A chemiluminescence-based GH assay with 30- to 100-fold increased sensitivity recently disclosed combined basal and pulsatile GH secretion in men. However, how age, sex steroid hormones, and obesity singly and jointly influence the basal vs. pulsatile modes of GH release is not known. We used the foregoing assay (detection threshold, 0.002-0.005 microgram/L) and high sensitivity and specificity (> or = 90% each) deconvolution analysis to quantitate basal and pulsatile GH secretion from 24-h serum GH concentration profiles in 26 healthy lean and obese men, whose ages spanned 18-63 yr and whose percentage body fat ranged from 12-47%. Concentrations of serum insulin-like growth factor I (IGF-I), IGF-I-binding protein-1 (IGFBP-1), and IGFBP-3 were related to specific measures of basal or pulsatile GH release. We observed that mean (24-h) serum GH concentrations embraced a 140-fold range from 0.013-1.8 micrograms/L and were related negatively to age (r = -0.50; P < 0.01), percentage body fat (r = -0.620; P < 0.01), and their interaction (r = -0.610; P < 0.01). In contrast, testosterone was a robustly positive statistical determinant of mean serum GH values (r = 0.628; P = 0.0006). Stepwise multivariate regression analysis disclosed that percentage body fat alone and jointly with the serum testosterone concentration controlled, respectively, 38% and 50% of the total variability in GH levels (P = 0.0013 and P = 0.0008). As assessed by deconvolution analysis, GH secretory burst mass was negatively related to percentage body fat (r = -0.621; P < 0.01) and positively to serum testosterone (r = 0.529; P = 0.0054). The calculated half-life of GH correlated positively with serum estradiol (r = 0.447; P = 0.032), and negatively with percentage body fat (r = -0.437; P = 0.048). Basal GH secretion rates were negatively related to serum estradiol (r = -0.485; P = 0.016). In contrast, GH secretory burst frequency and duration were unrelated to age, percentage body fat, or sex steroids. The fraction of total GH secreted in bursts was negatively correlated with the body mass index (r = -0.540; P < 0.01). Serum IGF-I concentrations were positively related to total pulsatile GH secretion (r = 0.690; P = 0.0011) and negatively to age (r = -0.597; P = 0.007) and percentage body fat (r = -0.611; P = 0.009).(ABSTRACT TRUNCATED AT 400 WORDS)

OBJECTIVE -An open-label, parallel-group, randomized, multicenter trial was conducted to compare efficacy and safety of repaglinide versus nateglinide, when used in a combination regimen with metformin for treatment of type 2 diabetes. RESEARCH DESIGN AND METHODS -Enrolled patients (n ϭ 192) had HbA 1cϾ7% and Յ12% during previous treatment with a sulfonylurea, metformin, or low-dose Glucovance (glyburide Յ2.5 mg, metformin Յ500 mg). After a 4-week metformin run-in therapy period (doses escalated to 1,000 mg b.i.d.), patients were randomized to addition of repaglinide (n ϭ 96) (1 mg/meal, maximum 4 mg/meal) or nateglinide (n ϭ 96) (120 mg/meal, reduced to 60 mg if needed) to the regimen for 16 weeks. Glucose, insulin, and glucagon were assessed after a liquid test meal at baseline and week 16. RESULTS -FinalHbA 1c values were lower for repaglinide/metformin treatment than for nateglinide/metformin (7.1 vs. 7.5%). Repaglinide/metformin therapy showed significantly greater mean reductions of HbA 1c (-1.28 vs. -0.67%; P Ͻ 0.001) and of fasting plasma glucose (FPG) (-39 vs. -21 mg/dl; P ϭ 0.002). Self-monitoring of blood glucose profiles were significantly lower for repaglinide/metformin before breakfast, before lunch, and at 2:00 A.M. Changes in the area under the curve of postprandial glucose, insulin, or glucagon peaks after a test meal were not significantly different for the two treatment groups during this study. Median final doses were 5.0 mg/day for repaglinide and 360 mg/day for nateglinide. Safety assessments were comparable for the two regimens. By reducing postprandial blood glucose peaks, these drugs lower 24-h blood glucose profiles and reduce HbA 1c levels. Both agents stimulate insulin secretion via closure of ATP-dependent potassium channels (K ATP channels) of the outer membrane of ␤-cells (1-3). The molecular binding sites of the two drugs are not identical (4). CONCLUSIONSTo date, no clinical trial has compared the efficacy and safety of repaglinide and nateglinide in a "head-to-head" design. In a combination therapy trial of up to 5 months of treatment with repaglinide plus metformin, reductions of HbA 1c values were much greater for the combination than the respective monotherapies; in the patients who had previously failed to show adequate glycemic control using metformin alone (HbA 1c Ͼ 7.0%), reductions of HbA 1c values were 1.1% greater than in those who continued metformin monotherapy (5). A comparable study of 24-week treatment using nateglinide plus metformin reported a reduction of HbA 1c levels by up to 0.6% compared with metformin monotherapy (6). Both of these studies collected data in patients who had earlier shown unsatisfactory response to metformin, and metformin treatment was continued up to randomization to the combination treatments.Preclinical research has indicated that nateglinide may have capabilities of stimulating certain glucose-elevating hormones (glucagon, growth hormone) that are not stimulated by repaglinide (7,8). Such drug actions could potentially reduce the effic...

