Role of Ghrelin, Leptin, and Adipokines in Diabetes Pathogenesis
Ghrelin, leptin, and adipokines create a perpetuating cycle of metabolic dysfunction in diabetes through their dysregulated effects on insulin sensitivity, energy balance, appetite control, and glucose metabolism—with adipose tissue dysfunction driving inflammation, fibrosis, and altered adipokine release that fundamentally impairs metabolic homeostasis. 1
Core Pathophysiological Mechanisms
Adipokine dysfunction is central to diabetes pathogenesis, as adipose tissue releases leptin and adiponectin in amounts necessary for glucose metabolism, and these hormones directly influence insulin sensitivity and energy balance 1. In obesity and type 2 diabetes, adipose tissue dysfunction involves inflammation, fibrosis, disrupted angiogenesis, and alterations in adipokine release, creating a self-perpetuating cycle of disease advancement 1. Adipose tissue fibrosis is specifically associated with accumulation of the adipokine endotrophin, inflammation, and insulin resistance 1.
Leptin plays a dual role in diabetes pathogenesis: it regulates energy balance in conjunction with insulin by minimizing the impact of acute energy flux changes through balancing anabolic and catabolic hypothalamic controls 1. In type 1 diabetes, leptin levels are lower at disease onset compared to healthy controls but are rapidly restored with insulin treatment, and levels are higher in individuals on intensive versus conventional insulin therapy 1. The mechanistic importance of leptin is demonstrated by animal models where leptin expression in the hypothalamus restored euglycemia, improved renal function, and extended lifespan 1. In humans with type 1 diabetes, metreleptin therapy produced modest reductions in weight (6.6%), adipose tissue (8%), and insulin dose (15%), though without improving glycemic control 1.
Ghrelin dysregulation contributes to diabetes through appetite and insulin responsiveness pathways: ghrelin is the only known circulating orexigenic hormone that stimulates food intake, and plasma ghrelin concentrations are reduced in obesity and insulin resistance 1, 2. Ghrelin levels are reduced in both adults and children with type 1 diabetes, with an inverse relationship between ghrelin and BMI 1. Defective communication circuits between the gut and brain involving ghrelin and other enteroendocrine hormones are implicated in the pathogenesis of obesity and type 2 diabetes 1, 2.
Integrated Metabolic Control
The incretin system, particularly GLP-1, works in concert with ghrelin to regulate glucose homeostasis and body weight: GLP-1 regulates body weight by diminishing appetite and delaying gastric emptying in coordination with other satiety hormones like PYY and CCK 1, 2. In the proinflammatory, insulin-resistant state common in obesity and type 2 diabetes, the incretin effect is decreased due to increased degradation of GLP-1 by the enzyme DPP-4 1, 2. Insulin and leptin together regulate energy balance through hypothalamic controls, and importantly, similar populations of hypothalamic neurons control both food intake and pancreatic hormone impact on glucose homeostasis 1.
Adiponectin has a unique regulatory paradigm in diabetes: it correlates with insulin sensitivity in type 1 diabetes similarly to controls but at slightly higher adiponectin concentrations for a similar degree of insulin resistance 1. Adipose tissue is a primary target of insulin-sensitizing drugs, underscoring the central role of adipokine function in therapeutic interventions 1.
Clinical Implications
The leptin/ghrelin ratio is significantly altered in obesity and diabetes: obese patients demonstrate higher leptin values and leptin/ghrelin ratios compared to overweight and normal weight individuals, with changes appearing even in overweight subjects 3. Mean leptin/BMI and leptin/ghrelin/BMI ratios are significantly higher, while ghrelin/BMI ratio is significantly lower in obese and diabetic patients 3. These hormonal alterations are strongly associated with inflammatory responses, immune system function, and play crucial roles in the pathophysiology of obesity, diabetes development, and insulin resistance 4, 5.