Intraislet glucagon signaling is critical for maintaining glucose homeostasis

Zhu, Lu; Dattaroy, Diptadip; Pham, Jonathan; Wang, Lingdi; Barella, Luiz F.; Cui, Yinghong; Wilkins, Kenneth J.; Roth, Bryan L.; Hochgeschwender, Ute; Matschinsky, Franz M.; Kaestner, Klaus H.; Doliba, Nicolai M.; Wess, Jürgen

doi:10.1172/jci.insight.127994

Cited by 112 publications

(139 citation statements)

References 42 publications

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“…Our findings corroborate recent findings from our group and others using in vitro systems to demonstrate that exogenous or endogenous glucagon stimulates insulin secretion and dictates β cell tone and by extension the glycemic set point (5)(6)(7). Moreover, inhibiting α cell function through a strategy invoking Gi-coupled DREADD (designer receptors exclusively activated by designer drugs) technology recapitulated the impaired insulin secretion in response to glucose or amino acids we previously described (5), while showing this impaired in vivo glucose tolerance (25). We have built on these recent observations in this paper, using mostly experiments in intact animals to demonstrate the physiologic relevance of glucagon as a β cell stimulus.…”

Section: Discussionsupporting

confidence: 91%

Glucagon lowers glycemia when β cells are active

Capozzi¹,

Wait²,

Koech³

et al. 2019

JCI Insight

127

106

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Section: Discussionsupporting

confidence: 91%

Glucagon lowers glycemia when β cells are active

Capozzi¹,

Wait²,

Koech³

et al. 2019

JCI Insight

127

106

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“…Through paracrine effects, cAMP signaling modulates glucose-stimulated insulin secretion 36 . Specifically, alpha cells release glucagon that signals on beta cells through the Gα s -coupled Glucagon receptor, increases cAMP levels and insulin secretion 37,38 . In parallel, delta cells secrete somatostatin that binds the G i -coupled somatostatin receptor 2 on beta cells, and decreases cAMP levels and insulin secretion 39 .…”

Section: Discussionmentioning

confidence: 99%

Regulated expression and function of the GABAB receptor in human pancreatic beta cell line and islets

Rachdi

Maugein

Pechberty

et al. 2020

Sci Rep

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G protein-coupled receptors are seven transmembrane signaling molecules that are involved in a wide variety of physiological processes. they constitute a large protein family of receptors with almost 300 members detected in human pancreatic islet preparations. However, the functional role of these receptors in pancreatic islets is unknown in most cases. We generated a new stable human beta cell line from neonatal pancreas. This cell line, named ECN90 expresses both subunits (GABBR1 and GABBR2) of the metabotropic GABA B receptor compared to human islet. In ECN90 cells, baclofen, a specific GABA B receptor agonist, inhibits cAMp signaling causing decreased expression of beta cellspecific genes such as MAFA and PCSK1, and reduced insulin secretion. We next demonstrated that in primary human islets, GABBR2 mRnA expression is strongly induced under cAMp signaling, while GABBR1 mRnA is constitutively expressed. We also found that induction and activation of the GABA B receptor in human islets modulates insulin secretion. Type 2 diabetes mellitus (T2DM) is the most common metabolic disease worldwide, affecting more than 350 million people. It is a multigenic disease showing increased insulin resistance progressively weakening pancreatic beta cell response. In patients with T2DM, both beta cell function and beta cell mass are decreased. Thus, understanding the regulation of beta cell function is critical to identify mechanisms underlying the development of T2DM 1. G protein-coupled receptors (GPCRs), which modulate a variety of physiological responses, are potential targets for anti-diabetic compounds 2. These seven transmembrane receptors are coupled to heterotrimeric G proteins, such as Gα s , Gα i/o , Gα q/11 and Gα 12/13. GPCR coupling to Gα s stimulates adenylyl cyclase, which increases cyclic AMP levels while coupling through Gα i/o inhibits adenylyl cyclase activation 3,4. Gamma aminobutyric acid (GABA) is an inhibitory neurotransmitter that acts in an autocrine and/or paracrine manner by activating GABA A and GABA B receptors at the plasma membrane. The GABA A receptor is a five-subunits chloride ion channel whereas the GABA B receptor (also known as the metabotropic receptor) is a GPCR heterodimer composed of two subunits, GABBR1 and GABBR2. The GABBR1 subunit binds GABA, whereas the GABBR2 subunit is responsible for Gα i/o-protein-coupled activation, leading to inhibition of adenylyl cyclase and consequently, to decreased cAMP signaling. Previous studies demonstrated that the presence of both subunits is necessary for GABA-induced signaling in individual cells 5,6. GABA plays major roles in the brain. Interestingly, beta cells express glutamic acid decarboxylase (GAD1/GAD67 in mice and GAD2/GAD65 in human) the enzyme involved in the synthesis of GABA from glutamate 7. However, how GABA signals in islets and particularly in human beta cells has not been fully explored. Whereas the expression of GABA A receptors in human islets and their altered expression and sensitivity in islets from T2DM patients has been re...

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“…Although controversial, α cells have been found to express the prohormone convertase 1/3 (PC1/3) that is required for posttranslational processing of proglucagon to GLP-1 (and other peptides including GLP-2) (17,29), and pancreatic levels of active GLP-1 increase with nutrient stimulation (17,30). However, recent perifusion experiments found that glucagon also acts on β cell GLP-1R, and not glucagon receptors, to regulate insulin secretion in response to amino acids (31)(32)(33). Together with our in vivo data, these data indicate that a major function of proglucagon peptides is to regulate insulin secretion in a paracrine fashion and this signaling is important in regulation of glucose tolerance.…”

Section: Discussionmentioning

confidence: 99%