SEARCH · Search PubMed

Results for “T2DM”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 613 records · Page 34Linked to original sources

PubMed2003

Oxidative stress status in patients with diabetes mellitus: relationship to diet.

OBJECTIVE: To investigate the relationship between dietary intakes and in vivo oxidative stress (OS) status in diabetic patients. DESIGN: Case-control study. SETTING: Outpatient-Clinic and Laboratory Endocrinology, University Antwerp. SUBJECTS AND METHODS: A total of 30 patients (24 type 1 diabetes mellitus (T1DM)/6 type 2 diabetes mellitus (T2DM) were asked to complete a 2 weekdays+1 weekend day food consumption questionnaire during the week preceding their yearly diabetes control consultation, when samples were collected for the assay of oxidative stress (OS) (blood levels of antioxidants, peroxides, malondialdehyde (MDA) and minerals). Blood samples were also collected from 25 age- and sex-matched healthy controls. RESULTS: Diabetic patients had lower glutathione (5.80+/-1.15 vs 6.75+/-1.03 micromol/g Hb in the controls, P=0.002) and higher MDA (0.687+/-0.212 vs 0.545+/-0.101 micromol/l, P=0.002). Although the group average intakes were within the Belgian RDA, intakes of fat >35% energy, fibre <15 g/1000 kcal, fruit <2 portions and vitamin E <10 mg/day were seen in more than 20 patients. Blood antioxidants did not correlate with intakes of energy, fat, protein or fibres or of their respective antioxidant. Vitamins A and E correlated with serum lipids (r=0.58, P <0.0005 between serum alpha-tocopherol and cholesterol). Blood peroxide levels were only related to intakes of saturated fat and cholesterol (P<0.05). In diabetic subjects but not in controls (P<0.05) MDA was related to glutathione and uric acid. CONCLUSIONS: In diabetic patients, blood levels of antioxidants are not related to their dietary intakes but to serum lipids. Levels of oxidative damage products are only related to intakes of saturated fats and cholesterol and to levels of endogenous antioxidants.

Adult↗

PubMed2006

Body mass index and waist circumference as determinants of coronary artery disease in Taiwanese adults with type 2 diabetes mellitus.

OBJECTIVE: This study examined the association between body mass index (BMI) and waist circumference (WC) and coronary artery disease (CAD) in Taiwanese type 2 diabetic patients. METHODS: A total of 1183 (558 men and 625 women) patients aged 62.4+/-11.6 years were studied. CAD was diagnosed by history or an electrocardiogram by Minnesota codes. RESULTS: The respective cutoffs of BMI and WC as determined by the receiver operating characteristic curves were 24.5 kg/m2 and 90 cm for men, and 25 kg/m2 and 80 cm for women. Distributions of CAD prevalence and multivariate-adjusted odds ratio (MAOR) for BMI cutoffs of 24.5 and 25 kg/m2 were quite similar in men. MAOR for WC above the respective cutoffs for men and women was 1.832 (1.267-2.648) and 1.450 (0.956-2.200, 0.05 or = 25 kg/m2 was 1.759 (1.213-2.551) and 1.471 (1.052-2.058) for men and women, respectively. Patients with BMI> or = 25 kg/m2 and WC > or = 90 cm for men or > or = 80 cm for women had the highest risk of CAD when compared to those without either risk factor, with respective MAOR of 2.053 (1.352-3.118) and 1.698 (1.071-2.691). CONCLUSION: The recommended BMI and WC cutoffs for obesity for Asian adults are associated with CAD in Taiwanese T2DM.

Adiposity↗

PubMed2006

The glucose clamp reveals an association between adiponectin gene polymorphisms and insulin sensitivity in obese subjects.

