Effect of a glucagon receptor antibody (REMD‐477) in type 1 diabetes: A randomized controlled trial

Pettus, Jeremy; Reeds, Dominic N.; Cavaiola, Tricia Santos; Boeder, Schafer; Levin, Michelle; Tobin, Garry S.; Cava, Edda; Thai, Dung; Shi, Jim; Yan, Hai; Bautista, Edgar; McMillan, John; Unger, Roger H; Henry, Robert R.; Klein, Samuel

doi:10.1111/dom.13202

Cited by 55 publications

(37 citation statements)

References 14 publications

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“…Previous studies suggest that some of the compensatory mechanisms in response to Gcgr deletion act by increasing insulin action. Hence, Gcgr −/− mice exhibit increased insulin sensitivity [36] , and treatment with a monoclonal antibody against Gcgr reduces insulin requirements in T1DM humans [37] . Our data suggest that factors other than different levels of basal plasma c-peptide (insulin) or insulin signaling measured as pAKT levels must contribute to the increased insulin action due to loss of GCGR signaling.…”

Section: Discussionmentioning

confidence: 99%

Deletion of the glucagon receptor gene before and after experimental diabetes reveals differential protection from hyperglycemia

Rivero-Gutiérrez

Haller

Holland

et al. 2018

Molecular Metabolism

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ObjectiveMice with congenital loss of the glucagon receptor gene (Gcgr−/− mice) remain normoglycemic in insulinopenic conditions, suggesting that unopposed glucagon action is the driving force for hyperglycemia in Type-1 Diabetes Mellitus (T1DM). However, chronic loss of GCGR results in a neomorphic phenotype that includes hormonal signals with hypoglycemic activity. We combined temporally-controlled GCGR deletion with pharmacological treatments to dissect the direct contribution of GCGR signaling to glucose control in a common mouse model of T1DM.MethodsWe induced experimental T1DM by injecting the beta-cell cytotoxin streptozotocin (STZ) in mice with congenital or temporally-controlled Gcgr loss-of-function using tamoxifen (TMX).ResultsDisruption of Gcgr expression, using either an inducible approach in adult mice or animals with congenital knockout, abolished the response to a long-acting Gcgr agonist. Mice with either developmental Gcgr disruption or inducible deletion several weeks before STZ treatment maintained normoglycemia. However, mice with inducible knockout of the Gcgr one week after the onset of STZ diabetes had only partial correction of hyperglycemia, an effect that was reversed by GLP-1 receptor blockade. Mice with Gcgr deletion for either 2 or 6 weeks had similar patterns of gene expression, although the changes were generally larger with longer GCGR knockout.ConclusionsThese findings demonstrate that the effects of glucagon to mitigate diabetic hyperglycemia are not through acute signaling but require compensations that take weeks to develop.

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Section: Discussionmentioning

confidence: 99%

Deletion of the glucagon receptor gene before and after experimental diabetes reveals differential protection from hyperglycemia

Rivero-Gutiérrez

Haller

Holland

et al. 2018

Molecular Metabolism

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“…Recent data from our group and others have shown that REMD 2.59, a fully competitive antagonistic human GCGR monoclonal antibody (mAb), has a strong hypoglycemic effect in type 1 diabetic (T1D) and T2D rodents and non-human primates 6–10. Importantly, a phase I/II randomized clinical trial showed that REMD 477, another human GCGR mAb that differs by only one amino acid (which is not involved in glucagon binding) and has an affinity for the GCGR equivalent to that of REMD 2.59, improved glycemic control in patients with T1D, and no serious adverse effects were detected 11. Interestingly, our previous study discovered that REMD 2.59 induced pancreatic β-cell regeneration, which derived at least partially from transdifferentiation of pancreatic α-cells or δ-cells 6 7.…”

Section: Introductionmentioning

confidence: 99%

Glucagon receptor antagonist upregulates circulating GLP-1 level by promoting intestinal L-cell proliferation and GLP-1 production in type 2 diabetes

