Spontaneous and amino acid-stimulated glucagon secretion in the immediate postnatal period. Relation to glucose and insulin.

The extent and significance of spontaneous glucagon secretion in the immediate postnatal period were investigated in groups of normal infants studied cross-sectionally and longitudinally. Arginine-and alanine-stimulated glucagon secretion was also studied. Plasma glucagon concentrations were correlated with prevailing glucose and insulin concentrations. The characteristic fall in blood glucose, reaching a nadir within hours of birth, was associated with a significant increase in glucagon concentration. Despite persistence of relative glucopenia, glucagon did not change appreciably between 2 and 24 h of life. A further significant elevation in glucagon concentration occurred from day 1 to day 3 of life associated with a return of glucose to euglycemic levels. In contrast to the sluggishness of pancreatic glucagon release, glucagon-like immunoreactivity rose markedly to mean levels of approximately 2,000 pg/ml after introduction of formula feeding. No significant changes in insulin levels were observed in these studies. Arginine infusion via an umbilical vein catheter into six infants within 6 h of birth elicited a brisk, almost threefold increment in glucagon concentration (from 339+/-85 to 940+/-254 pg/ml) in blood obtained from, or close to, the portal circulation. Bolus injection of alanine (1 mmol/kg) into a peripheral vein to six infants resulted in significant increments in glucagon (mean maximal, 128 pg/ml) as well as glucose and insulin. The observations suggest that spontaneous glucagon secretion may be an important factor in neonatal glucose homeostasis. Secretion seems more brisk in response to amino acid stimulation than to a falling glucose concentration.

Recruitment of a repressosome complex at the growth hormone receptor promoter and its potential role in diabetic nephropathy.

The growth hormone (GH)-GH receptor (GHR) axis modulates growth and metabolism and contributes to complications of diabetes mellitus. We analyzed the promoter region of the dominant transcript (L2) of the murine GHR to determine that a cis element, L2C1, interacts with transcription factors NF-Y, BTEB1, and HMG-Y/I. These proteins individually repress GHR expression and together form a repressosome complex in conjunction with mSin3b. The histone deacetylase inhibitor trichostatin A increases expression of the murine GHR gene, enhances association of acetyl-H3 at L2C1, inhibits formation of the repressosome complex, and decreases NF-Y's association with L2C1. Our studies reveal that murine models of experimental diabetes mellitus are characterized by reduced hepatic GHR expression, decreased acetyl-H3 associated with L2C1, and increased formation of the repressosome complex. In contrast, in the kidney diabetes mellitus is associated with enhanced GHR expression and lack of alteration in the assembly of the repressosome complex, thus permitting exposure of kidneys to the effects of elevated levels of GH in diabetes mellitus. Our findings define a higher-order repressosome complex whose formation correlates with the acetylation status of chromatin histone proteins. The delineation of the role of this repressosome complex in regulating tissue-specific expression of GHR in diabetes mellitus provides a molecular model for the role of GH in the genesis of certain microvascular complications of diabetes mellitus.

Prostaglandin synthesis inhibitors impair hepatic glucose production in response to glucagon and epinephrine stimulation.