Disordered reproductive function has long been recognized as a prevalent problem among women of reproductive age who suffer from insulin-dependent diabetes mellitus (IDDM). Delay in menarchial age is frequently seen if IDDM develops in the peripubertal years and some form of menstrual dysfunction is found in nearly one-third of all women of reproductive age with IDDM. This review summarizes some of the prevailing views regarding the mechanisms through which uncontrolled IDDM is thought to disrupt normal hypothalamic-pituitary-gonadal function. Although animal studies have suggested that poorly controlled IDDM may adversely affect the uterovaginal outflow tract and/or ovarian function, no clinical studies have suggested that abnormal uterine or ovarian function underlies the menstrual dysfunction observed in young diabetic women. Similarly, pituitary function as assessed by basal gonadotrophins and gonadotrophin-releasing hormone (GnRH)-stimulated gonadotrophin release appears to be normal in young women with IDDM. Moreover, although there has been some suggestion that pituitary function may decline with increasing duration of diabetes, this issue has not been thoroughly investigated. It appears that the oligo/amenorrhea noted in IDDM is principally hypothalamic in origin and may represent intermittent (and perhaps reversible) failure of the GnRH pulse generator, similar to the situation observed in women who engage in endurance training or who suffer from anorexia nervosa. Although the exact pathophysiological mechanisms that subserve dysfunction of the GnRH neuronal system are not well understood, attention has focused on increased central opioidergic activity, increased central dopaminergic activity, and central glucose deprivation. In this era of emphasis on tight glycaemic control and its impact in preventing diabetes complications, the consequences of IDDM on reproductive potential appear to be important and must be included in future investigative efforts.

To evaluate the role of the alpha 1-adrenergic system in the response to hemorrhage during development, lambs and adult sheep were chronically catheterized and hemorrhaged after pretreatment with prazosin or vehicle. The adults became markedly more hypotensive after alpha 1-blockade and hemorrhage than after vehicle and hemorrhage (26.1 +/- 4 vs. 10.7 +/- 2%, P less than 0.0001), whereas the lambs were no more hypotensive when hemorrhaged after prazosin (21.5 +/- 3.2 vs. 23.1 +/- 4.4%, P greater than 0.05). In the adults and the lambs, hemorrhage produced elevations in plasma renin activity and arginine vasopressin. However, after prazosin, the adults had a far greater increase in arginine vasopressin levels than after vehicle treatment (1,970 +/- 820 vs. 320 +/- 273%).