Insulin Resistance In Type 2 Diabetes Mellitus Research Articles

Dysregulation of brain insulin signaling: A mechanistic link between diabetes and Alzheimer's disease

Brain glucose uptake and utilization are impaired in Alzheimer's disease (AD). Type 2 diabetes mellitus (T2DM), which is characterized by deficient glucose uptake and utilization in the periphery due to insulin resistance, increases the risk for AD, but the underlying mechanism linking T2DM and AD is not understood. This study was aimed to understand whether brain insulin resistance is the link between T2DM and AD, which could contribute to AD via down-regulation of insulin-PI3K-AKT signaling. Autopsied frontal cortices from 9 AD, 10 T2DM, 8 T2DM-AD and 7 control cases were included in this study. All the groups had similar postmortem intervals (2.7 ± 0.6 hours) and ages (82.3 ± 4.9 years), The levels of the various components of the insulin-PI3K-AKT signaling pathway [including insulin receptor, insulin receptor substrate-1, phosphoinositide 3-kinase (PI3K), 3-phosphoinositide-dependent kinase-1, protein kinase B (AKT) and glycogen synthase kinase-3β (GSK-3β)], total tau, phosphorylated tau, and calpain I were determined by quantitative Western blots. The activities of the insulin-PI3K-AKT signaling components were estimated by measuring the levels of the active/phosphorylated forms of the proteins. We found down-regulation of both the levels and activities of several components of the insulin-PI3K-AKT signaling pathway in the postmortem brains from individuals with T2DM or with AD. The deficiency of insulin-PI3K-AKT signaling was more severe in those individuals suffering from both T2DM and AD. The down-regulation of insulin-PI3K-AKT signaling was accompanied by activation of GSK-3β, the major tau kinase in the brain. The levels and the activation of the insulin-PI3K-AKT signaling components were correlated negatively with the level of tau phosphorylation at several abnormal phosphorylation sites and with the activation of calpain I in the brain. Our results suggest that the down-regulation of insulin-PI3K-AKT signaling, which appeared to be caused by calpain over-activation, might be the mechanistic link between T2DM and AD. Brain insulin resistance in T2DM may increase the risk for AD by decreased insulin-PI3K-AKT signaling and the consequent promotion of abnormal tau hyperphosphorylation and neurodegeneration.

Effects of Pioglitazone on Intramyocellular Fat Metabolism in Patients with Type 2 Diabetes Mellitus

Lipotoxicity (increased tissue fat content) has been implicated in the development of muscle insulin resistance and type 2 diabetes mellitus (T2DM). The aim was to study the effect of pioglitazone on intramyocellular fat metabolism. Twenty-four T2DM subjects (glycosylated hemoglobin = 8.3 +/- 0.4%) participated in three similar study protocols before and after 4 months of 45 mg/d pioglitazone treatment: 1) 3-h euglycemic insulin (80 mU/m(2) . min) clamp with measurement of intramyocellular fat with proton nuclear magnetic resonance; 2) vastus lateralis muscle biopsy for measurement of LC-FACoAs 60 min before start of the insulin clamp; and 3) muscle biopsy for measurement of diacylglycerol 60 min before start of the insulin clamp. In all three protocols, pioglitazone similarly reduced (all P < 0.05) the glycosylated hemoglobin (Delta = 0.8-1.2%), fasting plasma glucose (39-76 mg/dl), fasting free fatty acid (132-236 mumol/liter), and increased insulin-stimulated glucose disposal (by 25-56%). Intramyocellular fat (protocol I) declined from 1.5 to 0.9% (P < 0.05) and correlated with the increase in glucose disposal rate (r = 0.65; P < 0.05). Long chain-fatty acyl-coenzyme A decreased from 12.5 to 8.1 nmol/g (P < 0.05) and correlated with the increase in disposal rate (r = 0.76; P < 0.05). Pioglitazone therapy had no effect on muscle diacylglycerol content. Pioglitazone improves insulin resistance in T2DM in association with mobilization of fat and toxic lipid metabolites out of muscle.

