William G. Blackard

Adrenergic receptor control mechanism for growth hormone secretion

The influence of catecholamines on growth hormone secretion has been difficult to establish previously, possibly because of the suppressive effect of the induced hyperglycemia on growth hormone concentrations. In this study, an adrenergic receptor control mechanism for human growth hormone (HGH) secretion was uncovered by studying the effects of alpha and beta receptor blockade on insulin-induced growth hormone elevations in volunteer subjects. Alpha adrenergic blockade with phentolamine during insulin hypoglycemia, 0.1 U/kg, inhibited growth hormon elevations to 30-50% of values in the same subjects during insulin hypoglycemia without adrenergic blockade. More complete inhibition by phentolamine could not be demonstrated at a lower dose of insulin (0.05 U/kg). Beta adrenergic blockade with propranolol during insulin hypoglycemia significantly enhanced HGH concentrations in paired experiments. The inhibiting effect of alpha adrenergic receptor blockade on HGH concentrations could not be attributed to differences in blood glucose or free fatty acid values; however, more prolonged hypoglycemia and lower plasma free fatty acid values may have been a factor in the greater HGH concentrations observed during beta blockade. In the absence of insulin induced hypoglycemia, neither alpha nor beta adrenergic receptor blockade had a detectable effect on HGH concentrations. Theophylline, an inhibitor of cyclic 35-AMP phosphodiesterase activity, also failed to alter plasma HGH concentrations. These studies demonstrate a stimulatory effect of alpha receptors and a possible inhibitory effect of beta receptors on growth hormone secretion.

Portal and Peripheral Vein Immunoreactive Insulin Concentrations Before and After Glucose Infusion

Catheterization of the portal vein via the umbilical vein was performed under local anesthesia in twelve nondiabetic subjects prior to exploratory laporatomy for a variety of conditions. Immunoreactive insulin (IRI) in simultaneously obtained portal and peripheral vein plasma was determined before, during, and after a two-minute glucose infusion (25 gm.). Two phases of insulin secretion were apparent from portal vein IRI concentrations. A rapid secretory phase beginning one minute after start of the infusion and lasting three to four minutes was followed by a slower secretory phase beginning approximately ten minutes after start of the glucose infusion. The absolute amount of “big” insulin (proinsulin-like material) in the portal vein was similar during the first phase and the early part of the second phase of insulin secretion. A significant positive correlation between portal vein and peripheral vein IRI responses to glucose was noted.

Portal and Peripheral Vein Immunoreactive Glucagon Concentrations After Arginine or Glucose Infusions

Catheterization of the portal vein via the umbilical vein was performed under local anesthesia in eight nondiabetic subjects before exploratory laparotomy for a variety of conditions. Levels of immunoreactive glucagon (IRG) and immunoreactive insulin (IRI) were determined in simultaneously obtained portal and peripheral vein plasma before, during and after a fifteen minute arginine infusion (30 gm.) in five subjects. The mean portal vein to peripheral vein glucagon ratio in the postabsorptive state was 1.7 ± 0.5. A biphasic portal vein IRG response to arginine was observed, with the initial glucagon peak occurring within one minute of the beginning of the infusion. Peripheral IRG concentrations did not reflect the biphasic response. The portal vein IRI response to arginine was also mildly biphasic, and the first phase occurred before a detectable increase in blood glucose. The portal vein IRG peak either preceded or coincided temporally with the portal vein IRI peak. In three nondiabetic subjects, portal vein IRG decreased rapidly to its nadir within two minutes after a two minute glucose infusion (25 gm.) was started.

Dehydroepiandrosterone: the "missing link" between hyperinsulinemia and atherosclerosis?

A well‐established epidemiologic association exists between hyperinsulinemia and macrovascular disease. However, the mechanism or mechanisms by which hyperinsulinemia promotes atherogenesis is unknown. Recent evidence indicates that the adrenal steroid dehydroepiandrosterone (DHEA) exerts multiple antiatherogenic effects and also suggests that hyperinsulinemia may reduce serum DHEA and DHEA‐sulfate levels by decreasing production and enhancing metabolic clearance. We advance the hypothesis that hyperinsulinemia promotes macrovascular disease in part by reducing serum DHEA and DHEA‐sulfate levels and illustrate how this may be the case in two clinical conditions characterized by hyperinsulinemic insulin resistance: aging and obesity.— Nestler, J. E., Clore, J. N., Blackard, W. G. Dehydroepiandrosterone: the “missing link” between hyperinsulinemia and atherosclerosis? FASEB J. 6: 3073‐3075; 1992.

The central role of obesity (hyperinsulinemia) in the pathogenesis of the polycystic ovary syndrome

Insulin resistance and hyperinsulinemia appear to be almost universal features of the polycystic ovary syndrome. We propose that obesity permits full phenotypic expression of the polycystic ovary syndrome in women predisposed to develop this condition by generating an insulin-resistant, and consequently hyperinsulinemic, state. The resultant hyperinsulinemia may produce hyperandrogenism by affecting multiple facets of androgen metabolism.

Insulin-secreting bronchial carcinoid tumor with widespread metastases

Abstract This is a report of a twenty-three year old woman with severe hypoglycemia, elevated plasma immunoreactive insulin concentrations and widespread malignancy. A bronchial carcinoid tumor was identified as the primary neoplasm and increased concentrations of immunoreactive insulin were found in the bronchial tumor and its metastases. This is believed to be the first reported case of a hypoglycemia-producing bronchial carcinoid tumor associated with increased plasma immunoreactive insulin. Diazoxide administration produced no beneficial effect in this patient.

