Additive Effects of Dorzagliatin and Glucagon-Like Peptide-1 Receptor Agonism in a Novel Mouse Model of GCK-MODY and in Obese db/db Mice.

New Medications for the Treatment of Diabetes

An Albumin-Exendin-4 Conjugate Engages Central and Peripheral Circuits Regulating Murine Energy and Glucose Homeostasis

Objective To identify the cause and its pathogenic mechanism in one case with permanent neonatal diabetes mellitus(PNDM). Methods One case of PNDM diagnosed in Peking Union Medical College Hospital was analyzed for clinical features. Genomic DNA was extracted, followed by amplification with polymerase chain reaction and direct sequencing of glucokinase (GCK) gene. Wild and mutant plasmids were constructed and then expressed in E.coli. The recombinant proteins were purified, then tested to clarify their enzyme kinetics and thermal stability. Data between two groups were analyzed by t test. Results Compound heterozygous mutation c.571 C>T(R191W) and c.1136 C>A(A379E) in GCK gene were detected in this child. Compared with the wild type, mutants R191W and A379E had lower protein yield ((86±9) vs (48±8) mg/L;(86±9) vs (54±5) mg/L; t=5.56, 5.36, both P<0.01), lower appetency for glucose(the half-saturating substrate concentration (S0.5) for glucose:(7.63±0.21) vs (35.27±2.20)mmol/L; (7.63±0.21) vs (13.30±0.44)mmol/L, t=-21.70, -20.32, both P<0.01), lower appetency for ATP(Km: (0.30±0.01) vs (0.42± 0.01) mmol/L; (0.30±0.01) vs (0.54±0.04) mmol/L, t=-17.02,-10.68, both P<0.01) and lower catalytic ability ((20.9±2.1)/s vs (6.5 ± 1.0)/s; (20.9±2.1)/s vs (10.5 ± 1.1)/s; t=10.61, 7.58, both P<0.01). The both mutants also showed increased thermal instability. Conclusion Compound heterozygous mutations R191W and A379E in GCK gene promote the development of PNDM by affecting enzyme kinetics of glucokinase as well as lowering protein stability. Key words: Permanent neonatal diabetes mellitus; Glucokinase; Gene mutation; Enzyme kinetics

Glucokinase (GK) is an isozyme of hexokinase that catalyzes the phosphorylation of glucose. GK is present in many organs of the human body, including the liver and pancreas. GK plays an important role in promoting the synthesis of hepatic glycogen and balancing postprandial blood glucose. Mutations in the GK gene can result in the inclusion of maturity-onset diabetes of the young (MODY2) and permanent neonatal Diabetes mellitus (PNDM). Glucokinase activators (GKAs) are a class of type 2 diabetes drugs designed for this target. In various animal models of type 2 diabetes, GKAs have been shown to have the ability to decrease blood glucose, and some GKAs also have the ability to stimulate β cell proliferation. However, due to the induction of hypoglycemia and increased liver burden, many candidates stopped in phase II clinical trials. Recently, dorzagliatin has reached the primary endpoint of phase III clinical trial, which can repair the core function of GK as a blood glucose sensor, and can delay or even reverse islet β -cell damage and functional decline. This provides a promising prospect for the study of GKAs as candidates for the treatment of type 2 diabetes. This review summarizes the clinical advances in GKAs.

ObjectiveTo evaluate sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes at varying cardiovascular and renal risk.DesignNetwork meta-analysis.Data sourcesMedline, Embase, and Cochrane CENTRAL...

