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Glucagon blockade restores functional β-cell mass in type 1 diabetic mice and enhances function of human islets
May-Yun Wang1,2, E Danielle Dean3,4, Ezekiel Quittner-Strom1,5
1Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549.
Abstract:
We evaluated the potential for a monoclonal antibody antagonist of the glucagon receptor (Ab-4) to maintain glucose homeostasis in type 1 diabetic rodents. We noted durable and sustained improvements in glycemia which persist long after treatment withdrawal. Ab-4 promoted β-cell survival and enhanced the recovery of insulin+ islet mass with concomitant increases in circulating insulin and C peptide. In PANIC-ATTAC mice, an inducible model of β-cell apoptosis which allows for robust assessment of β-cell regeneration following caspase-8-induced diabetes, Ab-4 drove a 6.7-fold increase in β-cell mass. Lineage tracing suggests that this restoration of functional insulin-producing cells was at least partially driven by α-cell-to-β-cell conversion. Following hyperglycemic onset in nonobese diabetic (NOD) mice, Ab-4 treatment promoted improvements in C-peptide levels and insulin+ islet mass was dramatically increased. Lastly, diabetic mice receiving human islet xenografts showed stable improvements in glycemic control and increased human insulin secretion.
Insights
A novel antibody targeting the glucagon receptor (Ab-4) demonstrated sustained glucose control in type 1 diabetes models. This antibody promotes beta-cell regeneration and survival, offering a potential new therapeutic avenue.
Area of Science:
- Endocrinology
- Immunology
- Regenerative Medicine
Background:
- Type 1 diabetes (T1D) is characterized by autoimmune destruction of insulin-producing beta cells.
- Maintaining glucose homeostasis in T1D remains a significant clinical challenge.
- Current therapies primarily focus on insulin replacement, with limited regenerative strategies.
Purpose of the Study:
- To investigate the efficacy of a monoclonal antibody antagonist of the glucagon receptor (Ab-4) in maintaining glucose homeostasis in type 1 diabetic rodent models.
- To assess the impact of Ab-4 on beta-cell survival, regeneration, and overall islet mass.
- To explore the potential of Ab-4 in promoting alpha-cell to beta-cell conversion.
Main Methods:
- Evaluation of Ab-4 in multiple T1D rodent models, including PANIC-ATTAC and nonobese diabetic (NOD) mice.
- Assessment of glycemic control, insulin and C-peptide levels, and islet mass.
- Utilizing lineage tracing to investigate cell conversion mechanisms.
- Testing Ab-4 in a human islet xenograft model in diabetic mice.
Main Results:
- Ab-4 treatment led to durable and sustained improvements in glycemia, persisting after treatment cessation.
- Significant promotion of beta-cell survival and enhanced recovery of insulin-positive islet mass.
- A 6.7-fold increase in beta-cell mass observed in PANIC-ATTAC mice, with evidence of alpha-cell to beta-cell conversion.
- Improved C-peptide levels and increased insulin-positive islet mass in NOD mice.
- Stable glycemic control and enhanced human insulin secretion in diabetic mice with human islet xenografts.
Conclusions:
- Monoclonal antibody Ab-4 shows significant potential for restoring glucose homeostasis in type 1 diabetes.
- Ab-4 promotes beta-cell regeneration and survival, potentially through alpha-cell to beta-cell conversion.
- These findings suggest Ab-4 as a promising therapeutic candidate for T1D, addressing both glycemic control and beta-cell restoration.
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