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Recent studies have found that glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism can enhance the metabolic efficacy of glucagon-like peptide–1 receptor agonist treatment by promoting both weight-dependent and -independent improvements on systemic insulin sensitivity. These findings have prompted new investigations aimed at better understanding the broad metabolic benefit of GIPR activation. Herein, we determined whether GIPR agonism favorably influenced the pharmacologic efficacy of the insulin-sensitizing thiazolidinedione (TZD) rosiglitazone in obese insulin-resistant (IR) mice. Genetic and pharmacological approaches were used to examine the role of GIPR signaling on rosiglitazone-induced weight gain, hyperphagia, and glycemic control. RNA sequencing was conducted to uncover potential mechanisms by which GIPR activation influences energy balance and insulin sensitivity. In line with previous findings, treatment with rosiglitazone induced the mRNA expression of the GIPR in white and brown fat. However, obese GIPR-null mice dosed with rosiglitazone had equivalent weight gain to that of wild-type (WT) animals. Strikingly, chronic treatment of obese IR WT animals with a long-acting GIPR agonist prevented rosiglitazone-induced weight-gain and hyperphagia, and it enhanced the insulin-sensitivity effect of this TZD. The systemic insulin sensitization was accompanied by increased glucose disposal in brown adipose tissue, which was underlined by the recruitment of metabolic and thermogenic genes. These findings suggest that GIPR agonism can counter the negative consequences of rosiglitazone treatment on body weight and adiposity, while improving its insulin-sensitizing efficacy at the same time. Article Highlights: Body weight gain resulting from treatment with the insulin-sensitizing thiazolidinedione rosiglitazone does not require the glucose-dependent insulinotropic polypeptide receptor (GIPR). Treatment with a GIPR agonist prevents the hyperphagic and obesogenic activity of rosiglitazone. Activation of the GIPR improves the insulin-sensitizing actions of rosiglitazone. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide 1 (GLP-1) is known to suppress glucagon secretion, but the mechanism by which GLP-1 exerts this effect is unclear. In this study, we demonstrated GLP-1 receptor (GLP-1R) expression in α-cells using both antibody-dependent and antibody-independent strategies. A novel α-cell-specific GLP-1R knockout (αGLP-1R-/-) mouse model was created and used to investigate its effects on glucagon secretion and glucose metabolism. Male and female αGLP-1R-/- mice both showed higher nonfasting glucagon levels than their wild-type littermates, whereas insulin and GLP-1 levels remained similar. Female αGLP-1R-/- mice exhibited mild glucose intolerance after an intraperitoneal glucose administration and showed increased glucagon secretion in response to a glucose injection compared with the wild-type animals. Furthermore, using isolated islets, we confirmed that αGLP-1R deletion did not interfere with β-cell function but affected glucagon secretion in a glucose-dependent bidirectional manner: the αGLP-1R-/- islets failed to inhibit glucagon secretion at high glucose and failed to stimulate glucagon secretion at very low glucose condition. More interestingly, the same phenomenon was recapitulated in vivo under hypoglycemic and postprandial (fed) conditions. Taken together, this study demonstrates that GLP-1 (via GLP-1R in α-cells) plays a bidirectional role, either stimulatory or inhibitory, in glucagon secretion depending on glucose levels. [ABSTRACT FROM AUTHOR]

