G-protein-coupled receptors and islet function—Implications for treatment of type 2 diabetes

Winzell, Maria Sörhede; Åhrén, Bo

doi:10.1016/j.pharmthera.2007.08.002

Cited by 161 publications

(97 citation statements)

References 146 publications

(161 reference statements)

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“…Increased insulin-releasing capacity of pancreatic islets from CLA-fed mice has been disclosed (34 -36); however, a molecular explanation for the acute insulinotropic action of CLAs is still lacking. In this study, we present several lines of evidence that acute insulinotropic effects of CLAs are mediated via activation of the ␤-cell-specific G proteincoupled receptor FFA1, an emerging therapeutic target to treat type 2 diabetes (15,16,21,27,37,38). First, increase of [Ca 2ϩ ] i and inositol phosphate production in response to CLAs was consistently observed in FFA1-expressing cells regardless of the cellular background, whereas it was not observed in cells lacking FFA1.…”

Section: Discussionmentioning

confidence: 81%

Conjugated Linoleic Acids Mediate Insulin Release through Islet G Protein-coupled Receptor FFA1/GPR40

Schmidt

Liebscher

Merten

et al. 2011

Journal of Biological Chemistry

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Among dietary components, conjugated linoleic acids (CLAs) have attracted considerable attention as weight loss supplements in the Western world because they reduce fat stores and increase muscle mass. However, a number of adverse effects are also ascribed to the intake of CLAs such as aggravation of insulin resistance and the risk of developing diabetes. However, the mechanisms accounting for the effects of CLAs on glucose homeostasis are incompletely understood. Herein we provide evidence that CLAs specifically activate the cell surface receptor FFA1, an emerging therapeutic target to treat type 2 diabetes. Using different recombinant cellular systems engineered to stably express FFA1 and a set of diverse functional assays including the novel, label-free non-invasive dynamic mass redistribution technology (Corning Epic biosensor), both CLA isomers cis-9, trans-11-CLA and trans-10, cis-12-CLA were found to activate FFA1 in vitro at concentrations sufficient to also account for FFA1 activation in vivo. Each CLA isomer markedly increased glucose-stimulated insulin secretion in insulin-producing INS-1E cells that endogenously express FFA1 and in primary pancreatic ␤-cells of wild type but not FFA1 ؊/؊ knock-out mice. Our findings establish a clear mechanistic link between CLAs and insulin production and identify the cell surface receptor FFA1 as a molecular target for CLAs, explaining their acute stimulatory effects on insulin secretion in vivo. CLAs are also revealed as insulinotropic components in widely used nutraceuticals, a finding with significant implication for development of FFA1 modulators to treat type 2 diabetes.

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Section: Discussionmentioning

confidence: 81%

Conjugated Linoleic Acids Mediate Insulin Release through Islet G Protein-coupled Receptor FFA1/GPR40

Schmidt

Liebscher

Merten

et al. 2011

Journal of Biological Chemistry

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“…Therefore, GLP-1 has been proposed as a potential therapeutic target for the treatment of patients with type 2 diabetes mellitus. The biological actions of GLP-1 on pancreatic cells are mainly mediated by the high-affinity GLP-1 receptor (GLP-1R) (Winzell and Ahrén 2007). GLP-1R is expressed not only in the pancreas, gut and hypothalamus, but also in the kidney (Bullock et al 1996).…”

Section: Introductionmentioning

confidence: 99%

The Glucagon-Like Peptide-1 Receptor Agonist, Liraglutide, Attenuates the Progression of Overt Diabetic Nephropathy in Type 2 Diabetic Patients

Imamura

Hirai

2013

Tohoku J. Exp. Med.

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Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Glucagon-like peptide-1 (GLP-1) is one of the incretins, gut hormones released from the intestine in response to food intake. GLP-1 receptor (GLP-1R) agonists have been used to treat type 2 diabetes. Here, we studied the effect of the administration of a GLP-1R agonist, liraglutide, on proteinuria and the progression of overt DN in type 2 diabetic patients. Twenty-three type 2 diabetic patients with overt DN, who had already been treated with blockade of renin-angiotensin system under dietary sodium restriction, were given liraglutide for a period of 12 months. Treatment with liraglutide caused a significant decrease in HbA1c from 7.4 ± 0.2% to 6.9 ± 0.3% (p = 0.04), and in body mass index (BMI) from 27.6 ± 0.9 kg/m 2 to 26.5 ± 0.8 kg/m 2 after 12 months (p < 0.001), while systolic blood pressure did not change. The progression of DN was determined as the rate of decline in estimated glomerular filtration rate (eGFR). The 12-month administration of liraglutide caused a significant decrease in proteinuria from 2.53 ± 0.48 g/g creatinine to 1.47 ± 0.28 g/g creatinine (p = 0.002). The administration of liraglutide also substantially diminished the rate of decline in eGFR from 6.6 ± 1.5 mL/min/1.73 m 2 /year to 0.3 ± 1.9 mL/min/1.73 m 2 /year (p = 0.003). Liraglutide can be used not only for reducing HbA1c and BMI, but also for attenuating the progression of nephropathy in type 2 diabetic patients.

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“…Insulin secretion can be modulated through cAMP-dependent and -independent pathways (1,20). Activation of G s in pancreatic β cells enhances insulin release through an adenylyl cyclase/ cAMP-mediated mechanism.…”

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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G-protein-coupled receptors and islet function—Implications for treatment of type 2 diabetes

Cited by 161 publications

References 146 publications

Conjugated Linoleic Acids Mediate Insulin Release through Islet G Protein-coupled Receptor FFA1/GPR40

Conjugated Linoleic Acids Mediate Insulin Release through Islet G Protein-coupled Receptor FFA1/GPR40

The Glucagon-Like Peptide-1 Receptor Agonist, Liraglutide, Attenuates the Progression of Overt Diabetic Nephropathy in Type 2 Diabetic Patients

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

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G-protein-coupled receptors and islet function—Implications for treatment of type 2 diabetes

Cited by 161 publications

References 146 publications

Conjugated Linoleic Acids Mediate Insulin Release through Islet G Protein-coupled Receptor FFA1/GPR40

Conjugated Linoleic Acids Mediate Insulin Release through Islet G Protein-coupled Receptor FFA1/GPR40

The Glucagon-Like Peptide-1 Receptor Agonist, Liraglutide, Attenuates the Progression of Overt Diabetic Nephropathy in Type 2 Diabetic Patients

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

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