Results concerning the association of adiponectin gene polymorphisms (single-nucleotide polymorphisms, SNPs) with obesity, type 2 diabetes (T2DM), metabolic disorders and insulin resistance have not lead to definite conclusions. The aim of our study was to investigate a possible association between the -11391G>A and -11377C>G SNPs of adiponectin gene and measure of insulin sensitivity evaluated by the hyperinsulinemic-euglycemic clamp in a group of 'uncomplicated' obese subjects (with no associated comorbidities) (n=99, mean age 35 years) with a history of obesity lasting at least 10 years. The study of uncomplicated obese subjects, free of possible confounding factors that could interfere with insulin sensitivity, such as pharmacological treatment, provides a good model to assess insulin sensitivity per se. We observed that subjects homozygous for the G allele at locus -11391 had lower M (mg/kg min)/fat-free mass (FFM) index and adiponectin levels compared to subjects with GA+AA genotypes (P=0.002 and P=0.03, respectively) and subjects carrying the -11377G variant had lower M (mg/kg min)/FFM index and adiponectin levels compared to noncarriers (P=0.003 and P=0.03, respectively). Our results imply that the two promoter SNPs, -11391G>A and -11377C>G, of the adiponectin gene are associated with a reduced insulin sensitivity evaluated by hyperinsulinemic-euglycemic clamp in obese subjects.

Adiponectin↗

PubMed2005

Glucokinase and glucose homeostasis: proven concepts and new ideas.

The enzyme GK (glucokinase), which phosphorylates glucose to form glucose 6-phosphate, serves as the glucose sensor of insulin-producing beta-cells. GK has thermodynamic, kinetic, regulatory and molecular genetic characteristics that are ideal for its glucose sensor function and allow it to control glycolytic flux of the beta-cells as indicated by control-, elasticity- and response-coefficients close to or larger than 1.0. GK operates in tandem with the K(+) and Ca(2+) channels of the beta-cell membrane, resulting in a threshold for glucose-stimulated insulin release of approx. 5 mM, which is the set point of glucose homoeostasis for most laboratory animals and humans. Point mutations of GK cause 'glucokinase disease' in humans, which includes hypo- and hyper-glycaemia syndromes resulting from activating or inactivating mutations respectively. GK is allosterically activated by pharmacological agents (called GK activators), which lower blood glucose in normal animals and animal models of T2DM. On the basis of crystallographic studies that identified a ligand-free 'super-open' and a liganded closed structure of GK, on thermostability studies using glucose or mannoheptulose as ligands and studies showing that mannoheptulose alone or combined with GK activators induces expression of GK in pancreatic islets and partially preserves insulin secretory competency, a new hypothesis was developed that GK may function as a metabolic switch per se without involvement of enhanced glucose metabolism. Current research has the goal to find molecular targets of this putative 'GK-switch'. The case of GK research illustrates how basic science may culminate in therapeutic advances of human medicine.

Crystallography, X-Ray↗

PubMed2001

Genetic analysis of pancreatic duct hyperplasia in Otsuka Long-Evans Tokushima Fatty rats: possible association with a region on rat chromosome 14 that includes the disrupted cholecystokinin-A receptor gene.

An Otsuka Long-Evans Tokushima Fatty (OLETF) strain of rat spontaneously developed hyperglycemia, hyperinsulinemia, insulin resistance and mild obesity, which had been studied as animal model for type II diabetes mellitus (T2DM). Recently, we observed that this strain coincidentally developed atypical hyperplasia of the choledocho-pancreatic ductal epithelium with a complete incidence. In an effort to locate genes responsible for this hyperplasia, we prepared 288 backcross progeny from a mating between OLETF rats and BN rats (which do not develop hyperplasia), and performed a genome-wide scan using 207 polymorphic genetic markers. We observed a prominent association of hyperplasia with a region involving a marker locus D14Mit4 (P = 0.00020, Fisher's exact test) and Cckar (the cholecystokinin-A receptor gene; P = 0.00025, Fisher's exact test) which is known to be disrupted in an OLETF strain. Our findings indicated that epithelial hyperplasia of the choledocho-pancreatic duct is associated with a region on rat chromosome 14 around the Cckar gene in an additive fashion with another two susceptible loci, each on chromosome 9 and 7. This implied the possibility that Cckar deficiency could result in a predisposition towards pancreatic duct hyperplasia.

Animals↗

PubMed2003

The Ala45Thr polymorphism of BETA2/NeuroD1 gene and susceptibility to type 1 diabetes mellitus in caucasians.