To investigate whether inhibition of prostaglandin synthesis affects hormone-induced glucose dynamics, we measured glucose turnover in response to glucagon alone (5 ng . kg-1 min-1) or combined with epinephrine (0.1 microgram . kg-1 min-1) in conscious trained dogs (N = 6) on three separate occasions in each animal: (1) during a control saline infusion, (2) during infusion of indomethacin, and (3) during infusion of sodium salicylate. Glucose production (Ra) and utilization (Rd) were determined by isotope dilution using the nonrecycling label 3-3H glucose. In controls, glucagon levels (IRG) rose from a basal of 44 +/- 12 to 260 +/- 40 pg/ml (mean +/- SEM) during glucagon infusion; basal epinephrine levels (EPI) of 150 +/- 20 pg/ml were unaffected by glucagon infusion but rose four- to fivefold during combined glucagon/epinephrine infusion. Plasma glucose rose transiently from 95 +/- 1 to a peak of 136 +/- 13 mg/dl after 20 min of glucagon; infusion of EPI resulted in a second glycemic response with a peak of 148 +/- 9 mg/dl. Ra increased transiently from 2.9 +/- 0.2 to a peak of 7.9 +/- 1.4 mg . kg-1 min-1 during glucagon alone with a second rise to 6.2 +/- 0.8 mg . kg-1 min-1 10 min after beginning EPI. With glucagon alone, Rd paralleled Ra but addition of EPI resulted in a relative fall in Rd. Insulin (IRI) rose from 9 +/- 1 microU/ml to 29 +/- 6 microU/ml with glucagon but IRI fell despite the second glycemic response during EPI. When either indomethacin or salicylate was infused, basal IRI, IRG, EPI, glucose, Ra and Rd were unaffected and were similar to controls. Although plasma levels of IRG and EPI during glucagon or glucagon plus epinephrine infusion were also similar to controls, the glycemic response was reduced (P less than 0.05). This attenuation of glycemic response was due to a reduction of stimulated Ra (P less than 0.05) and not to an increase in Rd. Changes in IRI paralleled the reduction in glycemic response. Thus, both indomethacin and salicylate blunt the glycemic response to glucagon and glucagon plus epinephrine by attenuating glucose production and not by enhancing glucose utilization or insulin secretion. These results with two prostaglandin synthesis inhibitors suggest that prostaglandins modulate the hepatic effects of glucagon and epinephrine.

Possible dissociation between insulin binding and insulin action in isolated fetal rat hepatocytes.

To directly examine the relationship between insulin receptors and insulin action in fetal tissue, we compared insulin receptor characteristics and insulin-mediated 14C-glucose incorporation into glycogen, as well as glycogen synthase activity, in freshly isolated hepatocytes from 21-day fetal (F) and adult (A) rats. Viability of hepatocytes was documented by trypan blue exclusion (greater than 90%), time-dependent 14C-leucine incorporation into protein, and dose-related incorporation of glucose into glycogen. Percent specific binding of 125I-insulin per unit protein was significantly higher in F than A liver plasma membranes (32.2 +/- 0.3 versus 18 +/- 2.4; P less than 0.01) and Scatchard plots revealed twice the number of receptors in F. Similarly, receptor number per cell surface area was threefold higher in F than in A (150 versus 50 sites/micron2). At a fixed medium glucose concentration of 11.2 mM, insulin stimulated 14C-glucose incorporation into glycogen in a dose-related manner in A with an apparent Km of 1.0 ng/ml and Vmax at 5-10 ng/ml corresponding to 30-40% of total receptor occupancy; no effect was obtained in F with insulin up to 100 ng/ml. Net glucose incorporation into glycogen (nmol/10(6) cells/h) increased progressively with increasing medium glucose concentrations ranging from 1.4 to 27.8 mM; incorporation by F was significantly greater than by A at each glucose concentration. However, whereas insulin at 100 ng/ml significantly augmented net glucose incorporation at each glucose concentration in A, no effect of insulin was apparent in F.(ABSTRACT TRUNCATED AT 250 WORDS)

Measurement of "true" glucose production rates in infancy and childhood with 6,6-dideuteroglucose.

"New" glucose production has been measured in 54 infants and children for the first time by continuous three-to-four-hour influsion of the safe, nonradioactive tracer 6,6-dideuteroglucose. The use of combined gas chromatography--mass spectrometry with monitoring of selected ions allowed deuterium enrichment in blood glucose to be measured on microliter samples with an error of less than 2 per cent. In the young child, glucose production increased in a slightly curvilinear manner from 1 kg. to 25 kg. body weight, when it reached 140 mg. per minute, almost the adult value of 173 mg. per minute (2.28 +/- 0.23 mg./kg.-min., mean +/- S.E.). Normalized for weight, glucose production in premature infants was 5.46 +/- 0.31 mg./kg.-min., in term neonates averaged 6.07 +/- 0.27 mg./kg.-min., in children below the age of six years was 7.1 +/- 0.27 mg./kg.-min., and in late childhood averaged 5.4 +/- 0.28 mg./kg.-min. Relative to estimated brain weight, however, glucose production was essentially linear from the 1-kg. premature infant to the 80-kg. adult. These data, the first measurements of "new" glucose production in childhood, suggest that brain size may be a principal determinant of those factors that regulate hepatic glucose output throughout life.

