Hypothalamic obesity sometimes occurs in children after therapy for brain tumors or acute lymphoblastic leukemia (ALL). However, its etiology and treatment remain obscure. In rats, damage to the ventromedial hypothalamus(VMH) causes hyperphagia, hyperinsulinism, and obesity; but is it true in humans, which pathology comes first, and can it be treated?

Insulin dynamics were assessed in 8 pts (4M, 4F; age 10-18) with marked obesity noted to start after therapy for ALL or brain tumors. Previous voluntary dietary restriction had no inhibitory effect on the rate of Δ Weight or Δ Body Mass Index (ΔBMI.). Patients' Δ Weight was+ 1.00 ± 0.12 kg/month and ΔBMI was +0.29 ± 0.04/month over the 6 months prior to study entry. Oral glucose tolerance testing (OGTT) showed normal fasting glucoses but mild biochemical glucose intolerance in 5/8 pts, with 2 hr glucoses of 131 ± 13 mg/dl. Fasting insulin levels (IRI) were minimally elevated (22.9 ± 4.9 μU/ml), but peak IRI to glucose were markedly exaggerated in 6/8 pts (mean peak 303.9 ± 50.5μU/ml).

Pts received the somatostatin analog octreotide (an inhibitor of insulin secretion by blocking β-cell G-protein effects on voltage-gated Ca++ channels), in increasing doses of 5 to 15 μg/kg/d SQ ÷ tid for 6 months without dietary restriction. Patients exhibited Δ Weight of -0.84 ± 0.31 kg/month (P = 0.0003) and ΔBMI of -0.31 ± 0.13/month (P = 0.003). Calorie counts by recall decreased by 750 cal/d by the end of the study (P = 0.01). OGTT showed glucose intolerance in only 2 pts, with 2 hr glucoses of 117 ± 12 mg/dl. HbA1C values were unchanged. Fasting IRI were unchanged (28.5± 13.5 μU/ml), but glucosestimulated peak IRI were decreased after 6 months of octreotide (100.0 ± 41.0 μU/ml; P = 0.04). Weight loss correlated with both decrease in insulin response (r2 = 0.74), and decrease in plasma leptin (r2 = 0.71). Small gallstones were visualized by U/S in 3/7 pts. 1 pt developed edema; no other complications were noted, 6/8 pts reported less malaise, more energy, and increased activity.

These results strongly suggest that pts with hypothalamic obesity have hyperstimulable insulin secretion, which promotes glucose mobilization into fat. The mild glucose intolerance suggests minimal insulin resistance initially. Treatment with octreotide promoted weight loss and BMI decrease. Reduction of insulin response correlated with reduction in weight, suggesting that the pathophysiology of the weight gain involved hyperinsulinism. These data suggest that cancer therapy leads to VMH lesions which result in insulin hypersecretion, with resultant obesity, and which can be reversed by somatostatin attenuation of β-cell function.