Time to Follow the Evidence: Glycemic Control and Cardiovascular Benefits of New Diabetes Medications

Spinal fusion is a widely performed surgical procedure for treating various spinal disorders, with lumbar fusion showing remarkably rapid growth worldwide. Despite positive outcomes after the procedure, it carries significant complications, most notably pseudarthrosis. Compromised blood supply is a key factor disrupting normal bone fusion, making optimal vascularization crucial for successful outcomes. Glucagon-like peptide-1 (GLP-1) receptor agonists, primarily used for diabetes management, demonstrate promising effects including enhanced glycemic control, improved vascular endothelial function, and direct enhancement of osteoblastic cell activity through GLP-1 receptors on bone precursor cells. Theoretically, GLP-1 receptor agonists should be beneficial for optimizing spinal fusion outcomes. We aim to systematically review and analyze the current evidence on the efficacy and safety of GLP-1 receptor agonists in promoting bone fusion and reducing complications in patients undergoing spinal fusion surgery.We conducted a comprehensive systematic review following Cochrane guidelines. We searched PubMed, Web of Science, Scopus, Embase, and Cochrane Library for studies examining GLP-1 receptor agonists in spinal fusion procedures. We used the Newcastle-Ottawa Scale for the quality assessment of the included studies. We conducted a statistical analysis using RevMan 5.4 with risk ratios for dichotomous outcomes.In total, 11 studies with a total of 14,344 participants were analyzed. GLP-1 receptor agonists significantly reduced pseudoarthrosis at six months (risk ratio (RR) = 0.63, 95% confidence interval (CI) = 0.54-0.74) and 12 months (RR = 0.64, 95% CI = 0.57-0.72), and significantly increased acute kidney injury (RR = 1.30, 95% CI = 1.03-1.65). No significant differences were observed for pseudoarthrosis at 24 months (RR = 1.03, 95% CI = 0.53-2.03), readmission rates (RR = 0.85, 95% CI = 0.48-1.51), cerebrovascular accidents (RR = 1.01, 95% CI = 0.63-1.62), and deep vein thrombosis (RR = 1.16, 95% CI = 0.78-1.72). Additionally, no significant reoperations or adverse effects were found. We also performed a subgroup analysis considering the diabetic stage, which showed valuable insights.GLP-1 receptor agonists showed promising results in reducing pseudoarthrosis at short- to medium-term follow-up, indicating potential therapeutic benefits in bone healing applications. However, the increased risk of acute kidney injury suggests the need for careful patient monitoring and risk stratification. The lack of sustained benefit at 24 months and significant heterogeneity observed in several outcomes indicate that further investigation is warranted. Future research should focus on conducting larger, well-designed randomized controlled trials with standardized outcome definitions, longer follow-up periods, and comprehensive safety monitoring to establish optimal dosing protocols and patient selection criteria for GLP-1 receptor agonist therapy in orthopedic applications.

ObjectivesTo evaluate the comparative effectiveness of sodium-glucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors in preventing hyperkalemia in people with type 2 diabetes in...

Understanding neonatal diabetes mellitus

ObjectiveSeveral glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1Ra) have been made recently available in Spain for type 2 diabetes mellitus (DM2) treatment. There are no published data on the clinical and...

BackgroundThe cardiovascular effects of glucagon-like peptide-1 (GLP-1) receptor agonists are still controversial in the treatment of type 2 diabetes mellitus (T2DM) patients. The purpose of this study was to evaluate the risk of cardiovascular events of GLP-1 (albiglutide, exenatide, liraglutide, semaglutide, lixisenatide and dulaglutide) receptor agonists in T2DM patients.MethodsPubMed and Embase were searched to find relevant randomized controlled trials (RCTs) from inception to June 2019 that evaluated the effect of GLP-1 receptor agonists on cardiovascular events in patients with T2DM. The T2DM patients of all the eligible trials received either GLP-1 therapy or placebo, and the cardiovascular outcomes included death from cardiovascular causes, fatal or non-fatal myocardial infarction and fatal or non-fatal stroke.ResultsWe included 6 multinational double-blind randomized placebo-control trials that included a total of 52821 T2DM patients. The results indicated that GLP-1 receptor agonists reduced the risk of death from cardiovascular causes (RR: 0.90; 95% CI: 0.83–0.97; P = 0.004) and fatal or non-fatal stroke (RR: 0.85; 95% CI: 0.77–0.94; P = 0.001) compared with the placebo controls. But GLP-1 receptor agonists did not significantly alter the fatal or non-fatal myocardial infarction compared with the placebo (RR: 0.91; 95% CI: 0.82 – 1.01; P = 0.06).ConclusionWe concluded that GLP-1 receptor agonist therapy could reduce the risk of death from cardiovascular causes and fatal or non-fatal stroke compared with the placebo in the treatment of T2DM patients in trials with cardiovascular outcomes.

