Targeted Deletion of Growth Hormone (GH) Receptor in Macrophage Reveals Novel Osteopontin-mediated Effects of GH on Glucose Homeostasis and Insulin Sensitivity in Diet-induced Obesity

Insulin clearance plays a major role in glucose homeostasis and insulin sensitivity in physiological and/or pathological conditions, such as obesity-induced type 2 diabetes as well as diet-induced obesity. The aim of the present work was to evaluate cafeteria diet-induced obesity-induced changes in insulin clearance and to explain the mechanisms underlying these possible changes. Female Swiss mice were fed either a standard chow diet (CTL) or a cafeteria diet (CAF) for 8 weeks, after which we performed glucose tolerance tests, insulin tolerance tests, insulin dynamics, and insulin clearance tests. We then isolated pancreatic islets for ex vivo glucose-stimulated insulin secretion as well as liver, gastrocnemius, visceral adipose tissue, and hypothalamus for subsequent protein analysis by western blot and determination of mRNA levels by real-time RT-PCR. The cafeteria diet induced insulin resistance, glucose intolerance, and increased insulin secretion and total insulin content. More importantly, mice that were fed a cafeteria diet demonstrated reduced insulin clearance and decay rate as well as reduced insulin-degrading enzyme (IDE) protein and mRNA levels in liver and skeletal muscle compared with the control animals. Furthermore, the cafeteria diet reduced IDE expression and alternative splicing in the liver and skeletal muscle of mice. In conclusion, a cafeteria diet impairs glucose homeostasis by reducing insulin sensitivity, but it also reduces insulin clearance by reducing IDE expression and alternative splicing in mouse liver; however, whether this mechanism contributes to the glucose intolerance or helps to ameliorate it remains unclear.

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Glucose homeostasis and insulin sensitivity in growth hormone-transgenic mice: a cross-sectional analysis

Biological Chemistry ◽

10.1515/bc.2010.124 ◽

2010 ◽

Vol 391 (10) ◽

Cited By ~ 21

Author(s):

Ravneet K. Boparai ◽

Oge Arum ◽

Romesh Khardori ◽

Andrzej Bartke

Keyword(s):

Growth Hormone ◽

Insulin Sensitivity ◽

Transgenic Mice ◽

Glucose Homeostasis ◽

Endocrine Control ◽

Cross Sectional ◽

Systematic Assessment ◽

Beneficial Effects ◽

Glucose Stimulated Insulin Secretion ◽

The Impact

Abstract In contrast to its stimulatory effects on musculature, bone, and organ development, and its lipolytic effects, growth hormone (GH) opposes insulin effects on glucose metabolism. Chronic GH overexposure is thought to result in insulin insensitivity and decreased blood glucose homeostatic control. Yet, despite the importance of this concept for basic biology, as well as human conditions of GH excess or deficiency, no systematic assessment of the impact of GH over- expression on glucose homeostasis and insulin sensitivity has been conducted. We report that male and female adult GH transgenic mice have enhanced glucose tolerance compared to littermate controls and this effect is not dependent on age or on the particular heterologous GH transgene used. Furthermore, increased glucose-stimulated insulin secretion, augmented insulin sensitivity, and muted gluconeogenesis were also observed in bovine GH overexpressing mice. These results show that markedly increased systemic GH concentration in GH-transgenic mice exerts unexpected beneficial effects on glucose homeostasis, presumably via a compensatory increase in insulin release. The counterintuitive nature of these results challenges previously held presumptions of the physiology of these mice and other states of GH overexpression or suppression. In addition, they pose intriguing queries about the relationships between GH, endocrine control of metabolism, and aging.

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Growth hormone receptor antagonism with pegvisomant in insulin resistant non-diabetic men: A phase II pilot study

F1000Research ◽

10.12688/f1000research.11359.1 ◽

2017 ◽

Vol 6 ◽

pp. 614 ◽

Cited By ~ 3

Author(s):

Ada P. Lee ◽

Kathleen Mulligan ◽

Morris Schambelan ◽

Elizabeth J. Murphy ◽

Ethan J. Weiss

Keyword(s):