Low-dose continuous insulin therapy for diabetic ketoacidosis. Prospective comparison with "conventional" insulin therapy.

Low-dose insulin infusion has recently been used to treat ketoacidosis. We have prospectively compared patients with ketoacidosis either treated with insulin infusion at the rate of 6 units per hour or with high-dose, intermittent subcutaneously administered insulin, with emphasis placed on the hormonal responses. Basal glucagon, cortisol, and growth hormone levels were elevated in both groups. Cortisol and growth hormone levels did not fall with therapy in either group but glucagon levels fell in parallel with glucose levels in both groups. There was no difference in the time taken for glucose levels to fall below 250 mg/100 ml between groups. Whereas both methods of therapy appeared to be equally effective, low-dose infusion had the advantages of ease of administration, a predictable, relatively linear rate of fall of glucose levels, and ability to be stopped abruptly in the event of hypoglycemia.

Effects of exercise training on insulin sensitivity in adolescents with type I diabetes.

We investigated the influence of a program of exercise training consisting of three weekly sessions, each 45 min long, for 12 wk, on indices of physical fitness, glycemic control, and insulin sensitivity in nine adolescents with type I diabetes; six age-matched adolescents with diabetes of equivalent duration served as nonexercised controls. All subjects were instructed not to change dialy insulin dose or caloric intake. In the exercised group, maximal oxygen uptake during graded cycle ergometry to volitional exhaustion increased by 9 +/- 2.7% (P less than 0.01) and lean body mass increased by 4 +/- 1.8% (P less than 0.05). Insulin sensitivity, assessed via the euglycemic clamp technique at insulin infusion rates of 100 mU/M2/min, showed an increase of insulin-mediated glucose disposal from 274 +/- 33 to 338 +/- 28 mg/M2/min, representing an increase in insulin sensitivity of 23 +/- 5% (P less than 0.01). None of these indices changed in the control group. Despite increased insulin sensitivity, glycohemoglobin levels remained at 12 +/- 1% before and after the 12 wk of exercise training, indicating no improvement in overall glycemic control. No increase in hypoglycemic reactions was reported in either group. We conclude that exercise training may be a valuable adjunct in managing type I diabetes providing there is concomitant attention to diet and insulin. Exercise training alone, however, does not improve glycemic control, although it improves physical fitness and insulin sensitivity.

Isolation of a liver-specific promoter for human growth hormone receptor gene.

The biological actions of growth hormone (GH) are mediated through the growth hormone receptor (GHR). The GHR gene is expressed in a tissue specific manner and multiple variants (V1 to V8) of GHR mRNA have been detected in human tissues. To understand the regulation of GHR gene expression, a human genomic clone containing the 5'-untranslated region (5'UTR) of the V1, V4, V7 and V8 exons of the GHR was isolated. The 2 kilobase (kb) 5' upstream sequence of the V1 specific UTR has promoter activity in transient transfection assays of the human hepatoma cell line, HepG2. The exclusive expression of the V1 variant in adult liver, and the lack of expression of the other variants in this tissue, suggests that the V1 5'UTR represents the liver specific 5' noncoding exon for the human GHR gene. The data are consistent with the first isolation of a liver specific promoter for human GHR.

Grtp1, a novel gene regulated by growth hormone.

