monocrotophos and Insulin-Resistance

Earlier, we demonstrated that chronic exposure to monocrotophos (MCP) elicits insulin resistance in rats along with increased white adipose tissue (WAT) weights. This study was carried out to delineate the biochemical and molecular changes in adipose tissues of rats subjected to chronic exposure to MCP (0.9 and 1.8 mg/kg bw/d for 180 days). Pesticide-treated rats exhibited increased fasting glucose and hyperinsulinemia as well as dyslipidemia. Tumor necrosis factor-alpha and leptin levels were elevated, while adiponectin level was suppressed in plasma of treated rats. MCP treatment caused discernable increase in the weights of perirenal and epididymal WAT. Acetyl coenzyme A carboxylase, fatty acid synthase, glyceraldehyde-3-phosphate dehydrogenase, lipin-1, and lipolytic activities were elevated in the WAT of MCP-treated rats. Corroborative changes were observed in the expression profile of proteins that are involved in lipogenesis and adipose tissue differentiation. Our results clearly demonstrate that long-term exposure to organophosphorus insecticides (OPIs) such as MCP has far-reaching consequences on metabolic health as evidenced by the association of adipogenic outcomes with insulin resistance, hyperinsulinemia, endocrine dysregulations, and dyslipidemia. Taken together, our results suggest that long-term exposure to OPI may be a risk factor for metabolic dysregulations.

Topics: Adipose Tissue, White; Animals; Blood Glucose; Homeostasis; Hyperinsulinism; Hypoglycemia; Insecticides; Insulin Resistance; Lipids; Lipolysis; Male; Metabolic Diseases; Monocrotophos; Rats; Rats, Wistar; Weight Gain

In our previous study, we demonstrated the potential of monocrotophos (MCP), an organophosphorus insecticide (OPI), to induce glucose intolerance, insulin resistance (IR), and dyslipidemia with hyperinsulinemia in rats after chronic exposure. As hyperinsulinemia is likely to exert an impact on hepatic lipid metabolism, we carried out this study to establish the effect of chronic MCP exposure (0.9 and 1.8 mg/kg/day for 180 days) on hepatic lipid metabolism in rats. The state of IR induced by MCP in rats was associated with an increase in the liver lipid content (triglyceride and cholesterol) and expression levels of sterol regulatory element-binding proteins, PPARγ, acetyl-CoA carboxylase, and fatty acid synthase in the liver. Similarly, activities of key enzymes (acetyl-COA carboxylase, fatty acid synthase, lipin 1, malic enzyme, glucose-6-phosphate dehydrogenase, and glycerol-3-phosphate dehydrogenase), which regulate lipogenesis, were enhanced in livers of pesticide-treated rats. A strong correlation was observed between insulin levels, hepatic lipid content, and plasma lipid profile in treated rats. Our study suggests that long-term exposure to OPIs not only has a propensity to induce a state of hyperinsulinemic IR, but it is also associated with augmented hepatic lipogenesis, which may explain dyslipidemia induced by chronic exposure to MCP.

Topics: Animals; Insulin Resistance; Lipid Metabolism; Liver; Male; Monocrotophos; Rats; Rats, Wistar

Our previous findings clearly suggested the role of duration of exposure to monocrotophos (MCP) in the development of insulin resistance. Rats exposed chronically to MCP developed insulin resistance with hyperinsulinemia without overt diabetes. In continuation of this vital observation, we sought to delineate the biochemical mechanisms that mediate heightened pancreatic β-cell response in the wake of MCP-induced insulin resistance in rats. Adult rats were orally administered (0.9 and 1.8mg/kgb.w/d) MCP for 180days. Terminally, MCP-treated rats exhibited glucose intolerance, hyperinsulinemia, and potentiation of glucose-induced insulin secretion along with elevated levels of circulating IGF1, free fatty acids, corticosterone, and paraoxonase activity. Biochemical analysis of islet extracts revealed increased levels of insulin, malate, pyruvate and ATP with a concomitant increase in activities of cytosolic and mitochondrial enzymes that are known to facilitate insulin secretion and enhanced shuttle activities. Interestingly, islets from MCP-treated rats exhibited increased insulin secretory potential ex vivo compared to those isolated from control rats. Further, MCP-induced islet hypertrophy was associated with increased insulin-positive cells. Our study demonstrates the impact of the biological interaction between MCP and components of metabolic homeostasis on pancreatic beta cell function/s. We speculate that the heightened pancreatic beta cell function evidenced may be mediated by increased IGF1 and paraoxonase activity, which effectively counters insulin resistance induced by chronic exposure to MCP. Our findings emphasize the need for focused research to understand the confounding environmental risk factors which may modulate heightened beta cell functions in the case of organophosphorus insecticide-induced insulin resistance. Such an approach may help us to explain the sharp increase in the prevalence of type II diabetes worldwide.

Topics: Adaptation, Physiological; Adenosine Diphosphate; Adenosine Triphosphate; Animals; Blood Glucose; Insecticides; Insulin; Insulin Resistance; Insulin-Secreting Cells; Malates; Male; Monocrotophos; Pyruvic Acid; Rats, Wistar

Our earlier studies had shown that monocrotophos (MCP), an organophosphorus insecticide (OPI), has the propensity to augment the secondary complications associated with type-1 diabetes. The present study investigates whether rats exposed for prolonged periods to monocrotophos would develop insulin resistance mediated by alteration in glucose homeostasis.. Male rats were administered sublethal doses of monocrotophos daily for 180 days. Interim blood samples were collected to measure alteration in blood glucose and lipid profile. Rats were also subjected to glucose and insulin tolerance test and fasting blood glucose and insulin levels were measured to calculate insulin resistance by HOMA-IR method. After 180 days, the rats were also evaluated for pancreatic histology and activities of hepatic gluconeogenetic enzymes.. Monocrotophos elicited a gradual and sustained increase in blood glucose and insulin resistance in rats with concomitant glucose intolerance and reduced insulin sensitivity. MCP exposure was also associated with increase in weights of key white adipose pads, activities of gluconeogenesis enzymes and increase in pancreatic islet diameter, all of which led to hyperglycemia, hyperinsulinemia and dyslipidaemia.. Long-term exposure of rats to MCP resulted in glucose intolerance with hyperinsulinemia, a hallmark of insulin resistance. Our data suggest that chronic exposure to low doses of monocrotophos, might lead to development of insulin resistance by altering lipid profile and glucose homeostasis.

Topics: Animals; Blood Glucose; Glucose Intolerance; Hyperglycemia; Hyperinsulinism; Insecticides; Insulin Resistance; Islets of Langerhans; Lipids; Male; Monocrotophos; Rats; Rats, Wistar