Glucoregulatory Hormone Concentrations Research Articles

Effect of AP102, a subtype 2 and 5 specific somatostatin analog, on glucose metabolism in rats.

Somatostatin analogs are widely used to treat conditions associated with hormonal hypersecretion such as acromegaly and metastatic neuroendocrine tumors. First generation somatostatin analogs, such as octreotide and lanreotide, have high affinity for somatostatin receptor subtype 2 (SSTR2), but have incomplete efficacy in many patients. Pasireotide targets multiple SSTRs, having the highest affinity for SSTR5, but causes hyperglycemia and diabetes mellitus in preclinical and clinical studies. AP102 is a new somatostatin analogs with high affinity at both SSTR2 and SSTR5. We aimed to characterize the effects of AP102 vs. pasireotide on random and dynamic glucose levels, glucoregulatory hormone concentrations and growth axis measures in healthy Sprague-Dawley rats. Three doses of each compound were evaluated under acute conditions (1, 10, and 30 µg/kg s.c.), and two doses during a chronic (4-week) infusion (3 and 10 µg/kg/h s.c.). Neither acute nor chronic AP102 administration altered blood glucose concentrations or dynamic responses following an intraperitoneal glucose tolerance test. In contrast, acute and chronic pasireotide dosing increased random and post-intraperitoneal glucose tolerance test blood glucose measures, compared to vehicle-treated controls. Both AP102 and pasireotide acutely suppressed growth hormone levels, although insulin-like growth factor-1 and somatic growth was suppressed to a greater extent with pasireotide. AP102 is a new dual SSTR2/SSTR5-specific somatostatin analog that acutely reduces growth hormone but does not cause hyperglycemia during acute or chronic administration in a healthy rat model. Further studies in diabetic animals and in humans are necessary to determine the potential utility of AP102 in the clinical setting.

Comparison of metabolic substrates in alligators and several birds of prey

On average, avian blood glucose concentrations are 1.5–2 times those of mammals of similar mass and high concentrations of insulin are required to lower blood glucose. Whereas considerable data exist for granivorous species, few data are available for plasma metabolic substrate and glucoregulatory hormone concentrations for carnivorous birds and alligators. Birds and mammals with carnivorous diets have higher metabolic rates than animals consuming diets with less protein whereas alligators have low metabolic rates. Therefore, the present study was designed to compare substrate and glucoregulatory hormone concentrations in several birds of prey and a phylogenetically close relative of birds, the alligator. The hypothesis was that the combination of carnivorous diets and high metabolic rates favored the evolution of greater protein and fatty acid utilization leading to insulin resistance and high plasma glucose concentrations in carnivorous birds. In contrast, it was hypothesized that alligators would have low substrate utilization attributable to a low metabolic rate. Fasting plasma substrate and glucoregulatory hormone concentrations were compared for bald eagles (Haliaeetus leucocephalus), great horned owls (Bubo virginianus), red-tailed hawks (Buteo jamaicensis), and American alligators (Alligator mississippiensis). Avian species had high circulating β-hydroxybutyrate (10–21mg/dl) compared to alligators (2.81±0.16mg/dl). In mammals high concentrations of this byproduct of fatty acid utilization are correlated with insulin resistance. Fasting glucose and insulin concentrations were positively correlated in eagles whereas no relationship was found between these variables for owls, hawks or alligators. Additionally, β-hydroxybutyrate concentrations were low in alligators. Similar to carnivorous mammals, ingestion of a high protein diet may have favored the utilization of fatty acids and protein for energy thereby promoting the development of insulin resistance and gluconeogenesis-induced high plasma glucose concentrations during periods of fasting in birds of prey.

