Metabolic Effects of Pertussis Sensitization in Mice and Rats

Gulbenkian, A.; Schobert, L.; Nixon, C. W.; Tabachnick, I. I. A.

doi:10.1210/endo-83-4-885

Cited by 53 publications

(39 citation statements)

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“…First, acute dosing of rodents with pertussis holotoxin has long been known to increase plasma insulin, and treatment of cultured islets and β cell lines with pertussis enhances insulin secretion (8)(9)(10)(11). This gain-of-function phenotype in β cells offered an opportunity to determine whether long-term expression of PTX in vivo might negatively affect the differentiation, development, or health of cells and tissues and whether it could indeed produce appropriate cell type-specific, cell-autonomous, and signaling pathway-specific phenotypes.…”

Section: Introductionmentioning

confidence: 99%

Probing cell type–specific functions of Gi in vivo identifies GPCR regulators of insulin secretion

Regard¹,

Kataoka²,

Cano³

et al. 2007

J. Clin. Invest.

167

242

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The in vivo roles of the hundreds of mammalian G protein-coupled receptors (GPCRs) are incompletely understood. To explore these roles, we generated mice expressing the S1 subunit of pertussis toxin, a known inhibitor of G i/o signaling, under the control of the ROSA26 locus in a Cre recombinase-dependent manner (ROSA26 PTX ). Crossing ROSA26 PTX mice to mice expressing Cre in pancreatic β cells produced offspring with constitutive hyperinsulinemia, increased insulin secretion in response to glucose, and resistance to dietinduced hyperglycemia. This phenotype underscored the known importance of G i/o and hence of GPCRs for regulating insulin secretion. Accordingly, we quantified mRNA for each of the approximately 373 nonodorant GPCRs in mouse to identify receptors highly expressed in islets and examined the role of several. We report that 3-iodothyronamine, a thyroid hormone metabolite, could negatively and positively regulate insulin secretion via the G i -coupled α 2A -adrenergic receptor and the G s -coupled receptor Taar1, respectively, and proteaseactivated receptor-2 could negatively regulate insulin secretion and may contribute to physiological regulation of glucose metabolism. The ROSA26 PTX system used in this study represents a new genetic tool to achieve tissue-specific signaling pathway modulation in vivo that can be applied to investigate the role of G i/o -coupled GPCRs in multiple cell types and processes.

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Section: Introductionmentioning

confidence: 99%

Probing cell type–specific functions of Gi in vivo identifies GPCR regulators of insulin secretion

Regard¹,

Kataoka²,

Cano³

et al. 2007

J. Clin. Invest.

167

242

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“…Activation of pathways mediated by G s and/or G q/11 stimulates insulin release from β cells (3,4). The involvement of G i /G o proteins as inhibitors of insulin secretion from β cells was originally uncovered in studies on the Bordetella pertussis toxin (PTX) in animals and cells (5,6). Previously called islet-activating protein (IAP), PTX was shown to lower glucose levels in the bloodstream by increasing insulin secretion from β cells (7).…”

mentioning

confidence: 99%

Augmented glucose-induced insulin release in mice lacking G _o2 , but not G _o1 or G _i proteins

Wang

Park

Bajpayee

et al. 2011

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

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Insulin secretion by pancreatic β cells is a complex and highly regulated process. Disruption of this process can lead to diabetes mellitus. One of the various pathways involved in the regulation of insulin secretion is the activation of heterotrimeric G proteins. Bordetella pertussis toxin (PTX) promotes insulin secretion, suggesting the involvement of one or more of three G i and/or two G o proteins as suppressors of insulin secretion from β cells. However, neither the mechanism of this inhibitory modulation of insulin secretion nor the identity of the G i/o proteins involved has been elucidated. Here we show that one of the two splice variants of G o , G o2 , is a key player in the control of glucose-induced insulin secretion by β cells. Mice lacking G o2 α, but not those lacking α subunits of either G o1 or any G i proteins, handle glucose loads more efficiently than wild-type (WT) mice, and do so by increased glucose-induced insulin secretion. We thus provide unique genetic evidence that the G o2 protein is a transducer in an inhibitory pathway that prevents damaging oversecretion of insulin.D iabetes mellitus is characterized by abnormalities in insulin secretion that may be either a primary defect, as seen in type I diabetes, or a secondary defect, where secretion is inadequate to overcome primary insulin resistance seen in type II diabetes. In either case, individuals are hyperglycemic. Insulin is the master controller of glucose metabolism, and its release from β cells is tightly regulated. Many factors, including hormones, neuropeptides, and neurotransmitters regulate insulin secretion by activating heterotrimeric G proteins, which can control the output of insulin in response to physiological demands (1, 2). Activation of pathways mediated by G s and/or G q/11 stimulates insulin release from β cells (3, 4). The involvement of G i /G o proteins as inhibitors of insulin secretion from β cells was originally uncovered in studies on the Bordetella pertussis toxin (PTX) in animals and cells (5, 6). Previously called islet-activating protein (IAP), PTX was shown to lower glucose levels in the bloodstream by increasing insulin secretion from β cells (7). The enhanced secretion resulted from the removal of tonic inhibition exerted by neurotransmitters/hormones, including adrenaline (8), galanin (9), and ghrelin (10). PTX catalyzes the ADP ribosylation of a carboxyl-terminal cysteine present in the α subunits of the G protein subgroup now referred to as G i /G o (11). This event causes these G proteins to become uncoupled from receptors and thereby disrupts the signal transduction process. The nonsensory PTX-sensitive G i /G o G proteins encompass three G i 's (G i1 , G i2 , and G i3 ), and two G o 's (G o1 and G o2 ). The α subunits of G i and G o display extensive homology and are functionally similar as they can be activated by the same or similar receptors and appear to signal to partially overlapping sets of effectors (12). This has raised questions whether the individual G i and G o proteins function dis...

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“…A hypo glycemic effect of pertussis vaccine has been recognized by several workers (Szentivanyi et al 1963;Gulbenkian et al 1968;Dhar and West 1972) since the report of Parfentjev and Schleyer (1949). The recent discovery that an active protein, reducing blood glucose to normal level, exists in the culture media of Bordetella pertussis (Yajima et al 1978a) has stimulated investigations on the nature of the active substance named islet-activating protein (IAP).…”

mentioning

confidence: 98%

Effects of islet-activating protein (IAP) on blood glucose and plasma insulin in healthy volunteers (Phase 1 studies).

Toyota

Kai

Kakizaki

et al. 1980

Tohoku J. Exp. Med.

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Metabolic Effects of Pertussis Sensitization in Mice and Rats

Cited by 53 publications

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Probing cell type–specific functions of Gi in vivo identifies GPCR regulators of insulin secretion

Probing cell type–specific functions of Gi in vivo identifies GPCR regulators of insulin secretion

Augmented glucose-induced insulin release in mice lacking G _o2 , but not G _o1 or G _i proteins

Effects of islet-activating protein (IAP) on blood glucose and plasma insulin in healthy volunteers (Phase 1 studies).

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Metabolic Effects of Pertussis Sensitization in Mice and Rats

Cited by 53 publications

References 0 publications

Probing cell type–specific functions of Gi in vivo identifies GPCR regulators of insulin secretion

Probing cell type–specific functions of Gi in vivo identifies GPCR regulators of insulin secretion

Augmented glucose-induced insulin release in mice lacking G o2 , but not G o1 or G i proteins

Effects of islet-activating protein (IAP) on blood glucose and plasma insulin in healthy volunteers (Phase 1 studies).

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Augmented glucose-induced insulin release in mice lacking G _o2 , but not G _o1 or G _i proteins