Insulin resistance is primarily due to an impaired insulin action in which increased pancreatic beta-cell secretory activity leads to a compensated metabolic state with chronic hyperinsulinemia. In non-insulin dependent diabetes mellitus (NIDDM) however, the augmented insulin secretion is inadequate to overcome the insulin resistance and hyperglycemia ensues. It has been suggested that either the impaired insulin action or the compensatory hyperinsulinemia may contribute to elevations in blood pressure and explain the connection between insulin resistance and hypertension but the mechanism remains obscure. The potent antihypertensive platelet-activating factor (1-0-alkyl-2-acetyl-sn- glycero-3-phosphorylcholine, PAF) is a potential link between hyperinsulinemia and hypertension. However, vasoactive eicosanoids which are antagonistic to PAF are also produced from the same precursor as PAF. It is hypothesized that the onset of hypertension associated with insulin resistance may require a long time to manifest during which time the delicate balance in the synthesis and metabolism of PAF and eicosanoids are disrupted. To examine this hypothesis, male adult Sprague-Dawley rats will be exposed to chronic hyperinsulinemia (1mU/kg/min) for periods up to 6 weeks while maintaining euglycemia (approximately 100 mg/dl) in one group and moderate hyperglycemia (approximately 200 mg/dl) in another., A control group will receive only saline. Using this model, the specific aims of this project are to examine the effect of chronic hyperinsulinemia on (l) the emergence of insulin resistance, (2) elevation of blood pressure and the vasodepressor effects of exogenous PAF and selected prostanoids in the rats that develop hypertension and (3) production of renal PAF and selected prostanoids such as prostaglandin E2 (PGE2) and prostacyclin (PGI2). For each rat, urinary PGE2 and PGI2 and aortic PGI2 synthesis, the assessment of insulin sensitivity (using the euglycemic insulin clamp), the assay of plasma PAF, plasma acetylhydrolase and renal PAF synthetic and catabolic enzymes will be collected within a 24-hour period, at the end of 1,2,3,4,5 and 6 weeks of insulin treatment.
| Kudolo, G B; DeFronzo, R A (1999) Urinary platelet-activating factor excretion is elevated in non-insulin dependent diabetes mellitus. Prostaglandins Other Lipid Mediat 57:87-98 |
| Kudolo, G B; Koopmans, S J; Haywood, J R et al. (1997) Chronic hyperinsulinemia inhibits platelet-activating factor (PAF) biosynthesis in the rat kidney. J Lipid Mediat Cell Signal 16:23-37 |
