Binding of GLP-1 to its receptor in pancreatic beta cells triggers activation of the cAMP pathway and phosphorylation of CREB, leading to induction of cellular target genes containing CREB binding sites. By contrast with their acute effects on beta cell gene expression, chronic exposure of beta cells to stable GLP-1 analogs like Exendin-4 stimulates sustained expression of beta cell-specific genes, leading to increases in beta cell viability and insulin secretion. In a proteomic screen for transcriptional coregulators that contribute to the transcriptional effects of GLP-1, we identified Med14, the scaffolding subunit of the conserved 30 subunit Mediator complex. Exposure to Exendin-4 and other GLP-1 receptor agonists stimulates sustained phosphorylation of Med14 at Ser983, which corresponds to a conserved PKA recognition site. Mutation of Med14 at Ser983 blocked Exendin-4 effects on cellular gene expression by interfering with CREB-mediated activation of beta cell-specific enhancers. Med14 mutation results in higher alpha-to-beta cell ratios and blunted gene regulation in response to Exendin-4 in Ser983-mutant primary mouse islets. Our work reveals how phosphorylation of a general transcription factor in response to GLP-1 analogs triggers a broad genomic response with salutary effects on beta cell function.

Objectives: This study aimed to identify factors influencing the magnitude of the difference between plasma glucose concentration (Glu(P)) and serum glucose concentration (Glu(S)). Methods: A total of 333 healthy Japanese adults aged 22–29 years (212 males and 121 females) were enrolled. Plasma samples were collected using glycolytic inhibitors, whereas serum samples were obtained without glycolytic inhibitors and kept at room temperature. Glu(P) and Glu(S) were measured and compared. Results: The median difference between Glu(P) and Glu(S), defined as Glu(P-S), was 4 mg/dL across all participants, with no gender-related differences. A strong positive correlation was observed between Glu(P) and Glu(S). Glu(P-S) was positively correlated with body mass index, Glu(P), triglyceride–glucose index, white blood cell count, serum sodium, magnesium, and zinc levels. In contrast, Glu(P-S) was negatively correlated with Glu(S), hemoglobin A1c (HbA1c), homeostasis model assessment of beta-cell function, and high-density lipoprotein cholesterol (HDL-C). Multiple regression analysis demonstrated that HDL-C and HbA1c were independent determinants of Glu(P-S) in the overall cohort. Among females, HDL-C, triglyceride, low-density lipoprotein cholesterol, ferritin, and C-reactive protein independently influenced Glu(P-S), whereas no independent determinants were identified in males. Conclusions: Plasma glucose concentrations measured with glycolytic inhibitors were significantly higher than serum glucose concentrations measured without inhibitors at room temperature. The magnitude of Glu(P-S) appears to be associated with markers of insulin resistance, particularly HDL-C levels.

Pancreatic beta cell dedifferentiation underlies the reversible reduction in beta cell mass and function in diabetes. Exploratory research into interventional targets and adjuvant therapies to prevent or reverse beta cell dedifferentiation and transdifferentiation may provide evidence to support the effective treatment of diabetes, although the underlying molecular mechanism remains elusive. Lactate dehydrogenaseA (LDHA) expression and activity were analysed in islets obtained from human donors with type 2 diabetes, hyperglycaemic db/db mice and a high-fat diet (HFD)-induced mouse model of diabetes. The impact of LDHA inhibition on beta cell function and identity was also investigated in HFD-fed mice and db/db mice. Chromatin immunoprecipitation (ChIP)-seq and RNA-seq were used to investigate the specific molecular mechanism underlying the effect of LDHA on histone H3 lysine9 lactylation (H3K9la) increases and beta cell function under glucotoxic conditions. We demonstrate that inhibition of LDHA effectively preserves beta cell identity, which not only delays disease progression in individuals with impaired fasting glucose, but also improves insulin output and glucose homeostasis in diabetic models. Mechanistically, activation of LDHA led to a marked increase in H3K9la in the promoter region of the beta cell dedifferentiation marker genes Sox9, Hes1 and Aldh1a3, and facilitated their transcription, thereby triggering beta cell dedifferentiation as well as impaired glucose homeostasis and beta cell function in mice. We unravelled the role of LDHA-mediated metabolic and epigenetic reprogramming in beta cell dedifferentiation during diabetes development. This study suggests that LDHA inhibition could be a novel therapeutic strategy for diabetes treatment.