The Effect of APOC3 Promoter Polymorphisms on the Risk of Hypertriglyceridemia in Chinese Han Population With or Without Type 2 Diabetes Mellitus

Background: Promoter polymorphisms in the apolipoprotein C3 (APOC3) gene are associated with hypertriglyceridemia (HTG), which is a complication of Type 2 Diabetes Mellitus (T2DM). Because there is a strong insulin resistance in T2DM, it is essential to investigate whether the APOC3 promoter variation affects plasma lipid profiles in the population with or without T2DM. Methods: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed to detect the genotypes of APOC3. The levels of serum lipid profiles were also studied by biochemical methods. Results: In the control group, the prevalence of the −455CC or −482TT variants was higher in persons with HTG compared to those with normal triglyceride (NTG). Compared with the most common genotype, −455TT or −482CC, the variants had a significantly increased HTG risk in this population. However, a similar association was not found in the T2DM group. Conclusions: There was no relationship between promoter rare allele −455C or −482T of APOC3 gene and HTG in T2DM, but both the rare alleles contributed to an increased risk of HTG in the control group without T2DM.

Dysregulation of Glycogen Synthase COOH- and NH2-Terminal Phosphorylation by Insulin in Obesity and Type 2 Diabetes Mellitus

Insulin-stimulated glucose disposal is impaired in obesity and type 2 diabetes mellitus (T2DM) and is tightly linked to impaired skeletal muscle glucose uptake and storage. Impaired activation of glycogen synthase (GS) by insulin is a well-established defect in both obesity and T2DM, but the underlying mechanisms remain unclear. Insulin action was investigated in a matched cohort of lean healthy, obese nondiabetic, and obese type 2 diabetic subjects by the euglycemic-hyperinsulinemic clamp technique combined with muscle biopsies. Activity, site-specific phosphorylation, and upstream signaling of GS were evaluated in skeletal muscle. GS activity correlated inversely with phosphorylation of GS site 2+2a and 3a. Insulin significantly decreased 2+2a phosphorylation in lean subjects only and induced a larger dephosphorylation at site 3 in lean compared with obese subjects. The exaggerated insulin resistance in T2DM compared with obese subjects was not reflected by differences in site 3 phosphorylation but was accompanied by a significantly higher site 1b phosphorylation during insulin stimulation. Hyperphosphorylation of another Ca(2+)/calmodulin-dependent kinase-II target, phospholamban-Thr17, was also evident in T2DM. Dephosphorylation of GS by phosphatase treatment fully restored GS activity in all groups. Dysregulation of GS phosphorylation plays a major role in impaired insulin regulation of GS in obesity and T2DM. In obesity, independent of T2DM, this is associated with impaired regulation of site 2+2a and likely site 3, whereas the exaggerated insulin resistance to activate GS in T2DM is linked to hyperphosphorylation of at least site 1b. Thus, T2DM per se seems unrelated to defects in the glycogen synthase kinase-3 regulation of GS.

A role of vitamin D in low-intensity chronic inflammation and insulin resistance in type 2 diabetes mellitus?

Evidence from different directions, including observational and experimental studies, points to a role of vitamin D status in low-intensity chronic inflammation and insulin resistance in type 2 diabetes mellitus (T2DM). It has been recognised that insulin resistance and low-intensity chronic inflammation are risk factors for T2DM. Thus, vitamin D status can be implicated in the aetiology of TD2M. It is suggested that the relationship between vitamin D and low-intensity chronic inflammation and insulin resistance in T2DM can be mediated in part by the immune-modulating properties of the active form of vitamin D (1-alpha,25-dihydroxyvitamin D3; 1,25(OH)2D3), which is able to down regulate the production of pro-inflammatory cytokines - particularly TNF-alpha, and IL-6. However, an association between vitamin D status and these features, which is independent of BMI, has been also reported. Non-calcaemic effects of vitaminD can be associated with health outcomes other than those traditionally attributed to the vitamin.