An in vitro model of GH-responsive cells was subjected to microarray analysis to identify a novel gene regulated by GH. This 258 amino acid protein, we term GH Regulated TBC Protein-1 (GRTP1), contains the TBC signature motif of GTPase activator proteins of Rab-like small GTPases. Northern blot analysis revealed a 1.3 kb major mRNA species, most abundant in testes. TaqMan assay confirmed that in the mouse, Grtp1 is expressed at highest levels in testes, with lesser abundance in intestine, kidney, lung, and liver. In the testis, expression of Grtp1 significantly increases post-pubertally. Administration of GH to mice increased levels of GRTP1 mRNA in testes (140%), but decreased GRTP1 mRNA abundance in kidney (50%) and liver (25%). Grtp1 was localized to mouse proximal chromosome 8. Orthologs of this protein are present in human, mouse, rat, and drosophila suggesting that GRTP1 has an important biological role(s).

Acromegaloid patients with type A insulin resistance: parallel defects in insulin and insulin-like growth factor-I receptors and biological responses in cultured fibroblasts.

A subset of patients with the syndrome of acanthosis nigricans and insulin resistance type A is characterized by acromegaloid features in addition to hyperinsulinemia, hyperandrogenemia, and an inherent defect in insulin receptor function. It has been proposed that the acromegaloid features result from the interaction of insulin at concentrations encountered in vivo, with a functionally intact insulin-like growth factor-I (IGF-I) receptor closely related to the insulin receptor. We investigated this possibility by examining binding and hormone-stimulated [14C]glucose uptake, [3H]thymidine uptake, and receptor autophosphorylation by both insulin and IGF-I in cultured fibroblasts from two affected patients. In comparison to normal fibroblasts, [125I]insulin binding, insulin-stimulated [14C]glucose, and [3H]thymidine uptake, and insulin-stimulated autophosphorylation were each reduced by approximately 50-60% of the absolute values in controls. In contrast to expectation, each of these apparent defects in insulin binding and action were mirrored by a parallel decrease in IGF-I binding and action. Thus, [125I]IGF binding was approximately 50%, IGF-I stimulated [3H]thymidine uptake was approximately 40% and 60% of the control value, and IGF-I-stimulated receptor autophosphorylation was reduced by 40%. Incubation of fibroblasts with insulin at 25 ng/mL reduced subsequent binding of [125I]IGF-I by approximately 20% and did not enhance maximal stimulation of [3H]thymidine incorporation. We conclude that in some patients with acanthosis nigricans and acromegaloid features, IGF-I receptors of cultured fibroblasts may share the inherent defects of insulin receptor function. These in vitro data do not explain the acromegaloid features observed in vivo, suggesting that acromegaloid features are mediated by other mechanisms.

Characteristics of hepatic receptors for somatomedin-C/insulin-like growth factor I and insulin in the developing human.

Insulin and the somatomedins (Sms) are putative regulators of cell proliferation and metabolism in the fetus. Since the liver is a potential target tissue of these hormones during fetal life, we characterized the hepatic receptors for Sm-C/insulin like growth factor I (Sm-C/IGF-I) and insulin during the second trimester of human fetal development. Membrane-enriched fetal liver homogenates specifically bound 8.9 +/- 1.5% (+/- SD) of added [125I]insulin and 5.1-7.2% of [125I]Sm-C/IGF-I. Binding of both hormones was constant from 12-20 weeks gestation and was much greater than that in adult liver membranes. Analysis of dose-response data indicated high affinity between each receptor and its respective ligand (Kd for the Sm-C/IGF-I receptor, 2.2 X 10(-10) M; Kd for insulin receptor, 5.2 X 10(-10) and 7.7 X 10(-9) M). Limited cross-reactivity (approximately 1:1,000) of insulin with the Sm-C/IGF-I receptor and Sm-C/IGF-I with the insulin receptor was found. Affinity labeling studies showed that each receptor possessed an approximately 135,000-dalton subunit which was a part of a larger disulfide-linked complex. Thus, the human fetal liver has specific receptors for Sm-C/IGF-I and insulin that are similar to those described for other tissues in terms of both hormone-binding characteristics and subunit structure, suggesting that these receptors mediate important cellular functions at this stage of fetal development.

