Insulin resistance in total lipodystrophy: evidence for a pre-receptor defect in insulin action.

The cause of insulin resistance in lipodystrophic diabetes is unknown but has generally been ascribed to dysfunction at either the receptor or post receptor level. In a 14 year-old girl with total acquired lipodystrophy, subcutaneous and intravenous insulin requirements approximated 600 units daily. However, circulating total and free insulin levels were not increased, and during testing by the euglycemic clamp method, the glucose response to increasing free insulin concentrations was within the range found in eight subjects with insulin-dependent diabetes. Insulin clearance during the euglycemic clamp was 43, 98, 115, and 116 mL/kg/min at each of four insulin infusion rates compared to means of 13, 13, 12, and 11 in the control subjects with diabetes. No detectable degrading activity was present in serum, and serum inhibited insulin degradation normally. Binding of insulin to IgG, IgM, and IgE was not increased, insulin binding to monocytes and erythrocytes was not sufficiently abnormal to account for the the insulin resistance, and insulin receptor increased insulin clearance or accelerated degradation of insulin by tissues.

Hamartoma of CNS associated with precocious puberty.

A male infant had precocious puberty and hamartoma of the CNS. Signs of puberty appeared and progressed from 6 months of age. A computed tomographic scan disclosed an interpedunculary tumor. A craniotomy was successfully performed at 11/2 years of age, and 90% of the tumor was removed. Histologically, the tissue was identified as a hypothalamic hamartoma. Pubertal development stopped. The patient is now 4 years 9 months old and well. Review of medical literature covering a span of 47 years showed 50 cases of hamartomas in or near the hypothalamus confirmed by surgical exploration or autopsy. The male-female ratio of hamartomas with precocious puberty derived from these data is 2:1. Convulsions, mental retardation, or behavioral disorders were present in 48% of the cases; 36% had precocious puberty.

Cartilage metabolism during growth retardation following irradiation of the head of the neonatal rat.

The heads of 2-day-old male and female rats were irradiated with a single dose of 600 rads X irradiation, a dose which is known to stunt body weight, tibial length, and tail length, in order to ascertain its effects on synthesis by cartilage of sulfated proteoglycans, DNA, chondroprotein, and collagen as determined by utilization of [35S]sulfate, [Me-3H]thymidine, [1-14C]leucine, and [3,4-3H]proline, respectively. Data have been collected at 20-21, 23, 41-45, and 70-71 days of age. In comparison to controls, growth in body weight, tibial length, and tail length was significantly retarded in irradiated rats of both sexes. Although slow catch-up growth was observed with respect to tail length in both sexes and tibial length in females, a significant deficit in body weight in irradiated rats in both sexes remained at 70-71 days. Cartilage metabolism as evidenced by incorporation of the labeled substances showed no significant disturbance just prior to weaning (20-21 days) or after completion of the principal growth surge (70-71 days). Reduced sulfate and thymidine incorporation attributable to a brief period of undernutrition associated with weaning occurred in head-irradiated rats immediately following weaning (23 days). Increased isotope incorporation occurred at 41-45 days of age in cartilage of irradiated rats incubated with labeled sulfate, leucine, and proline; it did not increase with labeled thymidine. We conclude that neonatal head irradiation slows the rate of growth through the age of most rapid postnatal growth in normal rats. The pattern of cartilage metabolism during this time can be the result either of stimulation by a factor other than somatomedin, or selective inhibition of cartilage thymidine incorporation acting in combination with somatomedin.

The effect of neonatal head-irradiation and subsequent fasting on the mechanisms of catch-up growth.

The heads of 2 day old male and female rats were X-irradiated with 600 rad. Non-irradiated littermates served as controls. At 40 days of age groups of irradiated and non-irradiated rats were subjected to a 48 hour fast. Non-fasted groups of irradiated and non-irradiated rats were fed ad lib. and were used for comparative studies. Growth of body weight and tail length was recorded at intervals through 70 days of age. At sacrifice, pituitary weight, tibial length, and tibial epiphyseal width were also determined. The results confirm earlier findings that whole head irradiation produces reduced growth of body weight and of tail length which remains uncompensated by catch-up growth. After fasting and then refeeding normal catch-up growth acceleration occurred in both male and female irradiated and nonirradiated animals. The fasted non-irradiated animals caught up to the non-irradiated control rat size for both body weight and tail length. Similarly, the fasted irradiated rats caught up to the irradiated, non-fasted rat size, but did not catch up to the size of the non-irradiated controls. Pituitary weight and tibial length were significantly reduced in irradiated males and females. At sacrifice, no significant difference existed between the fasted and non-fasted subgroups. The tibial epiphyseal growth plate was not narrowed in irradiated rats; fasted rats had increased epiphyseal width during recovery in only one group. We conclude that the catch-up growth control is intact in the head-irradiated stunted rat. The findings suggest that the mechanism which recognizes normal body size (set-point for body size) and which determines the limit of catch-up growth acceleration is reset for a smaller body size by the head-irradiation.