Type 2 diabetes is characterized by poor glucose uptake in metabolic tissues and manifests when insulin secretion fails to cope with worsening insulin resistance. In addition to its effects on skeletal muscle, liver, and adipose tissue metabolism, it is evident that insulin resistance also affects pancreatic β-cells. To directly examine the alterations that occur in islet morphology as part of an adaptive mechanism to insulin resistance, we evaluated pancreas samples obtained during pancreatoduodenectomy from nondiabetic subjects who were insulin-resistant or insulin-sensitive. We also compared insulin sensitivity, insulin secretion, and incretin levels between the two groups. We report an increased islet size and an elevated number of β- and α-cells that resulted in an altered β-cell–to–α-cell area in the insulin- resistant group. Our data in this series of studies suggest that neogenesis from duct cells and transdifferentiation of α-cells are potential contributors to the β-cell compensatory response to insulin resistance in the absence of overt diabetes.

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.

Although it is well established that type 2 diabetes (T2D) is generally due to the progressive loss of β-cell insulin secretion against a background of insulin resistance, the actual correlation of reduced β-cell mass to its defective function continues to be debated. There is evidence that a compensatory increase in β-cell mass, and the consequent insulin secretion, can effectively cope with states of insulin resistance, until hyperglycemia supervenes. Recent data strongly indicate that the mechanisms by which islets are able to compensate in response to insulin resistance in peripheral tissues is secondary to hyperplasia, as well as the activation of multiple cellular machineries with diverse functions. Importantly, islet cells exhibit plasticity in altering their endocrine commitment; for example, by switching from secretion of glucagon to secretion of insulin and back (transdifferentiation) or from an active secretory state to a nonsecretory quiescent state (dedifferentiation) and back. Lineage tracing (a method used to track each cell though its differentiation process) has demonstrated these potentials in murine models. A limitation to drawing conclusions from human islet research is that most studies are derived from human autopsy and/or organ donor samples, which lack in vivo functional and metabolic profiling. In this review, we specifically focus on evidence of islet plasticity in humans—from the normal state, progressing to insulin resistance to overt T2D—to explain the seemingly contradictory results from different cross-sectional studies in the literature. We hope the discussion on this intriguing scenario will provide a forum for the scientific community to better understand the disease and in the long term pave the way for personalized therapies.

Objective: It has been suggested that vitamin D may play a role in the pathogenesis of several endocrine diseases, such as hyperparathyroidism, type 1 diabetes (T1DM), type 2 diabetes (T2DM), autoimmune thyroid diseases, Addison's disease and polycystic ovary syndrome (PCOS). In this review, we debate the role of vitamin D in the pathogenesis of endocrine diseases.Methods: Narrative overview of the literature synthesizing the current evidence retrieved from searches of computerized databases, hand searches and authoritative texts.Results: Evidence from basic science supports a role for vitamin D in many endocrine conditions. In humans, inverse relationships have been reported not only between blood 25-hydroxyvitamin D and parathyroid hormone concentrations but also with risk of T1DM, T2DM, and PCOS. There is less evidence for an association with Addison's disease or autoimmune thyroid disease. Vitamin D supplementation may have a role for prevention of T2DM, but the available evidence is not consistent.Conclusions: Although observational studies support a potential role of vitamin D in endocrine disease, high quality evidence from clinical trials does not exist to establish a place for vitamin D supplementation in optimizing endocrine health. Ongoing randomized controlled trials are expected to provide insights into the efficacy and safety of vitamin D in the management of endocrine disease.

Recent compelling evidence suggests a role of vitamin D deficiency in the pathogenesis of insulin resistance and insulin secretion derangements, with a consequent possible interference with type 2 diabetes mellitus. The mechanism of this link is incompletely understood. In fact, vitamin D deficiency is usually detected in obesity in which insulin resistance is also a common finding. The coexistence of insulin resistance and vitamin D deficiency has generated several hypotheses. Some cross-sectional and prospective studies have suggested that vitamin D deficiency may play a role in worsening insulin resistance; others have identified obesity as a risk factor predisposing individuals to exhibit both vitamin D deficiency and insulin resistance. The available data from intervention studies are largely confounded, and inadequate considerations of seasonal effects on 25(OH)D concentrations are also a common design flaw in many studies. On the contrary, there is strong evidence that obesity might cause both vitamin D deficiency and insulin resistance, leaving open the possibility that vitamin D and diabetes are not related at all. Although it might seem premature to draw firm conclusions on the role of vitamin D supplementation in reducing insulin resistance and preventing type 2 diabetes, this manuscript will review the circumstances leading to vitamin D deficiency and how such a deficiency can eventually independently affect insulin sensitivity.