Glucagon receptor inhibition normalizes blood glucose in severe insulin-resistant mice

Okamoto, Haruka; Cavino, Katie; Na, Erqian; Krumm, Elizabeth A.; Kim, Sun Y.; Cheng, Xiping; Murphy, Andrew; Yancopouloš, George D.; Gromada, Jesper

doi:10.1073/pnas.1621069114

Cited by 61 publications

(66 citation statements)

References 52 publications

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“…Our observations in T1D rodent models have been replicated by others who have met these results with skepticism (7). The results presented in PNAS further refine these conclusions (2). Using REGN1193, a fully human Gcgr monoclonal antibody, Okamoto et al (8) (Regeneron) have reported effective glucose control in diabetic rodents and primates.…”

supporting

confidence: 57%

“…Pharmacological approaches to blunt gcg action have gained some traction as a potential antidiabetic approach. In PNAS, Okamoto et al (1,2) present two papers evaluating gcg blockade on islet physiology. First, they examine the mechanisms of α-cell hyperplasia, a phenomenon that stands as a potential roadblock in the use of these glucagon receptor (Gcgr) antagonists (1).…”

mentioning

confidence: 99%

“…Hyperglucagonemia and excess proliferation of α cells have also resulted following administration of REGN1193, which phenocopies global or liver-specific Gcgr −/− mice (9, 10). Using both REGN1193 and S961, Okamoto et al (2) …”

mentioning

confidence: 99%

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Glucagon antagonism in islet cell proliferation

Dean

Unger²,

Holland

2017

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

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The peptide hormones insulin and glucagon (gcg) are inextricably linked in the normal control of glucose homeostasis and in the dysregulated glucose homeostasis that defines diabetes mellitus. Pancreatic islets secrete both insulin and gcg in a manner that is tightly juxtaposed. β Cells secrete insulin, a peptide hormone that promotes the uptake and storage of carbohydrates and other nutrients in skeletal muscle and fat, while simultaneously repressing gcg secretion from pancreatic α cells and glucose efflux from the liver. Although loss of insulin function is the most conspicuous cause of both type 1 diabetes (T1D) and type 2 diabetes (T2D), hyperglucagonemia also drives hyperglycemia. Pharmacological approaches to blunt gcg action have gained some traction as a potential antidiabetic approach. In PNAS, Okamoto et al. (1, 2) present two papers evaluating gcg blockade on islet physiology. First, they examine the mechanisms of α-cell hyperplasia, a phenomenon that stands as a potential roadblock in the use of these glucagon receptor (Gcgr) antagonists (1). Second, they reveal that Gcgr antagonism when insulin action is absent can lead to normoglycemia and β-cell expansion ( Fig. 1; ref. 2).Despite five decades of biochemical, physiological, and morphological research demonstrating that aberrant gcg production correlates with diabetes and suppression of gcg corrects the hyperglycemia of diabetes, gcg is not widely accepted as the direct cause of the metabolic abnormality. Since developing the first RIA for gcg in 1959 (3), we have studied gcg physiology and pathophysiology in rodents, dogs, and humans. In 1978, we showed that the gcg-suppressing agent somatostatin could ameliorate the metabolic disturbances of insulin deficiency (4). More recently, targeted disruption has gained traction as a potential treatment for diabetes.Small-molecule antagonists, antisense oligonucleotides, and antibodies that block Gcgr action have all been investigated in preclinical models and clinical trials as novel therapeutics for the treatment of diabetes. Although all strategies have shown improvements in glycemic control, several side effects (e.g., hypercholesterolemia, hyperglucagonemia, α-cell hyperplasia) have slowed development of these drugs as a clinical class (5). For fear of such nonspecific side effects, biological approaches with strong specificity may be a safer approach to antagonize Gcgr. Both antisense oligonucleotides and human antibodies against Gcgr show promise to promote glycemic control in patients. Interrupting gcg signaling can normalize glycemia in T1D and T2D rodent models, suggesting that modifying gcg action may be therapeutic for patients with either form of diabetes (5). Unfortunately, although effective at lowering blood glucose, interrupting gcg signaling also results in hyperglucagonemia and α-cell hyperplasia. This side effect raises concerns for the long-term safety of gcg antagonism. However, glycemia in patients with inactivating mutations in insulin receptor (Insr) is refractory to traditional i...

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confidence: 57%

mentioning

confidence: 99%

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Glucagon antagonism in islet cell proliferation

Dean

Unger²,

Holland

2017

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

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“…Studies in glucagon receptor knockout mice rendered insulin deficient by streptozotocin have firmly demonstrated the metabolic benefits of absence of glucagon action without insulin administration . In addition, we have shown in mice with near absence of insulin receptor signaling that REGN1193 treatment is able to lower glucose to near normal ranges . Thus, patients with insulin receptor loss of function mutations, manifested as severe insulin resistance and diabetes, ie, Rabson‐Mendenhall syndrome and other related diseases, may benefit from anti‐glucagon receptor therapy.…”

Section: Discussionmentioning

confidence: 81%

A first‐in‐human pharmacodynamic and pharmacokinetic study of a fully human anti‐glucagon receptor monoclonal antibody in normal healthy volunteers

Kostić

King

Yang

et al. 2017

Diabetes Obesity Metabolism

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AimsGlucagon receptor (GCGR) blockers are being investigated as potential therapeutics for type 1 and type 2 diabetes. Here we report the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of REGN1193, a fully human glucagon receptor blocking monoclonal antibody from a first‐in‐human healthy volunteer randomized double‐blinded trial.MethodsHealthy men and women received single ascending doses of REGN1193 ranging from 0.05 to 0.6 mg/kg (n = 42) or placebo (n = 14) intravenously. Safety, tolerability and PK were assessed over 106 days. The glucose‐lowering effect of REGN1193 was assessed after induction of hyperglycaemia by serial glucagon challenges.ResultsREGN1193 was generally well tolerated. There were small (<3× the upper limit of normal) and transient dose‐dependent increases in hepatic aminotransferases. No increase in LDL‐C was observed. Hypoglycaemia, assessed as laboratory blood glucose ≤70 mg/dL, occurred in 6/14 (43%) subjects on placebo and 27/42 (57%) on REGN1193 across all dose groups. All episodes of hypoglycaemia were asymptomatic, >50 mg/dL, and did not require treatment or medical assistance. Concentration‐time profiles suggest a 2‐compartment disposition and marked nonlinearity, consistent with target‐mediated clearance. REGN1193 inhibited the glucagon‐stimulated glucose increase in a dose‐dependent manner. The 0.6 mg/kg dose inhibited the glucagon‐induced glucose area under the curve for 0 to 90 minutes (AUC0‐90 minutes) by 80% to 90% on days 3 and 15, while blunting the increase in C‐peptide. REGN1193 dose‐dependently increased total GLP‐1, GLP‐2 and glucagon, with plasma levels returning to baseline by day 29 in all dose groups.ConclusionREGN1193, a GCGR‐blocking monoclonal antibody, produced a safety, tolerability and PK/PD profile suitable for further clinical development. The occurrence of transient elevations in serum hepatic aminotransferases observed here and reported with several small molecule glucagon receptor antagonists suggests an on‐target effect of glucagon receptor blockade. The underlying mechanism is unknown.

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“…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).…”

Section: A Glucagon-like Peptide 1/glucagon Coagonismmentioning

confidence: 84%