Familial hyperinsulinism with apparent autosomal dominant inheritance: clinical and genetic differences from the autosomal recessive variant.

We describe three families with hypoglycemia caused by familial hyperinsulinism (HI) in whom vertical transmission of the disorder occurred, suggesting autosomal dominant (AD) inheritance. We therefore examined the relationship between the apparent AD disorder and the more common autosomal recessive (AR) form of HI, which has recently been linked to the sulfonylurea receptor on chromosome 11p15.1. The clinical features of the 11 patients with AD HI were milder than those seen in 14 patients with AR HI. Hypoglycemia was readily controlled with either diet alone or with diazoxide in 10 of 11 patients with AD HI but in none of those with the AR form. In one large pedigree, analysis of genomic DNA with polymorphic simple sequence repeat markers excluded linkage of AD HI to the SUR locus in a dominant manner. The possibility of linkage to the SUR locus could not be absolutely excluded in the two smaller pedigrees. None of the published mutations of the SUR gene identified in patients with AR HI were detected in the patients with the AD form. We conclude that the AD form of hyperinsulinism is phenotypically different from the AR variant. The identification of more families with this form of HI may make it possible to locate the responsible gene by the use of linkage analysis.

Insulin-like growth factor binding protein-1 levels in the diagnosis of hypoglycemia caused by hyperinsulinism.

The diagnosis of hypoglycemia caused by hyperinsulinism may be difficult because insulin levels are not uniformly elevated at the time of hypoglycemia. Insulin-like growth factor binding protein-1 (IGFBP-1) is a 28 kd protein whose secretion is acutely inhibited by insulin. We hypothesized that serum levels of IGFBP-1 would be a useful marker of hyperinsulinism. We measured IGFBP-1 levels during the course of standardized fasting studies in hospitalized children; 36 patients became hypoglycemic during the fasting studies, and samples obtained at the point of hypoglycemia were analyzed. On the basis of the currently used diagnostic criteria, 13 children had hyperinsulinism, 16 had ketotic hypoglycemia or no disorder, 3 had hypopituitarism or isolated growth hormone deficiency, 2 had glycogen storage disease type 1 and 2 had fatty acid oxidation disorders. In control subjects (children with ketotic hypoglycemia or no disorder), IGFBP-1 levels rose during fasting to a mean of 343.8 +/- 71.3 ng/ml in the sample drawn at the time of hypoglycemia. Mean IGFBP-1 levels at hypoglycemia for the entire group with hyperinsulinism were 52.4 +/- 11.5 ng/ml, significantly different from levels seen in control subjects (p < 0.0001). In children with moderately controlled hyperinsulinism (fasting tolerance > 4 hours), mean IGFBP-1 levels at the time of hypoglycemia were 71.5 +/- 16.9 ng/ml. IGFBP-1 levels in the children with poorly controlled hyperinsulinism (fasting tolerance < 4 hours) failed to rise during fasting, with a mean of 30.1 +/- 10.4 ng/ml in the final sample. IGFBP-1 levels were inversely correlated with serum insulin and C-peptide levels (r = -0.71 and -0.72, respectively; p < 0.0001). Patients with other endocrinologic or metabolic diseases that result in fasting hypoglycemia demonstrated a rise in IGFBP-1 levels similar to that seen in ketotic hypoglycemia. Low serum levels of IGFBP-1 at the time of hypoglycemia provide an additional marker of insulin action that might help to differentiate hyperinsulinism from other hypoglycemic disorders.

Role of proestrous progesterone secretion in suppressing basal pulsatile LH secretion during estrus of the estrous cycle.

These studies examined the mechanisms responsible for the paucity of basal LH pulses during estrus. We confirmed our earlier observations that constant infusion of naloxone during estrus results in the immediate appearance of pulsatile LH secretion during estrus, consisting of LH peak heights and LH interpulse intervals that are similar to those observed during other days of the estrous cycle. We then tested whether the proestrous surge of progesterone was responsible for the suppression of pulsatile LH secretion during estrus. Three treatment regimens were used on proestrus to either block progesterone secretion (pentobarbital) or block its action (progesterone antiserum or the progesterone antagonist, RU 486). After treatment at 12.00 h on proestrus, blood samples were collected during estrus every 10 min for 4 h, and the plasma samples were analyzed for the pattern of LH secretion. Treatment with pentobarbital (35 mg/kg at 12:00 h) blocked the proestrous surges of LH and progesterone and resulted in pulsatile LH secretion during estrus. The LH interpulse interval (72 +/- 7 min) was somewhat slower than that observed in the naloxone-infused animals (54 +/- 8 min). Simultaneous treatment with pentobarbital and progesterone at 12:00 h on proestrus completely prevented the appearance of LH pulses during estrus. Treatment with either progesterone antiserum (0.5 ml, i.v.) or RU 486 (1 mg s.c.) resulted in the initiation of pulsatile LH secretion during estrus. In the RU 486-treated animals, LH peak heights and LH interpulse intervals were similar to those observed in naloxone-infused animals and during other days of the estrous cycle.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose response effects of pulsatile GnRH administration on restoration of pituitary GnRH receptors and pulsatile LH secretion during lactation.