Diminished growth hormone-binding protein in children with insulin-dependent diabetes mellitus.

Two distinct GH-binding proteins (GHBP) are present in circulation in the human. The major GHBP (high affinity GHBP) is homologous to the extracellular portion of the GH receptor and the concentration of this protein in circulation may reflect the status of the GH receptor in the tissues. To gain information about the concentration of GHBPs in children with insulin-dependent diabetes mellitus (IDDM), we measured GHBP in the serum of 46 children with IDDM and compared it to that in 53 healthy control subjects matched for age and sexual maturity. The total GHBP concentration in the group of pubertal and postpubertal IDDM patients was lower than that measured in the control group (mean +/- SEM: 7.8 +/- 0.4 vs. 9.0 +/- 0.5%, P = 0.05). The diabetic children in stages II to IV of puberty had a lower GHBP level compared to their healthy controls (7.6 +/- 0.4 vs. 9.1 +/- 0.5%, P = 0.02), whereas the difference between the diabetic and control group of postpubertal children was not statistically different (8.3 +/- 0.7 vs. 9.7 +/- 0.7%, P = 0.1). In a randomly selected subset of eight patients and eight controls, the concentration of the individual GHBPs (i.e. high affinity and low affinity (GHBP) was estimated by gel chromatography. There was no difference in the low affinity GHBP between the two groups (9.9 +/- 0.6% vs. 9.9 +/- 0.4%), but the high affinity GHBP was less in the diabetic group than in the control group (10.5 +/- 0.9 vs. 15.6 +/- 1.0%, P less than 0.01). In the diabetic group, there was no correlation between the GHBP levels and age, duration of diabetes, hemoglobin A1, or insulin dose. We conclude that in IDDM there is less of the high affinity GHBP, suggesting a decrease in the number of GH receptors in these patients. This decrease may contribute to GH resistance manifesting as decreased insulin-like growth factor-I levels despite high GH levels in patients with IDDM.

The role of human growth hormone in the regulation of cholesterol and bile acid metabolism.

Cholesterol and bile acid metabolism was studied in 16 children with human GH (hGH) deficiency (11 with isolated hGH deficiency and 5 with multiple trophic hormone deficiency) before and after 6 months of hGH therapy. We measured plasma lipid concentrations, biliary lipid composition, and cholesterol saturation indices; calculated the bile acid pool size measured by the isotopic dilution technique using the stable isotope chenodeoxycholic-[11,12-d2] acid; and measured cholesterol and bile acid synthetic rates by sterol balance techniques. In all 16 patients, plasmas lipid concentrations were unchanged after hGH therapy; total plasma cholesterol was 182 +/- 10 (+/-SEM) mg/dl before and 179 +/- 9 mg/dl after treatment, high density lipoprotein-cholesterol was 47 +/- 2 mg/dl before and 49 +/- 3 mg/dl after treatment, low density lipoprotein-cholesterol was 112 +/- 10 mg/dl before and 111 +/- 8 mg/dl after therapy, and triglyceride was 113 +/- 13 mg/dl before and 107 +/- 10 mg/dl after hGH therapy. Biliary lipid composition and cholesterol saturation in 10 patients were similar to those in controls and unchanged with hGH therapy. Cholesterol synthesis (n = 14) was unchanged (7.6 +/- 1.4 vs. 9.6 +/- 1.2 mg/kg X day); however, bile acid synthesis (n = 15) increased from 3.1 +/- 0.4 to 4.3 +/- 0.6 mg/kg X day (P less than 0.025) after therapy. The chenodeoxycholate pool size (n = 8) was significantly reduced (P less than 0.025) before hGH treatment (416 +/- 64 mg/m2) compared to that in controls (617 +/- 45 mg/m2) and increased to 620 +/- 72 mg/m2 after hGH therapy (P less than 0.05). Chenodeoxycholate pool size expansion during hGH therapy was, at least in part, caused by an increase in hepatic bile acid synthesis. These findings suggest that hGH may indirectly modulate cholesterol metabolism through regulation of hepatic cholesterol 7 alpha-hydroxylase activity, the rate-limiting enzyme of bile acid synthesis.

