INSULIN-INDUCED CHANGES IN BLOOD GLUCOSE AND HGH IN NORMAL, GROWTH-RETARDED, AND OBESE SUBJECTS; A SURVEY OF 328 INSULIN TOLERANCE TESTS

We have studied the reproducibility of the thirst and arginine vasopressin (AVP) responses to osmotic and hypoglycemic stimulation in healthy volunteers undergoing repeat hypertonic (855 mmol/l) saline infusion and insulin tolerance tests (ITTs). Hypertonic saline infusion caused similar mean rises in plasma osmolality, AVP, and thirst on each occasion. Linear-regression analysis defined close relationships between the slopes (r = +0.72, P less than 0.05) and the abscissal intercepts (r = +0.89, P less than 0.001) of the regression lines relating plasma osmolality (Posmol) and plasma AVP (PAVP), and the group intraindividual component of the variance for the slopes and intercepts was 7 and 0.6%, respectively. There were close correlations between the slopes (r = +0.79, P less than 0.02) and the intercepts (r = +0.84, P less than 0.01) of the regression lines relating Posmol and thirst, and group intraindividual component of the variance was 14 and 0.7%, respectively. Hypertonic saline infusion was infused on four occasions in four subjects, and the results showed that the linear regression lines relating PAVP and Posmol and thirst and Posmol were reproducible within an individual. There were similar falls in blood glucose and elevations in PAVP in both ITTs. No relationship was defined between the fall in blood glucose and either the rise in PAVP or the area under the AVP curve (AUC). The intraindividual component of the variance for the rise in AVP and the AUC was 77 and 22.5%, respectively. The AVP and thirst responses to osmotic stimulation are highly reproducible, but there is considerable intraindividual variation in the AVP response to hypoglycemia.

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Hepatic handling of pancreatic glucagon and glucose during meals in rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1984.247.5.r827 ◽

1984 ◽

Vol 247 (5) ◽

pp. R827-R832 ◽

Cited By ~ 4

Author(s):

W. Langhans ◽

K. Pantel ◽

W. Muller-Schell ◽

E. Eggenberger ◽

E. Scharrer

Keyword(s):

Blood Glucose ◽

Portal Vein ◽

Hepatic Vein ◽

Blood Glucose Concentration ◽

Glucagon Secretion ◽

Liver Glycogen ◽

Pancreatic Glucagon ◽

Hepatic Portal Vein ◽

Hepatic Portal ◽

Induced Changes

Prandial changes in plasma pancreatic glucagon, blood glucose, and liver glycogen levels were studied during the first meal after 12 h of food deprivation in rats. To determine whether pancreatic glucagon secretion is influenced by the composition of the diet, the experiments were performed in rats fed high-carbohydrate (HC), high-fat (HF), or high-protein (HP) diets. Plasma glucagon levels in the hepatic portal vein increased about 100% during meals in all feeding groups, whereas glucagon levels in the hepatic vein changed very little. Blood glucose concentration in the hepatic portal vein increased during meals in HC diet-fed rats but decreased in HF and in HP diet-fed rats. Blood glucose in the hepatic vein also increased in HC and HP diet-fed rats. In addition, liver glycogen content decreased during meals in HC and HP diet-fed rats and by 14 min after the meal in HF diet-fed rats. These results demonstrate that a considerable amount of the glucagon released during meals in HC, HF, and HP diet-fed rats remains in the liver. This is consistent with the hypothesis that the liver is important for the satiety effect of glucagon. The results also suggest that glucagon contributes to the meal-induced changes in hepatic carbohydrate metabolism observed in all groups.

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The effect of drugs on stress-induced changes of myocardial glycogen and blood glucose concentration in rats

British Journal of Pharmacology ◽

10.1111/j.1476-5381.1972.tb07321.x ◽

1972 ◽

Vol 44 (4) ◽

pp. 814-816 ◽

Cited By ~ 3

Author(s):

S. Prabhu ◽

V. N. Sharma ◽

V. Singh

Keyword(s):

Blood Glucose ◽

Glucose Concentration ◽

Blood Glucose Concentration ◽

Induced Changes

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Comparison between insulin tolerance test, growth hormone (GH)-releasing hormone (GHRH), GHRH plus acipimox and GHRH plus GH-releasing peptide-6 for the diagnosis of adult GH deficiency in normal subjects, obese and hypopituitary patients

Acta Endocrinologica ◽

10.1530/eje.0.1490117 ◽

2003 ◽

pp. 117-122 ◽

Cited By ~ 46

Author(s):

F Cordido ◽

P Alvarez-Castro ◽

ML Isidro ◽

FF Casanueva ◽

C Dieguez

Keyword(s):

