ABSTRACT
[This corrects the article DOI: 10.1007/s13340-018-0347-1.].
ABSTRACT
In type 2 diabetes (T2D), the most significant pathological change in pancreatic islets is amyloid deposits, of which a major component is islet amyloid polypeptide (IAPP), also called amylin. IAPP is expressed in ß-cells and co-secreted with insulin. Together with the inhibitory effects of synthetic human IAPP (hIAPP) on insulin secretion, our studies, using hIAPP transgenic mice, in which glucose-stimulated insulin secretion was moderately reduced without amyloid deposit, and hIAPP gene-transfected ß-cell lines, in which insulin secretion was markedly impaired without amyloid, predicted that soluble hIAPP-related molecules would exert cytotoxicity on ß-cells. Human IAPP is one of the most aggregation-prone peptides that interact with cell membranes. While it is widely reported that soluble hIAPP oligomers promote cytotoxicity, this is still a hypothesis since the mechanisms are not yet fully defined. Several hIAPP transgenic mouse models did not develop diabetes; however, in models with backgrounds characterized for diabetic phenotypes, ß-cell function and glucose tolerance did worsen, compared to those in non-transgenic models with similar backgrounds. Together with these findings, many studies on metabolic and molecular disorders induced by risk factors of T2D suggest that in T2D subjects, toxic IAPP oligomers accumulate in ß-cells, impair their function, and reduce mass through disruption of cell membranes, resulting in ß-cell failure. IAPP might be central to ß-cell failure in T2D. Anti-amyloid aggregation therapeutics will be developed to create treatments with more durable and beneficial effects on ß-cell function.
ABSTRACT
AIMS/INTRODUCTION: We carried out an observational cohort study to examine the relationship between the efficacy of oral antidiabetic drugs and clinical features in type 2 diabetics. MATERIALS AND METHODS: We analyzed the CoDiC(®) database of the Japan Diabetes Data Management Study Group across 67 institutions in Japan. In a total of 3,698 drug-naïve patients who were initiated with metformin, dipeptidyl peptidase-4 inhibitor (DPP-4i) or sulfonylurea (SU) from 2007 to 2012, we evaluated body mass index (BMI) and hemoglobin A1c (HbA1c). The patients were stratified according to their clinical features, and matched using a propensity score to adjust for baseline factors. RESULTS: HbA1c was reduced with all drugs, with the largest effect elicited by DPP-4i and the smallest by SU (P = 0.00). HbA1c increased with SU after 6 months in the patients stratified by an age-of-onset of <50 years (P = 0.00). BMI increased with SU in the patients stratified by a BMI of <25 (P = 0.00), and decreased with metformin in the patients with a BMI >25 (P = 0.00). The reduction in HbA1c was larger in patients with HbA1c of ≥8%, compared with that in patients with HbA1c of <8% (P = 0.00). HbA1c during the study period was higher in patients who were added to or swapped with other drug(s), than in patients continued on the original drug (P = 0.00). CONCLUSIONS: The effect on bodyweight and glycemic control differed among metformin, DPP-4i and SU, and the difference was associated with clinical features.