Advances in the management of diabetes mellitus have come a long way in the 21st century. One of the most important developments in diabetes management has been the discovery of...

In patients with diabetes and monoclonal gammopathy of uncertain significance (MGUS), the impact of glucagon-like peptide-1 (GLP-1) receptor agonists on the natural history of MGUS is unknown. We aimed to assess the association of GLP-1 receptor agonist use in the progression of MGUS to multiple myeloma in patients with diabetes. This is a population-based cohort study of veterans diagnosed with MGUS from 2006 to 2021 with a prior diagnosis of diabetes. A validated natural language processing algorithm was used to confirm MGUS and progression to multiple myeloma. We performed 1:2 matching for individuals with and without GLP-1 receptor agonist exposure. The Gray test was performed to detect the difference in cumulative incidence functions for progression by GLP-1 receptor agonist use status. The association between time-varying GLP-1 receptor agonist use and progression was estimated through multivariable-adjusted hazard ratio using a stratified Fine-Gray distribution hazard model, with death as a competing event and stratum for the matched patient triad. Our matched cohort included 1097 individuals with MGUS who had ever used GLP-1 receptor agonists and the matched 2194 patients who had never used GLP-1 receptor agonists. Overall, 2.6% of individuals progressed in the GLP-1 receptor agonist ever use group compared with 5.0% in the GLP-1 receptor agonist never use group. Cumulative incidence functions were statistically significantly different between the exposed and unexposed groups (P = .02). GLP-1 receptor agonist use vs no use was associated with decreased progression to multiple myeloma (hazard ratio = 0.45, 95% confidence interval = 0.22 to 0.93, P = .03). For patients with diabetes and MGUS, GLP-1 receptor agonist use is associated with a 55% reduction in risk of progression from MGUS to multiple myeloma compared with no use.

New Glucose-Lowering Agents for Diabetic Kidney Disease.

The incretin system plays an important role in glucose homeostasis, largely through the actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Unlike GIP, the actions of GLP-1 are preserved in patients with type 2 diabetes mellitus, which has led to the development of injectable GLP-1 receptor (GLP-1R) agonists and oral dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1R agonists—which can be dosed to pharmacologic levels—act directly upon the GLP-1R. In contrast, DPP-4 inhibitors work indirectly by inhibiting the enzymatic inactivation of native GLP-1, resulting in a modest increase in endogenous GLP-1 levels. GLP-1R agonists generally lower the fasting and postprandial glucose levels more than DPP-4 inhibitors, resulting in a greater mean reduction in glycated hemoglobin level with GLP-1R agonists (0.4%–1.7%) compared with DPP-4 inhibitors (0.4%–1.0%). GLP-1R agonists also promote satiety and reduce total caloric intake, generally resulting in a mean weight loss of 1 to 4 kg over several months in most patients, whereas DPP-4 inhbitors are weight-neutral overall. GLP-1R agonists and DPP-4 inhibitors are generally safe and well tolerated. The glucose-dependent manner of stimulation of insulin release and inhibition of glucagon secretion by both GLP-1R agonists and DPP-4 inhibitors contribute to the low incidence of hypoglycemia. Although transient nausea occurs in 26% to 28% of patients treated with GLP-1R agonists but not DPP-4 inhibitors, this can be reduced by using a dose-escalation strategy. Other adverse events (AEs) associated with GLP-1R agonists include diarrhea, headache, and dizziness. The main AEs associated with DPP-4 inhibitors include upper respiratory tract infection, nasopharyngitis, and headache. Overall, compared with other therapies for type 2 diabetes mellitus with similar efficacy, incretin-based agents have low risk of hypoglycemia and weight gain. However, GLP-1R agonists demonstrate greater comparative efficacy and weight benefit than DPP-4 inhibitors.