Normal Subjects ◽

Tolerance Test ◽

Insulin Tolerance Test ◽

Maximal Response ◽

Gh Secretion ◽

Insulin Tolerance ◽

Adult Gh Deficiency ◽

Combined Test ◽

Severely Obese ◽

Obese Subjects

OBJECTIVE: It has been gradually realized that GH may have important physiological functions in adult humans. The biochemical diagnosis of adult GHD is established by provocative testing of GH secretion. The insulin-tolerance test (ITT) is the best validated. The ITT has been challenged because of its low degree of reproducibility and lack of normal range, and is contra-indicated in common clinical situations. Furthermore, in severely obese subjects the response to the ITT frequently overlaps with those found in non-obese adult patients with GHD. DESIGN: The aim of the present study was to evaluate the diagnostic capability of four different stimuli of GH secretion: ITT, GHRH, GHRH plus acipimox (GHRH+Ac), and GHRH plus GHRP-6 (GHRH+GHRP-6), in two pathophysiological situations: hypopituitarism and obesity, and normal subjects. METHODS: Eight adults with hypopituitarism (four female, four male) aged 41-62 Years (48.8+/-1.4 Years), ten obese normal patients (five female, five male) aged 38-62 Years (48.1+/-2.5 Years), with a body mass index of 34.2+/-1.2 kg/m(2), and ten normal subjects (five female, five male) aged 33-62 Years (48.1+/-2.8 Years) were studied. Four tests were performed on each patient or normal subject: An ITT (0.1 U/kg, 0.15 U/kg for obese, i.v., 0 min), GHRH (100 microg, i.v., 0 min), GHRH (100 microg, i.v., 0 min) preceded by acipimox (250 mg, orally, at -270 min and -60 min) (GHRH+Ac); and GHRH (100 microg, i.v., 0 min) plus GHRP-6 (100 microg, i.v., 0 min) (GHRH+GHRP-6). Serum GH was measured by radioimmunoassay. Statistical analyses were performed by Wilcoxon rank sum and by Mann-Whitney tests. RESULTS: After the ITT the mean peak GH secretion was 1.5+/-0.3 microg/l for hypopituitary, 10.1+/-1.7 microg/l (P<0.05 vs hypopituitary) for obese and 17.8+/-2.0 microg/l (P<0.05 vs hypopituitary) for normal. GHRH-induced GH secretion was 2+/-0.7 microg/l for hypopituitary, 3.9+/-1.2 microg/l (P=NS vs hypopituitary) for obese and 22.2+/-3.8 microg/l (P<0.05 vs hypopituitary) for normal. After GHRH+Ac, mean peak GH secretion was 3.3+/-1.4 microg/l for hypopituitary, 14.2+/-2.7 microg/l (P<0.05 vs hypopituitary) for obese and 35.1+/-5.2 microg/l (P<0.05 vs hypopituitary) for normal. GHRH+GHRP-6 induced mean peak GH secretion of 4.1+/-0.9 microg/l for hypopituitary, 38.5+/-6.5 microg/l (P<0.05 vs hypopituitary) for obese and 68.1+/-5.5 microg/l (P<0.05 vs hypopituitary) for normal subjects. Individually considered, after ITT, GHRH or GHRH+Ac, the maximal response in hypopituitary patients was lower than the minimal response in normal but higher than the minimal response in obese subjects. In contrast, after GHRH+GHRP-6 the maximal response in hypopituitary patients was lower than the minimal response in normal and obese subjects. CONCLUSIONS: This study suggests that, in this group of patients, although both acipimox and GHRP-6 partially reverse the functional hyposomamotropism of obesity after GHRH, but are unable to reverse the organic hyposomatotropism of hypopituitarism, the combined test GHRH+GHRP-6 most accurately distinguishes both situations, without the side effects of ITT.

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EFFECTS OF PROGESTERONE, OESTRADIOL AND/OR CLOMIPHENE ON LIVER GLYCOGEN AND BLOOD GLUCOSE IN INTACT AND ADRENALECTOMISED RATS DURING DELAYED IMPLANTATION

Acta Endocrinologica ◽

10.1530/acta.0.0760678 ◽

1974 ◽

Vol 76 (4) ◽

pp. 678-688

Author(s):

M. S. Sankaran ◽

M. R. N. Prasad

Keyword(s):

