A Novel Glucagon Receptor Antagonist, NNC 25-0926, Blunts Hepatic Glucose Production in the Conscious Dog

Abstract

Elevated glucagon is associated with fasting hyperglycemia in type 2 diabetes. We assessed the effects of the glucagon receptor antagonist (2R)-N- [4-({4-(1-cyclohexen-1-yl) [(3,5-dichloroanilino)carbonyl]anilino}methyl)benzoyl]-2-hydroxy-balanine (NNC 25-0926) on hepatic glucose production (HPG) in vivo, using arteriovenous difference and tracer techniques in conscious dogs. The experiments consisted of equilibration (Ϫ140 to Ϫ40 min), control (40 -0 min), and experimental [0 -180 min, divided into P1 (0 -60 min) and P2 (60 -180 min)] periods. In P1, NNC 25-0926 was given intragastrically at 0 (veh), 10, 20, 40, or 100 mg/kg, and euglycemia was maintained. In P2, somatostatin, basal intraportal insulin, and 5-fold basal intraportal glucagon (2.5 ng/kg/min) were infused. Arterial plasma insulin levels remained basal throughout the study in all groups. Arterial plasma glucagon levels remained basal during the control period and P1 and then increased to ϳ70 pg/ml in P2 in all groups. Arterial plasma glucose levels were basal in the control period and P1 in all groups. In P2, the arterial glucose level increased to 245 Ϯ 22 and 172 Ϯ 15 mg/dl in the veh and 10 mg/kg groups, respectively, whereas in the 20, 40, and 100 mg/kg groups, there was no rise in glucose. Net hepatic glucose output was ϳ2 mg/kg/min in all groups during the control period. In P2, it increased by 9.4 Ϯ 2 mg/kg/min in the veh group. In the 10, 20, 40, and 100 mg/kg groups, the rise was only 4.1 Ϯ 0.9, 1.6 Ϯ 0.6, 2.4 Ϯ 0.7, and 1.5 Ϯ 0.3 mg/kg/min, respectively, due to inhibition of glycogenolysis. In conclusion, NNC 25-0926 effectively blocked the ability of glucagon to increase HGP in the dog.Glucagon is secreted by the ␣ cells of the pancreas into the hepatic portal vein, thus exposing the liver to higher levels of the hormone than nonhepatic tissues. Plasma glucagon levels decrease in response to hyperglycemia, hyperinsulinemia, elevated plasma nonesterified fatty acid levels, and somatostatin (Ravier and Rutter, 2005;Young, 2005). Glucagon secretion is increased in response to hypoglycemia and elevated plasma amino acid levels (Burcelin et al., 1996;Cherrington, 1999;Jiang and Zhang, 2003;Young, 2005). The main physiological role of glucagon is to stimulate hepatic glucose production by activating glycogenolysis and gluconeogenesis, although its effect on the latter process is limited by its inability to increase gluconeogenic substrate delivery to the liver (Cherrington, 1999).Diabetes is characterized by fasting hyperglycemia and/or abnormal postprandial glycemia (Basu et al., 2004a,b). These abnormalities are associated with increased glucose production, which is the result of both glycogenolysis and gluconeogenesis. Several studies have shown that gluconeogenesis is increased in diabetes due to an increase in the availability of gluconeogenic amino acids, a rise in lipolysis, and the resulting elevation in free fatty acids and glycerol levels (Consoli et al., 1990;Puhakainen et al., 1992;Gastaldelli et al., 2000). Another contrib...

Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover

“…These findings agree with other work in which glucagon receptors were blocked with antibodies (73, 74) or with glucagon recep- tor antagonists (75). Such maneuvers also improved the metabolic state in insulin deficiency (76)(77)(78)(79)(80).…”

Anti-Obesity Therapy: from Rainbow Pills to Polyagonists

“…This is a seminal observation that was later confirmed by several independent research groups (Gerich et al, 1976;Felig et al, 1978;Butler and Rizza, 1991;Kelley et al, 1994). Subsequent studies showed that somatostatin-induced inhibition of postprandial glucagon secretion ameliorates hyperglycemia in patients with T2D (Gerich et al, 1974;Dinneen et al, 1995;Shah et al, 2000), and more recently that blocking glucagon action decreases hyperglycemia in a variety of species, including rodents (Mu et al, 2011;Kim et al, 2012b;Okamoto et al, 2017), rabbits (Brand et al, 1996), dogs (Rivera et al, 2007), nonhuman primates (Xiong et al, 2012;Okamoto et al, 2015), and humans (Petersen and Sullivan, 2001;Kelly et al, 2015;van Dongen et al, 2015;Kazda et al, 2016;Kostic et al, 2018). The virtues and limitations of antagonizing glucagon signaling for the treatment of diabetes have recently been highlighted in several review articles (Unger and Cherrington, 2012;Farhy and McCall, 2015;Lee et al, 2016b;Müller et al, 2017), with the implication that excess glucagon action can serve a greater role in the pathology of T2D than impaired insulin action (Unger and Cherrington, 2012).…”

Paracrinology of islets and the paracrinopathy of diabetes

“…3B). It has become increasingly certain that the lethal catabolic consequences of complete insulin deficiency do not occur if the hyperglucagonemia is suppressed by somatostatin (15)(16)(17) or by leptin (18,19) or if its action is blocked by drugs (20) or by genetic disruption of glucagon receptors. Glucagon receptornull mice remained completely normal for 2 to 3 mo despite complete insulin deficiency (18).…”