Ambient Plasma Free Fatty Acid Concentrations in Noninsulin-Dependent Diabetes Mellitus: Evidence for Insulin Resistance*

Abstract

Plasma glucose, insulin, and FFA concentrations were determined in 15 normal subjects and 15 patients with noninsulin-dependent diabetes mellitus (NIDDM) from 0800 to 1600 h. Breakfast and lunch were consumed at 0800 and 1200 h, respectively, and plasma concentrations were measured at hourly intervals from 0800-1600 h. Plasma glucose concentrations between 0800 and 1600 h were significantly elevated in patients with NIDDM, and the higher the fasting glucose level, the greater the postprandial hyperglycemia. Hyperglycemia in patients with NIDDM was associated with plasma insulin levels that were significantly higher (P less than 0.001) than those in normal subjects, and substantial hyperinsulinemia occurred between 0800 and 1600 h in patients with mild NIDDM (fasting plasma glucose concentrations, less than 140 mg/dl). Both fasting and postprandial FFA levels were also increased in patients with NIDDM (P less than 0.001), and the greater the plasma glucose response, the higher the FFA response (r = 0.70; P less than 0.001). However, there was no significant correlation between plasma insulin and FFA concentrations. More specifically, hyperinsulinemic patients with mild diabetes (fasting plasma glucose, less than 140 mg/dl) maintained normal ambient FFA levels, while FFA concentrations were significantly elevated in patients with severe NIDDM (fasting plasma glucose, greater than 250 mg/dl), with insulin concentrations comparable to those in normal subjects. These results demonstrate that patients with NIDDM are not capable of maintaining normal plasma FFA concentrations. This defect in FFA metabolism is proportionate to the magnitude of hyperglycemia and occurs despite the presence of elevated levels of plasma insulin. These results are consistent with the view that insulin resistance in NIDDM also involves the ability of insulin to regulate FFA metabolism.

Effects of Free Fatty Acids and Glycerol on Splanchnic Glucose Metabolism and Insulin Extraction in Nondiabetic Humans

“…Effects of FFAs and glycerol on splanchnic glucose uptake. Plasma FFAs are commonly elevated in a variety of disease states, including type 2 diabetes and obesity (1,5,6,55). After the observation by Randle et al (8) that increased FFAs decreased insulin-stimulated glucose uptake in perfused hearts, a number of studies have shown that they can also decrease either leg (and therefore presumably skeletal muscle) or whole-body glucose uptake in humans (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17).…”

“…The contribution of abnormal fat metabolism to these defects is an area of active investigation. People with type 2 diabetes commonly have elevated FFA and glycerol concentrations (1,5,6). Although it is well established that FFAs can blunt the response of muscle to insulin (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), elevated FFAs have been reported to increase (20), decrease (21), or have no effect (22,23) on initial splanchnic glucose extraction.…”

An Unsuspected Metabolic Role for Atrial Natriuretic Peptides

“…The adipose tissue of obese persons releases more NEFAs into the circulation, and subjects with type 2 diabetes have high NEFA concentrations. 8,9 A high plasma NEFA concentration is a risk factor for deterioration of glucose tolerance independent of the other insulin resistance or insulin secretion markers that characterize subjects at risk for type 2 diabetes. 10 Day-long elevations in plasma NEFA levels can lead to aggravation of impaired glucose homeostasis in obese and type 2 diabetes individuals.…”

Fatty acid metabolism and insulin secretion in pancreatic beta cells

“…Furthermore, obesity and insulin resistance are found in people who are at an increased risk for developing these disorders, suggesting that they could be common pathological factors, or at least early events in their development. Second, obesity and Type 2 diabetes are often associated with hypertriglyceridaemia or increased circulating concentrations of NEFA [2,3]. Therefore Type 2 diabetes can also be considered a lipid disorder as well as a disease of glucose tolerance [4] and it is possible that increased circulating lipid concentrations explain, at least in part, not only insulin resistance but also betacell dysfunction in Type 2 diabetes.…”