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Updated: Jun 28, 2026
Transplantation of Pancreatic Islets Into the Kidney Capsule of Diabetic Mice
Published on: October 31, 2007
Transplantation of PC1/3-Expressing alpha-cells improves glucose handling and cold tolerance in leptin-resistant mice
Rhonda D Wideman1, Sarah L Gray, Scott D Covey
1Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Abstract:
Type 2 diabetes (T2D) is characterized by elevated blood glucose levels owing to insufficient secretion and/or activity of the glucose-lowering hormone insulin. Glucagon-like peptide-1 (GLP-1) has received much attention as a new treatment for diabetes because of its multiple blood glucose-lowering effects, including glucose-dependent enhancement of insulin secretion, inhibition of gastric emptying, and promotion of the survival and growth of insulin-producing beta-cells. GLP-1, along with GLP-2 and oxyntomodulin, is produced in the intestinal L-cell via processing of proglucagon by prohormone convertase 1/3 (PC1/3), while in the pancreatic alpha-cell, coexpression of proglucagon and the alternate enzyme PC2 typically results in differential processing of proglucagon to yield glucagon. We used alginate-encapsulated alpha-cells as a model to evaluate continuous delivery of PC1/3- or PC2-derived proglucagon products. In high fat-fed and db/db mice, PC1/3-, but not PC2-expressing alpha-cells improved glucose handling and transiently lowered fasting glucose levels, suggesting that continuous delivery of PC1/3-derived proglucagon products via cell therapy may be useful for diabetes treatment. In addition, we show that long-term treatment with PC1/3-expressing, but not PC2-expressing, alpha-cells improved cold-induced thermogenesis in db/db mice, demonstrating a previously unappreciated effect of one or more PC1/3-derived alpha-cell products.
Insights
Cell therapy using alpha-cells engineered to produce specific proglucagon products shows promise for treating type 2 diabetes (T2D). This approach improved glucose control and enhanced thermogenesis in mouse models.
Area of Science:
- Endocrinology
- Cell Biology
- Metabolic Diseases
Background:
- Type 2 diabetes (T2D) involves impaired insulin secretion and activity, leading to hyperglycemia.
- Glucagon-like peptide-1 (GLP-1) offers therapeutic potential for T2D due to its glucose-lowering effects.
- Differential processing of proglucagon in intestinal L-cells versus pancreatic alpha-cells yields distinct peptides.
Purpose of the Study:
- To evaluate the therapeutic potential of continuous delivery of proglucagon processing products from engineered alpha-cells.
- To investigate the effects of PC1/3- versus PC2-derived proglucagon products on glucose metabolism and thermogenesis.
Main Methods:
- Alginate-encapsulated pancreatic alpha-cells expressing either PC1/3 or PC2 were used as a model.
- These engineered cells were tested in high fat-fed and db/db mouse models of diabetes.
- Glucose handling, fasting glucose levels, and cold-induced thermogenesis were assessed.
Main Results:
- PC1/3-expressing alpha-cells, but not PC2-expressing cells, improved glucose handling and transiently lowered fasting glucose in mouse models.
- Long-term treatment with PC1/3-expressing alpha-cells enhanced cold-induced thermogenesis in db/db mice.
- These findings suggest specific proglucagon-derived peptides have distinct physiological effects.
Conclusions:
- Continuous delivery of PC1/3-derived proglucagon products via cell therapy is a potential strategy for T2D treatment.
- PC1/3-derived alpha-cell products may offer benefits beyond glucose control, including thermogenesis regulation.
- Targeting proglucagon processing in alpha-cells presents a novel therapeutic avenue for metabolic disorders.
