The aim: To establish possible associations of the insulin receptor substrate-1 (IRS-1) gene polymorphism with the severity of the metabolic syndrome components in patients with arterial hypertension (AH).

Material and methods: 187 patients with AH aged 45-55 years and 30 healthy individuals. Methods: anthropometry, reactive hyperemia, color Doppler mapping, biochemical blood analysis, HOMA-insulin resistance (IR), glucose tolerance test, enzyme immunoassay, molecular genetic method.

Results: Among hypertensive patients, 103 had abdominal obesity, 43 - type 2 diabetes, 131 - increased blood triglycerides, 19 - decreased high density lipoproteins, 59 - prediabetes (33 - fasting hyperglycemia and 26 - impaired glucose tolerance), 126 had IR. At the same time, hypertensive patients had the following distribution of IRS-1 genotypes: Gly/Gly - 47.9%, Gly/Arg - 42.2% and Arg/Arg - 10.7%, whereas in healthy individuals the distribution of genotypes was significantly different: Gly/Gly - 86.8% (p <0.01), Gly/ Arg - 9.9% (p <0.01) and Arg/Arg - 3.3% (p <0.05). Hypertensive patients with Arg/Arg and Gly/Arg genotypes had significantly higher HOMA-IR (p <0.01), glucose, insulin and triglycerides levels (p <0.05), than in Gly/Gly genotype. At the same time, body mass index, waist circumference, blood pressure, adiponectin, HDL, interleukin-6, C-reactive protein, degree of endothelium-dependent vasodilation, as well as the frequency of occurrence of impaired glucose tolerance did not significantly differ in IRS-1 genotypes.

OBJECTIVE: This study sought to identify demographic, clinical, and genetic factors that may contribute to increased insulin resistance or worsening of glycaemic control in patients with T2DM.

SETTING: This prospective cohort study included 156 patients with T2DM and severe or acute hyperglycaemia who were treated with insulin at any medical ward of the National University of Malaysia Medical Centre.

METHOD: Insulin resistance was determined using the homeostatic model assessment-insulin resistance index. Glycaemic control during the episode of hyperglycaemia was assessed as the degree to which the patient achieved the target glucose levels. The polymerase chain reaction-restriction fragment length polymorphism method was used to identify polymorphisms in insulin receptor substrate (IRS) genes.

MAIN OUTCOME MEASURE: Identification of possible predictors (demographic, clinical, or genetic) for insulin resistance and glycaemic control during severe/acute hyperglycaemia.

RESULTS: A polymorphism in IRS1, r.2963 G>A (p.Gly972Arg), was a significant predictor of both insulin resistance [odds ratios (OR) 4.48; 95 % confidence interval (CI) 1.2-16.7; P = 0.03) and worsening of glycaemic control (OR 6.04; 95 % CI 0.6-64.6; P = 0.02). The use of loop diuretics (P < 0.05) and antibiotics (P < 0.05) may indirectly predict worsening of insulin resistance or glycaemic control in patients with severe/acute hyperglycaemia.

MATERIALS AND METHODS: In silico target prediction was first employed to predict the probability of the polyphenols interacting with key protein targets related to insulin signalling, based on a model trained on known bioactivity data and chemical similarity considerations. Next, CA was investigated in in vivo studies where induced type 2 diabetic rats were treated with CA for 28 days and the expression levels of genes regulating insulin signalling pathway, glucose transporters of hepatic (GLUT2) and muscular (GLUT4) tissue, insulin receptor substrate (IRS), phosphorylated insulin receptor (AKT), gluconeogenesis (G6PC and PCK-1), along with inflammatory mediators genes (NF-κB, IL-6, IFN-γ and TNF-α) and peroxisome proliferators-activated receptor gamma (PPAR-γ) were determined by qPCR.

RESULTS: In silico analysis shows that several of the top 20 enriched targets predicted for the constituents of CA are involved in insulin signalling pathways e.g. PTPN1, PCK-α, AKT2, PI3K-γ. Some of the predictions were supported by scientific literature such as the prediction of PI3K for epigallocatechin gallate. Based on the in silico and in vivo findings, we hypothesized that CA may enhance glucose uptake and glucose transporter expressions via the IRS signalling pathway. This is based on AKT2 and PI3K-γ being listed in the top 20 enriched targets. In vivo analysis shows significant increase in the expression of IRS, AKT, GLUT2 and GLUT4. CA may also affect the PPAR-γ signalling pathway. This is based on the CA-treated groups showing significant activation of PPAR-γ in the liver compared to control. PPAR-γ was predicted by the in silico target prediction with high normalisation rate although it was not in the top 20 most enriched targets. CA may also be involved in the gluconeogenesis and glycogenolysis in the liver based on the downregulation of G6PC and PCK-1 genes seen in CA-treated groups. In addition, CA-treated groups also showed decreased cholesterol, triglyceride, glucose, CRP and Hb1Ac levels, and increased insulin and C-peptide levels. These findings demonstrate the insulin secretagogue and sensitizer effect of CA.