It has recently been shown that mutations in BETA2/NeuroD1 are responsible for the development of type 2 diabetes mellitus (T2DM) in Caucasians. This gene is located near the IDDM7 region and one of its amino acid polymorphisms, Ala45Thr, has been associated with type 1 diabetes (T1DM) in Japanese and Danish populations. The aim of our study is to examine Ala45Thr for its role in T1DM in Caucasians. We used both population-based case-control analysis and family-based transmission/disequilibrium testing (TDT). Genotyping was carried out by the dot-blotting method using P32. Study subjects comprised 202 type 1 diabetes cases (mean age at diagnosis: 11.1 years, mean age at examination: 36.4 years) and 139 controls with normal fasting glucose. For the TDT study, allelic transmission was evaluated in 209 case family trios. The frequency of the Ala45 allele was 70.3 % in cases and 62.9 % in controls (p=0.04), and 47.5 % of cases were Ala45 homozygotes compared to 36.0 % of controls (p=0.03). The TDT component of the study did not achieve statistical significance. However, given the high frequency of this variant even among controls, exceptionally large data sets are needed to provide adequate power for this approach. Our case-control study suggests that the Ala45 variant of BETA2/NeuroD1 may be associated with T1DM in Caucasians (or in linkage disequilibrium with a causative variant). However, this finding should be confirmed by a much larger family-based study.

Adult↗

PubMed2006

Changes and relations of circulating visfatin, apelin, and resistin levels in normal, impaired glucose tolerance, and type 2 diabetic subjects.

Visfatin and apelin are two novel adipocyte- secreted hormone proposed to link obesity with insulin resistance. In this study we investigated whether plasma visfatin and apelin levels were altered in normal, impaired glucose tolerance, and type 2 diabetic subjects. We also assessed the association between plasma visfatin, or apelin and body composition, metabolic parameters, and resistin concentrations in these subjects. The visfatin levels of fasting and 2-h post-glucose load were found to be significantly decreased in diabetics compared with the controls ( P<0.05). In contrast, basal apelin levels were significantly increased in the IGT and diabetic subjects compared with the controls ( P<0.05 and P<0.01). The apelin levels of 2-h post-glucose load were significantly higher than the basal levels in every group (all P<0.05). Fasting plasma visfatin was found to correlate positively and significantly with BMI, WHR, and fasting plasma resistin, but negatively with HbA1c and 2 h OGTT glucose. Multiple regression analysis showed that WHR, HbA1c, 2 h OGTT glucose were independent related factors influencing plasma visfatin levels. Fasting plasma apelin levels correlated positively with HOMA-IR, BMI, TC, LDL-C, FBG and Fasting plasma insulin. Multiple regression analysis also showed that HOMA-IR, BMI, and TC were independent related factors influencing plasma apelin levels. The present work indicates the potential link of visfatin and apelin with the pathogenesis of insulin resistance and T2DM.

Adult↗

PubMed2006

Macroangiopathy in adults and children with diabetes: from molecular mechanisms to vascular damage (part 1).

Type 2 diabetes mellitus (T2DM) is an increasing problem in childhood; however type 1 diabetes mellitus (T1DM) remains by far the most common type of diabetes in this age group. In this review we will focus on T1DM, because this will have the greatest implication for patients diagnosed in childhood. During the atherosclerotic process, several molecular, receptorial and cellular factors provide a continous mechanism of vascular damage. In diabetic children this state seems to be enhanced and facilitated so that accelerated atherosclerosis is associated with an increased risk of cardiovascular events in respect to the non diabetic population. Hyperglycemia PER SE and associated with diabetes is an important risk factor for atherosclerosis. At present a substantial part of children with diabetes do not reach satisfactory glycemic control. Other risk factors for the development and progression of atherosclerosis may be inherited or develop in the course of the disease: hypertension, dyslipidemia, insulin resistance, obesity, cigarette smoking, physical inactivity, disturbance of platelet function, coagulation and fibrinolysis. The development and progression of atherosclerosis should be blocked at an early age, if possible. Primary prevention to all risk factors for cardiovascular disease is important and intervention is indicated if necessary. At the moment the best therapeutic strategy is to maintain metabolic control at a physiologic level and perform screening and early intervention for vascular complications.

Adult↗

PubMed2006

Macroangiopathy in adults and children with diabetes: risk factors (part 2).

