The central and renal hemodynamic effects of amino acid infusion in the study of renal reserve in the baboon.

Normal human renal function is characterized by a large renal reserve. Recruitment of this reserve is a compensatory and pathological response to renal injury. This study was designed to assess the renal reserve and central hemodynamics of young female baboons and, in doing so, the appropriateness of the use of these animals in a model of human renal disease.

Endogenous somatostatin-28 modulates postprandial insulin secretion. Immunoneutralization studies in baboons.

Somatostatin-28 (S-28), secreted into the circulation from enterocytes after food, and S-14, released mainly from gastric and pancreatic D cells and enteric neurons, inhibit peripheral cellular functions. We hypothesized that S-28 is a humoral regulator of pancreatic B cell function during nutrient absorption. Consistent with this postulate, we observed in baboons a two to threefold increase in portal and peripheral levels of S-28 after meals, with minimal changes in S-14.

Evidence that galanin is a parasympathetic, rather than a sympathetic, neurotransmitter in the baboon pancreas.

To determine whether galanin is a pancreatic sympathetic neurotransmitter regulating insulin secretion in the baboon, as it is in the dog, we evaluated galanin for inhibitory effects on insulin secretion in conscious baboons, determined if baboon pancreatic islets are innervated by galaninergic fibers using immunohistochemistry, and measured galanin content in the major sympathetic ganglion supplying the pancreas. Surprisingly, infusion of galanin (1 microgram/kg per min) had no effect on arginine-stimulated secretion of either insulin (71 +/- 14 vs. 88 +/- 17 microU/ml; P = NS) or glucagon (104 +/- 12 vs.

Elimination of the action of glucagon-like peptide 1 causes an impairment of glucose tolerance after nutrient ingestion by healthy baboons.

Glucagon-like peptide 1 (GLP-1) is an insulinotropic hormone released after nutrient ingestion which is known to augment insulin secretion, inhibit glucagon release, and promote insulin-independent glucose disposition. To determine the overall effect of GLP-1 on glucose disposition after a meal we studied a group of healthy, conscious baboons before and after intragastric glucose administration during infusions of saline, and two treatments to eliminate the action of GLP-1: (a) exendin-[9-39] (Ex-9), a peptide receptor antagonist of GLP-1; or (b) an anti-GLP-1 mAb. Fasting concentrations of glucose were higher during infusion of Ex-9 than during saline (4.

Estradiol inhibits the increase of hypothalamic neuropeptide Y messenger ribonucleic acid expression induced by weight loss in ovariectomized rats.

Anorexia and weight loss produced by estradiol (E2) may involve altered expression of neuropeptide Y (NPY) in the hypothalamus. We tested this hypothesis using ovariectomized (OVX) rats by replacing E2 with SILASTIC brand capsule implants and measuring NPY messenger RNA (mRNA) levels in the arcuate nucleus by in situ hybridization. To equalize the effects of weight loss on NPY mRNA expression, E2 deficient OVX rats were pair-fed (n = 10) for 2 days to an OVX group receiving E2 (n = 12).

Accelerated cholesteryl ester transfer in baboons with insulin-requiring diabetes mellitus.

Cholesteryl ester transfer (CET), plasma, lipoprotein lipid and phospholipid composition were studied in insulin-treated baboons with chronic streptozotocin-induced diabetes. In these diabetic animals, CET measured both as the mass (p < 0.001) and isotopic transfer (p < 0.

Perfusion with anti-insulin gamma globulin indicates a B to A to D cellular perfusion sequence in the pancreas of the rhesus monkey, Macaca mulatta.

The cellular sequence of intraislet vascular perfusion has been shown to be important in the regulation of islet hormone secretion in the rat and dog islet. In order to test whether a B to A to D sequence of islet cellular perfusion is also present in a nonhuman primate, pancreata from the rhesus monkey, Macaca mulatta, were isolated and perfused in vitro in the presence and absence of anti-insulin gamma globulin. In the presence of the insulin antibody, efflux concentration of insulin decreased rapidly (-95 +/- 1.

Correlations of in vivo beta-cell function tests with beta-cell mass and pancreatic insulin content in streptozocin-administered baboons.

