Michael Landt

Relationship Between Insulin Sensitivity and Plasma Leptin Concentration in Lean and Obese Men

Alterations in the production of or the sensitivity to leptin, the protein encoded by the ob gene, cause obesity and diabetes in rodents. We evaluated the isolated relationship between leptin and insulin sensitivity in lean and obese humans. Three groups of subjects who were carefully matched for either insulin sensitivity (determined by the modified intravenous glucose tolerance test and minimal model analysis) or adiposity (determined by hydrodensitometry) were studied: 1) lean insulin-sensitive men (percentage body fat, 15 ± 1%); 2) lean insulinresistant men (percentage body fat, 16 ± 1%), matched on percentage body fat and fat mass with the lean insulinsensitive group; and 3) obese insulin-resistant men (percentage body fat, 31 ± 3), matched on insulin sensitivity with the lean insulin-resistant group. Basal plasma leptin concentrations were significantly lower in the lean insulin-sensitive than in the lean insulin-resistant men (1.90 ± 0.4 vs. 4.35 ± 1.21 ng/ml, P < 0.05) despite identical body composition. Plasma leptin in the obese men (9.27 ± 1.4 ng/ml) was significantly higher than values in the two lean groups (P < 0.01). Marked alterations in plasma glucose and insulin concentrations induced by glucose and tolbutamide injection did not cause any change in plasma leptin levels. These results demonstrate that insulin resistance is associated with elevated plasma leptin levels independent of body fat mass. However, plasma insulin itself does not acutely regulate leptin production.

Plasma Leptin and Insulin Relationships in Obese and Nonobese Humans

Hyperinsulinemia is associated with an overexpression of mRNA for the ob protein leptin in rodent models of genetic obesity, and insulin has been reported to directly stimulate leptin mRNA in rat adipocytes. Human obesity is also associated with increased leptin mRNA as well as plasma levels, but there have been no reports of the effect of insulin on leptin secretion. We, therefore, tested the hypothesis that insulin stimulates leptin secretion in humans. Using a newly developed leptin assay, immunoreactive leptin was measured in fasting and postprandial plasma samples from 27 healthy adults and in samples before and during euglycemic-hyperinsulinemic then stepped hypoglycemic (hourly steps at 85, 75, 65, 55, and 45 mg/dl) clamps from 10 healthy subjects and 11 patients with IDDM. Plasma leptin was correlated (r = 0.84, P = 0.0005) with BMI in obese but not nonobese subjects and with fasting (r = 0.75, P = 0.008) but not postprandial plasma insulin levels. (Leptin levels did not change postprandially.) Euglycemic hyperinsulinemia did not alter leptin levels, nor did hyperinsulinemic hypoglycemia. Thus, because circulating leptin levels are not increased during postprandial hyperinsulinemia or during euglycemic (or hypoglycemic) hyperinsulinemia, we conclude that, at least in the short term, insulin does not increase leptin secretion in humans and that hyperleptinemia in obese individuals is not likely the result of hyperinsulinemia.

Amino acid clearance during acute metabolic decompensation in maple syrup urine disease treated with continuous venovenous hemodialysis with filtration.

Objective: Assessment of amino acid clearances by continuous venovenous hemodialysis with filtration in treatment of a metabolic decompensation in acute maple syrup urine disease. Design: Single patient assessment. Setting: Pediatric intensive care unit. Patients: A 10-yr-old male with known maple syrup urine disease (branched chain alpha-ketoacid dehydrogenase deficiency) with metabolic decompensation due to an acute viral illness, characterized by altered mental status, progressive obtundation, and severe acidosis. Interventions: Continuous venovenous hemodialysis with filtration. Measurements and Main Results: Continuous venovenous hemodialysis with filtration was instituted with both filtration (500 mL/m2/hr) and dialysis (1000 mL/m2/hr) utilized, allowing rapid correction of systemic ketoacidosis while providing amino acid clearance. Amino acid clearance was measured at initiation and at 24 hrs into therapy. The procedure was well tolerated, with near normal mental status within 12 hrs and resumption of enteral feedings. During the 24-hr period of continuous venovenous hemodialysis with filtration, serum leucine levels fell from 2352 to 381 &mgr;moles/L, isoleucine fell from 626 to 164, and valine fell from 1117 to 228. Leucine, isoleucine, and valine clearance rates averaged 13.1, 12.8, and 13.2 mL/min, respectively, and were constant during the 24 hrs of treatment. Clearance of other amino acids during this period did not vary significantly between cationic, anionic, neutral, or hydrophobic amino acids. Conclusions: Continuous venovenous hemodialysis with filtration provides an effective therapeutic alternative to intermittent hemodialysis during acute metabolic decompensation in maple syrup urine disease.