Disentangling Dual Threats: Premature Coronary Artery Disease and Early-Onset Type 2 Diabetes Mellitus in South Asians

Abstract

South Asian individuals (SAs) face heightened risks of premature coronary artery disease (CAD) and early-onset type 2 diabetes mellitus (T2DM), with grave health, societal, and economic implications due to the region's dense population. Both conditions, influenced by cardiometabolic risk factors such as insulin resistance, hypertension, and central adiposity, manifest earlier and with unique thresholds in SAs. Epidemiological, demographic, nutritional, environmental, sociocultural, and economic transitions in SA have exacerbated the twin epidemic. The coupling of premature CAD and T2DM arises from increased obesity due to limited adipose storage, early-life undernutrition, distinct fat thresholds, reduced muscle mass, and a predisposition for hepatic fat accumulation from certain dietary choices cumulatively precipitating a decline in insulin sensitivity. As T2DM ensues, the β-cell adaptive responses are suboptimal, precipitating a transition from compensatory hyperinsulinemia to β-cell decompensation, underscoring a reduced functional β-cell reserve in SAs. This review delves into the interplay of these mechanisms and highlights a prediabetes endotype tied to elevated vascular risk. Deciphering these mechanistic interconnections promises to refine stratification paradigms, surpassing extant risk-prediction strategies.

Keywords: and type 2 diabetes; atherosclerosis; dyslipidemia; insulin resistance; prediabetes; premature coronary artery disease; south Asia.

Figure 1.

Proposed shared causal pathways that couple premature heart disease and type 2 diabetes mellitus (T2DM). In the context of a positive caloric imbalance stemming from excessive caloric intake and a sedentary lifestyle, fat initially accumulates in subcutaneous tissue. Once its capacity is surpassed, triglycerides are ectopically stored in the liver, skeletal muscle, and visceral adipose tissue, inducing insulin resistance (IR). This storage threshold, influenced by genetics and environment, is hypothesized to be lower in South Asian individuals. South Asians (orange-filled circles) are less insulin sensitive compared to Europeans (green-filled circle). As IR develops, plasma insulin levels initially rise (A to B on the disposition curve), then decrease due to β-cell failure (point C), leading to impaired glucose tolerance. Concurrent hyperinsulinemia triggers hepatic steatosis, very-low-density lipoprotein (VLDL) overproduction, vascular inflammation, and endothelial dysfunction. This early IR and β-cell dysfunction predispose individuals to T2DM, while prolonged exposure to atherogenic factors accelerates atherosclerosis and premature coronary artery disease. (Created with BioRender.com).