Glucose tolerance and lipid profile in longterm exogenous subclinical hyperthyroidism and the effects of restoration of euthyroidism, a randomised controlled trial

The impact of prolonged subclinical hyperthyroidism on glucose and lipid metabolism is unclear. Therefore, we evaluated glucose and lipid metabolism in patients with differentiated thyroid carcinoma (DTC) on TSH suppressive thyroxine therapy as a model for subclinical hyperthyroidism and investigated whether restoration to euthyroidism affects metabolism. We performed a prospective, single-blinded, placebo-controlled, randomised trial of 6 months duration with 2 parallel groups. Twenty-five subjects with a history of differentiated thyroid carcinoma with > 10 years TSH-suppressive therapy with l-thyroxine completed the study. l-thyroxine dose was replaced by study medication containing l-thyroxine or l-thyroxine plus placebo. Medication was titrated to establish continuation of TSH suppression (low-TSH group, 13 patients) and euthyroidism (euthyroidism group, 12 patients). We evaluated glucose metabolism by glucose tolerance test and HOMA (IR) and lipid metabolism by lipid profile. In addition, we measured plasma concentrations of glucoregulatory hormones. At baseline, glucose tolerance, HOMA (IR), lipid profile and plasma concentrations of glucoregulatory hormones were within the normal range. No significant differences between the low TSH and euthyroidism group were observed. After 6 months, neither glucose nor lipid metabolism in the low TSH group were different from baseline values. In summary, glucose and lipid metabolism in patients with DTC and long-term subclinical hyperthyroidism in general are not affected. Restoration of euthyroidism in general does not affect glucose and lipid metabolism.

Insulin resistance in HIV protease inhibitor-associated diabetes.

Fasting hyperglycemia has been associated with HIV protease inhibitor (PI) therapy. To determine whether absolute insulin deficiency or insulin resistance with relative insulin deficiency and an elevated body mass index (BMI) contribute to HIV PI-associated diabetes. Cross-sectional evaluation. 8 healthy seronegative men, 10 nondiabetic HIV-positive patients naive to PI, 15 nondiabetic HIV-positive patients receiving PI (BMI = 26 kg/m2), 6 nondiabetic HIV-positive patients receiving PI (BMI = 31 kg/m2), and 8 HIV-positive patients with diabetes receiving PI (BMI = 34 kg/m2). All patients on PI received indinavir. Fasting concentrations of glucoregulatory hormones. Direct effects of indinavir (20 microM) on rat pancreatic beta-cell function in vitro. In hyperglycemic HIV-positive subjects, circulating concentrations of insulin, C-peptide, proinsulin, glucagon, and the proinsulin/insulin ratio were increased when compared with those of the other 4 groups (p < .05). Morning fasting serum cortisol concentrations were not different among the 5 groups. Glutamic acid decarboxylase (GAD) antibody titers were uncommon in all groups. High BMI was not always associated with diabetes. In vitro, indinavir did not inhibit proinsulin to insulin conversion or impair glucose-induced secretion of insulin and C-peptide from rat beta-cells. The pathogenesis of HIV PI-associated diabetes involves peripheral insulin resistance with insulin deficiency relative to hyperglucagonemia and a high BMI. Pancreatic beta-cell function was not impaired by indinavir. HIV PI-associated diabetes mirrors that of non-insulin-dependent diabetes mellitus and impaired insulin action in the periphery.

Indomethacin stimulates glucose production in adults with uncomplicated falciparum malaria

In healthy subjects, basal hepatic glucose production is (partly) regulated by paracrine intrahepatic factors. It is unknown if these paracrine factors also influence basal glucose production in infectious diseases with increased glucose production. We compared the effects of 150 mg indomethacin (n = 9), a nonendocrine stimulator of glucose production in healthy adults, and placebo (n = 7) on hepatic glucose production in Vietnamese adults with uncomplicated falciparum malaria. Glucose production was measured by primed, continuous infusion of [6,6- 2H 2]glucose. After indomethacin, the plasma glucose concentration and glucose production increased in all subjects from 5.3 ± 0.1 mmol/L to a maximum of 7.1 ± 0.3 mmol/L ( P < .05) and from 17.6 ± 0.8 μmol · kg −1 · min −1 to a maximum of 26.2 ± 2.5 μmol · kg −1 · min −1 ( P < .05), respectively. In the control group, the plasma glucose concentration and glucose production declined gradually during 4 hours from 5.4 ± 0.2 mmol/L to 5.1 ± 0.1 mmol/L ( P < .05) and from 17.1 ± 0.8 μmol · kg −1 · min −1 to 15.1 ± 1.0 μmol · kg −1 · min −1 ( P < .05), respectively. There were no differences in plasma concentrations of insulin, counterregulatory hormones, or cytokines between the groups. We conclude that indomethacin administration results in a transient increase in glucose production in patients with uncomplicated falciparum malaria in the absence of changes in plasma concentrations of glucoregulatory hormones or cytokines. Thus, this study indicates that in uncomplicated falciparum malaria, the rate of basal hepatic glucose production is also regulated by paracrine intrahepatic factors.