Lang

Yang

et al. 2020

BMJ Open Diab Res Care

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ObjectiveGlucagon receptor (GCGR) blockage improves glycemic control and increases circulating glucagon-like peptide-1 (GLP-1) level in diabetic animals and humans. The elevated GLP-1 has been reported to be involved in the hypoglycemic effect of GCGR blockage. However, the source of this elevation remains to be clarified.Research design and methodsREMD 2.59, a human GCGR monoclonal antibody (mAb), was administrated for 12 weeks in db/db mice and high-fat diet+streptozotocin (HFD/STZ)-induced type 2 diabetic (T2D) mice. Blood glucose, glucose tolerance and plasma GLP-1 were evaluated during the treatment. The gut length, epithelial area, and L-cell number and proliferation were detected after the mice were sacrificed. Cell proliferation and GLP-1 production were measured in mouse L-cell line GLUTag cells, and primary mouse and human enterocytes. Moreover, GLP-1 receptor (GLP-1R) antagonist or protein kinase A (PKA) inhibitor was used in GLUTag cells to determine the involved signaling pathways.ResultsTreatment with the GCGR mAb lowered blood glucose level, improved glucose tolerance and elevated plasma GLP-1 level in both db/db and HFD/STZ-induced T2D mice. Besides, the treatment promoted L-cell proliferation and LK-cell expansion, and increased the gut length, epithelial area and L-cell number in these two T2D mice. Similarly, our in vitro study showed that the GCGR mAb promoted L-cell proliferation and increased GLP-1 production in GLUTag cells, and primary mouse and human enterocytes. Furthermore, either GLP-1R antagonist or PKA inhibitor diminished the effects of GCGR mAb on L-cell proliferation and GLP-1 production.ConclusionsThe elevated circulating GLP-1 level by GCGR mAb is mainly due to intestinal L-cell proliferation and GLP-1 production, which may be mediated via GLP-1R/PKA signaling pathways. Therefore, GCGR mAb represents a promising strategy to improve glycemic control and restore the impaired GLP-1 production in T2D.

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“…In a recent proof-of-concept trial, one of these agents showed potential for improved glycemic control and decreased insulin doses in type 1 diabetes. 72 However, potential side effects of other developmental agents in this class include weight gain, increased cholesterol, and alpha-cell hyperplasia. Further research is needed to determine the clinical utility of this class.…”

Section: Incretin Mimeticsmentioning

confidence: 99%

Adjunctive therapy for glucose control in patients with type 1 diabetes

Harris¹,

Boland²,

Meade³

et al. 2018

DMSO

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Type 1 diabetes mellitus (T1DM) is characterized by relative or absolute insulin deficiency. Despite treatment with insulin therapy, glycemic goals are not always met, and insulin therapy is sometimes limited by adverse effects, including hypoglycemia and weight gain. Several adjunctive therapies have been evaluated in combination with insulin in patients with T1DM to improve glycemic control while minimizing adverse effects. Pramlintide, an amylin analog, can improve glycemic control, primarily through lowering postprandial blood glucose levels. Patients may experience weight loss and an increased risk of hypoglycemia and require additional mealtime injections. Metformin provides an inexpensive, oral treatment option and may reduce blood glucose, especially in overweight or obese patients with minimal risk of hypoglycemia. Metformin may be more effective in patients with impaired insulin sensitivity. Glucagon-like peptide-1 receptor agonists reduce primarily postprandial blood glucose and insulin dose and promote weight loss. They are expensive, cause transient nausea, may increase risk of hypoglycemia and require additional injections. Sodium–glucose transport-2 inhibitors improve glycemic control, promote weight loss and have low risk of hypoglycemia with appropriate insulin adjustment; however, these agents may increase the risk of diabetic ketoacidosis in patients with T1DM. Patient-specific characteristics should be considered when selecting adjunctive therapy for patients with T1DM. Close monitoring, insulin dose adjustments and patient education are all important to ensure safe and effective use of these agents.

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Effect of a glucagon receptor antibody (REMD‐477) in type 1 diabetes: A randomized controlled trial

Cited by 55 publications

References 14 publications

Deletion of the glucagon receptor gene before and after experimental diabetes reveals differential protection from hyperglycemia

Deletion of the glucagon receptor gene before and after experimental diabetes reveals differential protection from hyperglycemia

Glucagon receptor antagonist upregulates circulating GLP-1 level by promoting intestinal L-cell proliferation and GLP-1 production in type 2 diabetes

Adjunctive therapy for glucose control in patients with type 1 diabetes

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