Therapeutic engineering of glucagon-like peptide 1 (GLP-1) has enabled development of new medicines to treat type 2 diabetes. These injectable analogs achieve robust glycemic control by increasing concentrations of "GLP-1 equivalents" (∼50 pmol/L). Similar levels of endogenous GLP-1 occur after gastric bypass surgery, and mechanistic studies indicate glucose lowering by these procedures is driven by GLP-1. Therefore, because of the remarkable signaling and secretory capacity of the GLP-1 system, we sought to discover mechanisms that increase GLP-1 pharmacologically. To study active GLP-1, glucose-dependent insulinotropic polypeptide receptor (Gipr)-deficient mice receiving background dipeptidyl peptidase 4 (DPP4) inhibitor treatment were characterized as a model for evaluating oral agents that increase circulating GLP-1. A somatostatin receptor 5 antagonist, which blunts inhibition of GLP-1 release, and agonists for TGR5 and GPR40, which stimulate GLP-1 secretion, were investigated alone and in combination with the DPP4 inhibitor sitagliptin; these only modestly increased GLP-1 (∼5-30 pmol/L). However, combining molecules to simultaneously intervene at multiple regulatory nodes synergistically elevated active GLP-1 to unprecedented concentrations (∼300-400 pmol/L), drastically reducing glucose in Gipr null and Leprdb/db mice in a GLP-1 receptor-dependent manner. Our studies demonstrate that complementary pathways can be engaged to robustly increase GLP-1 without invasive surgical or injection regimens. [ABSTRACT FROM AUTHOR]

A correction is presented to the article related to GLP-1 Receptor in Pancreatic a-Cells Regulates Glucagon Secretion in a Glucose-Dependent Bidirectional Manner which published in 2019 issue of the periodical.

Rimonabant (SR-141716A) clinical trials demonstrate that antagonism of the CB1 cannabinoid receptor can result in better glucose control as indicated by a reduction in HbA[sub 1c] levels and an improvement in insulin sensitization in treated patients. These effects may be mediated in part through regulation of white adipose tissue lipolysis, the catabolic process whereby triglyceride stores are hydrolyzed to fatty acids and glycerol. In adipose tissue, catecholamine binding to β-adrenergic receptors activates adenylate cyclase through a G[sub s]-coupled mechanism, thereby increasing intracellular cAMP levels. Subsequent activation of protein kinase A by cAMP results in phosphorylation and activation of hormone-sensitive lipase, the rate-limiting enzyme in lipolysis. To explore the effect of cannabinoid modulation of adenlyate cyclase activity, an HTRF (Homogenous Time-Resolved Fluorescence) assay was established to measure the concentration of intracellular cAMP. The CB1 receptor agonist, R(+)-WIN55, 212-2, inhibited forskolin-stimulated cAMP production in CHO cells expressing the CB1 receptor, and SR-141716A blocked this effect in a dose-dependent manner. Consistent with a G[sub i]-coupling mechanism, pertussis toxin attenuated the CB1 receptor agonist-mediated inhibition but not the stimulation of cAMP production. Similar to the in vitro results, CB1 receptor agonist treatment of ob/ob mice acutely inhibited fasting-induced levels of plasma FFAs, an effect that was blocked by SR-141716A administration. Together, these data provide additional evidence that CB1 receptor antagonism regulates adipose tissue lipid metabolism. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide 1 (GLP-1) is known to suppress glucagon secretion, but the mechanism by which GLP-1 exerts this effect is unclear. In this study, we demonstrated GLP-1 receptor (GLP-1R) expression in α-cells using both antibody-dependent and antibody-independent strategies. A novel α-cell-specific GLP-1R knockout (αGLP-1R -/- ) mouse model was created and used to investigate its effects on glucagon secretion and glucose metabolism. Male and female αGLP-1R -/- mice both showed higher nonfasting glucagon levels than their wild-type littermates, whereas insulin and GLP-1 levels remained similar. Female αGLP-1R -/- mice exhibited mild glucose intolerance after an intraperitoneal glucose administration and showed increased glucagon secretion in response to a glucose injection compared with the wild-type animals. Furthermore, using isolated islets, we confirmed that αGLP-1R deletion did not interfere with β-cell function but affected glucagon secretion in a glucose-dependent bidirectional manner: the αGLP-1R -/- islets failed to inhibit glucagon secretion at high glucose and failed to stimulate glucagon secretion at very low glucose condition. More interestingly, the same phenomenon was recapitulated in vivo under hypoglycemic and postprandial (fed) conditions. Taken together, this study demonstrates that GLP-1 (via GLP-1R in α-cells) plays a bidirectional role, either stimulatory or inhibitory, in glucagon secretion depending on glucose levels., (© 2018 by the American Diabetes Association.)