Modulation of glucose production by indomethacin and pentoxifylline in healthy humans

Indomethacin, an inhibitor of prostaglandin synthesis that modulates cytokine production, increases hepatic glucose output (HGO) in humans. However, prostaglandins stimulate glucose production in vitro. To investigate the mechanism of HGO stimulation by indomethacin, we compared the effect of pentoxifylline, an inhibitor of cytokine production, versus saline (study 1, n = 6) and of indomethacin versus the combination of indomethacin and pentoxifylline (study 2, n = 5) on basal HGO. HGO was measured by primed, continuous infusion of 3- 3H-glucose. In study 1, pentoxifylline infusion resulted in an immediate, transient decrease of HGO of approximately 50% (from 12.9 ± 0.4 to 6.0 ± 1.7 μmol/kg/min after 15 minutes, P < .03 v control). There were no differences in concentrations of glucoregulatory hormones between the two experiments. In study 2, after indomethacin administration, HGO increased transiently by approximately 84% (from 9.7 ± 0.7 at baseline to 16.7 ± 2.4 μmol/kg/min after 135 minutes, P < .05). However, pentoxifylline did not affect the increase in HGO induced by indomethacin. There were no differences in concentrations of glucoregulatory hormones between the two experiments. Therefore, indomethacin stimulates HGO by mechanisms unrelated to glucoregulatory hormones, prostaglandins, or cytokines.

Truncal vagotomy does not affect postabsorptive glucose metabolism in humans.

To evaluate the effects of hepatic vagal denervation on the adaptation of glucose metabolism to short-term starvation (i.e., < 24 h), glucose metabolism was studied after 16 and again after 22 h of fasting in postsurgical patients with truncal vagotomy (n = 9; radical resection of esophageal carcinoma) and without truncal vagotomy (n = 5; partial resection of the large bowel for carcinoma). Glucose metabolism was studied 3-7.5 mo postoperatively by [3-3H]glucose turnover and by indirect calorimetry. Basal glucose production, plasma glucose concentration, glucose oxidation, serum free fatty acid concentration, and fat oxidation were not different between groups; neither were plasma concentrations of glucoregulatory hormones. The adaptation to prolongation of the fast by 6 h was not different for any of these parameters between both groups. In conclusion, truncal vagotomy does not affect the adaptation of glucose metabolism to the postabsorptive state (16-22 h of fasting).

Pentoxifylline inhibits basal glucose production in humans.

Adenosine stimulates hepatic glucose production in vitro. To investigate whether pentoxifylline, a xanthine derivative that blocks the adenosine receptor, inhibits basal glucose production, we measured hepatic glucose production in eight healthy postabsorptive subjects on two occasions: during continuous infusion of pentoxifylline and, in a control study, during saline infusion. Glucose production was measured by primed continuous infusion of [3-3H]glucose. Pentoxifylline infusion resulted in an approximately 22 (volume of distribution for glucose 40 ml/kg) to approximately 46% (volume of distribution for glucose 165 ml/kg) decrease in basal glucose production within approximately 1 h (P < 0.05), whereas in the control experiment glucose production declined by only approximately 4% in this time interval (P < 0.03 pentoxifylline vs. control). There were no differences in concentrations of insulin, C peptide, glucagon, or catecholamines between the two experiments. Because pentoxifylline inhibited glucose production in the absence of any changes in concentrations of glucoregulatory hormones, we conclude that pentoxyifylline inhibits hepatic glucose production through other mechanisms, e.g., by blocking the adenosine receptor.