Genetic Association, Post-translational Modification, and Protein-Protein Interactions in Type 2 Diabetes Mellitus

Type 2 diabetes mellitus is a complex disorder with a strong genetic component. Inherited complex disease susceptibility in humans is most commonly associated with single nucleotide polymorphisms. The mechanisms by which this occurs are still poorly understood. Here we focus on analyzing the effect of a set of disease-causing missense variations of the monogenetic form of Type 2 diabetes mellitus and a set of disease-associated nonsynonymous variations in comparison with that of nonsynonymous variations without any experimental evidence for association with any disease. Analysis of different properties such as evolutionary conservation status, solvent accessibility, secondary structure, etc. suggests that disease-causing variations are associated with extreme changes in the value of the parameters relating to evolutionary conservation and/or protein stability. Disease-associated variations are rather moderately conserved and have a milder effect on protein function and stability. The majority of the genes harboring these variations are clustered in or near the insulin signaling network. Most of these variations are identified as potential sites for post-translational modifications; certain predictions have already reported experimental evidence. Overall our results indicate that Type 2 diabetes mellitus may result from a large number of single nucleotide polymorphisms that impair modular domain function and post-translational modifications involved in signaling. Our emphasis is more on conserved corresponding residues than the variation alone. We believe that the approach of considering a stretch of peptide sequence involving a polymorphism would be a better method of defining the role of the polymorphism in the manifestation of this disease. Because most of the variations associated with the disease are rare, we hypothesize that this disease is a "mosaic model" of interaction between a large number of rare alleles and a small number of common alleles along with the environment, which is little contrary to the existing common disease common variant model.

Tumor necrosis factor alpha and insulin resistance in obese type 2 diabetic patients.

The relationship between basal serum tumor necrosis factor alpha (TNFalpha) levels and peripheral tissue (muscle) sensitivity to insulin was examined in 63 subjects with normal glucose tolerance (NGT), 18 subjects with impaired glucose tolerance (IGT), and 123 patients with type 2 diabetes mellitus (T2DM). The BMI was similar in NGT (28.8+/-0.7 kg/m(2)), IGT (31.1+/-1.0), and T2DM (30.0+/-0.4) groups. The fasting serum TNFalpha concentration in T2DM (4.4+/-0.2 pg/ml) was significantly higher than in NGT (3.1+/-0.2) and IGT (3.4+/-0.2; both P<0.05). In T2DM the fasting plasma glucose (FPG=183+/-5 mg/dl) and insulin (FPI=17+/-1 micro U/ml) concentrations were significantly higher than in NGT (FPG=95+/-1; FPI=10+/-1) and IGT (FPG=100+/-2; FPI=13+/-1; all P<0.01). The rate of total body insulin-mediated glucose disposal (Rd; 40 mU/m(2) min euglycemic insulin clamp in combination with (3)H-glucose) was reduced in T2DM (102+/-3 mg/m(2) min) compared with NGT (177+/-10) and IGT (151+/-14; both P<0.01). The serum TNFalpha concentration was inversely correlated with Rd (r=-0.47, P<0.0001) and positively correlated with both FPG (r=0.32, P=0.004) and FPI (r=0.32, P=0.004) in NGT plus IGT. No correlation was observed between serum TNFalpha and Rd (r=-0.02), FPG (r=0.15), or FPI (r=0.15) in T2DM. In stepwise multiple regression analysis using age, sex, BMI, FPG, FPI and serum TNFalpha concentration as independent variables, only BMI and serum TNFalpha concentration were significant and independent predictors of Rd (r(2)=0.29, P<0.0001) in the NGT plus IGT group, while FPG and FPI were significant and independent predictors of Rd (r(2)=0.13, P<0.0001) in T2DM. These results suggest that: (i) an increase in circulating TNFalpha concentration is associated with peripheral insulin resistance and increased plasma glucose and insulin levels prior to the onset of type 2 diabetes; and (ii) the further deterioration in peripheral insulin resistance in T2DM (compared with NGT and IGT) is unrelated to the increase in serum TNFalpha concentration.