Insulin resistance and impaired insulin secretion are hallmarks of type 2 diabetes (T2D) and may influence risks of complications including dementia. We investigated dementia risk across T2D subgroups defined by beta-cell function and insulin sensitivity. We used Homeostasis Model Assessment-2 indices of beta-cell function (HOMA2-B) and insulin sensitivity (HOMA2-S) to classify 7221 individuals with recently diagnosed T2D into insulinopenic (low HOMA2-B, high HOMA2-S), classical (low HOMA2-B, low HOMA2-S), and hyperinsulinemic (high HOMA2-B, low HOMA2-S) subgroups. Incident dementia was ascertained by validated hospital diagnosis codes and dementia-specific medication over 13 years. Absolute risks were estimated using the Aalen-Johansen estimator and adjusted hazard ratios (aHRs) using Cox regression. Over a median follow-up of 9 years, 179 (2.5%) developed dementia. The 10-year risk (95% CI) was 3.8% (2.4%-5.8%) in the insulinopenic subgroup versus 2.8% in both classical (2.3%-3.5%) and hyperinsulinemic (2.0%-3.8%) subgroups. Compared with classical T2D, aHRs (95% CI) were 1.31 (0.83-2.09) for insulinopenic and 1.10 (0.78-1.54) for hyperinsulinemic T2D. No robust associations with dementia were observed with insulin resistance (HOMA-IR) or C-peptide levels, although compared to the lowest C-peptide levels (quartile 1), aHRs (95% CI) were decreased at 0.67 (0.45-1.01) in quartile 2, 0.73 (0.48-1.09) in quartile 3, and 0.89 (0.59-1.33) in quartile 4. We found no clear associations between T2D subgroup, insulin resistance, or C-peptide level at T2D diagnosis and dementia risk. The numerically higher risk in those with lower insulin secretion was statistically imprecise and warrants further study.

This study investigated the therapeutic potential of cannabidiol (CBD) and aerobic training (AT), both alone and in combination, to ameliorate beta-cell dysfunction in a rat model of diet-induced obesity, with a specific focus on the phosphatidylinositol 3-kinase (PI3K)/ protein Kinase B (AKT)/pancreatic and duodenal homeobox 1 (PDX1) pathway. Thirty-two male Wistar rats were fed a high-fat diet (HFD) for 8 weeks to induce obesity. They were then randomly assigned to four groups (n = 8/group): HFD (sedentary), HFD + CBD (10mg/kg, 5x/week), HFD + AT (30-minute treadmill running,50-80% maximal speed, 5x/week, 8 week), and HFD + CBD+AT (combined treatment) for a further 8 weeks. Following the intervention, beta-cell function was assessed via the HOMA-Beta index, and pancreatic gene expression of PI3K, AKT, and PDX1 was analyzed using RT-PCR. Both the HFD + CBD and HFD + CBD+AT groups showed a significant improvement in beta-cell function, as indicated by a higher HOMA-Beta index compared to the HFD group (p = 0.002 and p = 0.001, respectively). AT alone (HFD + AT) did not significantly alter HOMA-Beta. In contrast, all intervention groups (HFD + CBD, HFD + AT, and HFD + CBD+AT) demonstrated a significant upregulation in the gene expression of PI3K, AKT, and PDX1 compared to the HFD group (p < 0.001 for all). Notably, the combined treatment of CBD and AT (HFD + CBD+AT) produced a synergistic effect, resulting in a greater increase in the expression of all three genes compared to either intervention alone. No significant correlation was found between HOMA-Beta and the gene expression levels within any group (p > 0.05). CBD and AT independently activate the pancreatic PI3K/AKT/PDX1 pathway, with their combination showing synergy. CBD, but not AT alone, improved functional beta-cell mass. This pathway activation represents a key mechanism for protecting beta-cells in obesity.