Insulin Resistance ◽

Growth Hormone ◽

Insulin Sensitivity ◽

Pilot Study ◽

Glucose Metabolism ◽

Phase Ii ◽

Whole Body ◽

Sensitivity Index ◽

Insulin Resistant ◽

Gh Receptor

Background: Growth hormone (GH) is known to affect insulin and glucose metabolism. Blocking its effects in acromegalic patients improves diabetes and glucose metabolism. We aimed to determine the effect of pegvisomant, a GH receptor antagonist, on insulin resistance, endogenous glucose production (EGP) and lipolysis in insulin resistant non-diabetic men. Methods: Four men between the ages of 18-62 with a BMI of 18-35kg/m2, with insulin resistance as defined by a HOMA-IR > 2.77, were treated for four weeks with pegvisomant 20 mg daily. Inpatient metabolic assessments were performed before and after treatment. The main outcome measurements were: change after pegvisomant therapy in insulin sensitivity as measured by hyperinsulinemic euglycemic clamp; and EGP and lipolysis assessed by stable isotope tracer techniques. Results: Insulin like growth factor-1 (IGF-1) concentrations decreased from 134.0 ± 41.5 (mean ± SD) to 72.0 ± 11.7 ng/mL (p = 0.04) after 4 weeks of therapy. Whole body insulin sensitivity index (M/I 3.2 ± 1.3 vs. 3.4 ± 2.4; P = 0.82), as well as suppression of EGP (89.7 ± 26.9 vs. 83.5 ± 21.6%; p = 0.10) and Ra glycerol (59.4 ± 22.1% vs. 61.2 ± 14.4%; p = 0.67) during the clamp were not changed significantly with pegvisomant treatment. Conclusions: Blockade of the GH receptor with pegvisomant for four weeks had no significant effect on insulin/glucose metabolism in a small phase II pilot study of non-diabetic insulin resistant participants without acromegaly.

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Relationship between Nocturnal Growth Hormone Concentrations, Serum IGF-I/IGFBP-3 Levels, Insulin Sensitivity and GH Receptor Allelic Variant in Small for Gestational Age Children

Hormone Research in Paediatrics ◽

10.1159/000100546 ◽

2007 ◽

Vol 68 (3) ◽

pp. 132-138 ◽

Cited By ~ 6

Author(s):

Verónica Mericq ◽

Rossana Román ◽

Germán Iñiguez ◽

Bárbara Angel ◽

Teresa Salazar ◽

...

Keyword(s):

Growth Hormone ◽

Insulin Sensitivity ◽

Gestational Age ◽

Small For Gestational Age ◽

Allelic Variant ◽

Gh Receptor ◽

Igf I ◽

Igfbp 3

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Growth Hormone (GH)/GH Receptor Expression and GH-Mediated Effects During Early Bovine Embryogenesis1

Biology of Reproduction ◽

10.1095/biolreprod64.6.1826 ◽

2001 ◽

Vol 64 (6) ◽

pp. 1826-1834 ◽

Cited By ~ 35

Author(s):

Sabine Kölle ◽

Miodrag Stojkovic ◽

Katja Prelle ◽

Michael Waters ◽

Eckhard Wolf ◽

...

Keyword(s):

Growth Hormone ◽

Receptor Expression ◽

Gh Receptor ◽

Mediated Effects

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Neuropeptide 26RFa (QRFP) is a key regulator of glucose homeostasis and its activity is markedly altered in obese/hyperglycemic mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00540.2018 ◽

2019 ◽

Vol 317 (1) ◽

pp. E147-E157 ◽

Cited By ~ 1

Author(s):

Gaëtan Prévost ◽

Arnaud Arabo ◽

Marie-Anne Le Solliec ◽

Justine Bons ◽

Marie Picot ◽

...

Keyword(s):

Insulin Sensitivity ◽

Glucose Homeostasis ◽

High Fat Diet ◽

Release Kinetics ◽

Oral Glucose ◽

High Fat ◽

Diet Induced Obesity ◽

Glucose Challenge ◽

Kinetics Of

Recent studies have shown that the hypothalamic neuropeptide 26RFa regulates glucose homeostasis by acting as an incretin and increasing insulin sensitivity. In this study, we further characterized the role of the 26RFa/GPR103 peptidergic system in the global regulation of glucose homeostasis using a 26RFa receptor antagonist and also assessed whether a dysfunction of the 26RFa/GPR103 system occurs in obese hyperglycemic mice. First, we demonstrate that administration of the GPR103 antagonist reduces the global glucose-induced incretin effect and insulin sensitivity whereas, conversely, administration of exogenous 26RFa attenuates glucose-induced hyperglycemia. Using a mouse model of high-fat diet-induced obesity and hyperglycemia, we found a loss of the antihyperglcemic effect and insulinotropic activity of 26RFa, accompanied with a marked reduction of its insulin-sensitive effect. Interestingly, this resistance to 26RFa is associated with a downregulation of the 26RFa receptor in the pancreatic islets, and insulin target tissues. Finally, we observed that the production and release kinetics of 26RFa after an oral glucose challenge is profoundly altered in the high-fat mice. Altogether, the present findings support the view that 26RFa is a key regulator of glucose homeostasis whose activity is markedly altered under obese/hyperglycemic conditions.