Autoimmune or type 1 diabetes mellitus (T1DM), accounts for 90-95% of all cases of diabetes, while type 2 diabetes mellitus (T2DM), characterized by impaired insulin sensitivity and production, accounts for the other 5-10%. Atherosclerotic process starts during childhood and recognize several mechanisms that are activated in response to NOXIUS STIMULI and participate in a complex state which is accepted to be a chronic inflammatory state. T1DM patients, especially those with a non-optimal metabolic control, have a higher risk of developing all macrovascular complications such as myocardial infarction, stroke and silent ischemia. Macrovascular disease is mainly associated with hyperglycemia, dyslipidemia, obesity, hypertension, hypercoagulable state, cigarette smoking, lack of exercise, endothelial dysfunction, hyperhomocysteinemia and vascular wall abnormalities. In this paper we review the importance of traditional and non-traditional risk factors for macrovascular complications in children with T1DM and discuss their role in the pathogenesis of the excess cardiovascular mortality in these patients.

Adult↗

PubMed2005

Abnormal glucose tolerance is a predictor of steatohepatitis and fibrosis in patients with non-alcoholic fatty liver disease.

OBJECTIVE: The majority of patients with non-alcoholic fatty liver disease (NAFLD) have simple steatosis. A minority, however, present with non-alcoholic steatohepatitis (NASH), a condition that can lead to advanced fibrosis and cirrhosis. The frequencies of NASH and fibrosis among patients with NAFLD and sustained elevation of liver function tests (LFT) are uncertain. Our aim was to estimate these frequencies. We characterize a population with NAFLD, with special emphasis on insulin resistance and the metabolic syndrome, and study possible predictors for different stages of the disease. MATERIAL AND METHODS: All referred patients with sustained elevation of LFT, radiological evidence or clinical suspicion of fatty liver, and absence of other liver disease, were invited to participate in our study in the period June 2002 to December 2004. RESULTS: Of 129 patients who met the inclusion criteria, 88 underwent liver biopsy. NAFLD was verified in 83 of them. Among these patients, 59 (71%) had the metabolic syndrome, 41 (49%) had NASH and 36 (43%) had fibrosis. Abnormal glucose tolerance (T2DM or impaired glucose tolerance) was the only independent risk factor for NASH (OR: 3.14; 95% CI: 1.20-8.23). Independent predictors for fibrosis were abnormal glucose tolerance (OR: 3.83; 95% CI: 1.29-11.40) and body mass index (OR: 1.20; 95% CI: 1.06-1.36) per kg/m2. CONCLUSIONS: Both NASH and fibrosis are frequently present among patients with NAFLD and sustained elevation of LFT. The probability of these potentially progressive stages of NAFLD increases with the presence of abnormal glucose tolerance.

Adult↗

PubMed2025

Impact of sodium-glucose cotransporter-2 inhibitors on aging biomarkers and plasma ceramide levels in type 2 diabetes: beyond glycemic control.

BACKGROUND: Aging is a complex biological process marked by the decline of physiological functions and heightened susceptibility to chronic illnesses, notably cardiometabolic disorders. Ceramides (Cer) are lipid derivatives linked to aging and metabolic diseases. Sodium-Glucose Cotransporter-2 inhibitors (SGLT2i), widely used in managing type 2 diabetes, have an unclear impact on aging biomarkers and Cer profiles. OBJECTIVE: This study explored the association between SGLT2i use, plasma Cer levels (CerC16:0, CerC18:0, CerC22:0, CerC24:0, and CerC24:1), and aging biomarkers-Human Insulin-Like Growth Factor 1 (IGF-1), mammalian target of rapamycin (mTOR), 5-Methylcytosine (5MC), and Human H2AFX (Histone H2AX) in patients with type 2 diabetes mellitus (T2DM). METHODS: In this retrospective study, 95 participants were divided into three groups: patients on SGLT2i (n = 34), patients on non-SGLT2i anti-diabetic treatments (n = 36), and healthy controls (n = 25). Plasma Cer and aging biomarkers were quantified using Liquid Chromatography with tandem mass spectrometry (LC-MS-MS) and ELISA, respectively. Principal component analysis (PCA) assessed group-based clustering, while ANCOVA evaluated group differences with confounder adjustment. RESULTS: SGLT2i-treated patients showed significantly lower CerC16:0, CerC22:0, and CerC24:1 levels (p < 0.01) and decreased 5MC and H2AX (p < 0.05) compared to non-SGLT2i patients. IGF-1 was significantly elevated in the SGLT2i group (p < 0.01), suggesting a possible protective effect on metabolic health. PCA distinguished control from diabetic groups but revealed overlap between SGLT2i and non-SGLT2i groups. CONCLUSION: Beyond glucose control, SGLT2i may improve plasma Cer and aging markers in diabetic patients, supporting their broader therapeutic potential in aging and age-related diseases. Further large-scale studies are warranted to confirm these effects and underlying mechanisms.

