Worsening baroreflex sensitivity on progression to type 2 diabetes: localized vs. systemic inflammation and role of antidiabetic therapy

Abstract

Cardiac autonomic neuropathy (CAN) is an early cardiovascular manifestation of type 2 diabetes (T2D) that constitutes an independent risk factor for cardiovascular mortality and morbidity. Nevertheless, its underlying pathophysiology remains poorly understood. We recently showed that localized perivascular adipose tissue (PVAT) inflammation underlies the incidence of parasympathetic CAN in prediabetes. Here, we extend our investigation to provide a mechanistic framework for the evolution of autonomic impairment as the metabolic insult worsens. Early metabolic dysfunction was induced in rats fed a mild hypercaloric diet. Two low-dose streptozotocin injections were used to evoke a state of late decompensated T2D. Cardiac autonomic function was assessed by invasive measurement of baroreflex sensitivity using the vasoactive method. Progression into T2D was associated with aggravation of CAN to include both sympathetic and parasympathetic arms. Unlike prediabetic rats, T2D rats showed markers of brainstem neuronal injury and inflammation as well as increased serum levels of IL-1b. Experiments on PC12 cells differentiated into sympathetic-like neurons demonstrated that brainstem injury observed in T2D rats resulted from exposure to possible pro-inflammatory mediators in rat serum rather than a direct effect of the altered metabolic profile. CAN and the associated cardiovascular damage in T2D only responded to combined treatment with insulin to manage hyperglycemia in addition to a non-hypoglycemic dose of metformin or pioglitazone providing an anti-inflammatory effect, coincident with the effect of these combinations on serum IL-1b. Our present results indicate that CAN worsening upon progression to T2D involves brainstem inflammatory changes likely triggered by systemic inflammation.

Modulatory Effect of Intermittent Fasting on Adipose Tissue Inflammation: Amelioration of Cardiovascular Dysfunction in Early Metabolic Impairment

“…Indeed, IF (15 or 39 h fast) was found to augment AMPK phosphorylation in rats (Kajita et al, 2008). Significantly, not only has our work shown a reduced AMPK activity in cardiovascular impairment associated with early metabolic dysfunction involving PVAT inflammation in HFD-fed rats (Al-Assi et al, 2018), our results also demonstrated autophagy suppression as a possible contributor to the observed phenotype (Bakkar et al, 2020b;Fakih et al, 2020). Moreover, a lack of AMPK activity was implicated in AC hypertrophy (Villena et al, 2004).…”

“…Limited changes in the status of immune cell and adipokine secretome of these depots could be sufficient to exert profound effects on cardiovascular structure and function. Interestingly, this highlights the importance and potential utility of IF protocols in the cardiovascular outcome of early metabolic impairment where adipose inflammation plays a more important role vs. hyperglycemia being a more predominant factor in more advanced conditions of metabolic decompensation in diabetes (Elkhatib et al, 2019;Bakkar et al, 2020b).…”

“…Yet in AMPKα1 KO mice, PVAT of both HFD and control fed animals showed a massive reduction in P-AMPK, adiponectin and abolished vasorelaxation (Almabrouk et al, 2018). More recent investigation showed that not only is the occurrence of PVAT inflammation linked to the early incidence of cardiovascular manifestations associated with metabolic dysfunction, but is also necessary for the progression of cardiac autonomic insult as the metabolism deteriorates further ending up in overt hyperglycemia and diabetes (Bakkar et al, 2020b). Taken together, one can conclude that HFDinduced negative remodeling of PVAT lead to a state of cardiometabolic dysfunction.…”

Phosphorus Supplementation Mitigates Perivascular Adipose Inflammation–Induced Cardiovascular Consequences in Early Metabolic Impairment

“…The hypercaloric diet composition was based on our previous studies showing that a 12‐week feeding of an hypercaloric diet, offering ≈39% calories from fat with a 5% saturated fat content by weight, led to a nonobese prediabetic phenotype. 13 , 14 , 18 , 34 , 35 A loss of 50% of the Pi content was assumed in the previous studies because of nutrient displacement during preparation. The 2 additional groups were fed a hypercaloric diet with phosphorus content of 0.75 (Group 3; hypercaloric: 0.75) and 1.5 mg/kcal (Group 4; hypercaloric: 1.5), which are equal to and twice as much as the AIN‐recommended content.…”

“… 14 In our hands, hyperinsulinemia, dyslipidemia, and localized adipose tissue inflammation (perivascular and perirenal) were consistent observations in the rat model receiving this diet. 14 , 18 , 35 , 46 The modification of the added amounts of starch, sucrose, and oil were necessary to maintain consistency as the amount of other semisolids and powders changed, as well as achieve the desired calorie density.…”