Generalized Lipodystrophy: In Vivo Evidence for Hypermetabolism and Insulin-Resistant Lipid, Glucose, and Amino Acid Kinetics zyxwvutsrqponmlkjihgfedc Samuel Klein, Farook Jahoor, Robert R. Wolfe, and Charles A. Stuart Stable isotope tracers and indirect calorimetry were used to evaluate whole-body energy, glucose, lipid, and amino acid metabolism in a patient with generalized lipodystrophy during basal conditions and in response to insulin therapy. The results were compared with those obtained in previous studies in normal volunteers. The basal rate of glucose production (33.7 Fmol/ kg-min) was three times higher than normal. The basal rate of glycerol appearance in blood, an index of lipolysis, was 60% greater than normal when expressed per kilogram body weight (3.62 pmol/kg*min), but was more than 10 times normal when expressed per kilogram body fat mass (123.2 pmol/ kg-min) because of the marked decrease in body fat in our patient (3% of total body weight). Leucine rate of appearance, an index of protein breakdown, and nonoxidative leucine disposal, an index of protein synthesis, were also greater than normal. Resting energy expenditure (REE) was 30% greater than normal. The effect of insulin infusion on these metabolic parameters was markedly blunted. These metabolic abnormalities help explain many of the clinical findings such as hyperglycemia, hypertriglyceridemia, fat depletion, hepatomegaly, and steatosis observed in patients with lipodystrophy. Ineffective insulin function in many tissues appears to be an important factor in the pathophysiol- ogy of lipodystrophy. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Copyright 0 1992 by W.B. Saunders Company zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA G ENERALJZED lipodystrophy is a rare disorder char- acterized by loss of body fat, muscular hypertrophy, acanthosis nigricans, hepatomegaly, hyperlipidemia, insulin resistant diabetes, and elevated metabolic rate.* The mech- anism(s) responsible for these abnormalities is not known. Although defects in insulin function with respect to glucose metabolism have been described,2 the effectiveness of insulin in regulating protein and lipid metabolism has not been studied. In this study we used stable isotopic tracers and indirect calorimetry to characterize energy, lipid, glu- cose, and amino acid metabolism in a patient with general- ized lipodystrophy during both basal conditions and insulin therapy. CASE REPORT A 24-year-old woman with generalized lipodystrophy was admit- ted to The University of Texas Medical Branch Hospital for surgical removal of a painful right paraovarian cyst. Body fat loss was first noted at age 7, followed by symptoms of diabetes (polyuria and polydypsia) as a teenager and acanthosis nigricans at age 23. She had severe insulin resistance and required a total of 1,100 U subcutaneous (SC) insulin per day to maintain blood glucose between 200 and 300 mg/dL. The patient had a voracious appetite and consumed approximately 3,500 kcal/d, containing approxi- mately 50% calories as fat, 35% as carbohydrate, and 15% as protein. while maintaining constant body weight. The patient was 169 cm in height and weighed 58.5 kg, which was 92% of ideal body weight based on the medium frame midpoint of the 1983 Metropolitan Life Insurance tables. She had muscular hypertrophy with generalized loss of SC fat. There was increased facial, axillary, and extremity hair. Typical skin lesions of acantho- sis nigricans were present in the axilla and inner thigh. She had acromegaloid features with large hands, feet, and facies. She was hypertensive (blood pressure, 146/96) and tachycardic (heart rate, 110 bpm). Her liver was 5 cm below the right costal margin and 14 cm in span. There were no stigmata of chronic liver disease or splenomegaly. The plasma triglyceride concentration was 1,317 mg/dL, choles- terol was 260 mg/dL, acetate was 0.4 mmol/L, and p-hydroxybu- tyrate was 0.5 mmol/L. Serum aspartate amino transaminase (86 U/L), alanine amino transaminase (175 U/L), and alkaline phos- phatase (322 U/L) levels were increased, while bihrubin, lactate dehydrogenase, and albumin levels and prothrombin time were Metabolism, Vol 41, No 8 (August), 1992: pp 893-896 normal. The serum creatinine level was 0.5 mg/dL, blood urea nitrogen level was 9 mg/dL, and creatinine clearance was normal. Serum catecholamines, testosterone, luteinizing hormone, follicle- stimulating hormone, dihydroepiandrosterone, cortisol, and thy- roid hormone levels were normal. The urinary vandelmandelic acid level was normal. Pelvic ultrasound showed a large paraovarian cyst in the right adnexa and two smaller cysts within the right ovary. The patient underwent surgery 8 days after admission to remove the right paraovarian cyst. At laparotomy. the paucity of intraab- dominal fat was striking and was estimated to be approximately 1% of normal. The liver was large and extended completely across the abdomen to the left abdominal wall. The metabolic studies described below were performed after admission to the hospital, before surgery. MATERIALS AND METHODS This study was approved by the Institutional Review Board of The University of Texas Medical Branch, and was performed in the Clinical Research Center after informed consent was obtained from the patient. An intravenous (IV) infusion of insulin was begun and continued for 42 hours. The infusion was started at 25 U/h and gradually reduced to a final rate of 10 U/h to maintain blood glucose at approximately 200 mg/dL. The first set of metabolic studies was performed during the last 2 hours of the insulin infusion, after the patient had fasted overnight (12 hours). IV lines were inserted into the antecubital vein of one arm for the infusion of isotopes, and into the contralateral dorsal hand vein, which was heated for arterialized venous sampling.3 Forty-five minutes after IV catheter placement, baseline breath and blood samples were obtained. Primed constant infusions of [l-13C]leucine (12.0 umolikg prime; 0.2 umol/kgmin constant infusion), [6,6- zyxwvutsr From the Departments of Internal Medicine, Preventive Medicine, and Community Health, Surgery, and Anesthesiology, The University of Texas Medical Branch and The Shnmers Bums Institute, Galveston, TX Supported by National Institutes of Health Grant No. CA 50330, Clinical Research Grant No. RR-00073, and a grant zyxwvutsrqponmlkji fro m the Shriners Hospitals. Address reprint requests to Samuel Klein, MD, Division of Gastroen- terology G-64, The University of Texas Medical Branch, Galveston, TX 77550. Copyright 0 I992 by W B. Saunders Company 0026-0495/92/4108-0015$03.00/0 893