Humans↗

PubMed2006

Platelet and monocyte activation by hyperglycemia and hyperinsulinemia in healthy subjects.

UNLABELLED: Type 2 diabetes mellitus (T2DM) patients have hyperglycemia and hyperinsulinemia and increased risk of atherosclerosis and acute vascular complications. We have reported elevated circulating tissue factor procoagulant activity (TF-PCA) during hyperglycemia (HG) and hyperinsulinemia (HI) in normal subjects. To evaluate the effect of hyperglycemia and hyperinsulinemia on blood cell activation, we assessed platelet CD40L and P-selectin, monocyte tissue factor (TF), and the formation of monocyte-platelet and neutrophil-platelet aggregates. These were assessed in the resting state and following activation with ADP and thrombin (SFLLRN). Healthy individuals were subjected to 24 h of hyperglycemia and hyperinsulinemia, selective hyperglycemia, selective hyperinsulinemia, or normal glucose and insulin. Platelet CD40L expression increased with high glucose/high insulin, selective hyperglycemia and selective hyperinsulinemia. Monocyte-platelet aggregates increased with high glucose/high insulin. Monocyte TF expression increased with high glucose/high insulin and with selective hyperinsulinemia. Upon stimulation with ADP and SFLLRN, monocyte-platelet and neutrophil-platelet aggregates, platelet CD40L and P-selectin, and monocyte TF increased compared to the resting state but was not different between 0 and 24 h, indicating that the responsiveness to those agonists was not altered. CONCLUSIONS: Hyperglycemia-hyperinsulinemia in healthy individuals induced platelet activation and monocyte TF expression promoting a procoagulant and proinflammatory state that may contribute to acute vascular events and atherogenesis. Platelet responsiveness to activation with ADP or SFLLRN appears not to be altered by hyperglycemia-hyperinsulinemia.

Adenosine Diphosphate↗

PubMed2026

Integrated multi-omics analyses identify an RAS-SLC11A2-associated molecular framework linking iron metabolism with PCOS-related cardiometabolic risk.

INTRODUCTION: PCOS is a common endocrine disorder with elevated cardiometabolic risk, yet the role of the renin-angiotensin system (RAS)-iron metabolism axis in this comorbidity remains unclear. We explored its underlying mechanisms and evaluated the therapeutic potential of gentiopicroside. METHODS: Integrated multi-omics analyses combining transcriptomics, single-cell RNA sequencing, Mendelian randomization, machine learning, molecular docking, and in vitro functional assays were performed to identify shared molecular pathways and therapeutic targets across PCOS, hypertension, NAFLD, and T2DM. RESULTS: SLC11A2 was consistently dysregulated in PCOS transcriptomic datasets, and associated with iron metabolism, inflammatory response and oxidative stress pathways. Genetic analyses validated RAS-related regulation in hypertension susceptibility and revealed shared genetic architecture between PCOS and cardiometabolic traits. Network and single-cell analyses characterized SLC11A2-associated molecular patterns in disease-relevant cell types; machine learning identified disease-classifying molecular signatures. Gentiopicroside alleviated inflammatory and oxidative stress phenotypes, including reduced IL-6 expression and reactive oxygen species accumulation. CONCLUSION: This study defines an RAS-SLC11A2 molecular framework linking iron metabolism dysregulation to PCOS-related cardiometabolic risk, elucidating the mechanisms connecting ovarian dysfunction, inflammation, oxidative stress and hypertension, and supports gentiopicroside as a promising therapeutic candidate.

Humans↗

PubMed2006

Association between plasma levels of heat shock protein 60 and cardiovascular disease in patients with diabetes mellitus.

