Role of Lipid Oxidation in Pathogenesis of Insulin Resistance of Obesity and Type II Diabetes

Abstract

Increased lipid oxidation is generally observed in subjects with obesity and diabetes and has been suggested to be responsible for the insulin resistance associated with these conditions. We measured, by continuous indirect calorimetry, lipid and glucose oxidation and nonoxidative glucose disposal in 82 obese subjects during a 100-g oral glucose tolerance test (OGTT) and in 26 during a euglycemic insulin (40 mU.min-1.m-2) clamp. The obese subjects were subdivided into those with normal glucose tolerance (group A), those with impaired glucose tolerance (group B), and those with overt diabetes (group C). Forty-five healthy nonobese subjects were subdivided into a young and an older control group, which were age-matched to the nondiabetic obese (groups A and B) and diabetic obese (group C) subjects, respectively. In the postabsorptive state, as well as in response to insulin stimulation (both OGTT and insulin clamp), lipid oxidation was significantly increased in all three obese groups in comparison with either young or older controls. Basal glucose oxidation was significantly decreased in obese nondiabetic and obese glucose--intolerant subjects (groups A and B) compared with age-matched controls. During the OGTT and during the insulin clamp, insulin-stimulated glucose oxidation was decreased in all three obese groups. In contrast, nonoxidative glucose disposal was markedly inhibited in nondiabetic and diabetic obese patients during the euglycemic insulin clamp but not during the OGTT. After glucose ingestion, nonoxidative glucose uptake was normal in nondiabetic obese and glucose-intolerant obese subjects and decreased in diabetic obese subjects. Statistical analysis revealed that lipid and glucose oxidation were strongly and inversely related in the basal state, during euglycemic insulin clamp, and during OGTT. The negative correlation between lipid oxidation and nonoxidative glucose uptake, although significant, was much weaker. Fasting and post-OGTT hyperglycemia were the strongest (negative) correlates of nonoxidative glucose disposal in both single and multiple regression models. We conclude that 1) reduced glucose oxidation and reduced nonoxidative glucose disposal partake of the insulin resistance of nondiabetic obese and diabetic obese individuals; 2) hyperglycemia provides a compensatory mechanism for the defect in nonoxidative glucose disposal in nondiabetic obese subjects; however, this compensation is characteristically lost when overt diabetes ensues; and 3) increased lipid oxidation may contribute, in part, to the defects in glucose oxidation and nonoxidative glucose uptake in obesity.

Prolonged fasting-induced metabolic signatures in human skeletal muscle of lean and obese men

“…As demonstrated in this study and by others [35,36], reduced insulin-stimulated glucose uptake in skeletal muscle of obese participants during 12 h of fasting is associated with increased lipid oxidation. This has been proposed in ‘the glucose fatty-acid cycle’ hypothesis by Randle et al in 1963 as the underlying mechanism for reduced insulin-stimulated glucose uptake [37].…”

Postprandial Free Fatty Acids Are Related to Total Visceral and Retroperitoneal Fat in Dibetic Men

“…In addition, after an oral fat load, a rather "physiological" condition, postprandial FFAs have been also found higher in diabetics, in accordance with previous studies suggesting elevated circulating FFAs in subjects with obesity, especially abdominal obesity (33)(34), and those with T2DM (35), compared to healthy individuals. Elevated levels of plasma FFAs may have a crucial role in the pathogenesis of T2DM by reducing the utilization of glucose in the peripheral tissues and by increasing the hepatic glucose release, as suggested by Boden G (36).…”

Coordination between Drosophila Arc1 and a specific population of brain neurons regulates organismal fat

“…5A). Numerous other metabolic changes are also consistent with obesity, including increased glycogenolysis and glucose availability, decreased glucose oxidation at the Krebs cycle level (Felber et al, 1987), higher glycerol-phosphate generation (Neschen et al, 2005), increased activity of transaminases (elevated aspartate (Hanley et al, 2004)) and accumulation of BCAA, phenylalanine and tryosine (Adams, 2011). …”