Indomethacin Stimulates Basal Glucose Production in Humans without Changes in Concentrations of Glucoregulatory Hormones

1. To investigate whether indomethacin affects basal glucose production, we measured hepatic glucose production in six healthy postabsorptive subjects on two occasions: once after administration of indomethacin (150 mg orally) and once after administration of placebo. 2. Glucose production was measured by primed, continuous infusion of [3-3H]-glucose. 3. Indomethacin administration resulted in an increase in glucose production from 10.9 (SEM 0.3) mumol min-1 kg-1 to a maximum of 16.5 (SEM 1.6) mumol min-1 kg-1 (P < 0.05) within approximately 1 h, whereas in the control experiment glucose production declined gradually (P < 0.01) (P < 0.05 indomethacin versus control). There were no differences in plasma concentrations of insulin, C-peptide and counter-regulatory hormones between the two experiments. 4. Since indomethacin administration resulted in an increase in glucose production in the absence of any changes in concentrations of glucoregulatory hormones, we conclude that indomethacin stimulates hepatic glucose production through other mechanisms.

Augmented glucoregulatory hormone concentrations during exhausting exercise in mildly iron-deficient rats

We hypothesized that augmented responses of glucoregulatory hormones in iron deficiency would enhance liver and muscle glycogenolysis, leading to increased gluconeogenic precursor (lactate) supply and upregulation of hepatic gluconeogenesis. Female weanling rats were randomly placed on either a mildly iron-deficient (-Fe; 15 mg Fe/kg diet) or an iron-sufficient (+Fe; 50 mg Fe/kg diet) diet for 4 wk and studied at rest and during exhaustive treadmill running. Hemoglobin was 9.0 +/- 0.2 and 13.1 +/- 0.3 g/dl in -Fe and +Fe, respectively, after 3.5 wk of dietary iron deficiency. Arterial plasma epinephrine (Epi), norepinephrine (NE), adrenocorticotropic hormone (ACTH), corticosterone, insulin, and glucagon levels were similar at rest in both groups, as were liver, gastrocnemius, and superficial and deep vastus medialis glycogen levels. Liver and kidney phosphoenolpyruvate carboxykinase (PEPCK) activities were similar in both groups. Maximum O2 consumption was decreased (22%) in -Fe. Respiratory exchange ratio (CO2 production/O2 consumption) was unaffected at rest but increased at maximum O2 consumption in -Fe. Time to exhaustion during a standardized running test (13.4 m/min, 0% grade) was decreased 45% in -Fe (63 +/- 5 vs. 116 +/- 10 min). During exercise, euglycemia was maintained in both groups, but blood lactate was elevated in -Fe. The mean net glycogen utilization during exercise was increased in liver (43%), soleus (33%), and superficial vastus medialis (106%) and decreased in the gastrocnemius (36%) in -Fe. Liver and kidney PEPCK activities were increased similarly at exhaustion in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypoglycemia, hormones and cytokines in fatal meningococcal septicemia

A unique case report with sequential measurements of the plasma concentrations of glucoregulatory hormones, interleukin-6 and tumor necrosis factor during development of hypoglycemia in fatal meningococcemia is presented. Hormonal explanations for hypoglycemia like hyperinsulinemia or defective hypoglycemic counter-regulation were excluded. Plasma concentrations of interleukin-6 and tumor necrosis factor were skyhigh. The putative relation between cytokines and hypoglycemia in sepsis is discussed.

Failure of substrate-induced gluconeogenesis to increase overall glucose appearance in normal humans. Demonstration of hepatic autoregulation without a change in plasma glucose concentration.