Mini-review. Vitamin D for the prevention of type 2 diabetes: Evidence and implications.

This narrative review explores the epidemiological evidence and potential underlying pathophysiological defects underlying the disproportionately greater risk of Type 2 diabetes (T2D) and cardiometabolic disease in people of South Asian and African Caribbean ancestry compared with White Europeans. Differences in (i) insulin dynamics, (ii) body composition and liver and pancreas triglyceride accumulation, and (iii) dysregulated fat metabolism likely contribute to this obesity-related susceptibility. Insulin resistance and hyperinsulinemia are key pathophysiological defects in T2D, although the primary defect is uncertain. Many believe that insulin resistance precedes compensatory hyperinsulinemia; much data suggest that hyperinsulinemia precedes insulin resistance. Hyperinsulinemia, related to reduced hepatic insulin clearance, may represent the primary defect in people of African Caribbean ancestry. Ectopic fat, particularly visceral, liver, and pancreatic fat, is associated with impairments in insulin action/secretion: Higher liver fat is specifically related to hepatic insulin resistance and higher pancreatic fat to impaired beta cell function. People of South Asian ancestry exhibit greater ectopic particularly liver fat, compared with White Europeans, and more severe insulin resistance, driving hyperinsulinemia. People of African Caribbean ancestry have lower visceral and liver fat and greater muscle mass. Dysregulated fat metabolism in adipose tissue/liver may increase serum fatty acids and triglyceride concentrations exposing non-adipose tissues to increased lipid. Differential T2D susceptibility likely reflects diverse but ethnic group-specific metabolic phenotypes representing genetic and environmentally mediated pathophysiological traits, consistent with the "palette" model of T2D.

Background. Innovations have been recently proposed in the treatment of type 2 diabetes. Metformin is recommended as a first-line drug now as before; but indications for the use of glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors are expanding. Review articles do not always mention that the hypoglycemic effect of glucagon-like peptide 1 receptor agonists is associated with the stimulation of the endocrine function of beta cells, which may be depleted over time. Objective. Unbiased comparison of the effectiveness and possible side effects of drugs used in the treatment of type 2 diabetes mellitus with overweight. Materials and methods. Review of Russian and international literature using the databases elibrary.ru, PubMed and Google Scholar, as well as library catalogs. Results. A brief overview of recent publications on sugar-lowering drugs that can be used in type 2 diabetes with overweight patients is presented. The effect of drugs on body weight and beta cell function, as well as relative cost of the treatment is discussed. Special attention is paid to the following groups of medicines. Glucagon-like peptide 1 receptor agonists stimulate the secretion of insulin, lowering appetite and the gastrointestinal motility, thus promoting weight loss. The relatively high cost of glucagon-like peptide 1 receptor agonists and subcutaneous administration are pointed out. Oral semaglutide is the only glucagon-like peptide 1 receptor agonist preparation used for the oral intake. Sodium-glucose cotransporter 2 inhibitors reduce renal glucose reabsorption, excrete glucose in the urine, lower blood pressure, and promote weight loss. Glycemic control is thus maintained in the long term. Weight loss can also be expected from intestinal alpha-glucosidase inhibitors (acarbose), which inhibit the digestion and absorption of complex carbohydrates in the intestine. The hypoglycemic effect of the drugs of last two groups (as well as metformin) is not associated with the stimulation beta cells, which can be depleted by prolonged stimulation. Combination therapy using sugar-lowering and anorexigenic drugs is discussed. Conclusion. Complications of diabetes mellitus are caused not only by hyperglycemia, but also by dyslipidemia, hypertension, physical inactivity, smoking and other factors, which requires an individual approach to drug therapy and lifestyle modification.

