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The long-chain fatty acid receptor GPR40 plays an important role in potentiation of glucose-induced insulin secretion (GIIS) from pancreatic β-cells. Previous studies demonstrated that GPR40 activation enhances Ca2+ release from the endoplasmic reticulum (ER) by activating inositol 1,4,5-triphosphate (IP3) receptors. However, it remains unknown how ER Ca2+ release via the IP3 receptor is linked to GIIS potentiation. Recently, stromal interaction molecule (STIM) 1 was identified as a key regulator of store-operated Ca2+ entry (SOCE), but little is known about its contribution in GPR40 signaling. We show that GPR40-mediated potentiation of GIIS is abolished by knockdown of IP3 receptor 1 (IP3R1), STIM1 or Ca2+-channel Orai1 in insulin-secreting MIN6 cells. STIM1 and Orai1 knockdown significantly impaired SOCE and the increase of intracellular Ca2+ by the GPR40 agonist, fasiglifam. Furthermore, β-cell-specific STIM1 knockout mice showed impaired fasiglifam-mediated GIIS potentiation not only in isolated islets but also in vivo. These results indicate that the IP3R1/STIM1/Orai1 pathway plays an important role in GPR40-mediated SOCE initiation and GIIS potentiation in pancreatic β-cells.

Procyanidins, the main ingredient of apple polyphenols, are known to possess antioxidative and anti-inflammatory effects associated closely with the pathophysiology of insulin resistance and type 2 diabetes. We investigated the effects of orally administered apple procyanidins (APCs) on glucose metabolism using diabetic ob/ob mice. We found no difference in body weight or body composition between mice treated with APCs and untreated mice. A 4 week oral administration of APCs containing water [0.5% (w/v)] ameliorated glucose tolerance, insulin resistance, and hepatic gluconeogenesis in ob/ob mice. APCs also suppressed the increase in the level of the pancreatic β-cell. Insulin-stimulated Akt phosphorylation was significantly enhanced; pro-inflammatory cytokine expression levels were significantly decreased, and c-Jun N-terminal kinase phosphorylation was downregulated in the liver of those mice treated with APCs. In conclusion, APCs ameliorate insulin resistance by improving hepatic insulin signaling through suppression of hepatic inflammation in ob/ob mice, which may be a mechanism with possible beneficial health effects of APCs in disturbed glucose metabolism.

Aims/IntroductionThe glucose‐lowering effects of the glucagon‐like peptide‐1 receptor agonist, liraglutide, have been shown to rely on remaining β‐cell function. However, the possible associations of remaining β‐cell function with the glucose‐lowering effects of liraglutide in combination with basal insulin remain unknown and warrant investigation.Materials and MethodsThis was a single‐center, retrospective, observational study carried out in a private hospital in Osaka, Japan. Type 2 diabetes patients who received a prescription change from insulin therapy, both multiple‐dose insulin and basal insulin‐supported oral therapy, to liraglutide and basal insulin combination and continued the therapy for 54 weeks without additional oral antidiabetic drugs or bolus insulin were retrospectively analyzed.ResultsAmong the 72 participants who received a prescription change from multiple‐dose insulin and basal insulin‐supported oral therapy to liraglutide and basal insulin combination, 57 continued the therapy for 54 weeks. Of those who continued the therapy without receiving additional oral antidiabetic drugs or bolus insulin, seven participants achieved glycated hemoglobin < 7.0% at 54 weeks, but 30 participants did not. The participants who achieved glycated hemoglobin < 7.0% at 54 weeks had a significantly higher C‐peptide immunoreactivity index, a β‐cell function‐related index frequently used in Japanese clinical settings. The receiver operating curve analysis showed that the C‐peptide immunoreactivity index cut‐off value for the achievement of glycated hemoglobin <7.0% at 54 weeks is 1.103.ConclusionsThe current findings show that the glucose‐lowering effects of liraglutide rely on remaining β‐cell function, even when used with basal insulin; and suggest that liraglutide and basal insulin combination might require additional bolus insulin to fully compensate insulin insufficiency in individuals with reduced β‐cell function.

