Search

Aim: Tirzepatide, a dual agonist of glucagon‐like peptide receptor and glucose‐dependent insulinotropic polypeptide receptor, is expected to exhibit high clinical efficacy in obese type 2 diabetic patients. We evaluated the effects of tirzepatide on pancreatic β‐cells and the liver, an insulin‐target organ, in a mouse model of obese type 2 diabetes mellitus. Materials and Methods: Obese type 2 diabetic db/db mice (BKS.Cg−/+ Leprdb/+ Leprdb/Jcl*) were used in this study. Starting at 7 weeks of age, mice were treated with tirzepatide (30 nmol/kg, subcutaneous injection twice a week) or semaglutide (200 nmol/kg, subcutaneous injection twice a week). The control group received phosphate‐buffered saline (40–50 μL/subcutaneous injection twice a week). After 4 weeks of drug administration, pancreatic β‐cells and the liver were removed and examined. Results: Compared to the control group, blood glucose and body weight were significantly reduced in the group that received either tirzepatide or semaglutide (p < 0.001 and p < 0.05, respectively). Fasting insulin was significantly higher in the semaglutide and tirzepatide groups compared to the control group (p < 0.001). β‐Cell mass and quality of insulin granules in β‐cells similarly increased in the semaglutide and tirzepatide groups compared to the control group (p < 0.05 and p < 0.001, respectively). The fat staining area in the liver in oil red O staining and the liver–spleen ratio in computed tomography showed improvement only in the tirzepatide group (p < 0.001 and p < 0.005, respectively). Liver macrophage M1/M2 ratio similarly improved with semaglutide and tirzepatide (p < 0.05). Conclusion: Tirzepatide and semaglutide exhibited similar potent glucose‐lowering effects. At concentrations used in the present experiments, tirzepatide exhibited more beneficial effects on β‐cell‐related gene expression, insulin granule count and glucose‐stimulated insulin secretion compared to semaglutide. In addition, tirzepatide exhibited a stronger favourable effect on hepatic fat deposition and improved inflammation in the liver. This is the first report showing that tirzepatide, a novel diabetes drug, exhibits a superior effect on pancreatic β‐cells and the liver of obese type 2 diabetic mice. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study is to directly compare the effects of SGLT2 inhibitors and DPP-4 inhibitors on β-cell function in patients with type 2 diabetes. Materials and methods: We conducted a 26-week, randomized, open-label, parallel-group study, including a 1-2 week drug washout period, in patients with type 2 diabetes with HbA1c ≥7.0% and <9.0% and BMI ≥20 kg/m2 despite treatment with a drug naïve or other than DPP-4 inhibitors or SGLT2 inhibitors. A total of 103 subjects were randomly assigned to receive once daily oral luseogliflozin (L) or teneligliptin (T). The primary endpoint was the effect of L vs. T on the change in logarithmus naturalis (Ln) disposition index (DI) (DI 0-120min; combining measures of insulin secretion and sensitivity) from baseline to week 25-26 (post intervention), which was calculated by conducting an oral glucose tolerance test. Results: Ln DI 0-120min were improved in both groups: -0.46 ± 0.68 to -0.20 ± 0.59 (p =0.03) in L group and -0.26 ± 0.60 to -0.05 ± 0.62 (p =0.01) in T group. The change in Ln serum proinsulin/C-peptide ratio, a marker of β-cell dysfunction, was reduced in L group (1.63 ± 0.63 to 1.56 ± 0.68, p =0.16), but rather increased in T group (1.70 ± 0.75 to 1.90 ± 0.51, p =0.01), with significant difference between the two groups (-0.27; p =0.004). Conclusions: Improvement of disposition index in subjects with obese type 2 diabetes was comparable between luseogliflozin and teneligliptin. On the other hand, it is likely that alleviation of β-cell dysfunction is more effective with luseogliflozin compared to tenegliptin. Clinical trial registration: https://rctportal.niph.go.jp/en , identifier jRCTs061190008. [ABSTRACT FROM AUTHOR]