Type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD) are increasing globally, with mitochondrial dysfunction being a core component in their development. While a 75g oral glucose tolerance test (OGTT) can be used to diagnose T2D, hepatic metabolic and mitochondrial dysfunction can be assessed using a 13C-methionine breath test (BT). We aimed to evaluate combining these tests for an efficient, non-invasive screening tool. On three study days, 26 subjects (11 [43.3%] female, 61± 16 years) subjects underwent either an OGTT, a 13C-methionine BT or both tests combined. Diagnostic outcomes of the individual and combined tests were compared using cumulative 13C percentage dose recovered (cPDR), plasma glucose concentrations and Homeostatic Model Assessment (HOMA)-indexes for insulin resistance and beta-cell function. In the combined test, cPDR90min was significantly lower (cPDR90min 2.3± 0.2% vs. 5.7± 0.5%; p< 0.0001), accompanied by a rightward shift of the 13C-increase towards later time points. When breath collection of the combined test was extended, cPDR145min (5.7± 0.4%) was practically identical to cPDR90min of the single test (p= 0.99). OGTT results, plasma glucose, and HOMA-indexes did not differ significantly between tests. Combining a 13C-methionine BT with an OGTT significantly impacts 13C-methionine kinetics, but not OGTT results. A potential mechanism includes a glucose-induced delay of gastric emptying. Combined testing may be feasible when time-adjusted measurements are used, potentially allowing simultaneous screening for both T2D and MASLD-associated mitochondrial dysfunction in clinical practice.

HLA-guided identification of monogenic diabetes in antibody-negative type 1 diabetes: frequency and characteristics.

Type 1 diabetes (T1D) is characterized by autoimmune beta-cell destruction and lifelong insulin dependence, yet early-stage disease (Stages 1-2) retains residual beta-cell function that may still respond to incretin signaling. Incretin hormones-mainly glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)-enhance postprandial insulin secretion and suppress glucagon, and GLP-1 also exhibits beta-cell protective effects in preclinical models. Although the incretin effect is markedly reduced in established T1D, intestinal GLP-1 secretion is largely preserved, creating a mechanistic rationale for strategies that increase endogenous GLP-1 during the "residual function" window. This narrative review summarizes dietary and lifestyle interventions that may enhance endogenous GLP-1 responses and discusses their potential role as adjuncts to insulin therapy, particularly when combined with emerging beta-cell-preserving immunomodulatory approaches that may prolong early disease stages. Mechanistically, high-fiber diets may increase GLP-1 via microbiota-derived short-chain fatty acids acting on L-cell receptors; low-glycemic index carbohydrates may favor distal nutrient delivery and a GLP-1-dominant incretin profile; and Mediterranean dietary patterns may promote GLP-1 secretion through unsaturated fatty acids, fiber, and polyphenols, including potential DPP-4-modulating effects. This narrative review examines nutrition and lifestyle interventions modulating residual incretins to elongate early T1D stages and enhance glycemic control as insulin adjuncts, per Nutrients' Special Issue. Available evidence is strongest in non-T1D populations, with limited T1D-specific trials, highlighting the need for stage-targeted studies incorporating GLP-1 dynamics, C-peptide, glycemic variability, and microbiome outcomes.

Type 2 diabetes and hypertension are common health conditions that often occur together, suggesting shared biological mechanisms. To explore this relationship, we analyse large-scale multiomic data to uncover genetic factors underlying type 2 diabetes and blood pressure comorbidity. We curate 1304 independent single-nucleotide variants associated with type 2 diabetes and blood pressure, grouping them into five clusters related to metabolic syndrome, inverse type 2 diabetes/blood pressure risk, impaired pancreatic beta-cell function, higher adiposity, and vascular dysfunction. Colocalization with tissue-specific gene expression highlights significant enrichment in pathways related to thyroid function and fetal development. Partitioned polygenic scores derived from these clusters improve risk prediction for type 2 diabetes/hypertension comorbidity, identifying individuals with more than twice the usual susceptibility. These results reveal a mechanistically heterogeneous genetic architecture shared between type 2 diabetes and blood pressure, enhancing comorbidity risk prediction. Partitioned polygenic risk scores offer a promising approach for early risk stratification, personalised prevention, and improved management of these interconnected conditions.

