The effect of diet upon carbohydrate metabolism, insulin resistance, and blood pressure in congenital total lipoatrophic diabetes

An 11-yr-old female with congenital total lipodystrophy had nonketotic hyperglycemia with resistance to both endogenous and exogenous insulin and systemic hypertension. Twenty-four hour patterns of secretion and mean concentrations of growth hormone, cortisol, Luteinizing Hormone (LH), and Follicle-Stimulating Hormone (FSH) were normal. Plasma glucagon was elevated during periods of hyperglycemia, but was normal during normoglycemia, even though insulin resistance was still evident. Insulin receptor density and affinity for insulin as determined in monocytes and erythrocytes were normal during hyperglycemia. Therapy with insulin and pimozide were not effective in controlling hyperglycemia. However, a diet restricted to 1800–2000 cal per day of average sodium content resulted in euglycemia and normal blood pressure without insulin therapy. Fasting serum glucose decreased from 393 to 65 mg/dl. In addition, triglycerides decreased from 304 to 115 mg/dl, glucagon from 421 to 126 pg/ml, and liver size returned to normal. There was a correlation between blood pressure and fasting glucose: systolic, r = 0.725, n = 54, p < 0.001; diastolic, r = 0.424, n = 54, p < 0.001. Plasma renin activity (PRA) and plasma aldosterone (PA) levels were mildly elevated in both the hypertensive and normotensive states. Plasma renin activity was 2.15 ± 0.73, (SD) ng/ml/hr supine and 5.32 ± 1.81 upright over an 11-day period when urinary sodium excretion was 96.0 ± 25.5 meq/day. When fasting glucose levels were 332–393 mg/dl, glucose turnover was 1967 μmole/min (normal, 696 ± 120, SD), net glucose decay during i.v. glucose tolerance (IVGTT) 15.6 g/50 min/1.73m² (normal, 16.7 ± 3.7), and Kg was 0.52%/min (normal, 1.86 ± 0.51, SD). After intensive diet therapy, fasting glucose was 97 and glucose turnover was 810 μmole/min, net glucose decay was 15.18 and Kg was 0.92. When the subject was hyperglycemic, plasma alanine concentration was normal, as was alanine conversion to glucose. Basal unbound insulin levels were elevated during hyperglycemia and normal during euglycemia. Insulin release, which was negligible during the first IVGTT, had a more normal pattern during the second test. In this patient with lipoatrophy, insulin resistance did not appear to derive from known insulin antagonists. The data suggested that insulin resistance may derive from a reversible loss of coupling of a normal insulin receptor to metabolic pathways. This loss may be tissue specific, involving adipose tissue and liver but not muscle, and appears to occur at insulin levels that are increased but lower than would otherwise cause a loss of hormone responsiveness in normal and obese individuals. An unknown antagonist, if present, must be diet-dependent.