Insulin Signaling Is Preserved in Skeletal Muscle During Early Diabetic Ketoacidosis

• Published in: The journal of clinical endocrinology and metabolism 2023-12, Vol.109 (1), p.e155-e162
• Main Authors: Fisker, Frederikke A, Voss, Thomas S, Svart, Mads V, Kampmann, Ulla, Vendelbo, Mikkel H, Bengtsen, Mads B, Lauritzen, Esben S, Møller, Niels, Jessen, Niels
• Format: Article
• Language: English
• Subjects: Cellular signal transduction; Cross-Over Studies; Dextrose; Diabetes Mellitus, Type 1 - drug therapy; Diabetes therapy; Diabetic acidosis; Diabetic Ketoacidosis - metabolism; Ethylenediaminetetraacetic acid; Fatty acids; Genetic translation; Glucose; Glucose - metabolism; Glycogen; Glycogen Synthase - metabolism; Humans; Insulin; Insulin - metabolism; Insulin resistance; Insulin Resistance - physiology; Ketoacidosis; Muscle, Skeletal - metabolism; Muscles; Protein binding; Protein biosynthesis; Protein kinases; Proteins; Signal Transduction; Synthesis; Type 1 diabetes
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/clinem/dgad464

Abstract Background and aims During diabetic ketoacidosis (DKA), muscle tissue develops a profound insulin resistance that complicates reversal of this potentially lethal condition. We have investigated mediators of insulin action in human skeletal muscle during total insulin withdrawal in patients with type 1 diabetes, under the hypothesis that initial phases of DKA are associated with impaired postreceptor signaling. Materials and methods Muscle biopsies were obtained during a randomized, controlled, crossover trial involving 9 patients with type 1 diabetes. The subjects were investigated during a high-dose insulin clamp preceded by either: (1) insulin-controlled euglycemia (control) or (2) total insulin withdrawal for 14 hours. Insulin action in skeletal muscle and whole-body substrate metabolism were investigated using western blot analysis and indirect calorimetry respectively. Results During insulin withdrawal, insulin-stimulated dephosphorylation of glycogen synthase decreased by ∼30% (P < .05) compared with the control situation. This was associated with a decrease in glucose oxidation by ∼30% (P < .05). Despite alterations in glucose metabolism, insulin transduction to glucose transport and protein synthesis (Akt, AS160, mammalian target of rapamycin, and eukaryotic translation initiation factor 4E binding protein) was intact, and glucose transporter (GLUT4) and mitochondrial proteins (succinate dehydrogenase complex, subunit A and prohibitin 1) protein expression were unaffected by the intervention. Conclusion DKA impairs insulin-stimulated activation of glycogen synthase, whereas insulin signal transduction to glucose transport and protein synthesis remains intact. Reversal of insulin resistance during treatment of DKA should target postreceptor mediators of glucose uptake. Clinical Trial Registration number NCT02077348.