Sitagliptin lowers glucagon and improves glucose tolerance in prediabetic obese SHROB rats.

The SHROB (spontaneously hypertensive rat - obese strain) is a model of prediabetes and metabolic syndrome with insulin resistance, glucose intolerance and hypertension. Inhibitors of dipeptidyl dipeptidase IV (DPP-IV) are effective hypoglycemic agents in type 2 diabetes through potentiation of incretin hormones that act in the pancreas to increase insulin and decrease glucagon release. We sought to determine whether the DPP-IV inhibitor sitagliptin might be effective in prediabetes relative to standard therapy with the sulfonylurea glyburide, by using the SHROB model. SHROB show normal fasting glucose but are insulin resistant and hyperglucagonemic. SHROB were treated for six weeks with vehicle, sitagliptin (30 mg/kg/d) or glyburide (1 mg/kg/d) and compared with untreated lean spontaneously hypertensive rats. Body weight, food intake and fasting glucose were all unchanged in all three SHROB groups, but glucagon was reduced by 33% by sitagliptin while remaining unchanged following glyburide or vehicle. In oral glucose (6 g/kg) tolerance testing, both sitagliptin and glyburide lowered plasma glucose. Both sitagliptin and glyburide shifted peak insulin secretion earlier (30 min for glyburide and 60 min for sitagliptin but 240 min for vehicle). Only sitagliptin significantly enhanced insulin secretion. Sitagliptin is effective in normalizing excess glucagon levels and delaying exaggerated insulin secretion in response to a glucose challenge in a prediabetic model.

Therapeutic actions of allylmercaptocaptopril and captopril in a rat model of metabolic syndrome.

BACKGROUND: Hypertension often coexists with hyperlipidemia, insulin resistance, and glucose intolerance in metabolic syndrome. Allylmercaptocaptopril is a conjugate of the angiotensin-converting enzyme inhibitor captopril with allicin, an active principle in garlic with multiple beneficial actions on metabolic-syndrome abnormalities. We sought to test the hypothesis that the conjugation of allicin to captopril may confer additional therapeutic actions in metabolic disease. METHODS: We compared allylmercaptocaptopril (53.5 mg/kg/day orally for 60 days) to an equimolar dose of captopril (40 mg/kg/day) in the spontaneously hypertensive, obese rat (SHROB) model. RESULTS: Allylmercaptocaptopril prevented progressive weight gain, without a detectable effect on food intake. Both captopril and allylmercaptocaptopril lowered blood pressure, but allylmercaptocaptopril was more effective. Allylmercaptocaptopril, but not captopril, improved cardiac hypertrophy, as indicated by heart weight and ventricular-wall thickness. Allylmercaptocaptopril improved, whereas captopril impaired, oral glucose tolerance after a fast. Triglycerides were decreased by both captopril and allylmercaptocaptopril. Total cholesterol and non-HDL cholesterol were reduced by captopril but not by allylmercaptocaptopril. The SHROB rats developed severe glomerulosclerosis and renal failure. Allylmercaptocaptopril showed significant nephro-protection, as indicated by reductions in urinary protein loss, urinary protein-to-creatinine ratio, and plasma creatinine. Captopril showed the same trends and also prevented the decline of creatinine clearance. Finally, both allylmercaptocaptopril and captopril reduced the basal level of lipolysis in isolated abdominal adipocytes, and restored the response to catecholamine stimulation. CONCLUSIONS: Both captopril and allylmercaptocaptopril are effective in attenuating multiple abnormalities of metabolic syndrome. Allylmercaptocaptopril may have additional effectiveness on improving glucose tolerance, further lowering blood pressure, reducing cardiac hypertrophy, preventing weight gain, and protecting against renal disease.

Metabolic actions of angiotensin receptor antagonists: PPAR-gamma agonist actions or a class effect?

Accumulating basic and clinical data support the hypothesis that angiotensin receptor blockers have beneficial effects on glucose and lipid metabolism that are not shared by other classes of antihypertensive agents. These metabolic actions might only partially be shared by angiotensin-converting enzyme inhibitors. Specific benefits beyond those of other angiotensin receptor blockers have been claimed for telemesartan and, to a lesser extent, irbesartan based on a partial agonist action on PPAR-gamma receptors. Although the evidence is strong in vitro, specific actions not shared by other angiotensin receptor blockers have not yet been convincingly demonstrated in vivo or in clinical trials. In many cases, a full range of doses has not been compared, and the apparent superiority of telmesartan could be an artifact of its higher receptor binding affinity, greater tissue penetration owing to lipophilicity, and longer half life.

Metabolic effects of antihypertensive agents: role of sympathoadrenal and renin-angiotensin systems.

