Impaired free fatty acid utilization by skeletal muscle in non-insulin-dependent diabetes mellitus.

Abstract

IntroductionThis study was undertaken to assess utilization of FFA by skeletal muscle in patients with non-insulin-dependent diabetes mellitus (NIDDM). 11 NIDDM and 9 nondiabetic subjects were studied using leg balance methods to Patients with non-insulin-dependent diabetes mellitus (NIDDM)' have a number of abnormalities of lipid metabolism which may contribute to the increased morbidity and mortality associated with this syndrome (1, 2). Among the abnormalities of lipid metabolism in NIDDM is increased plasma FFA (3). Increased fasting rates of lipolysis (4), insulin resistance in suppression of lipolysis (3, 5), and impaired clearance of plasma FFA, particularly in relation to hyperglycemia (6), contribute to elevated plasma FFA in NIDDM. During postabsorptive metabolism, lipid oxidation provides approximately three-quarters of energy production in healthy individuals and plasma FFA contribute substantially to lipid oxidation (7). Uptake and oxidation of plasma FFA occur in liver, kidney, skeletal muscle, and myocardium, as well as other tissues, so that the site(s) responsible for impaired systemic clearance of FFA in NIDDM is uncertain. However, it does seem unlikely that hepatic utilization of FFA is reduced in NIDDM, as it is generally considered that hepatic fat oxidation is increased and a key factor in potentiating gluconeogenesis (8,9). In skeletal muscle, lipid is the predominate oxidative substrate during postabsorptive conditions in nondiabetics, accounting for -80% of oxygen consumption by muscle (10-12). Previously, we found that RQ across the leg during postabsorptive conditions was increased in subjects with NIDDM during conditions of fasting hyperglycemia (13). The elevation of leg RQ suggests that skeletal muscle utilization of plasma FFA could be impaired in NIDDM during postabsorptive conditions. Capaldo et al. ( 14) found that forearm FFA uptake was similar in NIDDM and nondiabetic subjects, yet the NIDDM subjects in that study were lean and had been rendered euglycemic before measuring muscle FFA uptake. Therefore, the findings of the study by Calpaldo et al., which is the only previous investigation of muscle FFA uptake in NIDDM, may not fully apply to the majority of patients with NIDDM, most of whom are obese, nor may these findings pertain to hyperglycemic conditions. The current study was undertaken, therefore, to test the hypothesis that muscle FFA utilization is impaired in NIDDM during fasting hyperglycemia. The leg balance method was used in conjunction with an infusion of labeled oleate to measure uptake of FFA, and limb indirect calorimetry was used to obtain the RQ across the leg. Because the metabolic profile of skeletal muscle and fiber type characteristics can be important determinants of substrate utilization (15), vastus lateralis muscle was obtained by percutaneous biopsy for these characterizations. The leg balance measurements were conducted during postabsorptive conditions, then carried forward for 6 h after ingestion of a fat-enriched meal. The findings in...

Heterogeneity in limb fatty acid kinetics in type 2 diabetes

“…However, subsequent data on human cultured myotubes from the vastus lateralis did not indicate substantial differences between myotubes from diabetic patients and matched controls [29]. The decrease of palmitate uptake with insulin has been reported previously for the leg [7,30] and the arm [31] of healthy subjects. Nevertheless, when fatty acid levels were maintained during the insulin infusion, the fatty acid uptake by skeletal muscle was actually increased in rat muscle preparations [32,33] and in cultured cells from the vastus lateralis muscle [28,29].…”

“…Reduced fatty acid uptake has been observed in the forearm [8] and in the leg [7,27] of type 2 diabetic patients. A lower capacity for fatty acid uptake in the diabetic leg muscles is also in agreement with similar findings in human cultured vastus lateralis muscle cells [28].…”

“…Reduced plasma fatty acid uptake and oxidation by the leg [7] and the arm [8,9] have been observed in type 2 diabetics as compared to healthy individuals. Moreover, the relationship between intramuscular lipid accumulation and insulin resistance has been described [10,11].…”

Substrate source utilisation in long-term diagnosed type 2 diabetes patients at rest, and during exercise and subsequent recovery

“…In these patients, basal oxidation rates of whole-body total fat have been reported to be both increased [11][12][13] and similar [14][15][16][17][18][19] compared with lean [11][12][13] and overweight/obese [14][15][16][17][18][19] controls respectively. Whole-body plasma NEFA uptake and/or oxidation rates at rest have been reported to be either similar [17,18] or decreased [16] in the type 2 diabetes patient.…”

“…Whole-body plasma NEFA uptake and/or oxidation rates at rest have been reported to be either similar [17,18] or decreased [16] in the type 2 diabetes patient. However, data on arteriovenous differences in plasma NEFA concentrations over the leg or arm have more consistently displayed reduced fasting plasma NEFA uptake and/or oxidation in type 2 diabetes patients compared with normoglycaemic controls [11,14,20], despite elevated systemic plasma NEFA and glucose levels [14,20]. During exercise, in both the prediabetes and/or type 2 diabetes state, the uptake and oxidation of plasma NEFA and other lipid sources have been shown to be similar [17,18] or decreased [16,21].…”