Arthur Swislocki

Insulin Resistance and Hypertension: Glucose Intolerance, Hyperinsulinemia, and Elevated Free Fatty Acids in the Lean Spontaneously Hypertensive Rat

Recent evidence suggests that insulin resistance may be a feature of essential hypertension in humans. However, there is some dispute over suitable animal models. To clarify these issues, we performed oral glucose tolerance tests in lean spontaneously hypertensive rats (SHR) as well as in age-matched normotensive rats from the parent Wistar-Kyoto (WKY) strain. In response to feeding, SHR were significantly hyperglycemic and hyperinsulinemic compared to WKY. In addition, free fatty acids were significantly higher throughout the oral glucose tolerance tests in SHR compared to WKY. Furthermore, this apparent insulin resistance occurred despite the fact that SHR were significantly leaner than age-matched WKY. When growth curves were compared for the two strains fed ad libitum, both SHR and WKY gained weight appropriately during the period of observation, although SHR were significantly lighter throughout. It is concluded that SHR express insulin resistance in terms of glucose and fatty acid metabolism, and therefore are a suitable model for insulin resistance and essential hypertension in non-obese humans. Further studies are needed to clarify the pathophysiologic defects leading to insulin resistance in these animals.

Pioglitazone attenuates basal and postprandial insulin concentrations and blood pressure in the spontaneously hypertensive rat.

Subjects with hypertension are hyperinsulinemic and resistant to insulin-stimulated glucose uptake. A similar paradigm is found in the spontaneously hypertensive rat (SHR). These findings suggest the possibility that insulin resistance and hyperinsulinemia may play an important role in blood pressure regulation. Pioglitazone, a thiazolidinedione derivative, sensitizes target tissues to insulin and decreases hyperglycemia and hyperinsulinemia in various insulin-resistant animals. The purpose of this study was to assess the influence of pioglitazone administration on pre- and postprandial glucose and insulin concentrations and determine whether changes in beta-cell secretion resulted in any change in blood pressure measurements. Twelve SHR were fed custom diets ad libitum, six with and six without pioglitazone (20 mg/kg chow). Fasting and postprandial glucose levels were unaltered by pioglitazone treatment. Fasting insulin concentrations were similar at week 1, but were significantly lower (P < .01) in the pioglitazone group at weeks 3 (1.89 +/- 0.3 v7.94 +/- 1.5 ng/mL) and 4 (4.5 +/- 1.4 v9.1 +/- 0.7 ng/mL), compared with the control group. Pioglitazone also significantly (P < .01) lowered postprandial insulin concentrations after an oral glucose challenge. Systolic, mean, and diastolic blood pressures were significantly lower (P < .01), 177 +/- 3 v190 +/- 4.7 mm Hg, 162 +/- 2.1 v175 +/- 5.9 mm Hg, and 156 +/-2.1 v168 +/- 6.2 mm Hg, respectively, in the animals receiving pioglitazone versus the control group. Heart rate, body weight, serum cholesterol, and triglyceride levels were comparable between the two groups. In conclusion, pioglitazone significantly decreased fasting and postprandial insulin concentrations and effectively lowered blood pressure in the SHR.

Oral administration of the nitric oxide biosynthesis inhibitor, N-nitro-L-arginine methyl ester (L-NAME), causes hypertension, but not glucose intolerance or insulin resistance, in rats

While essential hypertension may be characterized by insulin resistance, it is unclear which defect is primary. We therefore compared normotensive Sprague-Dawley male rats who drank N-nitro-L-arginine methyl ester (L-NAME, 1 mg/mL in distilled water), with control rats who drank distilled water. Blood pressure was measured noninvasively, weight was controlled by dietary restriction, and glucose tolerance was assessed via oral glucose tolerance tests (OGTT). Blood pressure rose by the second day of L-NAME treatment, and remained elevated throughout the study, in contrast to the rats drinking water (P < .001). Weight rose similarly in both groups. OGTT were performed after 2 weeks of L-NAME. Serum glucose and insulin responses, assessed by two-way ANOVA, were similar in the two groups (P = NS). In summary, L-NAME administration resulted in hypertension, but not a deterioration in glucose tolerance in diet-controlled Sprague-Dawley rats. We conclude that the insulin resistance of some hypertensive states is not the result of hypertension per se, or increased vasoconstriction, such as might result from inhibition of endogenous nitric oxide synthesis, but rather indicates a fundamental metabolic disorder.

Insulin resistance and hypertension.