AIMS: Evidence is accumulating to support the hypothesis that the release of heat shock protein (Hsp)60 into the circulation is associated with the development of coronary heart disease (CHD). As diabetes is a risk factor for CHD, it was of interest to determine Hsp60 blood levels in a cross-sectional cohort of diabetic patients, some of whom had cardiovascular disease, and relate levels to relevant biochemical markers. METHODS AND RESULTS: A total of 855 patients with T1DM or T2DM, recruited as part of the UCL Diabetes and Cardiovascular disease Study (UDACS), were assayed for plasma levels of Hsp60. Immunoreactive Hsp60 was detected in 54% of the samples, with 26% having plasma levels > 1 microg/mL. Levels of Hsp60 were higher in Caucasians than in other ethnic groupings, with 56.5% of Caucasian subjects, 37.5% of African-Caribbean subjects, and 47.1% of Indian subjects having detectable levels (P = 0.007), and with a higher proportion of non-smokers having detectable Hsp60 levels than smokers (54.9 vs. 43.5%, P = 0.01). Of note was the finding of an association between higher mean plasma levels of Hsp60 in subjects with clinically manifest cardiovascular disease and those with a history of myocardial infarction having an adjusted odds ratio of having detectable Hsp60 of 2.17 (CI 1.26-3.73). CONCLUSION: This is the first report of circulating Hsp60 levels in diabetic patients, which suggests that this secreted mitochondrial cell stress protein may be playing an unexpected role in the cardiovascular pathology associated with diabetes.

Antioxidants↗

PubMed2005

Troglitazone inhibits long-term glycation and oxidation of low-density lipoprotein.

Troglitazone (T) is a member of a new class of antidiabetic drugs termed thiazolidinediones (TZDs), which has previously been used as an anti-diabetic agent. In this study we investigated the influence of T, a ligand for PPAR-gamma receptor, on copper-catalyzed or cell-mediated oxidation of native, glycated, and glycoxidated low-density lipoprotein (LDL). A dose-dependent inhibition of copper-mediated low-density lipoprotein-oxidation, as monitored by the formation of oxidation-specific fluorescence, was observed for both native and glycated low-density lipoprotein. At the concentration of 20 microg/mL the inhibition amounted from 14.7% to 64.7% by all low-density lipoprotein forms. For glycated low-density lipoprotein we obtained the highest oxidation rate, but the most pronounced inhibition by T was found for glycoxidated low-density lipoprotein (goLDL). Inhibitory effects of T were also investigated by measurement of relative electrophoretic mobility (REM) in the concentration range of 0 to 20 microg/mL. The inhibition of 4h oxidation of native low-density lipoprotein was found in the entire concentration range, but significance was seen at 10 microg/mL. The long-term glycation and glycoxidation of low-density lipoprotein as measured by 5-hydroxymethyl-2-furaldehyde (5-HMF) formation and binding of fructosamine was found to be inhibited by T. In endothelial cell-mediated oxidation of low-density lipoprotein cytotoxicity of T in the concentration range of 0 to 160 microg/mL during 2 to 24 h oxidation was investigated. In the non-cytotoxic concentration range of 5 to 20 microg/mL, a significantly reduced liberation of isoprostane 8-epi-PGF2alpha during 24 h cell-mediated oxidation of low-density lipoprotein and its modifications was found. This inhibitory action of T was most significant in the case of goLDL and amounted to approximately 20% to 60% inhibition at 5 to 20 microg/mL T, respectively. In the concentration range of 40 to 160 microg/mL, however, T showed an increasing cytotoxic action, as evidenced by loss of cell adhesion, loss of cellular protein, morphological changes, and cell disintegration as well as by strongly enhanced troglitazone-mediated isoprostane 8-IP liberation (fivefold to sixfold). T may be used as a model to explore the thiazolidinediones' mechanism on oxidation in a more general aspect for treatment for T2DM, because T is not clinically available.

Adult↗

PubMed2026

Inflammatory Cytokines Impair Glucagon Expression and Secretion in Pancreatic α-Cells.