The modified minimal model: application to measurement of insulin sensitivity in children.

The modified minimal model (MMM), a recently introduced method that assesses insulin sensitivity (SI) by a computed mathematical analysis of the relation between the change in insulin and glucose clearance after a bolus of iv glucose, followed 20 min later by a bolus of tolbutamide, has been standardized in adults, but this method has not been validated in children. We performed an abbreviated 90-min MMM test in 50 children who were siblings of patients with insulin-dependent diabetes mellitus and 7 healthy adult volunteers and compared the results to the standard 180-min MMM test in 11 of these subjects. The cohort consisted of 29 prepubertal children [16 males and 13 females; 8.7 +/- 2.0 (mean +/- SEM) yr old]; 16 pubertal children defined as less than 17 yr of age and Tanner stage 2-5 (8 males and 8 females; 13.4 +/- 1.8 yr old), and 12 postpubertal subjects (7 males and 5 females; 18.2 +/- 0.9 yr old), with no significant difference in the weight for length index (WLI) among the 3 groups and with sera of all subjects negative for islet cell antibodies and insulin autoantibodies. The test procedure consisted of 3 baseline blood samples over 30 min, followed at zero time by 0.3 g/kg 25% dextrose infused iv over 1 min and an iv injection of tolbutamide (5 mg/kg) 20 min later; sequential blood samples for glucose and insulin measurements were withdrawn from zero time until completion 90 or 180 min later. In the 11 subjects who underwent both the standard and the abbreviated tests, there was no significant difference between the SI estimated by the 2 methods provided that glucose and insulin values were interpolated at 180 min during the computer calculations of the abbreviated test. Using the 90-min abbreviated test, the SI of the pubertal subjects (2.92 +/- 0.45) was markedly less than that of the prepubertal subjects (6.57 +/- 0.45; P = 0.0001). While the postpubertal group value of 4.63 +/- 0.86 was significantly higher than that of the pubertal group (P = 0.0001), the pre- and postpubertal groups remained significantly different (P = 0.0001). The 10 obese subjects with WLI greater than 120% had a lower SI (3.5 +/- 0.53) than the 47 nonobese subjects with WLI less than 120% (SI = 5.48 +/- 0.42; P less than 0.04), and there was a negative correlation between SI and WLI. None of the study subjects experienced symptomatic hypoglycemia during the test.(ABSTRACT TRUNCATED AT 400 WORDS)

Insulin resistance in short children with intrauterine growth retardation.

Epidemiological studies have demonstrated an association between intrauterine growth retardation and an increased risk of adult diseases that include essential hypertension, noninsulin-dependent diabetes mellitus, and ischemic heart disease. A common feature of these diseases is insulin resistance. To investigate whether abnormal insulin sensitivity was a characteristic of subjects with intrauterine growth retardation (IUGR), we compared two groups of short prepubertal children: a group with IUGR (birth weight less than the tenth percentile; n = 15) and a normal birth weight group (n = 12). Subjects underwent a modified frequently sampled iv glucose tolerance test that permitted calculation of the acute insulin response, insulin sensitivity index, and glucose effectiveness. A marked difference in the insulin sensitivity index was noted between groups, with the IUGR group being less insulin sensitive [6.9 vs. 16.9 10(-4)min-1.(microU/mL); P = 0.0048]. The acute insulin response was also significantly different between groups, with IUGR subjects having higher insulin levels (445 vs. 174 microU/mL; P = 0.005). There was no difference in glucose effectiveness between groups. Short prepubertal IUGR children have a specific impairment in insulin sensitivity compared to their normal birth weight peers. In short IUGR children, impaired insulin sensitivity is a potential marker for the early identification and intervention in the development of late adult-onset noninsulin-dependent diabetes mellitus.

