Islet insulin content and release are increased in male mice with elevated endogenous GH and IGF-I, without evidence of systemic insulin resistance or alterations in β-cell mass

Córdoba-Chacón, José; Majumdar, Neena; Pokala, Naveen; Gahete, Manuel D.; Kineman, Rhonda D.

doi:10.1016/j.ghir.2015.04.002

Cited by 10 publications

(7 citation statements)

References 47 publications

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“…hGH can bind and activate the mouse growth hormone receptor, which can have significant physiological consequences including somatotrophic and lactotrophic effects ( 28 ). Consistent with our observations in MIP-CreERT mice, a two- to threefold increase in circulating growth hormone in mice has been shown to increase islet insulin content ( 29 ), and transgenic mice expressing hGH under the metallothionein promoter have increased islet size and number ( 30 ). Furthermore, culture of β-cells with recombinant hGH increases β-cell replication, insulin secretion, and insulin biosynthesis ( 31 ).…”

Section: Discussionsupporting

confidence: 89%

Phenotypic Characterization of MIP-CreERT1Lphi Mice With Transgene-Driven Islet Expression of Human Growth Hormone

et al. 2015

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There is growing concern over confounding artifacts associated with β-cell–specific Cre-recombinase transgenic models, raising questions about their general usefulness in research. The inducible β-cell–specific transgenic (MIP-CreERT1Lphi) mouse was designed to circumvent many of these issues, and we investigated whether this tool effectively addressed concerns of ectopic expression and disruption of glucose metabolism. Recombinase activity was absent from the central nervous system using a reporter line and high-resolution microscopy. Despite increased pancreatic insulin content, MIP-CreERT mice on a chow diet exhibited normal ambient glycemia, glucose tolerance and insulin sensitivity, and appropriate insulin secretion in response to glucose in vivo and in vitro. However, MIP-CreERT mice on different genetic backgrounds were protected from high-fat/ streptozotocin (STZ)-induced hyperglycemia that was accompanied by increased insulin content and islet density. Ectopic human growth hormone (hGH) was highly expressed in MIP-CreERT islets independent of tamoxifen administration. Circulating insulin levels remained similar to wild-type controls, whereas STZ-associated increases in α-cell number and serum glucagon were significantly blunted in MIP-CreERT1Lphi mice, possibly due to paracrine effects of hGH-induced serotonin expression. These studies reveal important new insight into the strengths and limitations of the MIP-CreERT mouse line for β-cell research.

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Section: Discussionsupporting

confidence: 89%

Phenotypic Characterization of MIP-CreERT1Lphi Mice With Transgene-Driven Islet Expression of Human Growth Hormone

et al. 2015

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“…Furthermore, we found that GH positively influenced insulin secretion. Since in GHD patients, insulin sensitivity did not change over the years, the enhanced insulin secretion, as reflected by an increased IGI, should not be considered secondary to increased tissue resistance as usually observed, but a direct trophic action of GH on β-cells, as previously reported [8,9,10,12]. As a matter of fact, it is puzzling that ghrelin, which is a potent stimulator of GH release and feeding, owns a strong insulinostatic action [20].…”

Section: Discussionmentioning

confidence: 65%

“…Moreover, Cordoba-Chacon et al [12] showed in an animal model that elevated endogenous GH levels were associated with increased IGF-I and insulin levels, while whole-body insulin sensitivity remained normal and glucose tolerance improved [12]. Therefore, the author concluded 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.…”

Section: Introductionmentioning

confidence: 99%

The Influence of Growth Hormone Treatment on Glucose Homeostasis in GrowthHormone-Deficient Children: A Six-Year Follow-Up Study