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Growth Hormone Receptor Antagonist Transgenic Mice Have Increased Subcutaneous Adipose Tissue Mass, Altered Glucose Homeostasis and No Change in White Adipose Tissue Cellular Senescence

Gerontology ◽

10.1159/000439050 ◽

2015 ◽

Vol 62 (2) ◽

pp. 163-172 ◽

Cited By ~ 9

Author(s):

Ross Comisford ◽

Ellen R. Lubbers ◽

Lara A. Householder ◽

Ozan Suer ◽

Tamara Tchkonia ◽

...

Keyword(s):

Growth Hormone ◽

Adipose Tissue ◽

Blood Glucose ◽

Insulin Sensitivity ◽

Transgenic Mice ◽

Glucose Homeostasis ◽

Cellular Senescence ◽

White Adipose Tissue ◽

Fasting Blood Glucose ◽

Deficient Mice

Background: Growth hormone (GH)-resistant/deficient mice experience improved glucose homeostasis and substantially increased lifespan. Recent evidence suggests that long-lived GH-resistant/deficient mice are protected from white adipose tissue (WAT) dysfunction, including WAT cellular senescence, impaired adipogenesis and loss of subcutaneous WAT in old age. This preservation of WAT function has been suggested to be a potential mechanism for the extended lifespan of these mice. Objective: The objective of this study was to examine WAT senescence, WAT distribution and glucose homeostasis in dwarf GH receptor antagonist (GHA) transgenic mice, a unique mouse strain having decreased GH action but normal longevity. Methods: 18-month-old female GHA mice and wild-type (WT) littermate controls were used. Prior to dissection, body composition, fasting blood glucose as well as glucose and insulin tolerance tests were performed. WAT distribution was determined by weighing four distinct WAT depots at the time of dissection. Cellular senescence in four WAT depots was assessed using senescence-associated β-galactosidase staining to quantify the senescent cell burden, and real-time qPCR to quantify gene expression of senescence markers p16 and IL-6. Results: GHA mice had a 22% reduction in total body weight, a 33% reduction in lean mass and a 10% increase in body fat percentage compared to WT controls. GHA mice had normal fasting blood glucose and improved insulin sensitivity; however, they exhibited impaired glucose tolerance. Moreover, GHA mice displayed enhanced lipid storage in the inguinal subcutaneous WAT depot (p < 0.05) and a 1.7-fold increase in extra-/intraperitoneal WAT ratio compared to controls (p < 0.05). Measurements of WAT cellular senescence showed no difference between GHA mice and WT controls. Conclusions: Similar to other mice with decreased GH action, female GHA mice display reduced age-related lipid redistribution and improved insulin sensitivity, but no change in cellular senescence. The similar abundance of WAT senescent cells in GHA and control mice suggests that any protection against generation of senescent cells afforded by decreased GH action, low insulin-like growth factor 1 and/or improved insulin sensitivity in the GHA mice may be offset by their severe adiposity, since obesity is known to increase senescence.

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Adipocyte JAK2 Mediates Growth Hormone-Induced Hepatic Insulin Resistance

10.1101/076265 ◽

2016 ◽

Author(s):

Kevin C. Corbit ◽

João Paulo G. Camporez ◽

Jennifer L. Tran ◽

Camella G. Wilson ◽

Dylan Lowe ◽

...

Keyword(s):

Insulin Resistance ◽

Growth Hormone ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Glucose Homeostasis ◽

Metabolic Stress ◽

Hepatic Insulin Resistance ◽

Whole Body ◽

Insulin Signal Transduction ◽

Conditional Deletion

ABSTRACTFor nearly 100 years, Growth Hormone (GH) has been known to impact insulin sensitivity and risk of diabetes. However, the tissue governing the effects of GH signaling on insulin and glucose homeostasis remains unknown. Excess GH reduces fat mass and insulin sensitivity. Conversely, GH insensitivity (GHI) is associated with increased adiposity, augmented insulin sensitivity, and protection from diabetes. Here we induce adipocyte-specific GHI through conditional deletion of Jak2 (JAK2A), an obligate transducer of GH signaling. Similar to whole-body GHI, JAK2A mice had increased adiposity and extreme insulin sensitivity. Loss of adipocyte Jak2 augmented hepatic insulin sensitivity and conferred resistance to diet-induced metabolic stress without overt changes in circulating fatty acids. While GH injections induced hepatic insulin resistance in control mice, the diabetogenic action was absent in JAK2A mice. Adipocyte GH signaling directly impinged on both adipose and hepatic insulin signal transduction. Collectively, our results show that adipose tissue governs the effects of GH on insulin and glucose homeostasis. Further, we show that JAK2 mediates liver insulin sensitivity via an extra-hepatic, adipose tissue-dependent mechanism.

