Diabetes & Metabolism Journal最新文献

Background: Metabolic disorders represent a significant challenge to human health, primarily due to their widespread prevalence and the limited availability of alternative pharmacological interventions. Drug repurposing offers a promising and expedited strategy to address these conditions.

Methods: To elucidate the efficacy and underlying mechanism of the combination of metformin with ropinirole on anti-obesity and obesity-related metabolic disorders.

Results: The results indicate that the combination treatment led to a significant reduction in body weight and improvements in hyperglycemia, dyslipidemia, and insulin resistance. These enhancements, along with increased energy expenditure, were significantly greater than those achieved with either drug alone. Additionally, we observed the browning of inguinal white adipose tissue (iWAT) and alterations of the whitened-brown adipose tissue (BAT), along with substantial increases in mitochondrial function-related proteins. However, the drug combination did not exhibit any enhanced effect on cell thermogenesis and these proteins in vitro, whereas combination of norepinephrine and metformin-induced an additive upregulation of mitochondrial function-related proteins. Furthermore, pharmacological blockade of the β3 adrenergic receptor inhibited the energy expenditure induced by the combination treatment, etc.

Conclusion: Our study underscores the combination of metformin and ropinirole-induced an amplified effectiveness in treating obesity-related metabolic disorders is dependent on the dopamine-control sympathetic nerve activity, and metformin acts directly on BAT and iWAT to improve mitochondrial function, which offering a new perspective for future clinical co-treatment of metabolic disorders with these two drugs.

Background: Immune cell infiltration in the renal interstitium contributes to the progression of diabetic nephropathy (DN), yet the precise mechanisms remain incompletely unclear.

Methods: Public multi-omics datasets were integrated for comprehensive bioinformatic analyses. Interactions between infiltrating immune cells and damaged tubular epithelial cells (TECs) were analyzed with the CellChat, and key regulators were identified by machine learning. DN was modeled in C57BL/6 mice by high-fat diet/streptozotocin. Human kidney 2 (HK-2) cells were exposed to high glucose plus palmitic acid (HGPA). Gene function was validated by Western blotting, real-time quantitative polymerase chain reaction, immunohistochemistry and surface plasmon resonance (SPR).

Results: Renal interstitium from DN patients displayed markedly increased infiltration of M1 macrophages, regulatory T-cells, natural killer cells and other immune subsets, all correlating with indices of renal injury. CellChat analysis indicated that damaged TECs communicated with infiltrating immune cells primarily through chemokine networks centered on C-X-C motif chemokine ligand (CXCL), C-X3-C motif chemokine ligand (CX3CL), and C-C motif chemokine ligand 2 (CCL2). Retinoic acid-induced 2 (RAI2) was upregulated in DN kidneys and showed significant associations with immune infiltration and renal injury via these chemokine pathways. Consistently, RAI2 expression was elevated in kidneys of DN mice and in HGPA-treated HK-2 cells. SPR demonstrated direct, high-affinity binding of resveratrol to human RAI2 protein. Knockdown of RAI2 or treatment with resveratrol attenuated HGPA-induced apoptosis and suppressed CCL2, CXCL, and CX3CL expression levels.

Conclusion: RAI2 is a pivotal mediator of tubule injury and immune cell infiltration in DN, and resveratrol via direct binding to RAI2 and suppressed its function.

Background: Diabetic cardiomyopathy (DCM) is the main cause of heart failure in diabetes patients with no effective therapies currently available. A deeper understanding of the mechanisms underlying DCM is essential for identifying novel therapeutic targets.

Methods: DCM model was established in C57BL/6J mice by administering multiple low-dose intraperitoneal injections of streptozotocin (STZ) in combination with a high-fat diet (HFD). Proteomic profiling was conducted on cardiac tissues from control and DCM mice to identify differentially expressed proteins. The expression of β-hydroxybutyrate dehydrogenase 1 (BDH1, also known as 3-hydroxybutyrate dehydrogenase) in cardiac tissues and cardiomyocyte were determined by immunoblot and quantitative polymerase chain reaction. The function and mechanism of BDH1 in DCM were investigated using a cardiac-specific BDH1-overexpressing mouse model, combined with cardiomyocyte cell lines with either BDH1 overexpression or knockdown.