In vivo beta-cell function tests are used increasingly in humans during the preclinical phase of insulin-dependent diabetes mellitus (IDDM), but the severity of the beta-cell loss responsible for the abnormalities seen in these tests is unknown. We have measured several physiological beta-cell function tests--fasting plasma glucose, glucose disappearance constant, fasting insulin, acute insulin responses to arginine (AIRarginine) and glucose (AIRglucose), and glucose potentiation of AIRarginine (delta AIRarginine/delta G) and two direct objective measurements (pancreatic insulin content [PIC] and quantitative beta-cell mass)--in adolescent male baboons (Papio anubis/cyanocephalus). We have correlated in vivo measurements obtained within 3 days after the animals were killed with in vitro estimates of PIC and beta-cell mass in 15 animals, (2 nondiabetic requiring insulin treatment and 13 after varying doses of streptozocin to induce degrees of beta-cell damage ranging from normoglycemia to severe hyperglycemia).

Effect of nicotinic acid-induced insulin resistance on pancreatic B cell function in normal and streptozocin-treated baboons.

To study the interaction between insulin secretion and insulin action in maintaining glucose homeostasis, we induced experimental insulin resistance in eight normal baboons, in six baboons treated with 40 mg/kg streptozocin (STZ-40), and in six baboons treated with 200 mg/kg streptozocin (STZ-200). Insulin resistance was induced by a 20-d continuous intravenous infusion of nicotinic acid (NA). Normal animals showed compensatory increases in several measures of insulin secretion (fasting insulin [FI], acute insulin response to arginine [AIRarg], acute insulin response to glucose [AIRgluc], and glucose potentiation slope [delta AIRarg/delta G]), with no net change in fasting plasma glucose (FPG) or glycosylated hemoglobin (HbAtc).

In vitro pancreatic hormonal pulses are less regular and more frequent than in vivo.

Spontaneous in vivo cyclic secretion of insulin and glucagon displays a pulse interval of 10 +/- 0.3 (SE) min and a constant phase relationship in fasting rhesus monkeys. When pancreata from six normal rhesus monkeys were perfused in vitro, the insulin pulse interval averaged 6.

Insulin binding to individual rat skeletal muscles.

Studies of insulin binding to skeletal muscle, performed using sarcolemmal membrane preparations or whole muscle incubations of mixed muscle or typical red (soleus, psoas) or white [extensor digitorum longus (EDL), gastrocnemius] muscle, have suggested that red muscle binds more insulin than white muscle. We have evaluated this hypothesis using cryostat sections of unfixed tissue to measure insulin binding in a broad range of skeletal muscles; many were of similar fiber-type profiles. Insulin binding per square millimeter of skeletal muscle slice was measured by autoradiography and computer-assisted densitometry.

Responses of the pancreatic A cell during hypoglycemia and hyperglycemia are dependent on the B cell.

It is controversial whether stimulation of glucagon secretion by hypoglycemia or suppression by hyperglycemia is a direct effect of glucose on the A cell or whether it is mediated indirectly through the B cell. To determine the role of the B cell in the mediation of glucagon secretion adolescent male baboons were studied before and after successive injections of streptozocin designed to cause B-cell destruction in a series of stages. Following one dose of streptozocin, B-cell function was impaired but fasting blood glucose remained normal.

Decreased insulin- and glucagon-pulse amplitude accompanying beta-cell deficiency induced by streptozocin in baboons.

The effect of beta-cell deficiency on the spontaneous pulsatile secretory pattern of the islets of Langerhans was studied in the baboon. Measures of beta-cell function were correlated with the secretory pattern before and at intervals after streptozocin administration. The degree of insulin deficiency was variable and ranged from mild to moderate.

Defects in beta-cell function and insulin sensitivity in normoglycemic streptozocin-treated baboons: a model of preclinical insulin-dependent diabetes.

During the preclinical period of human insulin-dependent diabetes, both impaired pancreatic beta-cell function and increased insulin resistance are found, although normoglycemia is preserved. To better understand the changes in beta-cell function and insulin sensitivity that occur in preclinical insulin-dependent diabetes, we performed a panel of in vivo beta-cell function tests and measured insulin sensitivity in adolescent male baboons both in normal health and after a small dose of streptozocin which did not induce hyperglycemia. Nine animals were studied before (stage 1) and 1 week after receiving a low dose of streptozocin (stage 2).

Effects of branched-chain amino acids on postprandial 3-OH butyrate and glucagon in the baboon.

Although chronic postprandial elevation of branched-chain amino acids (BCAAs) occurs in diabetic subjects and in subjects consuming high-protein diets, the metabolic effects of simultaneously increasing levels of these three amino acids are unclear. In this study, a mixture of the BCAAs was infused intravenously into baboons, beginning 30 minutes after the daily meal and continuing for 200 minutes on four consecutive days. Blood samples were collected on the last day of treatment.

Beta-adrenergic modulation of insulin binding in skeletal muscle.

