Effects of chronic glucagon administration on cholesterol and bile acid metabolism

Guettet, Catherine; Mathé, Denis; Riottot, Michel; Lutton, C.

doi:10.1016/0005-2760(88)90283-4

Cited by 33 publications

(33 citation statements)

References 28 publications

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“…This suggests that glucagon may play an important role in causing hyperglycaemia and, therefore, may contribute to increased insulin resistance in early Type 2 diabetes [2,31]. Indeed, many previous studies in humans or animals have demonstrated that glucagon administration for several hours or days was associated with or without increased fasting blood glucose levels and impaired glucose tolerance [11][12][13]. However, it has been very complicated to determine whether glucagon plays a direct role in these responses, because it is difficult to infuse glucagon to induce hyperglucagonaemia and then block its effects with its receptor antagonist [Des-His 1 -Glu 9 ]glucagon in human subjects for weeks or months.…”

Section: Discussionmentioning

confidence: 99%

“…Most previous studies have chronically infused (or injected) glucagon in humans or animals for only a few minutes, hours or days to determine the effects of glucagon on blood glucose levels, serum insulin and glucagon responses, hepatic glucose production and tissue uptake of glucose [6,[11][12][13]. None of these studies have lasted long enough to determine whether long-term hyperglucagonaemia may induce target tissue injury in a human or animal model of Type 2 diabetes.…”

Section: Introductionmentioning

confidence: 99%

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Long-term hyperglucagonaemia induces early metabolic and renal phenotypes of Type 2 diabetes in mice

Liao

Zhuo

2008

Clinical Science

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Clinical studies have shown that patients with early Type 2 diabetes often have elevated serum glucagon rather than insulin deficiency. Imbalance of insulin and glucagon in favouring the latter may contribute to impaired glucose tolerance, persistent hyperglycaemia, microalbuminuria and glomerular injury. In the present study, we tested the hypothesis that long-term glucagon infusion induces early metabolic and renal phenotypes of Type 2 diabetes in mice by activating glucagon receptors. Five groups of adult male C57BL/6J mice were treated with vehicle, glucagon alone (1 μg/h via an osmotic minipump, intraperitoneally), glucagon plus the glucagon receptor antagonist [Des-His 1 -Glu 9 ]glucagon (5 μg/h via an osmotic minipump), [Des-His 1 -Glu 9 ]glucagon alone or a high glucose load alone (2 % glucose in the drinking water) for 4 weeks. Glucagon infusion increased serum glucagon by 129 % (P < 0.05), raised systolic BP (blood pressure) by 21 mmHg (P < 0.01), elevated fasting blood glucose by 42 % (P < 0.01), impaired glucose tolerance (P < 0.01), increased the kidney weight/body weight ratio (P < 0.05) and 24 h urinary albumin excretion by 108 % (P < 0.01) and induced glomerular mesangial expansion and extracellular matrix deposition. These responses were associated with marked increases in phosphorylated ERK1/2 (extracellular-signalregulated kinase 1/2) and Akt signalling proteins in the liver and kidney (P < 0.01). Serum insulin did not increase proportionally. Concurrent administration of [Des-His 1 -Glu 9 ]glucagon with glucagon significantly attenuated glucagon-increased BP, fasting blood glucose, kidney weight/body weight ratio and 24 h urinary albumin excretion. [Des-His 1 -Glu 9 ]glucagon also improved glucagoninpaired glucose tolerance, increased serum insulin by 56 % (P < 0.05) and attenuated glomerular injury. However, [Des-His 1 -Glu 9 ]glucagon or high glucose administration alone did not elevate fasting blood glucose levels, impair glucose tolerance or induce renal injury. These results demonstrate for the first time that long-term hyperglucagonaemia in mice induces early metabolic and renal phenotypes of Type 2 diabetes by activating glucagon receptors. This supports the idea that glucagon receptor blockade may be beneficial in treating insulin resistance and Type 2 diabetic renal complications.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Long-term hyperglucagonaemia induces early metabolic and renal phenotypes of Type 2 diabetes in mice

Liao

Zhuo

2008

Clinical Science

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“…Overexpression of hepatic SR-BI leads to reduced plasma HDL levels (7,8), which supports the hypothesis that increased SR-BI expression is responsible for reduced plasma HDL levels. Furthermore, glucagon was shown to enhance cholesterol uptake into bile in rats (36). HDL cholesterol is known to be a major substrate source for bile acid production in both rats and humans (37).…”

Section: Discussionmentioning

confidence: 99%

Regulation of SR-BI protein levels by phosphorylation of its associated protein, PDZK1