It has been proposed that increased supply of gluconeogenic precursors may be largely responsible for the increased gluconeogenesis which contributes to fasting hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM). Therefore, to test the hypothesis that an increase in gluconeogenic substrate supply per se could increase hepatic glucose output sufficiently to cause fasting hyperglycemia, we infused normal volunteers with sodium lactate at a rate approximately double the rate of appearance observed in NIDDM while clamping plasma insulin, glucagon, and growth hormone at basal levels. In control experiments, sodium bicarbonate was infused instead of sodium lactate at equimolar rates. In both experiments, [6-3H]-glucose was infused to measure glucose appearance and either [U-14C]lactate or [U-14C]alanine was infused to measure the rates of appearance and conversion of these substrates into plasma glucose. Plasma insulin, glucagon, growth hormone, C-peptide, and glycerol concentrations, and blood bicarbonate and pH in control and lactate infusion experiments were not significantly different. Infusion of lactate increased plasma lactate and alanine to 4.48 +/- 3 mM and 610 +/- 33 microM, respectively, from baseline values of 1.6 +/- 0.2 mM and 431 +/- 28 microM, both P less than 0.01; lactate and alanine rates of appearance increased to 38 +/- 1.0 and 8.0 +/- 0.3 mumol/kg per min (P less than 0.01 versus basal rates of 14.4 +/- 0.4 and 5.0 +/- 0.5 mumol/kg per min, respectively). With correction for Krebs cycle carbon exchange, lactate incorporation into plasma glucose increased nearly threefold to 10.4 mumol/kg per min and accounted for about 50% of overall glucose appearance. Alanine incorporation into plasma glucose increased more than twofold. Despite this marked increase in gluconeogenesis, neither overall hepatic glucose output nor plasma glucose increased and each was not significantly different from values observed in control experiments (10.8 +/- 0.5 vs. 10.8 +/- 0.5 mumol/kg per min and 5.4 +/- 0.4 vs. 5.3 +/- 0.3 mM, respectively). We, therefore, conclude that in normal humans there is an autoregulatory process independent of changes in plasma glucose and glucoregulatory hormone concentrations which prevents a substrate-induced increase in gluconeogenesis from increasing overall hepatic glucose output; since this process cannot be explained on the basis of inhibition of gluconeogenesis from other substrates, it probably involves diminution of glycogenolysis. A defect in this process could explain at least in part the increased hepatic glucose output found in NIDDM.

Hypoglycemia during Diarrhea in Childhood

To determine the frequency and outcome of hypoglycemia during diarrhea in childhood, we screened 2003 consecutive patients less than 15 years of age who were admitted to a diarrhea treatment center in Dhaka, Bangladesh. Hypoglycemia, defined as a blood glucose concentration less than 2.2 mmol per liter, was found in 91 patients (4.5 percent), 39 (42.9 percent) of whom died. We also measured the plasma concentrations of glucoregulatory hormones and gluconeogenetic substrates in 46 of the patients with hypoglycemia who were 2 to 15 years old and in 25 normoglycemic patients matched with them for age and weight. The patients with hypoglycemia had had diarrhea for less time than the normoglycemic patients (median, 12 vs. 72 hours; P less than 0.05), and their last feeding had been 18 hours before admission, as compared with 9 hours for the normoglycemic patients (P less than 0.05). The groups were similar in terms of nutritional status, the proportion of patients who had fever, and the types of pathogens recovered from stool samples. The plasma C-peptide concentrations were low (less than 0.30 nmol per liter) in all the hypoglycemic patients. As compared with the normoglycemic patients, the patients with hypoglycemia had elevated median plasma concentrations of glucagon (44 vs. 11 pmol per liter; P = 0.001), epinephrine (3400 vs. 1500 pmol per liter; P = 0.012), norepinephrine (7500 vs. 2900 pmol per liter; P = 0.002), and lactate (3.5 vs. 2.1 mmol per liter; P = 0.020) and similar alanine and beta-hydroxybutyrate concentrations. Eighteen hypoglycemic patients with severe malnutrition had been ill longer than 26 better-nourished patients with hypoglycemia (median duration of illness, 18 vs. 10 hours; P = 0.023) and had lower median plasma concentrations of lactate (1.9 vs. 3.9 mmol per liter; P = 0.021) and alanine (173 vs. 293 micromol per liter; P = 0.040). We conclude that hypoglycemia is a major cause of death in association with diarrhea. Because the glucose counterregulatory hormones were appropriately elevated in the children with diarrhea and hypoglycemia, whereas the gluconeogenetic substrates were inappropriately low, we further conclude that the hypoglycemia observed in such patients is most often due to the failure of gluconeogenesis.