Ovariectomized (OVX) rats suckling 8 pups have a complete suppression of pulsatile LH secretion and a decrease in pituitary GnRH receptor (GnRH-R) content. Removing the suckling stimulus for 24 h results in a sharp increase in GnRH-R and a restoration of pulsatile LH secretion. These findings suggest that the suckling stimulus induces a suppression of GnRH secretion, and removal of the suckling stimulus permits the restoration of GnRH secretion. Indeed, if GnRH antiserum is injected at the time of pup removal, the restoration of pituitary GnRH-R and LH secretion is prevented. The present studies were designed to test our hypothesis that the deficits in pituitary gonadotroph function observed during lactation are due to suckling-induced suppression of GnRH. Exogenous GnRH was administered in a pulsatile regimen to OVX lactating rats on days 10 and 11 postpartum, and the effects on pituitary GnRH-R levels, pituitary sensitivity to GnRH, and pulsatile LH secretion were assessed. GnRH doses of 0, 0.5, 2.0 or 5.0 ng/pulse were administered every 50 min for 24 h beginning on day 10. Administration of 0.5 ng GnRH/pulse for 24 h increased GnRH-R from 35 +/- 3 to 63 +/- 8 fmol/pituitary. There was a clear GnRH dose-related upregulation of GnRH-R to approach nonsuckling levels (140-160 fmol/pituitary) with the 5 ng GnRH dose. At the beginning of GnRH administration, the pituitary was very unresponsive to GnRH. Consistent LH pulses were only observed with 5 ng GnRH/pulse.(ABSTRACT TRUNCATED AT 250 WORDS)

Suppression of pulsatile LH secretion, pituitary GnRH receptor content and pituitary responsiveness to GnRH by hyperprolactinemia in the male rat.

To assess whether gonadotropin-releasing hormone (GnRH) release from the hypothalamus might be altered by hyperprolactinemia in the male rat, we measured in chronically hyperprolactinemic rats the pituitary GnRH receptor content and described the pattern of luteinizing hormone (LH) release during the postcastration rise in gonadotropin secretion 24 and 72 h after gonadectomy. In intact rats, the effect of hyperprolactinemia was determined by describing the pattern of LH secretion, pituitary GnRH receptor content and assessment of pituitary responsiveness to small doses of GnRH (1.0 ng). In addition, to determine the role endogenous opioids might play in inhibiting GnRH release in hyperprolactinemic rats, we examined the effect of both a continuous infusion and a bolus injection of the opioid antagonist naloxone on the pattern of LH release. Chronic hyperprolactinemia was achieved by implanting 4 pituitaries under the kidney capsules 3-4 weeks before study. Acute hyperprolactinemia was achieved by injecting rats with 1 mg ovine prolactin every 12 h for 3 days. Control animals were untreated or were chronically hyperprolactinemic rats in which the hyperprolactinemia was transiently reversed by treatment for 3 days with the dopamine agonist 2-alpha-bromoergocryptine. The mean LH concentration was greatly decreased at 24 postcastration in chronically hyperprolactinemic rats relative to controls. This decrease was associated with a decrease in LH pulse height and pulse amplitude and pituitary GnRH receptor content, but not with an increase in the LH interpulse interval. In contrast, the decrease in mean LH concentrations in hyperprolactinemic animals at 72 h postcastration was primarily associated with a significantly longer LH interpulse interval than that observed in control animals. Chronic hyperprolactinemia in intact rats decreased the pituitary GnRH receptor content, in addition to decreasing the mean LH concentrations during pulsatile GnRH administration. Chronic hyperprolactinemia also inhibited LH release relative to controls during the continuous 4-hour infusion of naloxone and in response to a bolus injection of naloxone. However, in acutely hyperprolactinemic intact male rats a bolus injection of naloxone increase LH secretion 20 min later to levels similar to those obtained in control rats. In summary, these results indicate that chronic hyperprolactinemia decreased LH secretion by primarily decreasing GnRH secretion as suggested by a decrease in pituitary GnRH receptor content and a decrease in LH pulse frequency and pulse amplitude.(ABSTRACT TRUNCATED AT 400 WORDS)

Regulation of gonadotropin secretion during lactation.

Lactation in the rat is characterized by an inhibition of ovarian cyclicity which correlates with a suppression of basal gonadotropin secretion, a decrease in the magnitude of estrogen-induced LH surges and a decrease in the postcastration rise en LH and FSH. Furthermore, pulsatile administration of GnRH (0.4 ng GnRH every 50 min) fails to elicit LH pulses in females nursing 8 pups but produces normal basal LH pulses in females nursing 2 pups. There is a good correlation during lactation among pituitary GnRH receptor content, pituitary responsiveness to GnRH and basal LH secretion. All of these parameters are greatly decreased in the presence of an 8-pup suckling stimulus but are generally normal in the presence of a 2-pup suckling stimulus. Taken together with data from other laboratories suggesting that GnRH positively regulates its own receptors, these data suggest that a large suckling stimulus decreases GnRH release from the hypothalamus. This hypothesis is supported by studies in which GnRH release in lactating rats was indirectly assessed by examining the pulsatile pattern of LH secretion. In intact rats suckling 2 or 8 pups on day 10 postpartum, the pattern of LH secretion was uniformly nonpulsatile. The suppression of pulsatile GnRH release in intact females suckling 2 pups does not appear to be due to the small suckling stimulus itself, because ovariectomized females suckling 2 pups exhibited pulsatile LH secretion on day 10 postpartum, but may be due to some ovarian factor acting within the CNS to inhibit GnRH release. In contrast, in ovariectomized females suckling 8 pups, pulsatile LH secretion was completely suppressed.(ABSTRACT TRUNCATED AT 250 WORDS)