True precocious puberty complicating congenital adrenal hyperplasia: treatment with a luteinizing hormone-releasing hormone analog.

Congenital adrenal hyperplasia (CAH) is a recognized cause of precocious pseudopuberty. Some children with CAH also develop true precocious puberty with early maturation of the hypothalamic-pituitary-gonadal axis. We have seen four such children (three boys and one girl) who had the diagnosis of CAH made between the ages of 3 and 6 yr. These patients were treated with standard doses of hydrocortisone and fludrocortisone. A diagnosis of true precocious puberty was made because of testicular enlargement in the boys, breast development in the girl, progressive pubic hair development, rapid growth, and rapid bone age maturation. Plasma steroid levels were elevated for age, and gonadotropin levels were within the normal pubertal range, both basally and in response to LHRH stimulation. We treated these children with daily sc injections of a LHRH analog (LHRHa) for 6-18 months in addition to the standard hydrocortisone and fludrocortisone therapy for CAH. LHRHa significantly decreased basal plasma LH and FSH, peak LH and FSH responses to native LHRH, and testosterone levels. Testis size decreased in the males, and breast development regressed in the female. LHRHa therapy led to significant decreases in linear growth rate, ulnar growth rate, and rate of bone age advancement. These results suggest that LHRHa is an effective adjunct to hydrocortisone and fludrocortisone in the treatment of true precocious puberty complicating CAH.

Intestinal adaptation after jejunoileal bypass in man.

Gastrointestinal anatomy and function has been studied prospectively in 12 patients undergoing jejunoileal bypass surgery in order to investigate the adaptive response of the intestinal mucosa. The total thickness of the jejunal mucosa did not change after surgery, but the crypts became relatively deeper, suggesting a more rapid turnover of gastrointestinal cells. The absorption of oxalate was depressed in the immediate postoperative period but had improved toward preoperative levels by 6 months. Vitamin B12 absorption also declined postoperatively, and increased thereafter in the patients with an end-to-end jejunoileostomy, but showed a much smaller recovery in the group with an end-to-side anastomosis. The cholesterol concentration (lithogenicity) of the duodenal bile rose by 30% in the first 3 weeks after surgery, but had returned to preoperative levels by 6 months. The segmental absorption of glucose across the jejunum declined after surgery. Caloric intake also declined, whether measured as the quantity of food that patients elected to eat over a 24-hr period, or as the quantity of a liquid lunch which they consumed over a 20-min period. The level of basal gastric acid was increased postoperatively but the maximal output after histamine stimulation was not. The gastrin response to a standard liquid meal was also significantly increased after surgery. Enteroglucagon secretion showed an increase in 3 weeks and a further increase by 6 months after intestinal bypass surgery. The significance of these changes to intestinal adaptations is discussed.

Insulin as a growth factor.

Various clinical syndromes illustrate the essential role of insulin in modulating somatic growth both in utero and after birth. The effect of insulin on growth is a consequence of direct effects transduced via its homologous receptor and post-receptor signaling pathways and indirect effects on other modulators of growth, such as the growth hormone-IGF axis. Recent insights into the post-receptor mechanisms of insulin signaling provide a scientific framework for the distinction between the traditional role of insulin as a major modulator of metabolism and its role as a promoter of growth.

Hyperinsulinemic hypoglycemia of infancy. Recent insights into ATP-sensitive potassium channels, sulfonylurea receptors, molecular mechanisms, and treatment.

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI), previously termed "nesidioblastosis," is an important cause of hypoglycemia in infancy and childhood. Recent studies have defined this syndrome at the molecular, genetic, and clinical level. This article reviews the genetic and molecular basis of these entities, describes their clinical manifestations, and discusses the rationales for available therapeutic options.