Since infection with Helicobacter pylori has been suggested to play a pathogenic role in diabetes mellitus, we investigated whether eradication therapy for H. pylori might affect glycemic control in Japanese subjects with type 2 diabetes. A total of 72 subjects (55 males, 17 females; aged 63.7 years) with type 2 diabetes who received eradication therapy for H. pylori were included. The change of their blood glycosylated hemoglobin (A1C) levels 3 months before (−3 m) the H. pylori eradication, as well as 3 months (3 m) and 6 months (6 m) after were evaluated. Their A1C levels did not show any significant change after therapy {6.9 [0.1]% (−3 m) to 7.0 [0.1]% (3 m); P = 0.3, 7.0 [0.1] (6 m); P = 0.3}. Our findings suggest that the eradication therapy for H. pylori does not, at least profoundly, affect glycemic control in Japanese subjects with type 2 diabetes.

Summary Heterogeneity of gene expression and rarity of replication hamper molecular analysis of β-cell mass restoration in adult pancreas. Here, we show transcriptional dynamics in β-cell replication process by single-cell RNA sequencing of murine pancreas with or without partial pancreatectomy. We observed heterogeneity of Ins1 -expressing β-cells and identified the one cluster as replicating β-cells with high expression of cell proliferation markers Pcna and Mki67 . We also recapitulated cell cycle transition accompanied with switching expression of cyclins and E2F transcription factors. Both transient activation of endoplasmic reticulum stress responders like Atf6 and Hspa5 and elevated expression of tumor suppressors like Trp53 , Rb1 , and Brca1 and DNA damage responders like Atm , Atr , Rad51 , Chek1 , and Chek2 during the transition to replication associated fine balance of cell cycle progression and protection from DNA damage. Taken together, these results provide a high-resolution map depicting a sophisticated genetic circuit for replication of the β-cells.

The present study was designed to assess possible relationships between deterioration of the glycated hemoglobin (HbA1c)‐lowering effects in dipeptidyl peptidase‐4 inhibitor (DPP4i) monotherapy and macronutrient intake among individuals with type 2 diabetes. Type 2 diabetes patients who began and continued DPP4i monotherapy without any prescription change for 1 year were retrospectively stratified into two groups: (i) patients who maintained their HbA1c levels during the 0.5‐ to 1‐year period after DPP4i initiation (group A, ΔHbA1c [1–0.5 year] <0.4%, n = 53); and (ii) those whose HbA1c levels increased [group B, ΔHbA1c (1–0.5 year] ≥0.4%, n = 10). Group B had significantly higher ΔHbA1c (1–0.5 year), Δbodyweight (1–0.5 year) and fat intake, especially of saturated and monounsaturated fats; the carbohydrate and protein intake were similar between groups. Multiple regression analyses showed that fat intake, especially saturated fat intake, was significantly correlated with ΔHbA1c (1–0.5 year). Thus, dietary habits, especially saturated fat intake, might well contribute to deterioration of the HbA1c‐lowering effects in DPP4i monotherapy.

Pancreatic neuroendocrine tumors (PanNET) were classified into grades (G) 1 to 3 by the World Health Organization in 2017, but the precise mechanisms of PanNET initiation and progression have remained unclear. In this study, we used a genetically engineered mouse model to investigate the mechanisms of PanNET formation. Although pancreas-specific deletion of the Rb gene (Pdx1-Cre;Rb f/f ) in mice did not affect pancreatic exocrine cells, the a-cell/b-cell ratio of islet cells was decreased at 8 months of age. During long-term observation (18-20 months), mice formed well-differentiated Pan-NET with a Ki67-labeling index of 2.7%. In contrast, pancreasspecific induction of a p53 mutation (Pdx1-Cre;Trp53 R172H ) had no effect on pancreatic exocrine and endocrine tissues, but simultaneous induction of a p53 mutation with Rb gene deletion (Pdx1-Cre; Trp53 R172H ;Rb f/f ) resulted in the formation of aggressive PanNET with a Ki67-labeling index of 24.7% over the short-term (4 months). In Pdx1-Cre;Trp53 R172H ;Rb f/f mice, mRNA expression of Pten and Tsc2, negative regulators of the mTOR pathway, significantly decreased in the islet cells, and activation of the mTOR pathway was confirmed in subsequently formed PanNET. Thus, by manipulating Rb and p53 genes, we established a multistep progression model from dysplastic islet to indolent PanNET and aggressive metastatic PanNET in mice. These observations suggest that Rb and p53 have distinct roles in the development of PanNET.Significance: Pancreas-specific manipulation of Rb and p53 genes induced malignant transformation of islet cells, reproducing stepwise progression from microadenomas to indolent (grade 1) and subsequent aggressive PanNETs (grade 2-3).