Glucagon and autonomic responses in detection of disparate risk of cardiovascular

University Of North Texas Hlth Sci Ctr, Fort Worth TX

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Abstract

DESCRIPTION (provided by applicant): Pilot C: Patients with diabetes mellitus and/or the metabolic syndrome often present clinically with plasma insulin and glucagon concentrations that are physiologically inappropriate when evaluated in light of accompanying plasma glucose concentrations. The hyperglycemia that typically accompanies diabetes mellitus should suppress the pancreatic secretion of glucagon, yet glucagon is frequently normal or even elevated in diabetics with hyperglycemia. Glucagon aggravates the existing metabolic imbalance by further stimulating the synthesis and secretion of additional glucose. Glucagon also reduces glucose utilization by stimulating the release of fatty acids as an alternative fuel. This chronic excess in circulating glucose and fats gradually degrades normal cardiovascular function and the nerves that regulate it. In addition to the ability of glucagon to exaggerate disturbances in the production and disposal of plasma fuels, glucagon also stimulates heart rate and contractility. Although glucagon can be used episodically to support cardiac function, little is known about its contribution to heart disease when circulating glucagon is chronically elevated and/or unopposed by effective insulin. Chronic exposure to hormones typically results in target organ dysfunction. Similar responses may occur prior to the development of diabetes in susceptible individuals and/or those with metabolic syndrome. In support of this thesis, the kinetics of glucagon and insulin secretion are grossly aberrant in an animal model of the metabolic syndrome, the obese spontaneously hypertensive rat (OBSHR). Insulin is unusually high in the OBSHR and is relatively unresponsive to glucose challenge. In contrast, plasma glucagon triples during a glucose load and the very high Insulin/Glucagon (I/G) ratio plummets. Plasma glucagon falls rapidly following glucose administration in normal patients but remains elevated and may even rise in patients with diabetes mellitus. Thus, patients with metabolic syndrome/diabetes mellitus are chronically exposed to the metabolic and cardiac effects of glucagon. Cardiovascular diseases are virtually all associated with significant disturbances in the autonomic control of the heart. Indices of disturbances in vagal function are highly correlated with the survival of patients following documented coronary vascular events, sudden cardiac death and congestive heart failure. Thus, autonomic imbalance (particularly manifest as high sympathetic tone and low parasympathetic tone) is a recognized index of cardiovascular risk, but is not traditionally listed as a primary risk factor. In particular, the prompt recovery of parasympathetic reflexes has been associated with better cardiovascular outcomes in patients with coronary artery disease. The metabolic syndrome, diabetes and cardiovascular disease are disproportionately represented at higher rates among minority populations. A combination of physiologic, economic and cultural factors has been proposed to explain this increased pathology amongst African and Hispanic Americans. Most of the screening tools are complicated and costly. The proposed pilot study that follows is designed to identify and validate early markers among minority populations that might be easily used to screen large numbers of subjects in a cost effective manner. A combined measurement of autonomic and pancreatic responses in subjects with the metabolic syndrome may have significant predictive value regarding their progression into frank diabetes and subsequent risk of heart disease. Serial measurements in this regard may also be valuable in evaluating the prognosis of patients with cardiovascular events. Serial measures may also be useful for evaluating the efficacy and progress of therapeutic interventions. Once validated, the non-invasive autonomic responses may be particularly useful as first order screens to determine which subjects need more detailed follow-up studies.