Baronio

Mazzanti²,

Girtler³

et al. 2016

Horm Res Paediatr

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Background: Growth hormone (GH) influences glucose homeostasis by negatively affecting insulin sensitivity, leading to a compensatory increase in insulin secretion. It has recently been reported, in animals and humans, that GH might also stimulate insulin secretion by directly affecting the growth and function of pancreatic β-cells. The aim of this work was to longitudinally study the insulin sensitivity (HOMA-S), insulin secretion [insulinogenic index (IGI)] and capacity of β-cells to adapt to changes in insulin sensitivity [oral disposition index (ODI)] in GH-deficient (GHD) children under GH treatment. Methods: We studied 99 GHD (62 male, 37 female; age 8.9 ± 3.5 years) children for a median period of 6 years (range 1.5-16.2). Every year, our patients underwent an oral glucose tolerance test, which was used to calculate the HOMA-S, IGI and ODI. Results: Although HOMA-S remained unchanged, an increase in IGI and ODI was observed, becoming significant after 6 years of treatment (1.25 ± 1.28 vs. 2.35 ± 2.38, p < 0.05 and 0.57 ± 0.68 vs. 1.50 ± 1.92, p < 0.01, respectively). Conclusion: Our results suggest a positive influence of GH treatment on the β-cell secretory capacity in children with GH deficiency.

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“…Also, in control mice, HF-feeding increased body, liver and fat mass weight and elevated hepatic TAG content and plasma glucose, insulin and cholesterol levels, but plasma TAG and NEFA were reduced (Table 1). Although TAG and NEFA are reported to be elevated in HF-fed mice after an overnight fast, in the post-absorptive state (4h fasted mice at 1100h), TAG and NEFA levels are reported to be reduced (Cordoba-Chacon, et al 2014b; Cordoba-Chacon, et al 2015b; Guo, et al 2009; Horakova, et al 2016; Obrowsky, et al 2013), likely due to elevated insulin levels under these conditions.…”

Section: Resultsmentioning

confidence: 98%

Hepatocyte-specific, PPARγ-regulated mechanisms to promote steatosis in adult mice

Greenstein

Majumdar

Yang

et al. 2017

Journal of Endocrinology

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Peroxisome proliferator-activated receptor γ (PPARγ) is the target for thiazolidinones (TZDs), drugs that improve insulin sensitivity and fatty liver in humans and rodent models, related to a reduction in hepatic de novo lipogenesis (DNL). The systemic effects of TZDs are in contrast to reports suggesting hepatocyte-specific activation of PPARγ promotes DNL, triacylglycerol (TAG) uptake and fatty acid (FA) esterification. Since these hepatocyte-specific effects of PPARγ could counterbalance the positive therapeutic actions of systemic delivery of TZDs, the current study used a mouse model of adult-onset, liver (hepatocyte)-specific PPARγ knockdown (aLivPPARγkd). This model has advantages over existing congenital knockout models, by avoiding compensatory changes related to embryonic knockdown, thus better modeling the impact of altering PPARγ on adult physiology, where metabolic diseases most frequently develop. The impact of aLivPPARγkd on hepatic gene expression and endpoints in lipid metabolism was examined after 1 or 18wks (Chow-fed) or after 14wks of low- or high-fat [HF] diet. aLivPPARγkd reduced hepatic TAG content but did not impact endpoints in DNL or TAG uptake. However, aLivPPARγkd reduced the expression of the FA translocase (Cd36), in 18wk-Chow and HF-fed mice, associated with increased NEFA after HF-feeding. Also, aLivPPARγkd dramatically reduced Mogat1 expression, that was reflected by an increase in hepatic monoacylglycerol (MAG) levels, indicative of reduced MOGAT activity. These results, coupled with previous reports, suggest that Cd36-mediated FA uptake and MAG pathway-mediated FA esterification are major targets of hepatocyte PPARγ, where loss of this control explains in part the protection against steatosis observed after aLivPPARγkd.

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Islet insulin content and release are increased in male mice with elevated endogenous GH and IGF-I, without evidence of systemic insulin resistance or alterations in β-cell mass

Cited by 10 publications

References 47 publications

Phenotypic Characterization of MIP-CreERT1Lphi Mice With Transgene-Driven Islet Expression of Human Growth Hormone

Phenotypic Characterization of MIP-CreERT1Lphi Mice With Transgene-Driven Islet Expression of Human Growth Hormone

The Influence of Growth Hormone Treatment on Glucose Homeostasis in GrowthHormone-Deficient Children: A Six-Year Follow-Up Study

Hepatocyte-specific, PPARγ-regulated mechanisms to promote steatosis in adult mice

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