RESUMO
The association of obesity with type 2 diabetes has been recognized for years. Insulin resistance induced by obesity increases the chances of developing diabetes mellitus in which insulin release is markedly reduced. In type 2 diabetes, there is a possibility that an important part of the impaired insulin secretion is due to loss of the insulinotropic effect of the gastric inhibitory polypeptide [GIP] hormone. The aim of this study was to detect changes that occur in the pancreatic GIP receptor expression and in GIP secretion in obese and type 2 diabetic rats in response to oral glucose administration and its relation to glucose and insulin plasma levels during oral glucose tolerance test [OGTT]. Three groups of rats [n=10/ group] were included in this study: A control group receiving standard chow for 10 weeks, an obese group, in which obesity was induced by feeding rats standard chow with the addition of 32% of the caloric intake as fat for 10 weeks and a type 2 diabetic group, receiving the standard chow with the addition of fructose as 66% of the caloric intake for 10 weeks. Parameters measured in all groups included: Obesity index, systolic blood pressure, serum triglycerides as well as plasma glucose, insulin and GIP levels at 0, 5, 10, 20, 60, 90 and 120min. of an OGTT and pancreatic islets GIP receptors gene expression [GIP-Rs] using PCR method. At the end of 10 weeks, the obese and diabetic groups both had significantly increased fasting plasma glucose levels and insulin resistance indices [HOMA-IR], in addition to significantly higher blood pressure and serum triglycerides levels compared to the control group, indicating the presence of insulin resistance. In addition, the obese group had a significantly increased obesity index and fasting GIP level compared to the control and diabetic groups. During the first 20min. following oral glucose intake, both the obese and the diabetic rats had a significant increase in the glucose excursion compared to that of the control group, with a more significant increase in the diabetic group compared to the obese group. Both the obese and diabetic groups had a significant decrease of early-insulin secretion compared to control, with a more significant decrease in the diabetic group compared to the obese group. During the first 20min. of the OGTT, there was also a significant increase in the incremental change of GIP from 0 to 20min [GIP delta 0-20] in the obese group [60.1 +/- 6.66pmol/L] compared to that of the control [33.96 +/- 4.69pmol/L] and the diabetic [29.34 +/- 2.62pmol/L] groups, which were not significantly different from each other. However, there was a significant decrease of GIP-Rs expression in both the obese [88.07 +/- 10.36 micro g/ml] and the diabetic [87.51 +/- 4.72 micro g/ml] groups compared to the control group [120.35 +/- 8.06 micro g/ml], indicating that the loss of the GIP insulinotropic effect in obese and diabetic rats during the first 20min. of OGTT was due to a reduction in pancreatic GIP-Rs. During the next 20 to 120min. following oral glucose load, plasma GIP was decreasing in all groups, however, the obese group had a significantly increased plasma glucose level compared to the control group and a significant hyperinsulinemia compared to the other two groups. Such hyperinsulinemia in the presence of a decreasing GIP secretion and reduced GIP-Rs indicates the possibility of up-regulation of another compensatory mechanism to overcome the GIP-Rs defect. Moreover, the diabetic group had a significantly increased plasma glucose level compared to that of the other two groups and its plasma insulin level was significantly lower than that of the control group until the 90min. interval and thereafter it showed a non-significant difference with that of the control group. This study revealed that both obese and diabetic rats had an impaired insulinotropic effect of GIP in response to oral glucose administration during OGTT due to impaired gene expression of its pancreatic receptors and not due to impaired secretion. Also there was an associated compensatory hyperinsulinemia in obese rats during the second hour of the OGTT, which may lead to exhaustion of B-cells on the long run, increasing the incidence of diabetes mellitus. Therefore GIP-Rs could be a potential target to prevent transition of obesity to diabetes and to improve insulin secretion in type 2 diabetes mellitus