Defective activation of skeletal muscle and adipose tissue lipolysis in type 1 diabetes mellitus during hypoglycemia.
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-(2)H(2)]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 beta(2)-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.
Enoksson
Staffan
S
Department of Medicine, Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut 06510, USA. staffan.enoksson@karo.ki.se
Caprio
Sonia K
SK
Rife
Frances
F
Shulman
Gerald I
GI
Tamborlane
William V
WV
Sherwin
Robert S
RS
D000273:Adipose Tissue / Q000098:blood supply / Q000737:chemistry / Q000503:physiopathology*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000328:Adult; D001786:Blood Glucose / Q000032:analysis; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000503:physiopathology; D004837:Epinephrine / Q000097:blood; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005947:Glucose / Q000032:analysis / Q000378:metabolism; D015309:Glucose Clamp Technique; D005990:Glycerol / Q000032:analysis / Q000097:blood; D006706:Homeostasis; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced / Q000503:physiopathology*; D007328:Insulin / Q000009:adverse effects* / Q000097:blood; D019344:Lactic Acid / Q000032:analysis; D008066:Lipolysis; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply / Q000737:chemistry / Q000503:physiopathology*; D009638:Norepinephrine / Q000097:blood; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology; D013726:Terbutaline / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D018343:Receptors, Adrenergic, beta-2; D019344:Lactic Acid; D005947:Glucose; D013726:Terbutaline; D005990:Glycerol; D009638:Norepinephrine; D004837:Epinephrine