Aim: Recently, the development of the oral glucagon‐like peptide‐1 receptor agonist semaglutide has drawn a great deal of attention. This study aimed to compare the effectiveness of oral glucagon‐like peptide‐1 receptor agonist semaglutide and dipeptidyl peptidase‐4 (DPP‐4) inhibitors on glycaemic control and several metabolic parameters in patients with type 2 diabetes mellitus over a 6‐month period. Methods: Fifty‐nine participants were included, and we compared various clinical parameters between before and after switching from DPP‐4 inhibitors to oral semaglutide in 'study 1' (pre‐post comparison) and set the control group using the propensity score matching method in 'study 2'. Results: In 'study 1', 6 months after the switching, the glycated haemoglobin value was significantly reduced from 7.5% to 7.0%, and the body mass index was also decreased from 29.7 kg/m2 to 28.8 kg/m2. Such effects were more clearly observed in participants whose glycaemic control was poor. In 'study 2', after 1:1 propensity score matching, 51 participants from each group were matched, and glycaemic control as well as body weight management were improved in the switching group compared with the DPP‐4 inhibitor continuation group over the 6‐month observation period. Conclusion: In this study, including obese participants with poor glycaemic control, switching DPP‐4 inhibitors to oral semaglutide showed more beneficial effects on both glycaemic and weight control, irrespective of age, body weight and diabetes duration. Therefore, we should bear in mind that it would be better to start using an oral semaglutide in clinical practice, particularly in obese participants with poor glycaemic control with DPP‐4 inhibitors. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the correlation between C‐peptide index (CPI) at 2 h post‐meal and endogenous insulin secretory capacity and to develop clinical models to predict the possibility of withdrawal from insulin therapy in patients with type 2 diabetes. Method: This was a single‐centre retrospective study of patients with type 2 diabetes admitted to our hospital. Patients were divided into a withdrawal group (n = 72) and a non‐withdrawal group (n = 75) based on whether they were able to withdraw from insulin therapy at discharge, and the correlation between CPI at 2 h after meal and diabetes‐related parameters was evaluated. In addition, we created two clinical models to predict the possibility of withdrawal from insulin therapy using machine learning. Results: The glycated haemoglobin values of the study participants were 87.8 ± 22.6 mmol/mo. The CPI at 2 h post‐meal was 1.93 ± 1.28 in the non‐withdrawal group and 2.97 ± 2.07 in the withdrawal group (p < 0.001). CPI at 2 h post‐meal was an independent predictor of withdrawal from insulin therapy. In addition, CPI at 2 h post‐meal was a better predictor than fasting CPI. Six factors associated with insulin therapy withdrawal (age, duration of diabetes, creatinine, alanine aminotransferase, insulin therapy until hospitalization, and CPI at 2 h post‐meal) were used to generate two clinical models by machine learning. The accuracy of the generated clinical models ranged from 78.3% to 82.6%. Conclusion: The CPI at 2 h post‐meal is a clinically useful measure of endogenous insulin secretory capacity under non‐fasting conditions. [ABSTRACT FROM AUTHOR]

Introduction: Loss of muscle mass and the accumulation of visceral fat are known risk factors for the deterioration of glycemic control in type 2 diabetes mellitus. This study looked at the effects of such factors on glycemic control in Japanese patients with type 2 diabetes mellitus in the form of handgrip strength (HGS) and waist circumference (WC). Materials and Methods: In this prospective, observational study, 233 patients with type 2 diabetes mellitus and a HbA1c level of ≥7.0% were followed for around 1 year, during which time they were studied for an understanding of the association between handgrip strength, waist circumference, and glycemic control (HbA1c <7.0%). Hazard ratios (HRs) and 95% confidence intervals (CIs) for glycemic control improvement by Cox hazards models were analyzed for handgrip strength and waist circumference. Results: Compared with the low tertile, patients in the middle and high tertiles of handgrip strength when adjustment was carried out for waist circumference were 2.117 (1.142–3.924) and 4.670 (2.526–8.632), respectively. The HRs of patients in the middle and high tertiles of WC when adjustment was made for HGS were 0.442 (0.269–0.725) and 0.339 (0.191–0.604), respectively. Within the low, middle, and high HGS tertiles, the HRs for WC were 0.863 (0.797–0.934), 0.940 (0.899–0.982), and 1.009 (0.984–1.035), respectively, although the HRs for HGS within each WC tertile remained significant. Conclusions: Handgrip strength and waist circumference demonstrated independent associations for glycemic control, but the effect of waist circumference appeared to be at least partially canceled out by increased handgrip strength. The data suggest that handgrip strength might help to mitigate the negative impact of waist circumference on glycemic control. [ABSTRACT FROM AUTHOR]

