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Amelioration of perivascular adipose inflammation reverses vascular dysfunction in a model of nonobese prediabetic metabolic challenge: potential role of antidiabetic drugs

      The onset of vascular impairment precedes that of diagnostic hyperglycemia in diabetic patients suggesting a vascular insult early in the course of metabolic dysfunction without a well-defined mechanism. Mounting evidence implicates adipose inflammation in the pathogenesis of insulin resistance and diabetes. It is not certain whether amelioration of adipose inflammation is sufficient to preclude vascular dysfunction in early stages of metabolic disease. Recent findings suggest that antidiabetic drugs, metformin, and pioglitazone, improve vascular function in prediabetic patients, without an indication if this protective effect is mediated by reduction of adipose inflammation. Here, we used a prediabetic rat model with delayed development of hyperglycemia to study the effect of metformin or pioglitazone on adipose inflammation and vascular function. At the end of the metabolic challenge, these rats were neither obese, hypertensive, nor hyperglycemic. However, they showed increased pressor responses to phenylephrine and augmented aortic and mesenteric contraction. Vascular tissues from prediabetic rats showed increased Rho-associated kinase activity causing enhanced calcium sensitization. An elevated level of reactive oxygen species was seen in aortic tissues together with increased Transforming growth factor β1 and Interleukin-1β expression. Although, no signs of systemic inflammation were detected, perivascular adipose inflammation was observed. Adipocyte hypertrophy, increased macrophage infiltration, and elevated Transforming growth factor β1 and Interleukin-1β mRNA levels were seen. Two-week treatment with metformin or pioglitazone or switching to normal chow ameliorated adipose inflammation and vascular dysfunction. Localized perivascular adipose inflammation is sufficient to trigger vascular dysfunction early in the course of diabetes. Interfering with this inflammatory process reverses this early abnormality.

      Abbreviations:

      AGE (Advanced glycation end-products), AMPK (AMP-dependent protein kinase), DRP1 (Dynamin-related protein 1), Erk (Extra-cellular signal regulated kinase), HC (High-calorie diet), IL-1β (Interleukin-1β), MYPT1 (Myosin light chain phosphatase targeting subunit), PVAT (Perivascular adipose tissue), ROCK (Rho A-associated kinase), TGF-β1 (Transforming growth factor β1), UCP1 (Uncoupling protein 1)
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