Changes in the acinar activity patterns of phosphoenolpyruvate carboxykinase in livers of male and female rats upon feeding a high protein and a high fat diet

Phosphoenolpyruvate carboxykinase (PEPCK) activity was investigated in relation to its localization within the liver acinus of male and female rats after feeding either a high protein diet (77%) or a high fat diet (52%). Both diets led to sex-dependent changes in activity and acinar distribution patterns. In male rats high protein diet provoked a shift in the acinar activity pattern towards the perivenous parts of the acinus without increase in average activity. Yet in the livers of females the activity was increased in all parts of the acinus, but to a greater extent in the perivenous parts of the acinus. Feeding a high fat diet increased PEPCK activity in males and to an even greater extent in females. In both sexes the increase was greater in the perivenous zone when compared to the changes within the periportal zone. The results are discussed in relation to changes in the concentrations of glucoregulatory hormones.

An estimate of the effect of acute exsanguination on catecholamine and glucoregulatory hormone concentrations in the newborn rat.

We have determined the effect of acute exsanguination on plasma concentrations of glucose, insulin, glucagon, dopamine, epinephrine and norepinephrine in neonatal Sprague-Dawley rats. This was done by comparing concentrations of these substances in aliquots of blood obtained within 10 s of the initial bleeding to those in blood obtained over the next 50 s of the blood drawing process. Concentrations of glucose and insulin showed no change between early and late samples. Glucagon concentrations showed variable responses dependent upon the age of the animal. Concentrations were unchanged at birth, but increased 22% and 58% at 1 and 6 h of age respectively. Catecholamine concentrations increased greatly (57 to 215%) between blood aliquots regardless of age at the time of sampling. These findings indicate that hormonal responses occur during the relatively brief period of blood drawing in Sprague-Dawley rats, pointing out further limitations inherent in the use of small animals for acute metabolic and hormonal studies.

Transplacental arteriovenous gradients for glucose, insulin, glucagon and placental lactogen during normoglycaemia in human pregnancy at term

The potential contributions of placental extraction and degradation to glucoregulatory hormone turnover in late pregnancy were assessed by measuring arteriovenous differences for glucose, insulin, glucagon and human placental lactogen (hPL) across the uterine and fetal circulation in ten pregnant women at the time of elective caesarean section. The observations were made during stable conditions of euglycaemia; values for maternal arterial glucose, insulin, glucagon and hPL were 78.8 +/- 5.0 mg/dl, 10.1 +/- 2.1 microU/ml, 72.0 +/- 8.5 pg/ml and 5.18 +/- 0.59 micrograms/ml, respectively. The glucose decrements observed consistently across the uterus and fetus indicated uptake by the placenta and fetus, and in the maternal circulation the arterial-uterine vein increment for hPL was 2.10 +/- 0.44 micrograms/ml. However, within the limits of analytical accuracy, no significant gradient could be demonstrated for insulin across the uterine (maternal) or umbilical (fetal) circulations. A small (8.5 per cent) but significant arteriovenous difference for glucagon was observed across the uterus but none was found on the fetal side of the placenta. The findings indicate that detectable gradients for insulin cannot be demonstrated under basal conditions of metabolism and at normal rates of placental blood flow. The results do not exclude the possibility of more significant extraction ratios under other physiological conditions or at higher concentrations of glucoregulatory hormones.