AIMS: Insulin resistance and obesity-associated inflammation are key drivers in the pathogenesis of Type 2 diabetes mellitus (T2DM). Whilst inflammatory cytokines are well known to impair β-cell function, their impact on pancreatic α-cells and glucagon (GCG) regulation remains poorly understood. In this study, we investigated the effects of the pro-inflammatory cytokines interleukin (IL)-1β, tumour necrosis factor (TNF)-α and interferon (IFN)-γ on GCG expression and secretion. MATERIALS AND METHODS: The viability and endocrine function of α-cell line αTC1 and isolated islets were investigated by WST-1 assay, LDH assay, qRT-PCR, Western blot analysis and ELISA. The transcriptional activity of the GCG promoter was analysed by reporter gene assays. The cellular composition of isolated islets was assessed by immunohistochemistry. RESULTS: We found that exposure of the α-cell line αTC1 to a mix of these cytokines activates cellular stress responses characterised by induction of the nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) pathway and the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Moreover, cytokine treatment markedly reduced GCG gene expression and secretion through repression of GCG promoter activity. Mechanistically, this was associated with a disrupted transcriptional network. These findings were confirmed in isolated mouse islets, where cytokine exposure significantly reduced GCG expression and secretion in islets of both male and female donors. CONCLUSIONS: Taken together, these findings indicate that inflammatory cytokines are potent modulators of α-cell function as well as GCG secretion and provide novel insights into inflammation-driven dysregulation of the endocrine function of pancreatic islets.

Glucagon-Secreting Cells↗

PubMed2026

Molecular Signature of Prediabetes With High-Risk of Diabetes Revealed by Deep Plasma Proteome.

AIMS: Prediabetes is biologically heterogeneous, but molecular subtypes linked to diabetes progression remain poorly defined. We aimed to identify plasma proteome-based subtypes of impaired fasting glucose (IFG), characterise their molecular features and assess their association with future diabetes risk. MATERIALS AND METHODS: We quantified 2584 plasma proteins using liquid chromatography-mass spectrometry in 538 IFG participants from a prospective discovery cohort (Nutrition and Health of Aging Population in China, NHAPC). Proteomic subtypes were defined by consensus clustering, linked to longitudinal changes in insulin sensitivity and incident type 2 diabetes mellitus (T2DM), which were further validated in an independent Shanghai Brain Aging Study (SBAS) cohort. RESULTS: Two reproducible IFG molecular subtypes based on plasma proteomics were identified. The high-risk subtype showed higher incident diabetes and a greater 6-year decline in insulin sensitivity and was characterised by enrichment of glycolysis/gluconeogenesis, insulin signalling and neutrophil degranulation, together with a dyslipidemic lipidomic profile indicating co-dysregulation of glucose and lipid homeostasis. The low-risk subtype demonstrated a higher complement cascade and high-density lipoprotein particle remodelling signature. In the high-risk subtype, key proteins and lipids showed stronger associations with longitudinal declines in insulin sensitivity, including PPBP, PGK1 and ALDOA, as well as PE-P 18:0/20:3 and PE-P 18:1/20:3. CONCLUSIONS: Proteome-based molecular subtyping stratifies IFG individuals with similar fasting glucose levels but distinct biology and future diabetes risk, supporting earlier and more targeted prevention.

Humans↗

PubMed2004

Skeletal muscle lipid accumulation in obesity, insulin resistance, and type 2 diabetes.

In addition to obesity, many factors, including the distribution of body fat, contribute to the development of insulin resistance and type 2 diabetes mellitus (T2DM). Lipid contained within skeletal muscle as triglyceride is a parameter of regional fat accumulation thought to be an important link among obesity, insulin resistance, and type 2 diabetes, even in the pediatric population. Intramuscular triglycerides can also be a fuel source for healthy muscle during periods of physical activity. Thus, the balance between storage and efficient utilization of muscle triglycerides is likely a key to a better understanding of the interaction between dysregulated fat and glucose metabolism by muscle in both adults and children. This review examines the evidence that muscle lipid accumulation is linked with insulin resistance and type 2 diabetes of both adults and children. In addition, we explore the potential mechanisms for muscle lipid accumulation as well as the effects of weight loss and physical activity on muscle lipid. Further defining the links between muscle lipid accumulation and insulin action should help develop more effective strategies to prevent or treat type 2 diabetes and other obesity-associated disorders.

Adipose Tissue↗