Identification of the matricellular protein Fibulin-5 as a target molecule of glucokinase-mediated calcineurin/NFAT signaling in pancreatic islets

Glucokinase-mediated glucose signaling induces insulin secretion, proliferation, and apoptosis in pancreatic β-cells. However, the precise molecular mechanisms underlying these processes are not clearly understood. Here, we demonstrated that glucokinase activation using a glucokinase activator (GKA) significantly upregulated the expression of Fibulin-5 (Fbln5), a matricellular protein involved in matrix-cell signaling, in isolated mouse islets. The islet Fbln5 expression was induced by ambient glucose in a time- and dose-dependent manner and further enhanced by high-fat diet or the deletion of insulin receptor substrate 2 (IRS-2), whereas the GKA-induced increase in Fbln5 expression was diminished in Irs-2-deficient islets. GKA-induced Fbln5 upregulation in the islets was blunted by a glucokinase inhibitor, KATP channel opener, Ca2+ channel blocker and calcineurin inhibitor, while it was augmented by harmine, a dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) 1 A inhibitor. Although deletion of Fbln5 in mice had no significant effects on the glucose tolerance or β-cell functions, adenovirus-mediated Fbln5 overexpression increased glucose-stimulated insulin secretion in INS-1 rat insulinoma cells. Since the islet Fbln5 expression is regulated through a glucokinase/KATP channel/calcineurin/nuclear factor of activated T cells (NFAT) pathway crucial for the maintenance of β-cell functions, further investigation of Fbln5 functions in the islets is warranted

DPP-4 inhibition improves early mortality, β cell function, and adipose tissue inflammation in db/db mice fed a diet containing sucrose and linoleic acid

Additional file 3: Figure S2. Liver and epididymal fat weights in db/+ mice and db/db mice. The experiments were performed in db/+ or db/db mice fed an SL diet, SO diet, SL containing DPP-4 inhibitor (0.4% des-fluoro-sitagliptin) diet, or SO containing DPP-4 inhibitor diet for 8 weeks. (left) Liver weights as a proportion of body weight (n = 5). (right) Epididymal fat weights as a proportion of body weight (n = 5)

The Roles of the IGF Axis in the Regulation of the Metabolism: Interaction and Difference between Insulin Receptor Signaling and IGF-I Receptor Signaling

It has been well established that insulin-like growth factors (IGFs) mainly mediate long-term actions in cell fates, whereas insulin predominantly exerts its role on metabolic activity. Indeed, insulin mediates multiple anabolic biological activities in glucose and amino acid transport, lipid and protein synthesis, the induction of glycogen, the inhibition of gluconeogenesis, lipolysis, and protein degradation. The interactions and differences between insulin receptor signaling and IGF-I receptor signaling in the metabolism and the cell fates are quite complicated. Because of the overlapping actions of IGF-I singling with insulin signaling, it has been difficult to distinguish the role of both signaling mechanisms on the metabolism. Furthermore, comprehensive information on the IGF-I function in respective tissues remains insufficient. Therefore, we need to clarify the precise roles of IGF-I signaling on the metabolism separate from those of insulin signaling. This review focuses on the metabolic roles of IGFs in the respective tissues, especially in terms of comparison with those of insulin, by overviewing the metabolic phenotypes of tissue-specific IGF-I and insulin receptor knockout mice, as well as those in mice treated with the dual insulin receptor/IGF-I receptor inhibitor OSI-906

Usefulness of the octreotide test in Japanese patients for predicting the presence/absence of somatostatin receptor 2 expression in insulinomas

We investigated the relationship between the results of the octreotide test and somatostatin receptor (SSTR) 2 expression in insulinoma patients, to evaluate the usefulness of this test for predicting SSTR2 expression in insulinomas in Japanese patients. Five females and one male were included in the study. All patients underwent the octreotide test before the surgery carried out to resect the tumor, and histopathological examination of the resected tumor was performed by a single experienced pathologist. SSTR2 expression was evaluated by the SSTR2 immunohistochemistry scoring system. Insulinoma was clinically diagnosed and surgically resected in all six patients. In the octreotide test, suppression of insulin secretion was sufficient after loading in patients 1-4 and 6. In patient 5, however, the suppression of insulin secretion was insufficient, which resulted in severe hypoglycemia with endogenous relative hyperinsulinemia after the octreotide loading. The histopathological findings revealed SSTR2 expression in the insulinomas of patients 1-4 and 6, but not in the insulinoma of patient 5. In conclusion, improvement of hyperinsulinemic hypoglycemia by octreotide in Japanese insulinoma patients was associated with SSTR2 expression in the tumor. Our results suggest that the octreotide test could be useful for predicting SSTR2 expression in the tumor

Aging-like physiological changes in the skin of Japanese obese diabetic patients

Objective: Obesity-associated diabetes causes aging-like changes to skin physiology in animal models, but there have been no clinical studies focusing on human obese diabetic patients. The purpose of this study was to examine the hypothesis that obesity-associated diabetes accelerates aging-like skin changes in Japanese people. Methods: This cross-sectional study enrolled obese-diabetes patients (body mass index ≥ 25 kg m−2) and healthy volunteers (body mass index < 25 kg m −2 ) as controls. Skin physiology parameters relating to aging (stratum corneum hydration, transepidermal water loss, skin pH, advanced glycation end-products, and dermal collagen density) were evaluated in the two groups. Results: About 37 subjects participated (16 in a control group and 21 in an obese-diabetes group). Age was not significantly different between the groups. The stratum corneum hydration level was significantly lower in the obese-diabetes group. Transepidermal water loss and levels of advanced glycation end-products were significantly higher in this group. Skin pH was not significantly different between groups. Dermal collagen density decreased in the obese-diabetes group. Conclusion: We showed that obese-diabetes patients have decreased stratum corneum hydration, increased transepidermal water loss, higher skin advanced glycation end-products and decreased dermal collagen fiber density compared with normal-weight subjects. These results indicate that the ordinary age-related physiological skin changes seen in the elderly can also occur in obese-diabetes patients aged in their 40s