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Intraislet Ghrelin Signaling Does Not Regulate Insulin Secretion From Adult Mice.

ABSTRACT: Exogenous ghrelin reduces glucose-stimulated insulin secretion and endogenous ghrelin protects against hypoglycemia during starvation. Islet ?-cells produce ghrelin and ?-cells express growth hormone secretagogue receptor (GHSR), suggesting the possibility of a paracrine mechanism for islet ghrelin to reach high local concentrations and affect insulin secretion. GHSR has high constitutive activity and may act independently of ghrelin. The objective in this study was to determine whether an intraislet ghrelin-GHSR axis modulates insulin secretion and glucose metabolism using mouse models lacking ghrelin (Ghrl-/- ) or GHSR (Ghsr-/- ). Ghsr-/- and Ghsr+/+ mice had comparable islet ghrelin concentrations. Exogenous ghrelin decreased insulin secretion in perifused isolated islets in a GHSR-dependent manner. Islets isolated from Ghrl-/- or Ghsr-/- mice did not differ from controls in glucose-, alanine-, or GLP-1-stimulated insulin secretion during perifusion. Consistent with this finding, Ghrl-/- and Ghsr-/- male mice studied after either 6 or 16 h of fasting had blood glucose concentrations comparable with those of controls following intraperitoneal glucose, or insulin tolerance tests, or after mixed nutrient meals. Collectively, our data provide strong evidence against a paracrine ghrelin-GHSR axis mediating insulin secretion or glucose tolerance in lean, chow-fed adult mice.

SUBMITTER: Gray SM

PROVIDER: S-EPMC6702634 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Intraislet Ghrelin Signaling Does Not Regulate Insulin Secretion From Adult Mice.

Gray Sarah M SM Niu Jingjing J Zhang Amanda A Svendsen Berit B Campbell Jonathan E JE D'Alessio David A DA Tong Jenny J

Diabetes 20190614 9

Exogenous ghrelin reduces glucose-stimulated insulin secretion and endogenous ghrelin protects against hypoglycemia during starvation. Islet ε-cells produce ghrelin and δ-cells express growth hormone secretagogue receptor (GHSR), suggesting the possibility of a paracrine mechanism for islet ghrelin to reach high local concentrations and affect insulin secretion. GHSR has high constitutive activity and may act independently of ghrelin. The objective in this study was to determine whether an intra ...[more]

PMID: 31201280

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Project description:Suboptimal in utero environments such as poor maternal nutrition and gestational diabetes can impact fetal birth weight and the metabolic health trajectory of the adult offspring. Fetal growth is associated with alterations in placental mechanistic target of rapamycin (mTOR) signaling; it is reduced in fetal growth restriction and increased in fetal overgrowth. We previously reported that when metabolically challenged by a high-fat diet, placental mTORKO (mTORKOpl) adult female offspring develop obesity and insulin resistance, whereas placental TSC2KO (TSC2KOpl) female offspring are protected from diet-induced obesity and maintain proper glucose homeostasis. In the present study, we sought to investigate whether reducing or increasing placental mTOR signaling in utero alters the programming of adult offspring metabolic tissues preceding a metabolic challenge. Adult male and female mTORKOpl, TSC2KOpl, and respective controls on a normal chow diet were subjected to an acute intraperitoneal insulin injection. Upon insulin stimulation, insulin signaling via phosphorylation of Akt and nutrient sensing via phosphorylation of mTOR target ribosomal S6 were evaluated in the offspring liver, white adipose tissue, and skeletal muscle. Among tested tissues, we observed significant changes only in the liver signaling. In the male mTORKOpl adult offspring liver, insulin-stimulated phospho-Akt was enhanced compared to littermate controls. Basal phospho-S6 level was increased in the mTORKOpl female offspring liver compared to littermate controls and did not increase further in response to insulin. RNA sequencing of offspring liver identified placental mTORC1 programming-mediated differentially expressed genes. The expression of major urinary protein 1 (Mup1) was differentially altered in female mTORKOpl and TSC2KOpl offspring livers and we show that MUP1 level is dependent on overnutrition and fasting status. In summary, deletion of placental mTOR nutrient sensing in utero programs hepatic response to insulin action in a sexually dimorphic manner. Additionally, we highlight a possible role for hepatic and circulating MUP1 in glucose homeostasis that warrants further investigation.

Dataset Information

Intraislet Ghrelin Signaling Does Not Regulate Insulin Secretion From Adult Mice.

Publications

Intraislet Ghrelin Signaling Does Not Regulate Insulin Secretion From Adult Mice.

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