investigate its mechanisms of action and potentialities

The Interplay between Immune System and Microbiota in Diabetes

Diabetes is not a single and homogeneous disease, but a cluster of metabolic diseases characterized by the common feature of hyperglycemia. The pathogenesis of type 1 diabetes (T1D) and type 2 diabetes (T2D) (and all other intermediate forms of diabetes) involves the immune system, in terms of inflammation and autoimmunity. The past decades have seen an increase in all types of diabetes, accompanied by changes in eating habits and consequently a structural evolution of gut microbiota. It is likely that all these events could be related and that gut microbiota alterations might be involved in the immunomodulation of diabetes. Thus, gut microbiota seems to have a direct, even causative role in mediating connections between the environment, food intake, and chronic disease. As many conditions that increase the risk of diabetes modulate gut microbiota composition, it is likely that immune-mediated reactions, induced by alterations in the composition of the microbiota, can act as facilitators for the onset of diabetes in predisposed subjects. In this review, we summarize recent evidence in the field of gut microbiota and the role of the latter in modulating the immune reactions involved in the pathogenesis of diabetes

Duodenopancreatectomy as a model to demonstrate the fundamental role of dysfunctional \u3b2 cell in predicting diabetes

Background: The appearance of hyperglycemia is due to insulin resistance, functional deficits in the secretion of insulin and a reduction of \u3b2-cell mass. There is a long-standing debate as to the relative contribution of these factors to clinically manifest \u3b2-cell dysfunction. The aim of this study was to verify the acute effect of one of these factors, the reduction of \u3b2-cell mass, on the subsequent development of hyperglycemia. Methods: To pursue this aim, non-diabetic patients, scheduled for identical pancreaticoduodenectomy surgery, underwent oral glucose tolerance tests (OGTT) and hyperglycemic clamps (HC), followed by arginine stimulation before and after surgery. Based on post-surgery OGTT, subjects were divided into 3 groups depending on glucose tolerance: normal (post-NGT), impaired (post-IGT) or diabetic (post-DM). Results: At baseline, the three groups showed similar fasting glucose and insulin levels, however, examining the various parameters, we found that reduced first phase insulin secretion and reduced glucose sensitivity and rate sensitivity were predictors of eventual post-surgery development of impaired glucose tolerance and diabetes. Conclusion: Despite comparable functional mass and fasting glucose and insulin levels at baseline, and the very same 50% mass reduction, only reduced first phase insulin secretion and glucose sensitivity predicted the appearance of hyperglycemia. These functional alterations could be pivotal to the pathogenesis of type 2 diabetes (T2DM)

Bile modulates secretion of incretins and insulin: a study on human extrahepatic cholestasis

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 are still unclear. We here propose an alternative method to investigate the relation between alterations in physiological bile flow and insulin and incretin secretion by studying the changes in gut-pancreatic function in extrahepatic cholestasis in non-diabetic humans. METHODS: to pursue this aim, 58 non-diabetic patients with recent diagnosis of periampullary tumors underwent an 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 strong inverse correlation between total bilirubin levels and insulinogenic index. When subjects were divided on the basis of bilirubin levels, used as marker of altered bile flow, subjects with high bilirubin levels displayed inferior glucose control and decreased insulin secretion during OGTT. Altered bile flow elicited a markedly greater increase in glucagon and GLP-1 secretion at fasting state and following the meal both glucagon and GLP-1 levels remained increased over time. Conversely, GIP levels were comparable at the fasting state, while the increase following meal ingestion was significantly blunted in H-Bil. We revealed strong correlations between total bilirubin and glucagon and GLP-1 levels. CONCLUSIONS: Our findings suggest that acute extrahepatic cholestasis determines a significant impairment in the entero-endocrine gut-pancreatic secretory function. The altered bile flow might determine a direct deleterious effect on beta cell function perhaps mediated by the impairment of incretin hormone function