Both a high physiological concentration (13.1 nM) of epinephrine (E) and acute exercise (AEx) have previously been shown to increase 125I-insulin binding in skeletal muscle. To investigate the site and mechanism of the effect of epinephrine on binding and the possible link between epinephrine- and AEx-enhanced insulin binding, we measured insulin binding in three different preparations: 1) crude membranes derived from whole soleus muscle incubated in vitro with 13.

Metabolic changes during maturation of male monkeys: possible signals for onset of puberty.

There is a close relationship between the metabolic status of a maturing animal and the timing of puberty onset. However, the signals linking metabolic status to the maturation of the reproductive axis remain unknown. We looked for metabolic differences before and after puberty by comparing plasma profiles of insulin, glucose, amino acids, beta-hydroxybutyrate, and glycerol between juvenile and adult monkeys in fed and fasted states.

A model for augmentation of hepatocyte response to pulsatile glucagon stimuli.

We have reported that in the physiological concentration range pulsatile glucagon delivery (6 pulses in 90 min) is a more effective stimulus of rat hepatocyte glucose production than is continuous infusion of the same amount of hormone (pulsatile EC50 = 186 +/- 41 pg/ml, continuous EC50 = 884 +/- 190 pg/ml). At supraphysiological glucagon concentrations, however, the maximal response to continuous glucagon infusion exceeds the response to pulses (241 +/- 14 vs. 140 +/- 11 mumol X G-1 X 90 min-1).

Glucose counterregulation during recovery from neuroglucopenia: which mechanism is important?

Neuroglucopenia (NGP), which is a serious potential hazard for all insulin-treated diabetics, stimulates many neural and hormonal responses including increased glucagon secretion and activation of beta-adrenergic receptors of the autonomic nervous system. To determine which of these responses is important in recovery from NGP, we induced NGP in baboons by the intravenous (IV) injection of 2-deoxy-D-glucose with and without beta-adrenergic blockade (propranolol) and somatostatin. Thirty minutes after the induction of NGP the animals recovered, and the mean (+/- SEM) rise in arterial plasma glucose was 6.

Pulsatile release of growth hormone and prolactin from the primate pituitary in vitro.

Perifused anterior hemipituitaries from one male and 4 female monkeys released GH and PRL in a pulsatile pattern, with mean +/- SE interpulse intervals of 8.2 +/- 0.4 and 8.

Effects of branched chain amino acids on spontaneous growth hormone secretion in the baboon.

Blood concentrations of the branched chain amino acids (BCAAs) are elevated during fasting in healthy subjects and are abnormally high both postprandially and during fasting in diabetic patients. Despite evidence that these amino acids influence brain metabolism and neurotransmitter synthesis, there is little information on the neuroendocrine effects of the BCAAs. This study provides evidence that elevation of postprandial blood levels of the BCAAs alters the ultradian rhythm of GH secretion observed in the baboon during daylight hours.

Pulsatile glucagon delivery enhances glucose production by perifused rat hepatocytes.

We have compared the effects of pulsatile and continuous glucagon administration on hepatocyte glucose production in order to clarify the physiological role of pulsatile hormone secretion. Two identical columns containing freshly isolated rat hepatocytes mixed with polyacrylamide gel beads were perifused with oxygenated tissue culture medium. A fixed total amount of glucagon was delivered to one column as a continuous 90-min infusion and to the other column as a series of six 3-min pulses.

Glucoregulation during insulin and glucagon deficiency: role of catecholamines.

Glucose production decreases markedly following acute reduction in insulin and glucagon secretion (induced by somatostatin). After about an hour, however, glucose production is restored nearly to basal rates. To study the mechanism by which this occurs, islet hormone deficiency was superimposed on beta-adrenergic blockade.

Hepatic glucose production oscillates in synchrony with the islet secretory cycle in fasting rhesus monkeys.

Oscillations in the concentration of plasma glucose were found to reflect large fluctuations in hepatic glucose production. The fluctuations in glucose production were synchronous with fluctuations in the concentration of plasma insulin and glucagon. This synchrony suggests that hepatic pathways are entrained to the islet cycle with a minimal time delay.

Influence of nutritional state on periodicity in plasma insulin levels in monkeys.

Rapid sustained oscillations in basal plasma levels of insulin, glucose, and glucagon (9-12 min/cycle) have been identified in rhesus monkeys and in humans. To assess the possible regulatory role of nutritional state in the control of these plasma fluctuations, 12 chronically cannulated conscious rhesus monkeys were studied at varying intervals following ingestion of a mixed meal. Blood samples were withdrawn at 2-min intervals for periods of 10-30 min.