The Link Between Obesity and Type 2 Diabetes
Obesity and T2D
Obesity is widely recognized as a key risk factor associated with the development of type 2 diabetes (T2D). The World Health Organization estimates that 39% of the world’s adult population is overweight (BMI ≥25) with 13% being obese (BMI≥30). T2D is a prominent morbidity emerging from this epidemic, and understanding the molecular correlation between T2D and obesity will help to guide treatment and disease prevention.
Visceral Fat and Insulin Resistance
T2D is often signaled by insulin resistance. This occurs when cells are less effective at taking up glucose, even though they’re stimulated with previously effective pancreatic insulin secretion. This dysfunction leads to elevated basal circulating glucose levels and impaired postprandial glucose clearance. The resulting hyperglycemia has detrimental effects on vitality, immunity, and healing.
Adipose tissue can play beneficial roles in metabolism and body weight maintenance, such as through secretion of the insulin sensitizing hormones leptin and adiponectin. Conversely, an abundance of visceral (abdominal) fat has a specific association with the development of insulin resistance.
Adipose tissue is the source of many factors which profoundly effect signaling and metabolism within key glucose-consuming cells, including skeletal muscle cells and hepatocytes. Paradigms are emerging to explain the causal relationship between visceral adiposity and insulin resistance leading to T2D.
Excess Adipose Tissue and Insulin Sensitivity
Excess adipose tissue is chronically proinflammatory, negatively impacting insulin sensitivity both within adipose tissue and systemically. Adipose tissue secretes numerous bioactive molecules, several of which contribute to the maintenance of a chronic inflammatory state. Two cytokines in particular play outsized roles in the subsequent development of insulin resistance:
- Tumor necrosis factorα (TNFα).
- Interleukin-6 (IL6).
Adipocytes constitutively express TNFα, with elevated circulating levels routinely found in obesity and diabetes models. TNFα is an activator of regulatory kinases JNK and IKK, which in turn are inhibitors of IRS-1, a key element of the insulin receptor signaling pathways. TNFα also augments the intracellular concentration of ceramides. In skeletal muscle cells ceramides act as mediators that disrupt insulin signaling and glucose metabolism.
Adipocytes also express the innate immune Tollike receptor 4 (TLR4), which responds to pathogenic stimuli and saturated fatty acids. This triggers release of the key inflammatory cytokine IL6, which activates regulatory protein SOCS3 in adipocytes and hepatocytes. This is turn negatively regulates the insulin receptor. Through this pathway, adipocytes may exacerbate their own insulin resistance.
Within visceral adipose tissue, a second subset of cells makes significant contributions to chronic inflammation. Circulating macrophages are recruited to adipose tissue in response to proinflammatory antigens and chemokines. The chief attractant is monocyte chemotactic protein-1 (MCP-1).
Macrophages cluster around necrotic adipocytes and polarize toward the classically activated “M1” phenotype. This creates a major reservoir for more proinflammatory TNFα and IL6. In obese individuals, up to 12% of visceral adipose tissue is made of macrophages, compared with 3% in lean individuals.
Adipose Tisssue Overflow
When excess caloric intake pushes the expandability of adipose tissue to its limit, free fatty acid efflux forces lipid storage in nonadipose tissues. Insulin-resistant adipose cells are also more lipolytic, further increasing release of free fatty acids (FFA) into circulation.
In skeletal muscle cells, FFA metabolites (including acyl-CoA and ceramides) stimulate serine/threonine kinases. These include PKC and IKK (negative regulators of the insulin receptor cascade), which diminish glucose uptake and glycogen synthesis. NFκβ is also stimulated which promotes secretion of inflammatory cytokines including IL6.
In hepatic cells, lipid oversupply alters mitochondrial function toward increased rates of βoxidation. The accompanying generation of reactive oxygen species may partially explain the mechanisms for inflammation and toxicity observed in fatty liver disease. Additionally, lipid induced augmentation of hepatic diacylglycerol activates protein kinase C. This in turn inhibits the insulin receptor cascade leading to a desuppression of gluconeogenesis from hepatic glycogen stores.
In addition to its causal role in the development of T1D, obesity also contributes to development of type 2 diabetes. Triglyceride accumulation in pancreatic islets leads to inhibition of cell division and apoptotic βcell death. This occurs through:
- Triggering the production of toxic nitric oxide.
- Direct interference with the mitochondrial respiration chain.
- Inhibition of Akt kinase, an antiapoptotic factor.
Excess adiposity contributes numerous molecular drivers for the development of T2D. These include inflammatory cytokines and free fatty acids, which impair insulin response signaling and deleteriously affect glucose metabolism by skeletal muscle, liver, and even adipose tissue itself.
Deciphering the complex involvement of adiposity in insulin resistance and hyperglycemia will uncover new targets for therapeutic intervention into T2D.