Glucose-Fatty Acid Interaction in Skeletal Muscle and Adipose Tissue in Insulin Resistance

Abstract

Insulin resistance (IR) is the result of long-lasting positive energy balance and the imbalance between the uptake of energy rich substrates (glucose, lipids) and energy output. The defects in the metabolism of glucose in IR and type 2 diabetes are closely associated with the disturbances in the metabolism of lipids. In this review, we have summarized the evidence indicating that one of the important mechanisms underlying the development of IR is the impaired ability of skeletal muscle to oxidize fatty acids as a consequence of elevated glucose oxidation in the situation of hyperglycemia and hyperinsulinemia and the impaired ability to switch easily between glucose and fat oxidation in response to homeostatic signals. The decreased fat oxidation results into the accumulation of intermediates of fatty acid metabolism that are supposed to interfere with the insulin signaling cascade and in consequence negatively influence the glucose utilization. Pathologically elevated fatty acid concentration in serum is now accepted as an important risk factor leading to IR. Adipose tissue plays a crucial role in the regulation of fatty acid homeostasis. The adipose tissue may be the primary site where the early metabolic disturbances leading to the development of IR take place and the development of IR in other tissues follows. In this review we present recent evidence of mutual interaction between skeletal muscle and adipose tissue in the establishment of IR and type 2 diabetes.

Age and gender related differences in free fatty acid levels in patients with type 2 diabetes mellitus

“…Multiple disturbances in free fatty acid metabolism, including day-long elevated plasma FFA levels and accelerated rates of lipolysis, are characteristic features of T2D. Elevated plasma FFA concentrations impair glucose metabolism by inhibiting the more proximal steps of insulin action in muscle as well by augmenting basal hepatic gluconeogenesis and impairing the insulin-mediated suppression of hepatic glucose production (8,16,19). In addition to increased FFA plasma levels, Type 2 diabetic and obese patients have increased stores of triglycerides in muscle and liver, which correlates closely with IR in these tissues (16,(20)(21).…”

“…Elevated plasma FFA concentrations impair glucose metabolism by inhibiting the more proximal steps of insulin action in muscle as well by augmenting basal hepatic gluconeogenesis and impairing the insulin-mediated suppression of hepatic glucose production (8,16,19). In addition to increased FFA plasma levels, Type 2 diabetic and obese patients have increased stores of triglycerides in muscle and liver, which correlates closely with IR in these tissues (16,(20)(21). Chronic elevated plasma FFAs are also closely linked to the various components of the metabolic syndrome and represent a possible link between fatty acids levels and cardiovascular morbidity and mortality (7)(8).…”

“…Furthermore, overnight reduction in FFAs improved insulin sensitivity in vivo in obese patients, Type 2 diabetics and nondiabetics. In addition, substantial evidence from both, humans and animals, has indicated that essential fatty acid (EFA) metabolism is also abnormal in diabetes (15,16).…”

Impaired postprandial adipose tissue microvascular blood flow responses to a mixed-nutrient meal in first-degree relatives of adults with type 2 diabetes

“…Adipose tissue is well known for its ability to respond to meal-related insulin release to promote storage of triglycerides and glucose, inhibit release of non-esterified fatty acids (NEFA) (11,12) at the same time as there is reduced fat oxidation (13,14) -i.e. a net action to promote nutrient storage.…”

The Impact of CB1 Receptor on Nuclear Receptors in Skeletal Muscle Cells

“…Moreover, skeletal muscle serves as site of insulin resistance as well. As this tissue is capable of oxidizing fatty acid and glucose, its role in metabolic disorders is also important [ 25 ]. A number of scientists sometimes refer skeletal muscle as an endocrine organ considering discharge of inflammatory mediators by this tissue [ 17 ].…”