Results: BDH1 was markedly downregulated in cardiac tissues of DCM mice, as well as in cardiomyocytes treated with high glucose and palmitic acid (HGPA). Cardiac-specific overexpression of BDH1 markedly improved cardiac dysfunction and myocardial fibrosis in DCM mice. In vitro, BDH1 overexpression attenuated mitochondrial damage and inhibited apoptosis in cardiomyocytes induced by HGPA. Conversely, BDH1 knockdown exacerbated these pathological changes under HGPA conditions. Transcriptome analysis linked BDH1 expression to the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) pathway, and we confirmed that BDH1 overexpression reversed diabetes-induced inhibition of the AKT/glycogen synthase kinase 3β (GSK3β) pathway. The protective effects of BDH1 on mitochondrial function and cardiomyocytes apoptosis were abolished following treatment with AKT inhibitor (AKTi). Cardiac-specific overexpression of BDH1 markedly decreased β-hydroxybutyric acid (BHB, the predominant ketone body) levels in cardiac tissues of DCM mice. Elevated BHB levels suppressed AKT activation in cardiomyocytes, while BDH1 overexpression effectively restored AKT/GSK3β pathway activity and ameliorated BHB-induced mitochondrial dysfunction and cardiomyocytes apoptosis.

Conclusion: Our study demonstrates that BDH1 plays a protective role in DCM by regulating BHB level and activating the AKT/GSK3β pathway, thereby mitigating mitochondrial damage and cardiomyocyte apoptosis. BDH1 may be a promising therapeutic target for DCM.

Background: Obesity serves as a predominant factor in the progression of metabolic syndrome and type 2 diabetes mellitus. While sleeve gastrectomy (SG) is a well-established surgical intervention, its impact on appetite-regulating hormones, such as ghrelin (GHRL), is limited. Sleeve gastrectomy combined with fundoplication (SGFD) has emerged as a potential strategy to improve metabolic outcomes by modifying both gastric anatomy and gut-brain signaling.

Methods: Sixty-five Sprague-Dawley rats were enrolled. After 8 weeks of high-fat feeding, 48 rats developed diet-induced obesity (DIO). These rats were randomized into four experimental groups: DIO control, sham-operated, SG, and SGFD, alongside a normal control cohort. Biochemical indicators, hormonal fluctuations, and insulin responsiveness were analyzed. Molecular expressions were evaluated through quantitative real-time polymerase chain reaction and Western blotting.

Results: SGFD reduced body weight (-24.7%), food intake (-28.3%), fasting glucose (-37.5%), triglycerides (-42.6%), and serum GHRL (-51.2%) compared with the DIO group (P<0.01). Gastric GHRL, preproghrelin, and ghrelin O-acyltransferase (GOAT) expression were suppressed. Hypothalamic neuropeptide Y (NPY) was downregulated, and AMP-activated protein kinase (AMPK) signaling was robustly enhanced across various tissues. SGFD also improved insulin receptor substrate-1 (IRS-1), glucose transporter type 4 (GLUT4), β-cell function, hepatic lipid oxidation, and brown adipose thermogenesis. SGFD outperformed SG in most metabolic and molecular outcomes (P<0.05).

Conclusion: SGFD provides superior metabolic benefits over SG alone by suppressing GHRL signaling and activating systemic AMPK pathways. SGFD represents a promising surgical strategy for obesity and metabolic syndrome.

Backgruound: Immune checkpoint inhibitors (ICIs) have transformed the treatment of metastatic solid tumors; however, they induce immune-related adverse events, such as ICI-induced type 1 diabetes mellitus (ICI-T1DM), a rare but serious condition requiring lifelong insulin therapy. We aimed to identify the risk factors and survival outcomes associated with ICI-T1DM to optimize screening and mitigate adverse effects.

Methods: This retrospective cohort study analyzed 6,956 patients treated with ICIs at a tertiary care center between January 1, 2017, and February 28, 2023. ICI-T1DM was classified based on the need for persistent insulin therapy post-ICI and a C-peptide level <1.0 ng/mL. Patient demographics, clinical characteristics, treatment details, and survival outcomes were examined.

Results: ICI-T1DM was identified in 32 patients (0.46%) with a median onset time of 41 weeks. Significant risk factors included pre-existing diabetes (hazard ratio [HR], 2.352; 95% confidence interval [CI], 1.140 to 4.854), combination therapy with anti-programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors (HR, 3.666; 95% CI, 1.224 to 10.979), prolonged ICI treatment (≥12 weeks; HR, 4.789; 95% CI, 1.806 to 12.701), and thyroid dysfunction (HR, 4.027; 95% CI, 1.847 to 8.779). ICI-T1DM occurrence and thyroid dysfunction were associated with improved survival (HR, 0.224; 95% CI, 0.093 to 0.539; and HR, 0.616; 95% CI, 0.566 to 0.670).

Conclusion: Patients with pre-existing diabetes, combined anti-PD-1/PD-L1 and anti-CTLA-4 therapy, prolonged ICI treatment (≥12 weeks), and thyroid dysfunction are at high risk of developing ICI-T1DM. The observed survival benefits in patients with ICI-T1DM underscore the importance of aggressive glucose monitoring and patient education for early detection and management.