Nakamura

Shibata

Nishimoto-Shibata

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Scavenger receptor class B type I (SR-BI) is a high-density lipoprotein (HDL) receptor that mediates the selective uptake of HDL cholesterol and cholesterol secretion into bile in the liver. Previously, we identified an SR-BI-associated protein, termed PDZK1, from rat liver membrane extracts. PDZK1 contains four PSD-95͞ Dlg͞ZO-1 (PDZ) domains, the first of which in the N-terminal region is responsible for the association with SR-BI. PDZK1 controls hepatic SR-BI expression in a posttranscriptional fashion both in cell culture and in vivo. In this study, we demonstrated that the C-terminal region of PDZK1 is crucial for up-regulating SR-BI protein expression. Metabolic labeling experiments and phosphoamino acid analysis revealed that PDZK1 is phosphorylated at Ser residues within this region. Point-mutation analysis demonstrated that PDZK1 is phosphorylated at Ser-509. Interestingly, a mutant PDZK1, in which Ser-509 was replaced with Ala, lost the ability to up-regulate SR-BI protein. We identified Ser-509 of PDZK1 as the residue that is phosphorylated by the cAMP-dependent PKA in vitro as well as in cell culture. Ser-509 of PDZK1 in rat liver was also phosphorylated, as shown by an Ab that specifically detects phosphorylated Ser-509. Administration of glucagon to Wistar rats increased PDZK1 phosphorylation as well as hepatic SR-BI and PDZK1 expression while it decreased plasma HDL levels, indicating that PDZK1 phosphorylation is hormonally regulated. These findings suggest that phosphorylation of PDZK1 has an important role in the regulation of hepatic SR-BI expression and, thus, influences plasma HDL levels.glucagon ͉ high-density lipoprotein ͉ PKA

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“…In animal models, glucagon has potent hypolipidemic actions (Eaton 1973, Guettet et al 1991, Bobe et al 2003. Glucagon decreases triglyceride and very-LDL release by the liver (Guettet et al 1989, Bobe et al 2003, reduces plasma cholesterol (Guettet et al 1988(Guettet et al ,1989(Guettet et al , 1991, and increases b-oxidation (Prip-Buus et al 1990). Glucagon action on lipid metabolism is mediated through AMPK-, p38 MAPK-, PPARa-, Foxa2-, and FGF21-dependent mechanisms (Longuet et al 2008, Berglund et al 2010, von Meyenn et al 2013).…”

Section: Role Of Glucagon In Glucose and Lipid Homeostasismentioning

confidence: 99%

Lack of glucagon receptor signaling and its implications beyond glucose homeostasis

Charron¹,

Vuguin²

2015

Journal of Endocrinology

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Glucagon action is transduced by a G protein-coupled receptor located in liver, kidney, intestinal smooth muscle, brain, adipose tissue, heart, pancreatic b-cells, and placenta. Genetically modified animal models have provided important clues about the role of glucagon and its receptor (Gcgr) beyond glucose control. The PubMed database was searched for articles published between 1995 and 2014 using the key terms glucagon, glucagon receptor, signaling, and animal models. Lack of Gcgr signaling has been associated with: i) hypoglycemic pregnancies, altered placentation, poor fetal growth, and increased fetal-neonatal death; ii) pancreatic glucagon cell hyperplasia and hyperglucagonemia; iii) altered body composition, energy state, and protection from diet-induced obesity; iv) impaired hepatocyte survival; v) altered glucose, lipid, and hormonal milieu; vi) altered metabolic response to prolonged fasting and exercise; vii) reduced gastric emptying and increased intestinal length; viii) altered retinal function; and ix) prevention of the development of diabetes in insulin-deficient mice. Similar phenotypic findings were observed in the hepatocyte-specific deletion of Gcgr. Glucagon action has been involved in the modulation of sweet taste responsiveness, inotropic and chronotropic effects in the heart, satiety, glomerular filtration rate, secretion of insulin, cortisol, ghrelin, GH, glucagon, and somatostatin, and hypothalamic signaling to suppress hepatic glucose production. Glucagon (a) cells under certain conditions can transdifferentiate into insulin (b) cells. These findings suggest that glucagon signaling plays an important role in multiple organs. Thus, treatment options designed to block Gcgr activation in diabetics may have implications beyond glucose homeostasis.

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Effects of chronic glucagon administration on cholesterol and bile acid metabolism

Cited by 33 publications

References 28 publications

Long-term hyperglucagonaemia induces early metabolic and renal phenotypes of Type 2 diabetes in mice

Long-term hyperglucagonaemia induces early metabolic and renal phenotypes of Type 2 diabetes in mice

Regulation of SR-BI protein levels by phosphorylation of its associated protein, PDZK1

Lack of glucagon receptor signaling and its implications beyond glucose homeostasis

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