Search

Abstract: 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. [ABSTRACT FROM AUTHOR]

Abstract: Aims/Introduction: The 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 Methods: This 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. Results: Among 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. Conclusions: The 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. [ABSTRACT FROM AUTHOR]

Aims Materials and Methods Results Conclusions Imeglimin is a new oral anti‐diabetic drug with a similar structure to that of metformin; however, unlike metformin, clinical trials indicate that imeglimin elicits its glucose‐lowering effect mainly by enhancement of insulin secretion. The comparative effects of the two drugs on incretin secretion remains to be elucidated.A single‐center, open‐label, randomized controlled trial was conducted in patients with type 2 diabetes who were drug‐naïve or were on a single oral hypoglycaemic agent (OHA). For patients taking a single OHA, an 8‐week washout period was employed before randomization. Participants were randomized to the imeglimin group (IME, 2000 mg/day) or the metformin group (MET, 1000 mg/day), and OGTT was performed before treatment and after 12 and 24 weeks of treatment.The reduction in HbA1c at 24 weeks was similar in IME and MET. OGTT revealed a comparable decrease in post‐challenge blood glucose excursion in both groups, but insulin levels were increased only in IME. Total and active glucagon‐like peptide‐1 (GLP‐1) levels were increased in both IME and MET; however, total and active glucose‐dependent insulinotropic peptide (GIP) levels were increased only in IME. Interestingly, while an increase in insulin levels in IME was positively correlated with an increase in GLP‐1 at 12 weeks, it was correlated only with an increase in GIP at 24 weeks.Unlike metformin, imeglimin enhances GIP secretion as well as GLP‐1 secretion, in addition to its direct insulinotropic mechanism of glucose control, emphasizing its potential as a therapeutic option in the treatment of patients with diabetes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Store-operated Ca2+ entry (SOCE) is activated by endoplasmic reticulum (ER) Ca2+ sensor STIM1 which senses depletion of Ca2+ from the ER, and induces extracellular Ca2+ influx through Orai1 to the cytosol to maintain intracellular Ca2+ homeostasis in various cell types, however the role of SOCE in pancreatic β-cells remains largely unknown. GPR40 plays an important role in potentiation of glucose-induced insulin secretion (GIIS) by long-chain fatty acids and its activation enhances Ca2+-release from ER by activating inositol 1,4,5-triphosphate (IP3) receptor. Therefore, we hypothesized that SOCE contributed to GPR40-mediated GIIS potentiation. To test the hypothesis, we examined the role of SOCE modulator, STIM1 in MIN6 cells and β-cell specific STIM1-deficient mice (βSTIM1 cKO). Methods: Fasiglifam(fas) was used for GPR40 agonist. STIM1 or Orai1 knockdowned (KD) MIN6 cells were analyzed for insulin secretion or intracellular Ca2+-dynamics. MIN6 cells were also transfected with pEX-SP-YFP-STIM1(23-685) and Orai1-CFP to analyze intracellular trafficking of STIM1 in response to fas. Insulin secretion from βSTIM1 cKO islets and OGTT was also analyzed to reveal physiological role of STIM1. Results: STIM1 or Orai1 KD MIN6 cells and islets from βSTIM1 cKO similarly abolished fas-mediated potentiation of GIIS and fas-induced elevation of intracellular Ca2+ levels, while there was little effect on GIIS itself. STIM1-YFP was rapidly translocated from the ER to the plasma membrane and merged with Orai1-CFP in response to fas which was cancelled by pretreatment of IP3 receptor antagonist, xestospongin C. In OGTT, blood glucose levels were similar in control mice and βSTIM1 cKO without fas administration, however fas-mediated glucose lowering and insulin increasing effect were significantly lower compared with control. Conclusion: GPR40 signal activates STIM1 and SOCE activated by STIM1 is essential for GPR40-mediated potentiation of GIIS. Disclosure: R. Usui: None. D. Yabe: Advisory Panel; Self; Abbott. Research Support; Self; Astellas Pharma Inc. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. M. Fauzi: None. A. Botagarova: None. H. Goto: None. S. Tokumoto: None. H. Tatsuoka: None. Y. Tahara: None. S. Kobayashi: None. T. Manabe: None. Y. Baba: None. T. Kurosaki: None. M. Ogura: Research Support; Self; Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kyowa Hakko Kirin Co., Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Takeda Pharmaceutical Company Limited. K. Nagashima: None. N. Inagaki: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Japan Tobacco Inc., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Funding: Japan Society for the Promotion of Science; Japan Association for Diabetes Education and Care [ABSTRACT FROM AUTHOR]

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 Ca 2+ release from the endoplasmic reticulum (ER) by activating inositol 1,4,5-triphosphate (IP3) receptors. However, it remains unknown how ER Ca 2+ 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 Ca 2+ 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 Ca 2+ -channel Orai1 in insulin-secreting MIN6 cells. STIM1 and Orai1 knockdown significantly impaired SOCE and the increase of intracellular Ca 2+ 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.