The author has reviewed the development of the concept that insulin resistance is related not only to the hypertensive state but potentially to the initiation and maintenance of high blood pressure. Potential sequelae of insulin resistance and hyperinsulinemia, as they apply to atherogenesis, are also discussed. The impact of present antihypertensive pharmacologic therapy on insulin resistance is addressed, as are future directions in pharmacologic and nonpharmacologic management of hypertension. In addition, the author speculates on possible mechanisms leading to insulin resistance in hypertension.

Docosahexaenoic Acid Supplementation Improved Lipocentric but Not Glucocentric Markers of Insulin Sensitivity in Hypertriglyceridemic Men

BACKGROUNDnIncrease in obesity and metabolic syndrome are associated with increases in insulin resistance (IR) and type 2 diabetes mellitus. Results from animal intervention studies and human epidemiological studies suggest that n-3 polyunsaturated fatty acids can prevent and reverse IR, but results from human intervention studies have varied. Results from some human and animal studies suggest that docosahexaenoic acid (22:6n-3; DHA) may be more effective than eicosapentaenoic acid (20:5n-3; EPA) in the prevention of IR.nnnMETHODSnBy using a placebo-controlled, parallel study design, we examined the effects of DHA supplementation (3 grams/day, 90 days) in the absence of EPA on glucocentric and lipocentric markers of IR in hypertriglyceridemic men (n=14-17/group).nnnRESULTSnDHA supplementation increased fasting plasma glucose concentration by 4.7% (P<0.05), but did not alter other indices of IR based on fasting (insulin and homeostasis model assessment of insulin resistance [HOMA-IR]) or postprandial insulin and glucose concentrations (areas under curves for insulin and glucose, Matsuda index). Glucose increased by 2.7% in the placebo group and was not significant; increases in glucose in the two groups did not differ from each other. DHA decreased circulating concentrations of several lipocentric markers of IR, including plasma concentrations of nonesterified fatty acids (13.0%), small, dense low-density lipoprotein (LDL) particles (21.7%), and ratio of tryglycerides to high-density lipoprotein cholesterol (TG/HDL-C) (34.0%) (P<0.05). None of the variables changed in the placebo group.nnnCONCLUSIONSnOur results suggest that lipocentric markers of IR are more responsive to DHA supplementation than the glucocentric markers. Future studies with DHA in prediabetic subjects and direct measures of insulin sensitivity are needed.

Metabolic, hemodynamic, and cardiac effects of captopril in young, spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR) demonstrate elevated blood pressure, cardiac hypertrophy, glucose intolerance, and insulin resistance compared with age-matched Wistar-Kyoto rats (WKY). We investigated concurrent effects of captopril on blood pressure, cardiac mass, myocardial enzyme activities, glucose tolerance, and insulin action in young male SHR. At 10 weeks of age, SHR were randomized into two groups, one receiving distilled water, the other a captopril solution (50 mg/kg body weight/day). We also examined age-matched WKY receiving distilled water. Blood pressure was measured by tail-cuff during the 4-week treatment period and oral glucose tolerance was tested at the end of treatment. Hearts were weighed and ventricular tissue was assayed for activities of 3-hydroxyacyl-CoA dehydrogenase, citrate synthase, and hexokinase. Growth rates were similar between captopril-treated and control SHR, but less than those of WKY. Captopril reduced blood pressure (134 +/- 8 v 177 +/- 8 mm Hg, P < .05) and left ventricular mass (-18%, P < .05) in SHR. Cardiac enzyme activities also changed with captopril treatment, reflecting an increased capacity for beta-oxidation of fatty acids and reduced potential for glucose phosphorylation in the left ventricle of SHR. Serum concentrations of glucose, insulin, and free fatty acids after a brief fast and in response to oral glucose were not different after captopril treatment, suggesting no improvement in insulin action or glucose tolerance. In summary, treatment of young male SHR with captopril reduces blood pressure and cardiac mass, and promotes a small but significant increase in cardiac capacity for oxidation of fatty acids and reduction of glucose phosphorylation. In contrast, metabolic effects of captopril on oral glucose tolerance and insulin action were not evident.

Smokeless nicotine administration is associated with hypertension but not with a deterioration in glucose tolerance in rats

Cigarette smoking is a major risk factor for coronary heart disease. To further investigate the relationship of nicotine with other cardiac risk factors, we studied the impact of nicotine on blood pressure and glucose tolerance. Adult male Sprague-Dawley rats were randomly assigned to receive nicotine or placebo pellets implanted subcutaneously. Weight gain was controlled by pair-feeding, and was not significantly different between nicotine- and placebo-treated animals. Blood pressure (in mm Hg) increased throughout a 3-week treatment period in nicotine-treated animals and was significantly higher [P < .05 by two-way ANOVA] than in placebo-treated rats. Blood pressure returned to normal within 1 week following exhaustion of the pellets. Oral glucose tolerance tests performed 2.5 weeks after pellet placement showed similar glucose, insulin, and free fatty acid (FFA) profiles by two-way ANOVA. In summary, smokeless nicotine exposure leads to sustained but reversible hypertension without deterioration in glucose tolerance or insulin action when weight gain is controlled. We conclude that in rats smokeless nicotine adversely affects the coronary risk profile by increasing blood pressure.

