The Gly972Arg Polymorphism in the Insulin Receptor Substrate-1 Gene Contributes to the Variation in insulin Secretion in Normal Glucose-Tolerant Humans

Background: Insulin is released from the pancreas in a biphasic manner in response to arterial glucose concentration. The assumption has been generally made that the 30-minute response reflected first-phase insulin release, whereas the 120-minute response reflected second-phase insulin release.Objectives: The aim of this study was to identify the defect in first and second phases of insulin secretion in pre-diabetes and newly diagnosed T2DM.Methods: This case-control study was conducted in the department of Biochemistry, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka from March 2013 to June 2014. All the study subjects (n = 94) were collected from the one point centre, BSMMU as newly diagnosed T2DM, pre-diabetes and healthy normal glucose tolerant subjects according to fasting plasma glucose and 2 hour plasma glucose status. A total of 32 newly diagnosed T2DM and 32 pre-diabetes were included on the basis of inclusion criteria as cases. Another 30 healthy normal glucose tolerant subjects were emolled as control. Fasting blood samples were collected from study subjects to estimate the plasma glucose and insulin level. Again blood samples were taken for measurement of plasma glucose and insulin level at 30 minute and 120 minute on OGTT.Results: Fasting plasma insulin was significantly higher in pre-diabetes than control and T2DM (p = 0.011). Plasma insulin at 30 minute and 120 minute of OGTT were significantly lower in T2DM than control and pre- diabetes (p = 0.001 & 0.016). The insulin secretion in first and second phases were significantly lower in T2DM patients than controls and pre-diabetes (p = 0.000). Beta-cell function was also significantly lower in T2DM than controls and pre-diabetes (p = 0.000). Median values of HOMA-IR were higher in pre-diabetes (1.68) and T2DM (1.53) than control (1.37), but not statistically significant (p = 0.153). There was significant positive correlation of both phases of insulin secretion with FPI, beta-cell function and insulin resistance in T2DM, pre-diabetes and controls.Conclusions: The study reveals that 1st and 2nd phase insulin secretory defect was detected in T2DM, but in pre-diabetes, we have failed to identify insulin secretory defects in both phases.

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Abstract 175: High Glucose Pre-treatment Suppresses Rankl-induced Macrophage Activation via Down-regulation of Glucose Uptake Through Decreased Insulin Receptor and Insulin Receptor Substrate 1 Expression

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.175 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Chitaru Kurihara ◽

Teruyoshi Tanaka ◽

Dai Yamanouchi

Keyword(s):

Insulin Receptor ◽

Glucose Uptake ◽

High Glucose ◽

Macrophage Activation ◽

Insulin Receptor Substrate ◽

Membrane Translocation ◽

Down Regulation ◽

Insulin Receptor Substrate 1 ◽

Glut 1 ◽

Normal Glucose

Background: Previous studies have suggested that the pathogenesis of abdominal aortic aneurysm (AAA) is associated with the local proteinases activation and the degradation of matrix proteins by matrix metalloproteinases (MMPs) produced from activated macrophages. One of the major features of diabetes mellitus (DM)-induced vascular pathology is severe arterial calcification. Although recent large epidemiological studies have shown that DM is an independent negative risk factor for AAA, the effects of hyperglycemia on macrophages are still controversial. We have hypothesized that hyperglycemia suppresses macrophage activation through altered glucose transportation. Methods and Results: RAW264.7 cells, a murine macrophage cell line were cultured under high glucose conditions (HG group, 15.5 mM glucose) or normal glucose conditions (NG group, 5.5 mM glucose) for 7days. Cells from both groups were then transferred to normal glucose condition and stimulated with recombinant murine sRANKL. Macrophage activation, confirmed by TRAP staining positive cells, and MMP-9 expression were induced in NG group but were significantly suppressed in HG group. Glucose uptake was increased during osteoclastogenesis in NG group but not in HG group. To elucidate the underlying mechanism for this observation, we studied glucose transporters (GLUTs). Although GLUT-1 and GLUT-3 expression were not affected in either groups, the membrane translocation of GLUT-1 was significantly increased in NG group during macrophage activation but not in HG group. Insulin receptor and insulin receptor substrate-1 (IRS-1) mRNA, known to stimulate membrane translocation of GLUT, were both decreased in HG group compared to NG group. Conclusions: Our results showed hyperglycemia suppresses macrophage activation. Our results also indicated that under normal conditions, recombinant murine sRANKL increases glucose uptake during macrophage activation. In contrast, this increase is impaired in high glucose pre-treated cells. We conclude that this impairment is due, in part, to suppressed GLUT-1 membrane translocation through down regulation of insulin receptor and IRS-1

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