Blood Glucose ◽

Clomiphene Citrate ◽

Insulin Level ◽

Liver Glycogen ◽

Hepatic Glycogen ◽

Prolonged Administration ◽

Glucose Levels ◽

Delayed Implantation ◽

Blood Glucose Levels ◽

Induced Changes

ABSTRACT Prolonged administration of progesterone alone caused significant changes in liver glycogen. Oestradiol-17β increased the liver glycogen 18 hours after the treatment. A single administration of clomiphene citrate on day 9 post-coitum (pc) inhibited the oestradiol or progesterone induced increase in hepatic glycogen. Bilateral adrenalectomy on day 3 pc abolished the changes in liver glycogen induced by progesterone, oestradiol and/or clomiphene. Administration of progesterone, oestradiol or clomiphene caused a decrease in blood glucose levels in rats during delayed implantation. Although the effects of progesterone and oestradiol on blood glucose levels were abolished by adrenalectomy, clomiphene induced changes persisted in the adrenalectomised rats. It is concluded that progesterone, oestradiol and/or clomiphene induced changes in liver glycogen are mediated through the adrenal glands. Changes in the blood glucose levels are discussed in relation to increased insulin level in the blood and also in relation to the increased glucocorticoid secretion following various treatments.

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Deciphering the Hypoglycemic Glucagon Response: Development of a Graded Hyperinsulinemic Hypoglycemic Clamp Technique in Female Mice

Endocrinology ◽

10.1210/en.2015-1314 ◽

2015 ◽

Vol 156 (10) ◽

pp. 3866-3871 ◽

Cited By ~ 5

Author(s):

Siri Malmgren ◽

Bo Ahrén

Keyword(s):

Blood Glucose ◽

Defense Mechanisms ◽

Tolerance Test ◽

Glucose Lowering ◽

Insulin Tolerance ◽

Hyperbolic Curve ◽

Glucose Lowering Therapy

Glucose lowering therapy in type 1 and type 2 diabetes is often associated with hypoglycemic events. To avoid this, glucose lowering therapies need to be developed that support the hypoglycemic defense mechanisms. Such development needs a tool for evaluating counterregulatory mechanisms in vivo. A sustained glucagon release during hypoglycemia is of most importance to hypoglycemic defense mechanisms. We have therefore developed a graded hyperinsulinemic hypoglycemic clamp in mice and used it to evaluate counterregulatory glucagon dynamics. Glucose was clamped at narrow intervals aiming at 2.5, 3.5, 4.5, and 6.0 mmol/L. Glucagon levels were increased during hypoglycemia in a glucose-dependent way with a glucagon counterregulatory threshold between 3.5 and 4.0 mmol/L. Modelling the glucose-glucagon relationship using a hyperbolic curve with the equation: plasma glucagon = −4.20 + 90.79/blood glucose showed high correlation. When comparing this method to the insulin tolerance test as an approach to study glucagon dynamics in vivo, we found that the graded clamp more efficiently evoked a robust, predictable, glucagon response with considerably less variation in blood glucose. In conclusion, we have developed a tool for the study of in vivo glucagon dynamics during hypoglycemia in mice and demonstrated a hyperbolic glucose-counterregulatory glucagon relationship.

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ADP Induces Blood Glucose Through Direct and Indirect Mechanisms in Promotion of Hepatic Gluconeogenesis by Elevation of NADH

Frontiers in Endocrinology ◽

10.3389/fendo.2021.663530 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xinyu Cao ◽

Xiaotong Ye ◽

Shuang Zhang ◽

Li Wang ◽

Yanhong Xu ◽

...

Keyword(s):

Insulin Resistance ◽

Blood Glucose ◽

Signaling Pathway ◽

Liver Tissue ◽

Hepatic Insulin Resistance ◽

Indirect Pathway ◽

Hepatic Gluconeogenesis ◽

Insulin Tolerance ◽

Elevated Expression

Extracellular ADP, a derivative of ATP, interacts with the purinergic receptors in the cell membrane to regulate cellular activities. This signaling pathway remains unknown in the regulation of blood glucose in vivo. We investigated the acute activity of ADP in mice through a peritoneal injection. In the lean mice, in response to the ADP treatment, the blood glucose was elevated, and pyruvate tolerance was impaired. Hepatic gluconeogenesis was enhanced with elevated expression of glucogenic genes (G6pase and Pck1) in the liver. An elevation was observed in NADH, cAMP, AMP, GMP and citrate in the liver tissue in the targeted metabolomics assay. In the primary hepatocytes, ADP activated the cAMP/PKA/CREB signaling pathway, which was blocked by the antagonist (2211) of the ADP receptor P2Y13. In the circulation, gluconeogenic hormones including glucagon and corticosterone were elevated by ADP. Insulin and thyroid hormones (T3 and T4) were not altered in the blood. In the diet-induced obese (DIO) mice, NADH was elevated in the liver tissue to match the hepatic insulin resistance. Insulin resistance was intensified by ADP for further impairment in insulin tolerance. These data suggest that ADP induced the blood glucose through direct and indirect actions in liver. One of the potential pathways involves activation of the P2Y13/cAMP/PKA/CREB signaling pathway in hepatocytes and the indirect pathway may involve induction of the gluconeogenic hormones. NADH is a signal for gluconeogenesis in the liver of both DIO mice and lean mice.

