Topics in type 2 diabetes and insulin resistance.
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ABSTRACT:
SUBMITTER: Bloomgarden ZT
PROVIDER: S-EPMC2628712 | biostudies-literature | 2009 Feb
REPOSITORIES: biostudies-literature
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Project description:Global transcript profiling to identify differentially expressed skeletal muscle genes in insulin resistance, a major risk factor for Type II (non-insulin-dependent) diabetes mellitus. Compared gene expression profiles of skeletal muscle tissues from 18 insulin-sensitive versus 17 insulin-resistant equally obese, non-diabetic Pima Indians. Keywords: other
2002-12-17 | GSE121 | GEO
Project description:Type 2 diabetes (T2D) is an emerging health risk in obese children and adolescents. Both environmental (lack of physical activity, excess nutritional intake, sedentary lifestyle) and genetic factors contribute to this global epidemic. The growing prevalence of T2D in youth is also associated with a consistently increased incidence of metabolic and cardiovascular complications. Insulin resistance (IR), i.e., whole-body decreased glucose uptake in response to physiological insulin levels, determines impaired glucose homeostasis and it is recognized as cardinal trigger of T2D and cardiovascular disease in both adults and children. In particular, IR and beta-cell dysfunction lead to the persistent hyperglycemia which characterizes T2D. Indeed, both pathological states influence each other and presumably play a crucial, synergistic role in the pathogenesis of T2D, although the precise mechanisms are not completely understood. However, beta-cell dysfunction and IR induce impaired glucose metabolism, thus leading to the progression to T2D. Therefore, understanding the mechanisms correlated with the decline of beta-cell function and IR is crucial in order to control, prevent, and treat T2D in youth. This review focuses on the current knowledge regarding IR and T2D in children and adolescents and showcases interesting opportunities and stimulating challenges for the development of new preventative approaches and therapeutic strategies for young patients with T2D.
| S-EPMC7788344 | biostudies-literature
Project description:AimsTo examine candidate insulin resistance single nucleotide polymorphisms (SNPs) for associations with glycemic control, insulin resistance, BMI, and complications in an observational type 1 diabetes (T1D) cohort: the Pittsburgh Epidemiology of Diabetes Complications (EDC) study.MethodsIn 422 European-ancestry participants, we assessed associations using additive models between 15 candidate SNPs and 25-year mortality, cardiovascular disease, microalbuminuria, overt nephropathy and proliferative retinopathy, and 25-year mean HbA1c, estimated glucose disposal rate (eGDR, inverse measure of insulin resistance), and BMI.ResultsThe A allele of rs12970134 was associated with higher mean HbA1c (β = +0.34 ± 0.09, p = 0.00009) and nominally associated with worse eGDR (p = 0.02). Further analyses suggest the HbA1c association may be modified by diabetes therapy regimen: rs12970134 AA genotype was associated with higher HbA1c under non-intensive therapy conditions (<3 insulin injections/day or monitoring blood glucose<3 times/day [p = 0.004]), but not under intensive therapy (≥3 injections/day or insulin pump and monitoring glucose≥3 times/day [p = 0.71]). There were no significant associations between any SNPs and BMI or complications.Conclusionsrs12970134, near MC4R, is strongly associated with HbA1c in this cohort. Further exploration of this genomic region is warranted, as it may hold promise for discovering new therapeutic targets to improve glycemic control in T1D.
| S-EPMC7936951 | biostudies-literature
Project description:ObjectiveThis study evaluates insulin sensitivity, pancreatic beta-cell function (BCF), and the balance between the two in youth with type 2 diabetes and assesses the relationship of diabetes duration and HbA(1c) to insulin sensitivity and BCF.Research design and methodsThe subjects were 14 adolescents with type 2 diabetes and 20 obese control subjects of comparable age, BMI, body composition, and puberty. Insulin sensitivity was evaluated with a 3-h hyperinsulinemic (80 mU . m(-2) . min(-1)) euglycemic clamp. First-phase insulin secretion (FPIS) and second-phase insulin secretion (SPIS) were evaluated with a 2-h hyperglycemic (12.5 mmol/l) clamp. Fasting glucose rate of appearance was determined with the use of [6,6-(2)H(2)]glucose.ResultsFasting glucose rate of appearance was higher in type 2 diabetic patients than in obese control subjects (16.5 +/- 1.1 vs. 12.3 +/- 0.5 micromol . kg(-1) . min(-1); P = 0.002). Insulin sensitivity was lower in type 2 diabetic patients than in obese control subjects (1.0 +/- 0.1 vs. 2.0 +/- 0.2 micromol . kg(-1) . min(-1) per pmol/l; P = 0.001). Fasting insulin was higher in type 2 diabetic patients than in obese control subjects (289.8 +/- 24.6 vs. 220.2 +/- 18.0 pmol/l; P = 0.007), and FPIS and SPIS were lower (FPIS: 357.6 +/- 42.0 vs. 1,365.0 +/- 111.0 pmol/l; SPIS: 652.2 +/- 88.8 vs. 1,376.4 +/- 88.8 pmol/l; P < 0.001 for both). The glucose disposition index (GDI = insulin sensitivity x FPIS) was approximately 86% lower in type 2 diabetic patients than in obese control subjects. HbA(1c) correlated with FPIS (r = -0.61, P = 0.025) with no relationship to insulin sensitivity.ConclusionsDespite the impairment in both insulin sensitivity and BCF in youth with type 2 diabetes, the magnitude of the derangement is greater in BCF than insulin sensitivity when compared with that in obese control subjects. The inverse relationship between BCF and HbA(1c) may either reflect the impact of deteriorating BCF on glycemic control or be a manifestation of a glucotoxic phenomenon on BCF. Future studies in youth type 2 diabetes should target the natural course of beta-cell failure and means of retarding and/or preventing it.
