The Role of Free Fatty Acid Metabolism in the Pathogenesis of Insulin Resistance in Obesity and Noninsulin-Dependent Diabetes Mellitus*

Abstract

To investigate the mechanisms of insulin resistance in obesity and noninsulin-dependent diabetes mellitus (NIDDM), we examined oxidative and nonoxidative pathways of free fatty acid (FFA) and glucose metabolism in 14 lean and 17 obese (with normal oral glucose tolerance) nondiabetic subjects and in 8 lean and 8 obese subjects with NIDDM. FFA and glucose metabolism were measured using the sequential insulin clamp technique in combination with indirect calorimetry and infusion of [3-3H]glucose and [1-14C]palmitate. Obesity was characterized by enlarged fat mass, which correlated positively with the plasma FFA concentration (r = 0.62; P less than 0.01). FFA metabolism was less sensitive to insulin in obese than in lean nondiabetic subjects, but this defect could be overcome by increasing the plasma insulin concentration. NIDDM patients showed normal sensitivity to the inhibitory action of insulin on FFA metabolism; however, maximal suppression by insulin was impaired. The combination of obesity and NIDDM was associated with a further enhancement of reesterification of FFA than observed in either condition alone. In both obesity and NIDDM, the dose-response curve for suppression of hepatic glucose production by insulin was impaired. While obesity was primarily characterized by reduced sensitivity to the stimulatory action of insulin on oxidative and nonoxidative pathways of glucose metabolism, resistance to the effect of insulin on glucose metabolism in NIDDM was characterized by a reduced maximal response. The combination of obesity and NIDDM further impaired the sensitivity of liver glucose output and glucose oxidation to insulin. The hypothesis is advanced that in uncomplicated obesity, increased availability and oxidation of FFA leads, by the FFA/glucose cycle, to the impairment in glucose utilization. In NIDDM, on the other hand, the defect in glucose utilization is primary, and the enhanced rate of FFA oxidation may represent a compensatory phenomenon.

Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms

“…Furthermore, in this condition, hepatic insulin resistance is usually more severe and results in absolute glucose overproduction [52]. However, the NEFA turnover rate and total lipid oxidation have been reported to be only mildly abnormal in non-obese type 2 patients and in first-degree relatives of diabetic patients [53,54]. In non-diabetic patients with liver cirrhosis, basal endogenous glucose production is normal and is normally suppressed by insulin; skeletal muscle is insulin resistant because of reduced glycogen formation [55,56], whereas glucose oxidation has been found to be normal in the basal state and after insulin administration.…”

In situ lipolytic regulation in subjects born small for gestational age

“…[27][28][29] From a metabolic point of view, it can be speculated that the greater reactivity might result in increased FFA production in subjects born SGA, increasing thereby the circulating FFA known to be deleterious in the control of insulin sensitivity. 11,12 Furthermore, regarding the interplay between insulin and catecholamines in the adipocyte lipolytic regulation, it has been shown that the magnitude of the lipolytic effect induced by catecholamines overrides the antilipolytic effect of insulin. 30,31 This is clearly evidenced in the present study by the pattern of glycerol production in the two probes.…”

“…The contribution of the adipose tissue in the pathophysiology of insulin resistance is mostly based on its lipolytic activity, resulting in free fatty acids (FFA) production and mobilization, 11,12 which has been largely documented to be deleterious on glucose utilization and insulin action. 12,13 In humans, insulin and catecholamines are the major hormonal regulators of the lipolytic activity.…”

Long-chain fatty acid uptake is upregulated in omental adipocytes from patients undergoing bariatric surgery for obesity

“…9,11,13,27,28 Altered LCFA disposition is typical of both obesity and NIDDM. 29,30 Indeed, some believe that such changes are the primary disturbances in these conditions. [31][32][33][34] Animal models have been very useful in studying this process.…”