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Defective Activation of Skeletal Muscle and Adipose Tissue Lipolysis in Type 1 Diabetes Mellitus during Hypoglycemia

Department of Medicine, Section of Endocrinology (S.E., R.S.S.), Pediatric Endocrinology (S.K.C., W.V.T.), the General Clinical Research Centers (F.R.), and Howard Hughes Medical Institute (G.I.S.), Yale University School of Medicine, New Haven, Connecticut 06510

Address all correspondence and requests for reprints to: Staffan Enoksson, M.D., Ph.D., Department of Vascular Surgery, C1:88, Huddinge University Hospital at the Karolinska Institute, 14186 Huddinge, Sweden. E-mail: staffan.enoksson{at}karo.ki.se.

The increased risk of hypoglycemia during intensified treatment of type 1 diabetes mellitus (T1DM) patients, who have a deficient glucagon secretory response, is largely attributed to the development of suppressed adrenomedullary responses. A consequence of this impairment of catecholamine secretion might be reduced lipolysis in major target tissues (muscle and adipose) and, in turn, increased glucose metabolism. To test this hypothesis, we used microdialysis to monitor glycerol (index of lipolysis) in the extracellular fluid of skeletal muscle and adipose tissue and assessed whole-body glucose use by measuring [6,6-²H₂]glucose enrichment in plasma in seven intensively treated T1DM patients and eight nondiabetic subjects who received a 3-h insulin infusion (0.8 mU/kg·min) on two occasions: during mild-moderate hypoglycemia or euglycemia. In the hypoglycemic study, the rise in plasma epinephrine was approximately 50% less in the T1DM patients despite a greater fall in plasma glucose (to 3.0 vs. 3.5 mM in controls; P < 0.05). Moreover, the rate of glucose flux and the plasma-extracellular fluid glucose gradient in muscle was increased during hypoglycemia in T1DM subjects compared with controls. Glycerol levels in muscle, adipose, and plasma fell similarly in both groups in the first hour. Thereafter, tissue glycerol remained suppressed in the T1DM patients but rebounded significantly (P < 0.01) in the control subjects. The glycerol response in muscle and adipose tissue was significantly correlated with plasma epinephrine concentration (r = 0.73, P = 0.002; and r = 0.52, P = 0.04, respectively), and inversely correlated with whole-body glucose disposal (r = -0.51, P = 0.05; and r = -0.50, P = 0.05). To determine whether the absence of the lipolytic response is limited to deficient catecholamine release, we perfused muscle and adipose tissue in situ with the selective ß₂-agonist terbutaline during hyperinsulinemic euglycemia. Local addition of agonist increased glycerol and blood flow in both muscle and adipose (P < 0.01 and P < 0.05, respectively) similarly in T1DM and control subjects. We conclude that deficient release of (rather than impaired responsiveness to) catecholamines in T1DM prevents the local fat breakdown within muscle and adipose tissue that normally occurs during mild-moderate hypoglycemia. This defect within peripheral tissues may lead to a delayed increase in glucose disposal that could contribute to the severity of hypoglycemia when it is prolonged.

This work was supported by grants from the National Institutes of Health (DK20495, DK45735, and RR00125) as well as the Juvenile Diabetes Research Foundation Center for the Study of Hypoglycemia. S.E. was supported by a mentor-based fellowship from the American Diabetes Association, the Swedish Institute, and the foundation of Johan Throne Holst.

Abbreviations: ECF, Extracellular fluid; FFA, free fatty acid; NEFA, nonesterified fatty acids; R_d, rate of glucose disappearance; T1DM, type 1 diabetes mellitus.

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