Low-carbohydrate diets (LCDs) are widely adopted for metabolic management, but their long-term cardiometabolic effects in diverse populations remain unclear. We aimed to evaluate the association between self-selected moderate LCD adherence and cardiometabolic parameters in individuals with and without diabetes. This prospective cohort study included 9658 participants from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil; baseline: 2008-2010; follow-up: 2017-2019). LCD adherence (carbohydrate <45% of total energy) was assessed through validated food frequency questionnaires. Quantile regression models, adjusted for sociodemographic, lifestyle, and clinical factors, were used to analyze changes in body mass index (BMI), blood pressure, insulin, and homeostatic model assessment for insulin resistance (HOMA-IR) and beta cell function (HOMA-B). Among individuals without diabetes, those who followed an LCD only at the follow-up showed decreased insulin levels (β = -0.33 [95% CI, -0.6 to -0.1] μIU/ml), HOMA-IR (-0.11 [-0.2 to -0.1] μIU/ml), and HOMA-B (-4.95 [-7.2 to -2.1] μIU/ml) alongside modest BMI increases (0.16 [0.1-0.3]). Consistent LCD adherents (at both time points) showed a decrease in HOMA-B (-3.21 [-6.4 to -0.1] μIU/ml) and an increase in BMI (0.29 [0.2-0.4]). In individuals with diabetes, LCD adherence led to reduced HOMA-IR (-1.25 [-2.2 to -0.3] μIU/ml) and insulin levels (-3.61 [-6.0 to -1.2] μIU/ml). Moderate LCD adherence improved insulin sensitivity and reduced pancreatic demand in individuals without diabetes. Despite slight BMI increases, LCD may be a feasible dietary strategy for metabolic risk management in middle-aged and older adults. Personalized nutrition approaches are recommended to optimize outcomes.

We aimed to investigate whether maternal and fetal genetic predispositions to insulin deficiency and resistance affect offspring fetal growth through distinct pathways in multi-ethnic populations. In 5065 multi-ethnic mother-infant pairs, we examined the conditional associations of maternal and fetal partitioned polygenic risk scores (pPRSs) for type 2 diabetes-related pathways with fetal growth outcomes, including birthweight, sum of skinfold thicknesses (SSF), large-for-gestational-age (LGA) births and small-for-gestational-age (SGA) births. Two-sample Mendelian randomisation (2SMR) in Europeans was performed for triangulation. Exposures were eight type 2 diabetes-related pathways (n=1,812,017), eight beta cell function indices (n=26,356) and two insulin sensitivity indices (n=53,657). Outcomes were maternal and fetal genetically determined birthweight (n=406,063). Mediation analysis was used to assess the mediation effects of maternal glucose levels and BMI on maternal genetic effects and of cord blood C-peptide on fetal genetic effects. Co-localisation analyses were performed to test for shared causal variants. Fetal type 2 diabetes polygenic risk score (PRS) and pPRSs for lipodystrophy-related insulin resistance and impaired fasting glucose (IFG)-related insulin deficiency were associated with lower birthweight and SSF, while maternal type 2 diabetes PRS and pPRSs for IFG-related insulin deficiency and obesity-related insulin resistance were associated with higher offspring birthweight, SSF and LGA. These associations were consistent across five ethnic groups. Maternal post-load hyperglycaemia mediated 44.2% and 34.2% of the effects of type 2 diabetes PRS and IFG pPRS, respectively, while maternal BMI mediated 43.4% of the effect of Obesity pPRS. 2SMR found consistent results in Europeans and further revealed that fetal insulin sensitivity index and corrected insulin response were associated with higher birthweight. Some loci with shared causal variants acted through multiple pathways, including CDKAL1, TCF7L2, ADCY5 and MACF1. Reduced fetal growth may be driven by lipodystrophy-related insulin resistance and IFG-related insulin deficiency pathways. Targeting pregnant women with high type 2 diabetes PRS/pPRS and prescribing interventions to reduce their post-load hyperglycaemia and BMI may help reduce offspring risk of LGA.