Voluntary running improves glucose tolerance and insulin resistance in female spontaneously hypertensive rats

We evaluated the effects of voluntary exercise training on glucose metabolism and measures of insulin sensitivity in female spontaneously hypertensive rats (SHR). Age-matched Wistar-Kyoto rats (WKY) were used as normotensive controls. Exercising SHR were housed in running wheels for 8 weeks (SHRx8) or 16 weeks (SHRx16). At 22 weeks of age, we measured systolic blood pressure, performed oral glucose tolerance tests, and determined hexokinase activity and glucose transporter (GLUT) 4 content in skeletal muscle to assess intracellular glucose metabolism. Blood pressure was lower in WKY (139+/-12 mm Hg) than untrained SHR (216+/-13 mm Hg). Exercise training caused a reduction in blood pressure (-18 mm Hg) for SHRx8. After a brief (5-h) fast, serum glucose was lower in SHR that exercised compared with sedentary SHR, whereas insulin concentrations were identical between all SHR and WKY. Corresponding free fatty acids (FFA) were twofold higher in SHR than in WKY. In response to glucose, SHR demonstrated higher glucose and FFA responses, with exercise decreasing the glucose values in a dose-dependent manner. Although the insulin response was comparable in all groups, the glucose-to-insulin ratio was higher in SHR, indicating a relative insulin resistance for both glucose disposal and suppression of free fatty acids. Hexokinase activity and GLUT4 content were elevated 1.4- and 2.8-fold, respectively, in plantaris muscle of SHRx16, suggesting an improvement in the capacity for glucose transport and phosphorylation with exercise. These results provide evidence that voluntary running in female SHR lowers blood pressure and selectively increases glucose uptake and insulin action, but not suppression of FFA.

Pharmacotherapy for the Metabolic Syndrome

The Metabolic Syndrome (MetS) confers a greater risk for both diabetes and cardiovascular diseases. Both insulin resistance and low grade inflammation appear to be pivotal in the pathogenesis of this disorder. The cornerstone of treatment presently is therapeutic lifestyle change with the emphasis on weight loss by diet and exercise. It appears that the evidence base will support statins as first line therapy for the dyslipidemia. Also, there is a limited role for both bile acid sequestrants and fibrates in certain subgroup of patients. It would appear that the Angiotensin converting enzyme inhibitors (ACEs) and angiotensin II receptor blockers (ARBs) are the preferred therapies for hypertension but invariably a combination therapy with additional drugs is required keeping in mind that certain drugs can exacerbate the dyslipidemia and or glycemia of MetS. Whilst metformin appears to be the drug of choice for the dysglycemia, thiazolidinediones (TZDs) like pioglitazone can also be beneficial but recent concern about bladder cancer has resulted in its discontinuation in certain countries in Europe. Metformin therapy has been shown to prevent new onset MetS. Modulating the incretin axis can prove very fruitful. A drug targeting all 3 disorders would be ideal but to date does not exist.

Effects of Antihypertensives on Glucose Metabolism

Treatment with different antihypertensive drug classes has varied effects on glucose metabolism. Thiazide diuretic use in hypertensives has been associated with the development of glucose intolerance and diabetes. Some findings suggest that the probability of worsening glucose metabolism and the development of new diabetes after thiazide initiation is associated with increasing body mass index. Nonselective or beta(1) selective beta-blockers may also lead to decreased insulin sensitivity in hypertensive patients. Newer beta-blockers that cause vasodilatation and beta-blockers that have intrinsic sympathomimetic activity may not have these deleterious effects on insulin sensitivity and glucose metabolism. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers may exert beneficial effects on glycemic control through a variety of mechanisms related to the inhibition of angiotensin II. These agents may be particularly useful in patients with microalbuminuria to slow the progression of renal disease. While there may be some small differences among different classes of calcium channel blockers, there is little net effect of these agents on glucose metabolism. The prevalence of obesity, hypertension, and type 2 diabetes mellitus is increasing in the US. In this setting, it is important to individualize antihypertensive therapy and to monitor its metabolic consequences so that potential adverse effects that would negate some of the benefits of blood-pressure lowering are minimized.