Effect of lipids on growth hormone secretion in humans

To determine the effect of elevations of plasma lipids on growth hormone secretion in humans, paired insulin hypoglycemia tests and paired arginine infusion tests were performed on eight and six normal female volunteers respectively. On 1 of the 2 test days for each growth hormone stimulus, subjects were given 60 g corn oil (Lipomul) 3 hr before testing followed by intravenous heparin (5000 U) at the time of insulin or arginine administration. Lipomul plus heparin administration inhibited both insulin- and arginine-induced plasma HGH elevations with almost complete suppression of the response to arginine. The plasma HGH (human growth hormone) inhibition was associated with elevation in plasma triglycerides and inhibition of plasma FFA (free fatty acid) depression after insulin or arginine. Neither the hypoglycemic response to insulin nor the blood glucose and plasma immunoreactive-insulin responses to arginine were altered by Lipomul plus heparin administration. In four additional subjects in whom Lipomul was given without heparin, the elevated plasma triglyceride values were not associated with suppression of arginine-induced plasma HGH elevations. In the same four subjects, heparin administration without Lipomul neither suppressed arginine-induced plasma HGH elevations nor prevented the depression in plasma FFA after arginine as much as when Lipomul plus heparin had been given. These latter observations suggest that the elevation in plasma FFA was responsible for suppression of growth hormone secretion by Lipomul plus heparin. These studies indicate a possible role of plasma FFA in regulation of growth hormone secretion.

Increased Transcapillary Escape Rate of Albumin in Nondiabetic Men in Response to Hyperinsulinemia

Diabetic patients manifest increased vascular permeability. To determine whether insulin per se might increase vascular permeability, five nondiabetic men were studied by the hyperinsulinemic-euglycemic clamp technique. Each subject received a 0.72-nmol/kg body wt i.v. insulin bolus, followed by a 72-pmol · kg−1 ·min−1 insulin infusion for 4 h. Euglycemia was maintained by the Biostator glucose controller. At 7 h of study, 10 μCi i.v. 125I-labeled albumin was injected as bolus dose. Frequent blood samples were drawn during the next 70 min for determination of the transcapillary escape rate (TER) of albumin. Subjects returned 1–2 wk later for a control study, during which 0.45% saline was infused at a rate identical to the dextrose and insulin infusion rates during the hyperinsulinemic clamp. The mean ± SE serum insulin levels during the hyperinsulinemic clamp and saline infusion were 9786 ± 126 and 46 ± 4 pM, respectively, whereas serum glucose during the two sessions was similar (5.0 ± 0.2 vs. 4.8 ± 0.1 mM, NS). Identical fluid volumes were infused during the two sessions (1767 ± 197 ml/7 h), and urine outputs did not differ significantly (1615 ± 309 vs. 1035 ± 248 ml/7 h). The TER of albumin was greater in all five men after hyperinsulinemia than after saline infusion (18.3 ± 2.7 vs. –2.8 ± 2.3%/h, P = 0.01). The serum albumin level at the end of the hyperinsulinemic-euglycemic clamp study was 14% lower than the value at the start of the study (37 ± 1 vs. 42 ± 1 g/L, P < 0.05), whereas no significant change in serum albumin levels occurred during the saline infusion. These observations suggest that acute hyperinsulinemia can increase the TER of radiolabeled albumin, probably by increasing vascular permeability.

Pump-induced Insulin Aggregation: A Problem with the Biostator

A fall in plasma IRI despite constant C-peptide levels during prolonged insulin euglycemic clamp studies using the Biostator (Ames Division, Miles Laboratories, Elkhart, Indiana) prompted a meticulous evaluation of the Biostators insulin delivery system. At slow infusion rates, a striking loss of immunoreactive and biologically active insulin was observed after 6 h of the Biostator run. Studies with labeled insulin indicated that the loss of insulin was not due to adsorption of insulin to the tubing since recovery of labeled insulin was close to 100%. A variety of techniques (gel filtration, polyacrylamide gel electrophoresis, centrifugation, and Coomassie Brilliant Blue protein assay) indicated that the loss of insulin activity was due to insulin coming out of solution. The insoluble nature of the immunologically and biologically inactive insulin was confirmed by centrifugation, i.e., 88% 125I-insulin precipitated into the pellet. The dependency of this loss of insulin activity on flow rate was clearly demonstrable with activity (IRI) less than 20% of expected at flow rates of 2.1 ml/h, and 30% at 4.2 ml/h. Full recovery was observed only with flow rates of 16.8 ml/h or greater. At each flow rate, IRI rose only after delivery of the effluent between the pump and exit port, demonstrating that insulin alteration occurs within the pump assembly presumably from heat-induced aggregation. Investigators employing the Biostator should carefully examine their systems for this time- and flow ratedependent alteration of insulin. The loss of IRI at low flow rates (low-dose insulin clamp or insulin delivery during basal periods) will profoundly influence data generated from the Biostator.

Downregulation of Insulin Receptors in Obese Man

In an attempt to determine whether the decreased number of insulins receptors in obesity is a result of downregulation of the receptors, diazoxide (5 mg/kg/d) was given to 10 obese subjects. Insulins suppression by diazoxide in these 10 subjects resulted in a mild glucose intolerance and an increase in insulins receptors in seven of the 10 subjects. The subjects could be divided into three groups by analyzing the Scatchard plots of their insulin receptor studies before and after diazoxide. Four subjects exhibited an increase in both high affinity and low. affinity receptors, three showed an increase only in high affinity receptors, and three failed to demonstrate any change in receptors in response to diazoxide. These studies support the concept that the decreased number of insulins receptors observed in obesity is a result of the downregulation of the receptors and is not the primary, underlying cause of insulin resistance in obesity, although a contributory role cannot be ruled out.