Gestational diabetes (GDM) is associated with long-term risk for type 2 diabetes (T2D). We evaluated metabolic characteristics and β-cell function during pregnancy and at 12 months postpartum among individuals with varying levels of gestational glucose intolerance. This was a planned 12-month postpartum follow-up to the Gestational Diabetes Diagnostic Methods (GDM2) trial, which randomized pregnant individuals to GDM testing using either the IADPSG or Carpenter-Coustan (CC) criteria. All GDM2 participants with treated GDM (diagnosed by either CC or IADPSG), those with untreated glucose intolerance in the CC arm, and half of the participants with normal glucose tolerance were invited for 12-month follow-up. Glucose values, Stumvoll and Matsuda Indices to evaluate insulin sensitivity and resistance, the Disposition Index (DI), lipids, leptin, and adiponectin were assessed at 12-months postpartum. . Of the 407 individuals seen at 12 months, 49 (12%) had untreated glucose intolerance and 53 (13%) had treated GDM (CC and IADPSG). Both during pregnancy and at 12-months postpartum, there were significant differences in insulin sensitivity, beta cell function, dyslipidemia, and alterations in leptin and adiponectin among individuals with both untreated glucose tolerance and treated GDM when compared to those with normal glucose testing. Individuals with untreated glucose intolerance in pregnancy by the CC Criteria have impaired β-cell function and significant metabolic abnormalities at 12 months postpartum similar to individuals with treated GDM, highlighting the need for ongoing preventive attention in this population to prevent T2D later in life.

Ketoacidosis at childhood type 1 diabetes onset negatively affects residual beta-cell functions during the first year after diagnosis.

Early Combination Therapy versus Stepwise Escalation in Newly Diagnosed Type 2 Diabetes: A Systematic Review and Meta-Analysis of Multiple Clinical Outcomes.

Diabetes and malaria co-morbidity in malaria-endemic areas has significant therapeutic implications. Evidence suggests that diabetes mellitus promotes malaria pathogenicity while malaria exposure is thought to modulate blood glucose and insulin levels in diabetes mellitus. Here, we extensively reviewed clinical studies and molecular interactions underlying the diabetes mellitus and malaria coexistence. Malaria-related inflammation, oxidative stress, and immune activation disrupt insulin signaling and beta-cell function, resulting in increased hyperglycemia in diabetics. On the other hand, chronic hyperglycemia in diabetics damages the endothelium, raises oxidative stress, and impairs immunity, all of which contribute to an environment that facilitates malaria parasite survival and growth. Tumor necrosis factor-alpha (TNF-α) and insulin signaling pathways emerge as a pivotal link between malaria and diabetes, orchestrating inflammatory responses that contribute to both disease pathogenesis and metabolic dysregulation. These observations were related to higher subclinical infection rates and prolonged parasitemia links among diabetic patients in malaria-endemic areas. This bidirectional relationship could be exploited in the development of novel therapeutic strategy against both malaria and diabetes in tandem, particularly in sub-Saharan Africa, where the two diseases co-exist and are endemic.

C-peptide in polycystic ovary syndrome.

Sulfonylureas, commonly used to treat type 2 diabetes (T2D), often lose effectiveness over time when used as monotherapy; however, the underlying mechanisms remain unclear. To investigate the mechanisms of sulfonylurea failure, glibenclamide-releasing pellets were implanted in KK mice, a polygenic model that spontaneously develops T2D. KK mice receiving placebo pellets (KK-Placebo) developed hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance. Notably, KK mice implanted with glibenclamide (KK-Glib) showed improved blood glucose levels during the first 7 days, returning to KK-Placebo levels thereafter. KK-Glib mice exhibited reduced plasma insulin levels and insulin secretion in response to a glucose challenge compared with the markedly elevated levels in KK-Placebo mice. KK-Glib mice showed islet hypertrophy, reduced β-cell mass and number, and increased α-cell number, resulting in elevated α:β cell ratio compared with KK-Placebo. Although mRNA expression of β-cell identity markers remained unchanged, their protein levels were reduced in KK-Glib, suggesting β-cell identity loss, which may underlie the observed impaired insulin secretion. Remarkably, KK-Glib mice showed elevated mRNA levels of Ngn3 (dedifferentiation) and α-cell identity markers along with glucagon content, suggesting α-cell neogenesis. These findings suggest that secondary failure of sulfonylurea therapy may, in part, result from loss of β-cell identity-function and increased α-cell number-identity.