Backgruound: Menopausal status can increase the risk of cardiocerebrovascular diseases (CCVDs) in women with type 2 diabetes mellitus (T2DM). Regular exercise is well-known to reduce this risk. This study explored the impact of exercise on CCVD and mortality in women with T2DM according to their menopausal status.

Methods: A total of 32,477 premenopausal and 53,690 postmenopausal Korean women with T2DM aged 40 to 60 years from a national health examination cohort (2009 to 2018) were included. We evaluated risks for stroke, myocardial infarction (MI), and mortality based on exercise intensity. Cox proportional hazard regression analyses were performed to obtain the adjusted hazard ratio (aHR) and 95% confidence interval.

Results: Exercise reduced stroke, MI, and mortality risks in women with T2DM, regardless of menopausal status. The highest effects of aHR compared to the sedentary group were 0.68 for stroke, 0.66 for MI, and 0.81 for mortality. Postmenopausal women experienced significant MI risk reductions at most exercise intensities, with the greatest reduction in the ≥1,500 metabolic equivalent of task score group unlike premenopausal women. However, stroke and mortality risk reductions in postmenopausal women were less pronounced compared to premenopausal women.

Conclusion: Exercise reduces CCVD risk in women with T2DM across menopausal status. Postmenopausal women with T2DM had more benefits from exercise on MI but fewer benefits on stroke and mortality than premenopausal women. In premenopausal women with T2DM, exercise was not associated with a lower MI risk.

Backgruound: The potassium voltage-gated channel subfamily Q member 1 (KCNQ1) gene has recently received much attention as a candidate susceptibility gene for type 2 diabetes mellitus, especially in Asian populations. We previously reported that Kcnq1 mutant mice exhibit reduced insulin secretion and hyperglycemia due to a decrease in pancreatic β-cell mass. Through in vivo and in vitro analyses, we ascertained that this mechanism is the result of the downregulation of the non-coding RNA 'Kcnq1ot1,' which is expressed in the paternal allele of the Kcnq1 gene region, causing an increase in the expression of the cell cycle inhibitor cyclin dependent kinase inhibitor 1C (Cdkn1c). It was found that decreased Kcnq1ot1 expression resulted in pancreatic β-cell failure; however, the degree of pancreatic β-cell volume reduction was not severe.

Methods: We induced obesity in Kcnq1ot1 truncation mice by feeding them a high-fat diet and evaluated pancreatic β-cell mass.

Results: In the present study, we reveal that CCAAT/enhancer binding protein beta (C/EBPβ), which is expressed at higher levels in pancreatic β-cells in obese individuals, further increases the expression of Cdkn1c, which is upregulated by the Kcnq1 gene mutation. We found that simultaneous Cdkn1c hypomethylation and C/EBPβ overexpression in pancreatic β-cells causes a synergistic decrease in pancreatic β-cell mass.

Conclusion: This finding suggests that the synergistic effect of genetic factors such as Kcnq1 gene mutations and environmental factors such as obesity and overeating, which lead to increased expression of C/EBPβ, contribute to the regulation of pancreatic β-cell mass. This study is the first to show that the Kcnq1 gene is related to pancreatic β-cell mass through genetic-environment interactions.

Backgruound: Excess intake of added sugars contributes to obesity, type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), and premature mortality. Sugar-sweetened beverages (SSBs), the main source of added sugars, are consistently linked to adverse outcomes. Artificially sweetened beverages (ASBs) have been suggested as short-term substitutes, but evidence regarding benefits and harms remains inconclusive, and guidance is lacking.

Methods: This consensus statement draws on a structured evidence review combining two approaches: an updated meta-analysis of randomized controlled trials (RCTs) assessing short- to intermediate-term effects of replacing SSBs with ASBs on weight and metabolic outcomes; and an umbrella review of systematic reviews of cohort studies evaluating long-term associations of SSBs and ASBs with major outcomes, including mortality, CVD, and T2DM.

Results: In 14 RCTs (3-76 weeks), replacing SSBs with ASBs produced modest reductions in body weight (-0.73 kg) and body fat (-0.72%), with inconsistent effects on glycemic and cardiometabolic markers. Evidence from 20 systematic reviews of cohorts (up to 34 years follow-up) showed that higher intake of both SSBs and ASBs was associated with increased risks of T2DM, CVD, and mortality, with relative risks for ASBs similar to those for SSBs.

Conclusion: ASBs may serve as a short-term substitution for individuals with high SSB intake, particularly those at elevated metabolic risk. However, regular or long-term use is not recommended due to uncertain safety and potential reinforcement of sweet preference. Public health strategies should emphasize reducing both SSBs and ASBs, prioritizing water and unsweetened beverages as the ultimate goal.