Diabetes & Metabolism Journal最新文献

Background: This study assessed the efficacy and safety of HD-6277, a novel oral G protein-coupled receptor 40 (GPR40) agonist in adults with inadequate control of type 2 diabetes mellitus (T2DM).

Methods: This double-blind, randomized, placebo-controlled phase 2 trial recruited 112 individuals aged 18-75 years with T2DM and glycosylated hemoglobin (HbA1c) levels between 7.0% and 10.0% while on diet and exercise alone for at least 8 weeks before screening. Parallel-group randomized trials of HD-6277 (50 and 100 mg groups vs. placebo) were conducted for 12 weeks. The primary outcome was the change in HbA1c levels from baseline to week 12. Secondary outcomes included changes in HbA1c, fasting plasma glucose (FPG), postprandial glucose, insulin, glycoalbumin, and C-peptide at weeks 4, 8, and 12.

Results: At week 12, HD-6277 at 50 and 100 mg demonstrated statistically significant reductions in HbA1c compared to placebo, with least square (LS) mean differences of -0.73% (95% confidence interval [CI], -1.11 to -0.35; P=0.0002) and -0.85% (95% CI, -1.21 to -0.50; P<0.0001), respectively. Both doses also produced clinically meaningful reductions in FPG. Additionally, HD- 6277 at 100 mg significantly increased the insulinogenic index compared to placebo, with an LS mean difference of 1.91 (95% CI, 0.34 to 3.48; P=0.0175). No clinically relevant treatment-related adverse events were observed.

Conclusion: HD-6277 at 50 and 100 mg improved glycemic control and was well-tolerated in adults with T2DM inadequately managed with diet and exercise. GPR40 agonists may offer a promising new therapeutic option for T2DM.

Background: The study evaluated the efficacy and safety of enavogliflozin, a novel, promising selective sodium-glucose cotransporter 2 inhibitor, as an add-on in adults with type 2 diabetes mellitus (T2DM) inadequately controlled with insulin alone or combined with other antidiabetic drugs (OADs).

Methods: The double-blind, placebo-controlled, multicenter trial was conducted in South Korea and Thailand. Individuals with glycosylated hemoglobin (HbA1c) ≥7.5% after ≥8-week treatment with background insulin alone or combined with ≤2 OADs were randomized to receive enavogliflozin 0.3 mg or placebo (n=116 each) for 24 weeks. The primary outcome was a change in HbA1c at week 24. Secondary outcomes included, among others, changes in body weight, blood pressure, and other measures of glycemic control. Adverse events (AEs) were investigated throughout the study (Clinical trial registration number: NCT05466643).

Results: At week 24, the placebo-adjusted mean change in HbA1c from baseline in the enavogliflozin group was -0.9% (P<0.001). Also, placebo-adjusted mean changes in fasting plasma glucose (-32.4 mg/dL, P<0.001), body weight (-1.3 kg, P<0.001), and total daily dose of insulin (-1.3 units, P=0.010) at week 24 were statistically significant. In addition, a significant decrease in blood pressure and fasting C-peptide was observed in the enavogliflozin group, along with a significant increase in homeostasis model assessment of β-cell function, yet without a concomitant change in homeostasis model assessment of insulinresistance. No significant increase in treatment-related AEs was observed for enavogliflozin.

Conclusion: Enavogliflozin 0.3 mg/day is an efficacious and safe add-on treatment option in T2DM patients controlled inadequately with insulin alone or combined with OADs.

Background: Diabetes is a multifactorial disease with significant genetic predisposition. Polygenic risk scores (PRS) have been developed to estimate an individual's genetic risk of a disease. Traditionally, PRS utilize sex-combined genome-wide association studies (GWAS) due to the limited availability of sex-stratified summary statistics. This study explores sex-dimorphic genetic effects and evaluates the potential benefits of incorporating sex-stratified effects in PRS for type 2 diabetes mellitus (T2DM) and glycemic traits by comparing PRS performance derived from sex-combined versus sex-stratified GWAS.

Methods: We performed a sex-heterogeneity test across sex-specific GWAS and identified nine signals with sex-dimorphic effects for T2DM. PRS[sex-combined] and PRS[sex-stratified] were developed using sex-combined and sex-stratified GWAS results for T2DM (41,444 cases and 354,539 controls), fasting glucose (n=120,595) and fasting insulin (n=98,210). We evaluated these PRS models in 8,379 participants (1,303 cases and 7,076 controls) from the Framingham Heart Study not included in the PRS derivation.

Results: Our findings suggest that sex-combined PRS currently offer better predictive performance for T2DM and glycemic traits.

Conclusion: These results highlight the need for larger sex-stratified studies and the optimization of sex-stratified risk models for clinical practice.

