High‐calorie Diet Induces Vascular and Hemodynamic Abnormalities in Absence of Change in Blood Glucose or Insulin Levels: Modulation by Oral Anti‐hyperglycemic Drugs

While the effect of hyperglycemia associated with diabetes on vascular function is well‐established by experimental and clinical evidence, few studies examined the early onset vascular changes occurring within the context of diabetes development before the establishment of frank hyperglycemia. Moreover, recent clinical evidence suggests a vasculoprotective effect for anti‐hyperglycemic drugs that is not a direct consequence of their effect on blood glucose level. Thus, an early intervention with diabetic vascular complications, be it through anti‐hyperglycemic drugs or otherwise, requires an adequate understanding of the underlying pathophysiological mechanism. In this study, we used a high calorie‐fed rat model, known to develop stable fasting hyperglycemia on long‐term feeding, to study changes in vascular function prior to the development of diabetes. Rats were fed a high fat (15% saturated fat), high fructose (20%) diet for 12 weeks, at which point there was no increase in fasting serum glucose, serum insulin, nor mean arterial pressure (MAP). Aortic rings from these rats showed an increased contractile response to phenylephrine (PE) compared to rings from age‐matched control animals, with an increased sensitivity (reduced EC50). The PE‐induced contractions were resistant to Ca‐free physiological solution and appeared to be more sensitive to Rho kinase inhibition. In parallel, the hypercontractile phenotype was manifested as an increase in the pressor effect of PE upon administration in vivo with a poor reflex bradycardiac response, despite the absence of a change in basal MAP. On the other hand, aortic rings from the high‐calorie fed rats showed an impaired endothelium‐dependent relaxation in response to acetylcholine (ACh), with increased constriction with higher ACh concentrations. Cyclo‐oxygenase‐mediated relaxation appeared to be most affected in these vessels, whereas nitric oxide donor‐mediated relaxations were not affected. Both ACh‐mediated relaxation and constriction were abolished in denuded rings from high‐calorie fed rats or upon treatment with a nitric oxide synthase inhibitor. Again, the altered dilatory effect was reflected in a reduced in vivo depressor response. Histopathology and immunohistochemistry showed an increased intimal thickness of aorta from these rats together with increased TGF‐β1 and Smad 3 expression. A two‐week treatment with either pioglitazone or metformin reversed the increased contractility to PE, increased intimal thickness, and increased TGF‐β1 expression with no change in fasting serum glucose. Our results suggest that early vascular dysfunction associated with high calorie intake involve inflammatory changes that could be linked to adipose inflammation. Anti‐hyperglycemic drugs showed a possible vascular anti‐inflammatory effect that is distinct from their effect on glycemic control. Support or Funding Information Faculty of Medicine Bridge Fund, American University of Beirut