Cordoba-Chacon Jose, Majumdar Neena, Pokala Naveen K, Gahete Manuel D, Kineman Rhonda D
Research and Development Division, Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA; Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, IL 60612, USA.
Research and Development Division, Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA; Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, IL 60612, USA; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, 14014, Spain; Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/Hospital Universitario Reina Sofia, Córdoba, 14014, Spain; CIBER de la Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, 14014, Spain.
Growth Horm IGF Res. 2015 Aug;25(4):189-95. doi: 10.1016/j.ghir.2015.04.002. Epub 2015 Apr 17.
It is clear that elevations in circulating GH can lead to an increase in insulin levels. This increase in insulin may be due to GH-mediated insulin resistance and enhanced lipolysis. However, there is also in vitro and in vivo evidence that GH acts directly to increase β-cell proliferation and insulin production. Our laboratory recently developed an animal model with elevated endogenous GH levels associated with a small (25%), but significant, increase in IGF-I (HiGH mice). As expected, insulin levels were elevated in HiGH mice; however, whole body insulin sensitivity was not altered and glucose tolerance was improved. This metabolic phenotype suggests that modest elevations in circulating GH and IGF-I may enhance β-cell mass and/or function, in the absence of systemic insulin resistance, thus improving glucose homeostasis.
To determine if β-cell mass and/or function is altered in HiGH mice.
Male HiGH mice and their littermate controls were fed a low-fat or high-fat diet. Body composition and circulating metabolic endpoints were monitored overtime. The pancreas was recovered and processed for assessment of β-cell mass or in vitro basal and glucose-stimulated insulin secretion.
HiGH mice showed elevated circulating insulin and normal glucose levels, while non-esterified FFA levels and triglycerides were reduced or normal, depending on diet and age. β-cell mass did not differ between HiGH and control mice, within diet. However, islets from HiGH mice contained and released more insulin under basal conditions, as compared to control islets, while the relative glucose-stimulated insulin release did not differ.
Taken together, these results suggest moderate elevations in circulating GH and IGF-I can directly increase basal insulin secretion without impacting β-cell mass, independent of changes in whole body insulin sensitivity and hyperlipidemia.
显然，循环中生长激素（GH）水平升高可导致胰岛素水平升高。胰岛素的这种升高可能是由于GH介导的胰岛素抵抗和脂解增强。然而，也有体外和体内证据表明，GH直接作用可增加β细胞增殖和胰岛素生成。我们实验室最近开发了一种动物模型，其内源GH水平升高，同时胰岛素样生长因子-I（IGF-I）有小幅（25%）但显著的增加（高GH小鼠）。正如预期的那样，高GH小鼠的胰岛素水平升高；然而，全身胰岛素敏感性未改变，葡萄糖耐量得到改善。这种代谢表型表明，在没有全身胰岛素抵抗的情况下，循环中适度升高的GH和IGF-I可能增强β细胞质量和/或功能，从而改善葡萄糖稳态。
确定高GH小鼠的β细胞质量和/或功能是否发生改变。
雄性高GH小鼠及其同窝对照小鼠分别喂食低脂或高脂饮食。随时间监测身体组成和循环代谢终点。取出胰腺并进行处理，以评估β细胞质量或体外基础及葡萄糖刺激的胰岛素分泌。
高GH小鼠循环胰岛素水平升高，血糖水平正常，而非酯化脂肪酸水平和甘油三酯水平根据饮食和年龄降低或正常。在相同饮食条件下，高GH小鼠和对照小鼠的β细胞质量没有差异。然而，与对照胰岛相比，高GH小鼠的胰岛在基础条件下含有并释放更多胰岛素，而相对葡萄糖刺激的胰岛素释放没有差异。
综上所述，这些结果表明，循环中适度升高的GH和IGF-I可直接增加基础胰岛素分泌，而不影响β细胞质量，与全身胰岛素敏感性和高脂血症的变化无关。