Reports of beneficial, neutral and adverse impacts of antihypertensive drug classes on glucose and lipid metabolism can be found in human data. Furthermore, mechanisms for these diverse effects are often speculative and controversial. Clinical trial data on the metabolic effects of antihypertensive agents are highly contradictory. Comparisons of clinical trials involving different agents are complicated by differences in the spectrum of metabolic disturbances that accompany hypertension in different groups of patients. Two physiological systems are predominant at the interface between metabolic and cardiovascular regulation: the sympathetic nervous system (SNS) and the renin-angiotensin system (RAS). These two systems are major targets of antihypertensive drug actions, and also mediate many of the beneficial and adverse effects of antihypertensive agents on glucose and lipid metabolism. Thiazides and beta-adrenergic antagonists can adversely affect glucose and lipid metabolism, which are frequently compromised in human essential hypertension, and increase the incidence of new cases of diabetes. Laboratory studies confirm these effects, and suggest that compensatory activation of the SNS and RAS may be one mechanism. Other antihypertensives directly targeting the SNS and RAS may have beneficial effects on glucose and lipid metabolism, and may prevent diabetes. Resolution of the controversies surrounding the metabolic effects of antihypertensive agents can only be resolved by further laboratory studies, in addition to controlled clinical trials.

The role of I(1)-imidazoline receptors and alpha(2)-adrenergic receptors in the modulation of glucose and lipid metabolism in the SHROB model of metabolic syndrome X.

Hypertension is commonly accompanied by obesity, hyperlipidemia, and insulin resistance in humans, a cluster of abnormalities known as metabolic syndrome X. With the notable exception of inhibitors of the renin-angiotensin system, which have mildly beneficial effects on insulin resistance, most antihypertensive agents worsen one or more components of metabolic syndrome X. Second-generation centrally acting antihypertensive agents such as rilmenidine and moxonidine have mixed effects on components of metabolic syndrome X, which might reflect in part actions on two different receptors: I(1)-imidazoline and alpha(2)-adrenergic. Using a rat model of metabolic syndrome X, we sought to separate the influence of these two receptors on glucose and lipid metabolism by using selective antagonists. Rilmenidine and moxonidine acutely raised glucose and lowered insulin, thereby further worsening glucose tolerance. These effects were entirely mediated by alpha(2)-adrenergic receptors. Rilmenidine and moxonidine also lowered glucagon, an effect that was mediated solely by I(1)-imidazoline receptors since it was potentiated by alpha(2)-blockade, but eliminated in the presence of I(1)-antagonists. Lowering of triglyceride and cholesterol levels followed the same pattern as glucagon, implicating I(1)-imidazoline receptors in lipid-lowering actions. Chronic treatment with moxonidine reproduced the beneficial effects on glucagon and lipids while the acute hyperglycemic response did not persist. Thus, alpha(2)-adrenergic receptors mediate an acute deterioration of glucose tolerance, whereas in contrast I(1)-imidazoline receptors appear to mediate the persistent long-term improvements in glucose tolerance. The therapeutic action of I(1)-imidazoline agonists may be primarily mediated through reduced glucagon secretion.

Plasma glucagon and free fatty acid responses to a glucose load in the obese spontaneous hypertensive rat (SHROB) model of metabolic syndrome X.

Metabolic Syndrome X is a cluster of abnormalities including insulin resistance, hyperlipidemia, hypertension, and obesity. We sought to determine if excess plasma glucagon and free fatty acids (FFA) might contribute to the insulin resistance in the obese spontaneous hypertensive rat (SHROB), a unique animal model of leptin resistance and metabolic Syndrome X. SHROB were extremely hyperinsulinemic and mildly glucose intolerant compared with lean SHR. SHROB had elevated fasting plasma glucagon and FFA, and showed paradoxical responses to an oral glucose challenge, with increased glucagon at 30 and 60 min postchallenge (200% plus minus 45% and 91% plus minus 13%, respectively; n = 9). In lean SHR, glucagon was nearly unchanged by glucose loading (<30% increase, P > 0.05; n = 5). Plasma FFA were not affected by a glucose load in SHROB, whereas SHR showed a decrease of 40% plus minus 6% (n = 5--9). The I/G molar ratio changed in opposite directions in the two genotypes, with a decrease in SHROB at 30 and 60 min, in contrast to the appropriate increase at 30 and 60 min postchallenge in the lean SHR (P < 0.01; n = 5--9). Administration of 500 ng/kg exogenous glucagon to SHR raised glucagon 56% plus minus 5% to a level that was similar to fasting SHROB. This level of circulating glucagon was sufficient to elevate glucose and insulin during the 7 hr of observation (n = 9). Based on these results, we suggest that fasting hyperglucagonemia and impaired suppression of glucagon secretion and FFA in response to an oral glucose load may contribute to insulin resistance and glucose intolerance in the SHROB model of metabolic Syndrome X.