Effect of Ghrelin on Glucose-Insulin Homeostasis: Therapeutic Implications

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Abstract

Ghrelin is a 28-amino-acid peptide that displays a strong growth hormone- (GH-) releasing activity through the activation of the growth hormone secretagogue receptor (GHSR). The first studies about role of ghrelin were focused on its orexigenic ability, but despite indisputable pharmacological data, the evidence for a physiological role for ghrelin in the control of appetite is much less clear. Mice with targeted deletion of either ghrelin or the GHSR exhibit an essentially normal metabolic phenotype when fed a regular chow diet, suggesting that ghrelin may have a redundant role in the regulation of food intake. RNAs for ghrelin as well as GHSR are expressed in the pancreas of rats and humans and several studies propose that ghrelin could have an important function in glucose homeostasis and insulin release, independent of GH secretion. Low plasma ghrelin levels are associated with elevated fasting insulin levels and insulin resistance, suggesting both physiological and pathophysiological roles for ghrelin. For this reason, at least theoretically, ghrelin and/or its signalling manipulation could be useful for the treatment or prevention of diseases of glucose homeostasis such as type 2 diabetes.

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Glycogen synthase kinase-3 (GSK3) is implicated in the regulation of several physiological processes, including the control of glycogen and protein synthesis by insulin, modulation of the transcription factors AP-1 and CREB, the specification of cell fate in Drosophila and dorsoventral patterning in Xenopus embryos. GSK3 is inhibited by serine phosphorylation in response to insulin or growth factors and in vitro by either MAP kinase-activated protein (MAPKAP) kinase-1 (also known as p90rsk) or p70 ribosomal S6 kinase (p70S6k). Here we show, however, that agents which prevent the activation of both MAPKAP kinase-1 and p70S6k by insulin in vivo do not block the phosphorylation and inhibition of GSK3. Another insulin-stimulated protein kinase inactivates GSK3 under these conditions, and we demonstrate that it is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC). Like the inhibition of GSK3 (refs 10, 14), the activation of PKB is prevented by inhibitors of phosphatidylinositol (PI) 3-kinase.

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Ali Mokdad, Earl S. Ford, Barbara BOWMAN … (2003)

Obesity and diabetes are increasing in the United States. To estimate the prevalence of obesity and diabetes among US adults in 2001. Random-digit telephone survey of 195 005 adults aged 18 years or older residing in all states participating in the Behavioral Risk Factor Surveillance System in 2001. Body mass index, based on self-reported weight and height and self-reported diabetes. In 2001 the prevalence of obesity (BMI > or =30) was 20.9% vs 19.8% in 2000, an increase of 5.6%. The prevalence of diabetes increased to 7.9% vs 7.3% in 2000, an increase of 8.2%. The prevalence of BMI of 40 or higher in 2001 was 2.3%. Overweight and obesity were significantly associated with diabetes, high blood pressure, high cholesterol, asthma, arthritis, and poor health status. Compared with adults with normal weight, adults with a BMI of 40 or higher had an odds ratio (OR) of 7.37 (95% confidence interval [CI], 6.39-8.50) for diagnosed diabetes, 6.38 (95% CI, 5.67-7.17) for high blood pressure, 1.88 (95% CI,1.67-2.13) for high cholesterol levels, 2.72 (95% CI, 2.38-3.12) for asthma, 4.41 (95% CI, 3.91-4.97) for arthritis, and 4.19 (95% CI, 3.68-4.76) for fair or poor health. Increases in obesity and diabetes among US adults continue in both sexes, all ages, all races, all educational levels, and all smoking levels. Obesity is strongly associated with several major health risk factors.

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A. D. Howard, S D Feighner, D F Cully … (1996)

Small synthetic molecules termed growth hormone secretagogues (GHSs) act on the pituitary gland and the hypothalamus to stimulate and amplify pulsatile growth hormone (GH) release. A heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPC-R) of the pituitary and arcuate ventro-medial and infundibular hypothalamus of swine and humans was cloned and was shown to be the target of the GHSs. On the basis of its pharmacological and molecular characterization, this GPC-R defines a neuroendocrine pathway for the control of pulsatile GH release and supports the notion that the GHSs mimic an undiscovered hormone.