Lactate induces insulin resistance in skeletal muscle by suppressing glycolysis and impairing insulin signaling

Abstract

tion of plasma lactate levels induces peripheral insulin resistance, but the underlying mechanisms are unclear. We examined whether lactate infusion in rats suppresses glycolysis preceding insulin resistance and whether lactate-induced insulin resistance is accompanied by altered insulin signaling and/or insulin-stimulated glucose transport in skeletal muscle. Hyperinsulinemic euglycemic clamps were conducted for 6 h in conscious, overnight-fasted rats with or without lactate infusion (120 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) during the final 3.5 h. Lactate infusion increased plasma lactate levels about fourfold. The elevation of plasma lactate had rapid effects to suppress insulin-stimulated glycolysis, which clearly preceded its effect to decrease insulin-stimulated glucose uptake. Both submaximal and maximal insulin-stimulated glucose transport decreased 25-30% (P Ͻ 0.05) in soleus but not in epitrochlearis muscles of lactate-infused rats. Lactate infusion did not alter insulin's ability to phosphorylate the insulin receptor, the insulin receptor substrate (IRS)-1, or IRS-2 but decreased insulin's ability to stimulate IRS-1-and IRS-2-associated phosphatidylinositol 3-kinase activities and Akt/protein kinase B activity by 47, 75, and 55%, respectively (P Ͻ 0.05 for all). In conclusion, elevation of plasma lactate suppressed glycolysis before its effect on insulin-stimulated glucose uptake, consistent with the hypothesis that suppression of glucose metabolism could precede and cause insulin resistance. In addition, lactate-induced insulin resistance was associated with impaired insulin signaling and decreased insulin-stimulated glucose transport in skeletal muscle. glucose transport; euglycemic clamp; rat GLUT4

Metabolic and hormonal response to intermittent high-intensity and continuous moderate intensity exercise in individuals with type 1 diabetes: a randomised crossover study

“…The role of lactate as a glucose-competing agent is supported by recent clamp studies showing that increased lactate utilisation was associated with decreased glucose disappearance during moderate intensity exercise [30]. Similarly, animal studies observed reduced glucose uptake by the muscle in the presence of hyperlactataemia [31][32][33]. Due to the design of the present study we can only speculate on potential mechanisms related to elevated lactate levels during IHE.…”

Chronically increased glucose uptake by adipose tissue leads to lactate production and improved insulin sensitivity rather than obesity in the mouse

“…Glucose homeostasis in glucokinase-expressing transgenic mice It has been suggested that high levels of circulating lactate observed during obesity may contribute to insulin resistance [32][33][34][35][36][37]. However, no difference in serum insulin concentration was observed in fed or starved transgenic mice compared with controls (Table 1).…”

“…It has been suggested that high levels of circulating lactate observed during obesity contribute to insulin resistance by decreasing glucose utilisation by skeletal muscle and enhancing hepatic gluconeogenesis [32][33][34][35][36][37]. Plasma lactate is elevated in obese individuals and this increase is higher when obesity is associated with type 2 diabetes [32].…”

High-Intensity Training Improves Plasma Glucose and Acid-Base Regulation During Intermittent Maximal Exercise in Type 1 Diabetes

“…Hyperglycemia during and after HIE in type 1 diabetes was likely due to a lack of physiological hyperinsulinemia (10). Interestingly, based on findings in rodent muscle (18), the high plasma lactate in both groups may have induced acute insulin resistance. This may have further contributed to the hyperglycemia in type 1 diabetes and likely explains the lack of fall in plasma glucose during recovery in control subjects, despite high insulin.…”