Oral glucose augments the counterregulatory hormone response during insulin-induced hypoglycemia in humans.

It has been suggested that the counterregulatory hormone (CRH) response to acute hypoglycemia is triggered via glucose sensors situated in either the hypothalamus or the portohepatic area. If the latter were critical during hypoglycemia, one would anticipate that ingestion of glucose, by raising glucose levels in the portal circulation, should attenuate CRH responses previously described in animal studies. To evaluate the effect of raising portal, but not peripheral, glucose levels during insulin-induced hypoglycemia, we performed hypoglycemic clamp studies in five healthy adult males on two occasions. On one occasion, subjects received oral glucose (OG) (25 g) during hypoglycemia; and on one occasion, noncarbohydrate-containing drink of equal volume, while maintaining plasma glucose at 55 +/- 2 mg/dL (3.08 mmol/L). As a result, there were no significant differences in systemic plasma glucose levels between the two hypoglycemic clamp studies, and basal CRH concentrations were also similar. As expected, there was a brisk rise in all CRH during the control (hypoglycemia+noncarbohydrate drink) study. In the experimental study, administration of OG (hypoglycemia+OG), to raise intraportal glucose levels during systemic hypoglycemia, did not attenuate CRH responses. Indeed, OG enhanced the rise in epinephrine, glucagon, and GH. Increases in cortisol and norepinephrine did not differ between the two studies. Therefore, our data suggest that increasing the level of glucose in the portal vein above that in the systemic circulation, during hypoglycemia, enhances (rather than suppresses) CRH responses. Thus, ingestion of glucose may reverse hypoglycemia directly by provision of substrate, as well as indirectly by stimulating counteregulatory mechanisms.

Augmentation of alimentary insulin secretion despite similar gastric inhibitory peptide (GIP) responses in juvenile obesity.

Insulin secretion rates are greater after oral glucose than after parenteral administration of an equivalent glucose load. This augmented beta-cell secretory response to an oral glucose load results from the release of mainly two gut hormones: gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1, which potentiate glucose-induced insulin secretion. Because of their insulinotropic action, their abnormal secretion may be involved in the pathogenesis of the hyperinsulinemia of childhood obesity. In this study, we used the hyperglycemic clamp with a small oral glucose load to assess the effect of childhood obesity on GIP response in seven prepubertal lean and 11 prepubertal obese children and in 14 lean adolescents and 10 obese adolescents. Plasma glucose was acutely raised to 11 mM by infusing i.v. glucose and kept at this concentration for 180 min. Each subject ingested oral glucose (30 g) at 120 min, and the glucose infusion was adjusted to maintain the plasma glucose plateau. Basal insulin and C-peptide concentrations and insulin secretion rates (calculated by the deconvolution method) were significantly greater in obese children compared with lean children (p < 0.001). Similarly, during the first 120 min of the clamp, insulin secretion rates were higher in obese than lean children. After oral glucose, plasma insulin, C-peptide, and insulin secretion rates further increased in all four groups. This incretin effect was 2-fold greater in obese versus lean adolescents (p < 0.001). Circulating plasma GIP concentrations were similar at baseline in all four groups and remained unchanged during the first 120 min of the clamp. After oral glucose, plasma GIP concentrations rose sharply in all groups (p < 0.002). Of note, the rise in GIP was similar in both lean and obese children. In conclusion, under conditions of stable hyperglycemia, the ingestion of a small amount of glucose elicited equivalent GIP responses in both lean and obese children. However, despite similar GIP responses, insulin secretion was markedly augmented in obese adolescents. Thus, in juvenile obesity, excessive alimentary beta-cell stimulation may be independent of the increased release of GIP.

Familial medullary thyroid carcinoma: presymptomatic diagnosis and management in children.

Two kindreds with familial medullary thyroid carcinoma (MTC) are described in which affected family members had variable clinical and pathologic manifestations. Genetic testing in 2 children from one kindred revealed a mutation in exon 10, codon 618 (TGC to AGC) in the extracellular cysteine-rich region of the RET gene. In this kindred an 11-year-old had microscopic evidence of MTC; however, a 17-year-old had no evidence of pathology on thyroidectomy. In a second kindred a rare mutation in exon 14, codon 804 (GTG to TTG) of the intracellular tyrosine kinase region of the RET gene was detected. In this kindred MTC has occurred in the 4th to 5th decades of life, with a clinical spectrum in mutation-positive family members ranging from no disease and C-cell hyperplasia to carcinoma with lymph node metastasis; a 7-year-old with the mutation and a normal response to provocative testing was also identified. Management recommendations in children from families with clearly defined familial MTC may be individualized to reflect emerging genotype-phenotype correlations.

Decreased insulin sensitivity and compensatory hyperinsulinemia after hormone treatment in children with short stature.

To assess the effects of GH treatment on carbohydrate and protein metabolism, we studied eight patients with short stature before and after the commencement of GH treatment. The hyperglycemic clamp procedure was employed to produce a hyperglycemic stimulus of 50 mg/dL above fasting levels for 120 min. These patients were then treated with 0.3 mg/kg. week GH for 6 months, after which they were restudied. Patients were compared to eight healthy control children matched for age, sex, and Tanner stage. Fasting plasma glucose did not change significantly, but fasting plasma insulin levels were higher after GH therapy (P < 0.005). Despite identical glucose increments during the glucose clamp procedure, both first, and second phase insulin responses were markedly greater after instituting GH treatment. Even in the face of higher mean plasma insulin levels after GH treatment, the rate of insulin-stimulated glucose metabolism did not differ during the last 60 min of both studies. Hence, the rate of insulin-stimulated glucose metabolism/mean plasma insulin ratio (an index of insulin sensitivity) was sharply reduced after GH treatment (P < 0.01). During the clamp, the fall in circulating branched chain amino acid levels was significantly greater after GH therapy (P < 0.02). We conclude that glucose-stimulated insulin responses are increased in short children treated with GH and that such hyperinsulinemic responses compensate for reductions in insulin sensitivity. The compensatory hyperinsulinemic responses induced by GH therapy may serve a beneficial role by augmenting insulin's anabolic effects on protein metabolism.