Rizza, Robert A.

The splanchnic bed produces cortisol at rates approximating extraadrenal tissues by converting cortisone to cortisol via the 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 pathway. It is not known whether splanchnic cortisol production is regulated by nutrient ingestion and/or by the accompanying changes in hormone secretion. To address this question, 18 healthy humans were randomized to ingest either a mixed meal or to receive an intravenous saline infusion while total-body, splanchnic, and d3 cortisol production (an index of 11β-HSD type 1 activity) were measured using the combined hepatic catheterization and d4 cortisol infusion methods. Fasting glucose and insulin concentrations did not differ on the meal and saline study days. Glucose and insulin concentrations increased after meal ingestion, peaking at 11.0 ± 1.0 mmol/l and 451 ± 64 pmol/l, respectively, at 45 min, then fell to baseline thereafter. In contrast, glucose and insulin concentrations slowly fell to 5.1 ± 0.1 mmol/l and 27 ± 6 pmol/l during the 6 h of observation on the saline study day. Fasting cortisol concentration did not differ on the meal and saline study days. Cortisol increased (P < 0.05) to a peak of 353 ± 55 nmol/l after meal ingestion but did not change after saline infusion. The increase in cortisol after meal ingestion was associated with an increase in both total body cortisol (from 748 ± 63 to 1,620 ± 235 nmol/min; P < 0.01) and total body d3 cortisol (from 99 ± 11 to 143 ± 11 nmol/min; P < 0.01) production, whereas there was no change in either on the saline study day. The increase in total-body cortisol and d3 cortisol production after meal ingestion originated in extrasplanchnic tissues since splanchnic cortisol production (mean 0–360 min: 254 ± 83 vs. 262 ± 36 nmol/min) and splanchnic d3 cortisol production (mean 0–360 min: 72 ± 22 vs. 77 ± 14 nmol/min) did not differ on the meal and saline study days. We conclude that ingestion of a mixed meal does not alter either splanchnic cortisol production or the conversion of d4 cortisol to d3 cortisol or, therefore by implication, flux via the splanchnic 11β-HSD type 1 pathway.

Abstract Context: Cortisol is a potent regulator of carbohydrate, fat, and protein metabolism. Objective: The objective of the study was to determine whether obesity alone or in combination with type 2 diabetes increases splanchnic and/or leg cortisol production. Design: Splanchnic and leg cortisol production were measured using the hepatic and leg catheterization technique combined with infusion of D4-cortisol. Setting: The study was conducted in a General Clinical Research Center. Participants: Nine lean nondiabetic, 10 obese nondiabetic, and 11 obese diabetic subjects were studied. Interventions: Diabetic volunteers were withdrawn from their glucose-lowering medications before study. Main Outcome Measures: Rates of total body, splanchnic and leg cortisol, and D3-cortisol production were measured. Results: Rates of splanchnic cortisol production equaled or exceeded those occurring in extrasplanchnic tissues (e.g. the adrenals) in all three groups. However, because concurrent splanchnic cortisol uptake also occurred, net splanchnic cortisol release was minimal. Splanchnic cortisol production and splanchnic D3-cortisol production (an index of splanchnic 11β-hydroxysteroid dehydrogenase type 1 activity) did not differ among the three groups. In addition, splanchnic cortisol production did not correlate with either visceral fat or endogenous glucose production. On the other hand, splanchnic cortisol uptake was greater in the obese diabetic than lean nondiabetic subjects (25 ± 2.9 vs. 15.3 ± 2.5 μg/min; P < 0.05). Splanchnic, but not leg, D3-cortisol production was correlated with total body D3-cortisol production (r = 0.70; P < 0.001). Conclusions: Although large amounts of cortisol are produced within the splanchnic bed, implying high intrahepatic glucocorticoid concentrations, rates do not differ in lean and obese nondiabetic humans and are not influenced by the presence of type 2 diabetes mellitus. On the other hand, obesity but not diabetes increases splanchnic cortisol uptake.

In vitro data have recently suggested that sulfonylureas (SUs) enhance GH secretion by modulating the effects of GHRH and somatostatin in pituitary cells. The present study was undertaken to explore in more detail a possible influence of a single dose of SU (glibenclamide) and a non-SU (repaglinide) insulin secretagogue on circulating GH dynamics. Ten C-peptide-negative type 1 diabetic individuals were examined on three occasions in random order. Either glibenclamide (10.5 mg), repaglinide (8 mg), or placebo was administered after overnight normalization of plasma glucose by iv insulin infusion. Subsequently, GH concentrations were measured regularly after stimulation with GHRH (bolus 0.1 μg/kg) alone and during concomitant infusion with somatostatin (7 ng·kg–1·min–1). Insulin was replaced at baseline levels (0.25 mU·kg–1·min–1) and plasma glucose clamped at 5–6 mmol/liter. Overall, there were no significant statistical differences in GH responses determined as either GH peak concentrations, integrated levels of GH, or secretory burst mass of GH during the experimental protocol. In contrast, plasma glucagon concentrations were significantly increased during glibenclamide and repaglinide exposure. The present experimental design does not support the hypothesis that acute administration of pharmacological doses of the oral antihyperglycemic agents glibenclamide and repaglinide per se enhance GH release in humans. Additionally, this study shows that these potassium channel inhibitors seem to stimulate glucagon secretion in people who have severe intraislet insulin deficiency (e.g. type 1 diabetes). However, extrapolation of our findings to type 2 diabetic individuals should be done with some caution.

The objective of this study was to define the workforce needs for the specialty of endocrinology, diabetes, and metabolism in the United States between 1999 and 2020. An interactive model of factors likely to influence the balance between the supply and demand of endocrinologists during the next 20 yr was constructed. The model used data from a wide range of sources and was developed under the guidance of a panel of experts derived from sponsoring organizations of endocrinologists. We determined current and projected numbers and demographics of endocrinologists in the United States workforce and the anticipated balance between supply and demand from 1999 to 2020. There were 3,623 adult endocrinologists in the workforce in 1999, of which 2,389 (66%) were in office-based practice. Their median age was 49 yr. Both total office visits and services performed by endocrinologists (particularly for diabetes) increased substantially during the 1990s. Waiting time for an initial appointment is presently longer for endocrinologists than for other physicians. Compared with a balanced, largely closed-staff health maintenance organization, the current national supply of endocrinologists is estimated to be 12% lower than demand. The number of endocrinologists entering the market has continuously fallen over the previous 5 yr, from 200 in 1995 to 171 in 1999. Even if this downward trend were abruptly stopped, the model predicts that demand will exceed supply from now until 2020. Whereas this gap narrows from 2000 to 2008 due to projected growth of managed care, it widens thereafter due to the aging of both the population and the endocrine workforce. Inclusion of other factors such as projected real income growth and increased prevalence of age-related endocrine disorders (e.g. diabetes and osteoporosis) further accentuates the deficit. If the number of endocrinologists entering the workforce remains at 1999 levels, demand will continue to exceed supply from now through 2020 for adult endocrinologists, and the gap will widen progressively from 2010 onward. The present analysis indicates that the number of endocrinologists entering the workforce will not be sufficient to meet future demand. These data suggest that steps should be taken to stop the ongoing decline in the number of endocrinologists in training and consideration should be given to actions designed to increase the number of endocrinologists in practice in the years ahead.