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Leptin, insulin sensitivity and growth hormone binding protein in chronic heart failure with and without cardiac cachexia

Acta Endocrinologica ◽

10.1530/eje.0.1450727 ◽

2001 ◽

pp. 727-735 ◽

Cited By ~ 77

Author(s):

W Doehner ◽

CD Pflaum ◽

M Rauchhaus ◽

IF Godsland ◽

K Egerer ◽

...

Keyword(s):

Growth Hormone ◽

Body Composition ◽

Insulin Sensitivity ◽

Body Fat ◽

Fat Mass ◽

Receptor Expression ◽

Cardiac Cachexia ◽

Gh Receptor ◽

Growth Hormone Binding Protein ◽

Hormone Binding Protein

OBJECTIVE: Regulation of growth hormone (GH) receptor expression and hence tissue GH sensitivity may be important for the conflicting results found in treatment studies with recombinant growth hormone in chronic heart failure (CHF). Growth hormone-binding protein (GHBP) corresponds to the extracellular domain of the GH receptor and is closely related to measures of body composition and, specifically, to size of visceral fat tissue. Leptin, the adipocyte specific (ob) gene product, has been proposed as the signal linking adipose tissue and GHBP/GH-receptor expression. CHF has recently been shown to be a hyperleptinaemic and insulin-resistant state regardless of aetiology. This study aimed to examine the influence of leptin on GHBP in CHF patients with and without cardiac cachexia compared with healthy control subjects. METHODS: We studied 47 male patients with CHF (mean age 61+/-2 years, New York Heart Association (NYHA)-class 2.7+/-0.1, left ventricular ejection fraction (LVEF) 28+/-2%, peak oxygen consumption 16.8+/-0.9 ml/kg/min) and 21 male healthy controls of similar age. Of the CHF patients, 19 were cachectic (cCHF; non-oedematous weight loss >7.5% over at least 6 months) and 28 non-cachectic (ncCHF; similar for age and LVEF). Insulin sensitivity was assessed by an intravenous glucose tolerance test using the minimal model approach. RESULTS: Compared with healthy controls, patients had elevated levels of leptin (7.6+/-0.7 vs 4.8+/-0.7 ng/ml, P<0.05), insulin (76.2+/-8.9 vs 41.4+/-6.0 pmol/l, P<0.01), and reduced insulin sensitivity (2.43+/-0.2 vs 3.48+/-0.3 min(-1).microU.ml(-1).10(4), P<0.005) but similar GHBP levels (901+/-73 vs 903+/-95 pmol/l). Leptin levels were increased in ncCHF (9.11+/-1.0 ng/ml, P=0.001) but were not different from normal in cCHF (5.32+/-0.7 ng/ml, P>0.5). After correction for total body fat mass, both ncCHF and cCHF were hyperleptinaemic (41.8+/-3.8 and 37.9+/-0.38 vs 24.4+/-2.1 ng/ml/100 g, ANOVA P=0.001). In both patients and controls there was a direct correlation between leptin levels and GHBP (r=0.70 and r=0.71 respectively, both P<0.0001). This relationship was stronger than between GHBP and several parameters of body composition (body mass index (BMI), total and regional body fat mass or % body fat) and held true when sub-groups were tested individually (ncCHF r=0.62, P<0.001; cCHF r=0.79, P<0.0001). In multivariate regression analysis in all CHF patients, serum leptin levels emerged as the strongest predictor of GHBP, independent of age, BMI, total and regional fat mass or % body fat, fasting insulin level and insulin sensitivity. CONCLUSION: Fat mass corrected leptin levels are elevated in CHF patients with and without cachexia. Reduced total fat mass may account for lower leptin levels in cachectic CHF patients compared with non cachectic patients. Leptin strongly predicts GHBP levels in CHF regardless of its hyperleptinaemic state or severely altered body composition as in cardiac cachexia. Leptin could be the signalling link between adipose tissue and GHBP/GH receptor expression in CHF.

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