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Suppression of Prolactin Secretion Partially Explains the Antidiabetic Effect of Bromocriptine in ob/ob Mice

Endocrinology ◽

10.1210/en.2018-00629 ◽

2018 ◽

Vol 160 (1) ◽

pp. 193-204 ◽

Cited By ~ 5

Author(s):

Isadora C Furigo ◽

Miriam F Suzuki ◽

João E Oliveira ◽

Angela M Ramos-Lobo ◽

Pryscila D S Teixeira ◽

...

Keyword(s):

Insulin Resistance ◽

Blood Glucose ◽

Insulin Sensitivity ◽

Glucose Homeostasis ◽

Prolactin Secretion ◽

Dopamine Receptor Agonist ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Insulin Tolerance ◽

Promising Therapeutic Approach

Abstract Previous studies have shown that bromocriptine mesylate (Bromo) lowers blood glucose levels in adults with type 2 diabetes mellitus; however, the mechanism of action of the antidiabetic effects of Bromo is unclear. As a dopamine receptor agonist, Bromo can alter brain dopamine activity affecting glucose control, but it also suppresses prolactin (Prl) secretion, and Prl levels modulate glucose homeostasis. Thus, the objective of the current study was to investigate whether Bromo improves insulin sensitivity via inhibition of Prl secretion. Male and female ob/ob animals (a mouse model of obesity and insulin resistance) were treated with Bromo and/or Prl. Bromo-treated ob/ob mice exhibited lower serum Prl concentration, improved glucose and insulin tolerance, and increased insulin sensitivity in the liver and skeletal muscle compared with vehicle-treated mice. Prl replacement in Bromo-treated mice normalized serum Prl concentration without inducing hyperprolactinemia. Importantly, Prl replacement partially reversed the improvements in glucose homeostasis caused by Bromo treatment. The effects of the Prl receptor antagonist G129R-hPrl on glucose homeostasis were also investigated. We found that central G129R-hPrl infusion increased insulin tolerance of male ob/ob mice. In summary, our findings indicate that part of Bromo effects on glucose homeostasis are associated with decrease in serum Prl levels. Because G129R-hPrl treatment also improved the insulin sensitivity of ob/ob mice, pharmacological compounds that inhibit Prl signaling may represent a promising therapeutic approach to control blood glucose levels in individuals with insulin resistance.

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Voluntary physical activity protects against olanzapine-induced hyperglycemia

Journal of Applied Physiology ◽

10.1152/japplphysiol.00876.2020 ◽

2020 ◽

Author(s):

Hesham Shamshoum ◽

Greg Lawrence McKie ◽

Kyle D. Medak ◽

Kristin E. Ashworth ◽

Bruce E. Kemp ◽

...

Keyword(s):

Physical Activity ◽

Blood Glucose ◽

Glucose Metabolism ◽

Wheel Running ◽

Whole Body ◽

Light Cycle ◽

Triglyceride Accumulation ◽

Insulin Tolerance ◽

Voluntary Physical Activity ◽

Running Wheels

Olanzapine (OLZ) is used in the treatment of schizophrenia and a growing number of "off‐label" conditions. While effective in reducing psychoses, OLZ causes rapid impairments in glucose and lipid homeostasis. The purpose of this study was to investigate if voluntary physical activity via wheel running (VWR) would protect against the acute metabolic side effects of OLZ. Male C57BL/6J mice remained sedentary or were provided with running wheels overnight, prior to treatment with OLZ either at the beginning of the light cycle, or 7 or 24 hours following the cessation of VWR. Prior VWR protected against OLZ-induced hyperglycemia immediately and 7 hours following a bout of overnight wheel running. Protection against, hyperglycemia immediately following VWR was associated with increased insulin tolerance and an attenuated OLZ-induced increase in the serum glucagon:insulin ratio. The protective effect of VWR against OLZ-induced increases in hyperglycemia and glucagon:insulin ratio were maintained in high fat fed, and AMPK b1 deficient mice, models which display a potentiated OLZ-induced increase in blood glucose. Repeated OLZ treatment did not impair VWR performance and protection against the acute effects of OLZ on blood glucose was present after 1 week of daily OLZ treatment in mice given access to running wheels. In contrast to the effects on glucose metabolism, VWR, for the most part, did not impact OLZ induced perturbations in lipolysis, liver triglyceride accumulation or whole-body substrate oxidation. Collectively our findings demonstrate the efficacy of voluntary physical activity as an approach to protect against OLZ-induced impairments in glucose metabolism.

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