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. Although gene-environment interactions have been implicated in the etiology of several disorders, the impact of paternal and/or maternal metabolic syndrome on the clinical phenotypes of offspring and the underlying genetic and epigenetic contributors of NAFLD have not been fully explored. To this end, we used the liver-specific insulin receptor knockout (LIRKO) mouse, a unique nondietary model manifesting 3 hallmarks that confer high risk for the development of NAFLD: hyperglycemia, insulin resistance, and dyslipidemia. We report that parental metabolic syndrome epigenetically reprograms members of the TGF-[beta] family, including neuronal regeneration-related protein (NREP) and growth differentiation factor 15 (GDF15). NREP and GDF15 modulate the expression of several genes involved in the regulation of hepatic lipid metabolism. In particular, NREP downregulation increases the protein abundance of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and ATP-citrate lyase (ACLY) in a TGF-[beta] receptor/PI3K/protein kinase B-dependent manner, to regulate hepatic acetyl-CoA and cholesterol synthesis. Reduced hepatic expression of NREP in patients with NAFLD and substantial correlations between low serum NREP levels and the presence of steatosis and nonalcoholic steatohepatitis highlight the clinical translational relevance of our findings in the context of recent preclinical trials implicating ACLY in NAFLD progression., Introduction The liver receives dietary lipids and fatty acids derived from adipose tissue and hepatocytes, generally retaining no more than about 5% of its weight in lipids in normal physiological [...]

Aim: To compare the clinical usefulness of once‐weekly glucagon‐like peptide‐1 receptor agonists dulaglutide and semaglutide at the doses approved for use in Japanese patients with type 2 diabetes. Methods: In total, 120 patients with glycated haemoglobin (HbA1c) ≥7% were randomly assigned to dulaglutide (n = 59) or semaglutide group (n = 61), and 107 participants (dulaglutide/semaglutide = 53/54) completed the 24‐week trial. The primary endpoint was the difference of HbA1c level between the two groups at 24 weeks. Results: HbA1c level at 24 weeks was significantly lower in the semaglutide group (7.9 ± 0.5%‐6.7 ± 0.5%) compared with the dulaglutide group (8.1 ± 0.6%‐7.4 ± 0.8%) (p <.0001). Reduction in body mass index and visceral fat area were also more significant in the semaglutide group (p <.05, respectively). The achievement rate of HbA1c <7% was higher in the semaglutide group (p <.0001). The parameters such as low‐density lipoprotein cholesterol, alanine aminotransferase and γ‐glutamyl transpeptidase were decreased in the semaglutide group. Surprisingly, only semaglutide group significantly improved the apolipoprotein B/A1 ratio, which is considered a useful myocardial infarction risk index. Using computed tomography, the liver to spleen ratio was significantly elevated only in the semaglutide group. In contrast, gastrointestinal symptoms were observed in 13.2% of dulaglutide and 46.3% of semaglutide group (p <.01). The Diabetes Treatment‐Related Quality of Life scores related to pain and gastrointestinal symptoms were also superior in the dulaglutide group. Conclusions: This prospective trial showed that semaglutide has more pronounced glucose‐ and body mass index‐lowering effects and reduces liver fat percentage and visceral fat area and that dulaglutide has less gastrointestinal symptoms and superior Diabetes Treatment‐Related Quality of Life scores related to pain and gastrointestinal symptoms. [ABSTRACT FROM AUTHOR]

It has been shown that chronic hyperglycemia gradually decreases insulin biosynthesis and secretion which is accompanied by reduced expression of very important insulin gene transcription factors MafA and PDX-1. Such phenomena are well known as β-cell glucose toxicity. It has been shown that the downregulation of MafA and/or PDX-1 expression considerably explains the molecular mechanism for glucose toxicity. However, it remained unknown which molecules can enhance MafA and/or PDX-1 expression levels. In this study, we comprehensively searched for G protein-coupled receptor (GPCR) compounds which can enhance MafA and/or PDX-1 expression levels using a small molecule compound library in pancreatic β-cell line MIN6 cells and islets isolated from nondiabetic C57BL/6 J mice and obese type 2 diabetic C57BL/KsJ-db/db mice. We found that fulvestrant and dexmedetomidine hydrochloride increased MafA, PDX-1, or insulin expression levels in MIN6 cells. We confirmed that fulvestrant and dexmedetomidine hydrochloride increased MafA, PDX-1, or insulin expression levels in islets from nondiabetic mice as well. Furthermore, these reagents more clearly enhanced MafA, PDX-1, or insulin expression levels in islets from obese type 2 diabetic db/db mice in which MafA and PDX-1 expression levels are reduced due to glucose toxicity. In conclusion, fulvestrant and dexmedetomidine hydrochloride increased MafA, PDX-1, or insulin expression levels in MIN6 cells and islets from nondiabetic mice and obese type 2 diabetic db/db mice. To the best of our knowledge, this is the first report showing some molecule which can enhance MafA and/or PDX-1 expression levels. Therefore, although further extensive study is necessary, we think that the information in this study could be, at least in part, useful at some point such as in the development of new antidiabetes medicine based on the molecular mechanism of β-cell glucose toxicity in the future. [ABSTRACT FROM AUTHOR]