Background: Lactate, traditionally considered a metabolic byproduct, is increasingly recognized as a signaling molecule involved in metabolic regulation. Its role in hepatic steatosis, particularly through G-protein-coupled receptor 81 (GPR81)-mediated pathways, remains underexplored.

Methods: We investigated the effects of lactate on hepatic lipid metabolism using in vitro alpha mouse liver 12 (AML12) cells, zebrafish, and two diet-induced nonalcoholic fatty liver disease (NAFLD) mouse models. Lipid accumulation, gene/protein expression, and 5' adenosine monophosphate-activated protein kinase (AMPK) signaling were assessed under lactate exposure, GPR81 knockdown, monocarboxylate transporter 1 (MCT1) inhibition, and AMPK activation conditions.

Results: Lactate treatment in hepatocytes increased de novo lipogenesis and fatty acid uptake while suppressing fatty acid oxidation and AMPK phosphorylation. These effects were reversed by GPR81 knockdown but not by MCT1 inhibition, suggesting a GPR81-dependent mechanism. AMPK activation with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) reduced lactate-induced lipid accumulation. In zebrafish, 10 mM lactate treatment for 24 hours significantly increased hepatic lipid content. In mice fed high-fat diet (HFD) or high-fat high-cholesterol (HFHC) diets for 12 weeks, hepatic lactate levels and GPR81 expression were elevated. Interestingly, p-AMPK expression decreased in HFD livers but increased in the HFHC group, indicating dietspecific regulation.

Conclusion: Our findings demonstrate that lactate promotes hepatic steatosis primarily via the GPR81-AMPK signaling axis. GPR81 activation enhances lipogenesis and lipid uptake, independent of MCT1-mediated transport. These results position GPR81 as a promising therapeutic target for NAFLD.

Background: Galectins (gal) are glycan-binding proteins that regulate maternal adaptations during pregnancy, but their role in pregnancy-associated metabolic homeostasis is unclear. This study characterizes the maternal galectin profile in response to an oral glucose tolerance test (OGTT) in pregnant women with varying body weight.

Methods: In a two-center prospective study, pregnant women were recruited into two cohorts: low-risk (LR) with normal weight and high-risk (HR) with overweight or obesity. Circulating levels of gal-1, -3, -7, and -9 were measured at fasting, 1 hour, and 2 hours during the OGTT between 24 and 28 weeks of gestation. Correlations with clinical and metabolic parameters were assessed (HMO study: ClinicalTrials.gov Identifier NCT05496712; FitFor2 trial: trial registration number NTR1139).

Results: Fasting gal-3 and gal-9 were elevated in the HR cohort compared to the LR cohort. Body mass index was positively associated with gal-3 and gal-9, while gal-3 was also linked to insulin sensitivity. After glucose challenge, gal-1, -3, -7, and -9 decreased in the LR cohort; in the HR cohort, only gal-1 and gal-7 decreased after 2 hours, while gal-3 and gal-9 remained unchanged. Gal-1 correlated positively with homeostasis model assessment for insulin resistance (HOMA-IR) and inversely with insulin sensitivity across the OGTT in the LR cohort, but some of these correlations were not observed in the HR cohort.

Conclusion: Galectins exhibited distinct patterns of association with glucose homeostasis during the second trimester of pregnancy. Gal-3 and gal-9 are associated with chronic conditions such as pre-pregnancy obesity and insulin resistance, whereas gal-1 appears to be particularly sensitive to the acute glucose challenge.

Background: Bariatric metabolic surgery (BMS) has been established as an effective intervention for obesity and type 2 diabetes mellitus (T2DM). However, systematic research addressing the onset of diabetes and post-surgical remission in severely obese populations remains scarce. This study aims to identify risk factors for T2DM in populations with severe obesity undergoing BMS and develop and validate a prediction model for the primary outcome of diabetes remission (DR) 1 year after BMS. This research provides a precise tool for managing T2DM in populations with severe obesity.

Methods: This research utilizes the China Obesity and Metabolic Surgery Database, retrospectively analyzing 3,670 severely obese populations who underwent BMS between January 2014 and January 2024. Differential analysis identified risk factors for T2DM onset, while univariate and multivariate regression analyses identified independent risk factors for DR post-surgery. A prediction model for DR was developed and internally validated.

Results: Factors associated with T2DM onset in severely obese populations included family history of diabetes, hypertension, hyperlipidemia, glycosylated hemoglobin (HbA1c) levels, and fasting plasma glucose. Independent factors influencing DR postsurgery included diabetes duration, surgical method, HbA1c, and insulin requirement. Subsequent model validation confirmed stable performance metrics (area under the curve values training, 0.71; validation, 0.72).

Conclusion: This study identifies risk factors for T2DM onset and a prediction model for DR following BMS in the Chinese severely obese population. It provides a more precise risk assessment tool for patients with severe obesity and T2DM, and lays the groundwork for future multicenter studies and international collaborations.