Role of the Adipocyte, Free Fatty Acids, and Ectopic Fat in Pathogenesis of Type 2 Diabetes Mellitus: Peroxisomal Proliferator-Activated Receptor Agonists Provide a Rational Therapeutic Approach

Abstract

Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance in liver and muscle and impaired insulin secretion. Considerable evidence also implicates deranged adipocyte metabolism and altered fat topography in the pathogenesis of glucose intolerance in T2DM. 1) Fat cells are resistant to insulin's antilipolytic effect, leading to day-long elevated plasma FFA levels. Chronically increased plasma FFA stimulates gluconeogenesis, induces hepatic/muscle insulin resistance, and impairs insulin secretion in genetically predisposed individuals. These FFA-induced disturbances are referred to as lipotoxicity. 2) Dysfunctional fat cells produce excessive amounts of insulin resistance-inducing, inflammatory, and atherosclerotic-provoking cytokines and fail to secrete normal amounts of insulin-sensitizing adipocytokines. 3) Enlarged fat cells are insulin resistant and have diminished capacity to store fat. When adipocyte storage capacity is exceeded, lipid "overflows" into muscle, liver, and perhaps ␤-cells, causing muscle/ hepatic insulin resistance and impaired insulin secretion. Thiazolidinediones enhance adipocyte insulin sensitivity, inhibit lipolysis, reduce plasma FFA, and favorably influence the production of adipocytokines. Thiazolidinediones also redistribute fat within the body (decreased visceral and hepatic fat; increased sc fat) and decrease intracellular concentrations of triglyceride metabolites in muscle, liver, and ␤-cells, contributing to improvements in muscle/hepatic insulin sensitivity and pancreatic function in type 2 diabetics.

Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus

“…Consistent with previous studies in man [16][17][18][19]35], PIO in the present study enhanced adipocyte sensitivity to the antilipolytic effect of insulin, leading to a decrease in fasting plasma NEFA concentration and improved insulinmediated suppression of plasma NEFA concentration. These results are consistent with the concept that the insulin-sensitising effect of PPAR-γ agonists, at least in part, are indirect and mediated via a reduction in plasma NEFA and intramyocellular concentration of toxic lipid metabolites [1,35]. In a recent study [36], PIO was shown to enhance the clearance of very-low-density-lipoprotein (VLDL) triacylglycerol-rich particles from the circulation.…”

“…Although PPAR-α-null mice do not manifest any obvious alteration in insulin sensitivity [42], PPAR-α activation in nutritional (high-fat diet), genetic (Zucker obese fa/fa rat), and lipoatrophic (A-ZIP/ F-1) models of insulin resistance markedly improves insulin sensitivity [4,7,43] and reduces visceral fat in the two former models. Intracellular fatty acids and their derivatives interfere with insulin-stimulated glucose metabolism, through an effect on the insulin-signalling pathway, possibly by activating protein kinase C [1,44]. In rodents it has been suggested that PPAR-α activation increases fatty acid oxidation, thus decreasing intramyocellular lipid content and improving insulin sensitivity [4][5][6][7].…”

“…Peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ are members of the nuclear receptor superfamily which have been proposed to play key roles in lipid and carbohydrate metabolism [1]. PPAR-α agonists have been used to treat hypertriacylglycerolaemia and reduce cardiovascular risk [2,3].…”

JNK and Tumor Necrosis Factor-α Mediate Free Fatty Acid-induced Insulin Resistance in 3T3-L1 Adipocytes

“…In insulin-resistant states, signal transduction via the insulin receptor (IR) 2 is impaired with decreased activation of downstream obligate molecular intermediates, such as IRS-1, Akt, and PKC (1), that are involved in stimulating translocation of GLUT4 proteins to the cell surface.…”

“…Many factors have been reported to induce insulin resistance in vitro and in vivo, including lipid-and fat-derived free fatty acids (FFAs) (2). Lipid infusion and high fat feeding promote insulin-resistant states in rodents (3) and humans (4,5), and elevated plasma FFA concentrations typically correlate with obesity and decreased target tissue insulin sensitivity in humans.…”