| S-EPMC3428068 | biostudies-literature
Project description:ObjectiveThe objective of this study was to determine the role of maximum mitochondrial capacity on the variation in insulin sensitivity within a population of patients with type 2 diabetes mellitus (T2DM).Research design and methodsFifty-eight participants enrolled in a cross-sectional design: eight active controls [maximum aerobic capacity (VO(2max)) > 40 ml/kg · min], 17 healthy sedentary controls without a family history (FH-) and seven with a family history (FH+) of diabetes, four obese participants, and 21 patients with T2DM. Mitochondrial capacity was measured noninvasively using (31)P magnetic resonance spectroscopy of the vastus lateralis. Maximal ATP synthetic rate (ATP(max)) was determined from the rate of phosphocreatine (PCr) recovery after short-term isometric exercise.ResultsATP(max) was lower (P < 0.001) in T2DM and higher (P < 0.001) in active as compared with healthy sedentary FH- (active, 1.01 ± 0.2; FH-, 0.7 ± 0.2; FH+, 0.6 ± 0.1; obese, 0.6 ± 0.1; T2DM, 0.5 ± 0.2 mm ATP/sec; ANOVA P < 0.0001). Insulin sensitivity, measured by euglycemic-hyperinsulinemic (80 mIU/m(2) · min) clamp was also reduced in T2DM (P < 0.001) (active, 12.0 ± 3.2; FH-, 7.8 ± 2.2; FH+, 6.8 ± 3.5; obese, 3.1 ± 1.0; T2DM, 3.4 ± 1.6; mg/kg estimated metabolic body size · min; ANOVA P < 0.0001). Unexpectedly, there was a broad range of ATP(max) within the T2DM population where 52% of subjects with T2DM had ATP(max) values that were within the range observed in healthy sedentary controls. In addition, 24% of the T2DM subjects overlapped with the active control group (range, 0.65-1.27 mm ATP/sec). In contrast to the positive correlation between ATP(max) and M-value in the whole population (r(2) = 0.35; P < 0.0001), there was no correlation between ATP(max) and M-value in the patients with T2DM (r(2) = 0.004; P = 0.79).ConclusionsMitochondrial capacity is not associated with insulin action in T2DM.
| S-EPMC3070252 | biostudies-literature
Project description:BackgroundObesity is associated with an increased risk of insulin resistance and type 2 diabetes mellitus (T2DM). However, some obese individuals maintain their insulin sensitivity and exhibit a lower risk of associated comorbidities. The underlying metabolic pathways differentiating obese insulin sensitive (OIS) and obese insulin resistant (OIR) individuals remain unclear.MethodsIn this study, 107 subjects underwent untargeted metabolomics of serum samples using the Metabolon platform. Thirty-two subjects were lean controls whilst 75 subjects were obese including 20 OIS, 41 OIR, and 14 T2DM individuals.ResultsOur results showed that phospholipid metabolites including choline, glycerophosphoethanolamine and glycerophosphorylcholine were significantly altered from OIS when compared with OIR and T2DM individuals. Furthermore, our data confirmed changes in metabolic markers of liver disease, vascular disease and T2DM, such as 3-hydroxymyristate, dimethylarginine and 1,5-anhydroglucitol, respectively.ConclusionThis pilot data has identified phospholipid metabolites as potential novel biomarkers of obesity-associated insulin sensitivity and confirmed the association of known metabolites with increased risk of obesity-associated insulin resistance, with possible diagnostic and therapeutic applications. Further studies are warranted to confirm these associations in prospective cohorts and to investigate their functionality.
