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Elevated GH/IGF-I, due to somatotrope-specific loss of both IGF-I and insulin receptors, alters glucose homeostasis and insulin sensitivity in a diet-dependent manner.

ABSTRACT: A unique mouse model was developed with elevated endogenous GH (2- to 3-fold) and IGF-I (1.2- to 1.4-fold), due to somatotrope-specific Cre-mediated inactivation of IGF-I receptor (IgfIr) and insulin receptor (Insr) genes (IgfIr,Insr(rGHpCre), referred to as HiGH mice). We demonstrate that the metabolic phenotype of HiGH mice is diet dependent and differs from that observed in other mouse models of GH excess due to ectopic heterologous transgene expression or pituitary tumor formation. Elevated endogenous GH promotes lean mass and whole-body lipid oxidation but has minimal effects on adiposity, even in response to diet-induced obesity. When caloric intake is moderated, elevated GH improves glucose clearance, despite low/normal insulin sensitivity, which may be explained in part by enhanced IGF-I and insulin output. However, when caloric intake is in excess, elevated GH promotes hepatic lipid accumulation, insulin resistance, hyperglycemia, and ketosis. The HiGH mouse model represents a useful tool to study the role endogenous circulating GH levels play in regulating health and disease.

SUBMITTER: Gahete MD

PROVIDER: S-EPMC3230054 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Elevated GH/IGF-I, due to somatotrope-specific loss of both IGF-I and insulin receptors, alters glucose homeostasis and insulin sensitivity in a diet-dependent manner.

Gahete Manuel D MD Córdoba-Chacón José J Anadumaka Chike V CV Lin Qing Q Brüning Jens C JC Kahn C Ronald CR Luque Raúl M RM Kineman Rhonda D RD

Endocrinology 20111011 12

A unique mouse model was developed with elevated endogenous GH (2- to 3-fold) and IGF-I (1.2- to 1.4-fold), due to somatotrope-specific Cre-mediated inactivation of IGF-I receptor (IgfIr) and insulin receptor (Insr) genes (IgfIr,Insr(rGHpCre), referred to as HiGH mice). We demonstrate that the metabolic phenotype of HiGH mice is diet dependent and differs from that observed in other mouse models of GH excess due to ectopic heterologous transgene expression or pituitary tumor formation. Elevated ...[more]

PMID: 21990313

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Project description:ObjectiveTo investigate the concordance/discordance of IGF-1 and peak stimulated GH in identifying subjects with reduced GH secretion and to determine the physiological significance of any discordance in obese subjects.Design, patients and methods95 obese and 43 normal weight men and women underwent measurement of IGF-1 and GH stimulation testing with GH releasing hormone (GHRH)-arginine. Reduced IGF-1 and GH secretion were defined using pre-determined cut-points. Cardiovascular disease risk was determined by measuring carotid intima-media thickness (cIMT). In a second study, IGF-1 was measured in 52 obese men and women who underwent GH stimulation testing and overnight frequent blood sampling. The association of IGF-1 and peak stimulated GH with parameters of endogenous GH secretion was assessed.Results60% of obese subjects had normal IGF-1 and peak stimulated GH while 8.4% of obese subjects had reduced IGF-1 and GH secretion. Discordance rate for IGF-1 and peak GH was 31.6%. Subjects with both low IGF-1 and low peak GH had the highest cIMT, while subjects with both normal IGF-1 and peak GH had the lowest cIMT. Subjects with reduction in either IGF-1 or peak GH, had intermediate cIMT (P=0.02). IGF-1 and peak stimulated GH were associated with maximum and mean overnight serum GH and GH AUC as well as maximum peak mass and median pulse mass. Peak stimulated GH, but not IGF-1, was also associated with nadir overnight serum GH concentration and basal GH secretion.ConclusionPeak stimulated GH and IGF-1 demonstrate significant discordance in identification of subjects with reduced GH secretion in obesity. Subjects with reduction of either IGF-1 or peak GH had higher cIMT compared to subjects with both normal IGF-1 and peak GH. Subjects with reductions in both IGF-1 and peak GH had the highest cIMT. Peak GH, compared to IGF-1, has broader associations with various parameters of endogenous GH secretion which support its utility in identifying those with reduced GH secretion.

Project description:PurposeTo compare the difference in anterior segment biometrics derived from anterior segment optical coherence tomography (AS-OCT) between treatment-naïve acromegaly patients and normal controls and evaluate the correlations between above biometrics and insulin-like growth factor 1 (IGF-1) and growth hormone (GH) levels.MethodsSixty eyes of 30 acromegaly patients and 60 eyes of 30 normal controls were included in this case-control study. Central corneal thickness, pupil diameter, iris thickness (IT), iris curvature (IC), anterior chamber depth (ACD), anterior chamber width, lens vault (LV), angle open distance (AOD) 500, AOD750, and trabecular iris space area (TISA) 500 and TISA750 were measured by AS-OCT. General linear regression models were constructed to evaluate the independent endocrine factors affecting iris morphology and anterior chamber angle (ACA) width.ResultsThe acromegaly patients had an evenly thicker iris (P < 0.001), a smaller IC (P < 0.05), a smaller LV (P = 0.040) and significantly larger AOD500, AOD750, TISA500 and TISA750 (P < 0.001). There was a positive correlation between the serum GH level and ACD in the acromegaly patients (P = 0.031). Linear regression models showed the lower LV and smaller IC were independent influencing factors of the increase in the AOD500, AOD750, and TISA750 and nasal TISA500. Serum IGF-1 was an independent factor for the increase in pupil diameter (β = 0.002, P = 0.031) and both the average nasal (β = 6.781*10-5, P = 0.049) and temporal (β = 7.736*10-5, P = 0.045) IT values and for the decrease in temporal IC (β < 0.001, P = 0.037). GH was an independent factor for the increase in temporal AOD750 (β = 0.001, P = 0.030) and temporal TISA750 (β = 0.002, P = 0.016).ConclusionsPatients with acromegaly have a thicker IT, smaller IC, and lower LV with a wider ACA than normal controls. Serum GH is independently correlated with the temporal ACA width, whereas serum IGF-1 is independently correlated with IT, pupil diameter, and IC.

Dataset Information

Elevated GH/IGF-I, due to somatotrope-specific loss of both IGF-I and insulin receptors, alters glucose homeostasis and insulin sensitivity in a diet-dependent manner.

Publications

Elevated GH/IGF-I, due to somatotrope-specific loss of both IGF-I and insulin receptors, alters glucose homeostasis and insulin sensitivity in a diet-dependent manner.

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