| S-EPMC6805293 | biostudies-literature
Project description:Obesity is associated with an increased risk of insulin resistance (IR) and type 2 diabetes mellitus (T2DM) which is a multi-factorial disease associated with a dysregulated metabolism and can be prevented in pre-diabetic individuals with impaired glucose tolerance. A metabolomic approach emphasizing metabolic pathways is critical to our understanding of this heterogeneous disease. This study aimed to characterize the serum metabolomic fingerprint and multi-metabolite signatures associated with IR and T2DM. Here, we have used untargeted high-performance chemical isotope labeling (CIL) liquid chromatography-mass spectrometry (LC-MS) to identify candidate biomarkers of IR and T2DM in sera from 30 adults of normal weight, 26 obese adults, and 16 adults newly diagnosed with T2DM. Among the 3633 peak pairs detected, 62% were either identified or matched. A group of 78 metabolites were up-regulated and 111 metabolites were down-regulated comparing obese to lean group while 459 metabolites were up-regulated and 166 metabolites were down-regulated comparing T2DM to obese groups. Several metabolites were identified as IR potential biomarkers, including amino acids (Asn, Gln, and His), methionine (Met) sulfoxide, 2-methyl-3-hydroxy-5-formylpyridine-4-carboxylate, serotonin, L-2-amino-3-oxobutanoic acid, and 4,6-dihydroxyquinoline. T2DM was associated with dysregulation of 42 metabolites, including amino acids, amino acids metabolites, and dipeptides. In conclusion, these pilot data have identified IR and T2DM metabolomics panels as potential novel biomarkers of IR and identified metabolites associated with T2DM, with possible diagnostic and therapeutic applications. Further studies to confirm these associations in prospective cohorts are warranted.
| S-EPMC7768025 | biostudies-literature
Project description:Type 2 diabetes (T2D) affects ~10% of the US population, a subset of whom have severe insulin resistance (SIR) (>200 units/d). Treatment of these patients with high-dose insulin presents logistical and compliance challenges. We hypothesized that mild caloric restriction would reduce insulin requirements in patients with T2D and SIR.This was a retrospective study at the National Institutes of Health Clinical Center. Inclusion criteria were as follows: T2D, and insulin dose >200 units/d or >2 units/kg/d. The intervention consisted of mild caloric restriction during a 3 to 6-day hospitalization. The major outcomes were change in insulin dose and blood glucose from admission to discharge.Ten patients met inclusion criteria. Baseline glycated hemoglobin A1c was 10.0 ± 1.6% and body mass index 38.8 ± 9.0 kg/m. Food intake was restricted from 2210 ± 371 kcal/d preadmission to 1810 ± 202 during the hospital stay (16.5% reduction). Insulin dose decreased from 486 ± 291 units/d preadmission to 223 ± 127 at discharge (44% reduction, P = 0.0025). Blood sugars decreased nonsignificantly in the fasting state (from 184 ± 85 to 141 ± 42, P = 0.20), before lunch (239 ± 68 to 180 ± 76, P = 0.057), and at bedtime (212 ± 95 to 176 ± 48, P = 0.19), and significantly decreased before dinner (222 ± 92 to 162 ± 70, P = 0.016).Mild caloric restriction, an accessible and affordable intervention, substantially reduced insulin doses in patients with T2D and SIR. Further studies are needed to determine if the intervention and results are sustainable outside of a hospital setting.
| S-EPMC4554137 | biostudies-literature
Project description:Mitochondrial diabetes (MD) is generally classified as a genetic defect of β-cells. The main pathophysiology is insulin secretion failure in pancreatic β-cells due to impaired mitochondrial ATP production. However, several reports have mentioned the presence of insulin resistance (IR) as a clinical feature of MD. As mitochondrial dysfunction is one of the important factors causing IR, we need to focus on IR as another pathophysiology of MD. In this special issue, we first briefly summarized the insulin signaling and molecular mechanisms of IR. Second, we overviewed currently confirmed pathogenic mitochondrial DNA (mtDNA) mutations from the MITOMAP database. The variants causing diabetes were mostly point mutations in the transfer RNA (tRNA) of the mitochondrial genome. Third, we focused on these variants leading to the recently described "tRNA modopathies" and reviewed the clinical features of patients with diabetes. Finally, we discussed the pathophysiology of MD caused by mtDNA mutations and explored the possible mechanism underlying the development of IR. This review should be beneficial to all clinicians involved in diagnostics and therapeutics related to diabetes and mitochondrial diseases.
| S-EPMC9855690 | biostudies-literature
Project description:In this review, we explore the concept of 'double diabetes', a combination of type 1 diabetes with features of insulin resistance and type 2 diabetes. After considering whether double diabetes is a useful concept, we discuss potential mechanisms of increased insulin resistance in type 1 diabetes before examining the extent to which double diabetes might increase the risk of cardiovascular disease (CVD). We then go on to consider the proposal that weight gain from intensive insulin regimens may be associated with increased CV risk factors in some patients with type 1 diabetes, and explore the complex relationships between weight gain, insulin resistance, glycaemic control and CV outcome. Important comparisons and contrasts between type 1 diabetes and type 2 diabetes are highlighted in terms of hepatic fat, fat partitioning and lipid profile, and how these may differ between type 1 diabetic patients with and without double diabetes. In so doing, we hope this work will stimulate much-needed research in this area and an improvement in clinical practice.
| S-EPMC3671104 | biostudies-other