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Exenatide Is an Effective Antihyperglycaemic Agent in a Mouse Model of Wolfram Syndrome 1
Tuuli Sedman1, Kertu Rünkorg1, Maarja Krass1
1Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, 19 Ravila Street, 50411 Tartu, Estonia; Centre for Translational Medicine, Institute of Biomedicine and Translational Medicine, University of Tartu, 19 Ravila Street, 50411 Tartu, Estonia.
Abstract:
Wolfram syndrome 1 is a very rare monogenic disease resulting in a complex of disorders including diabetes mellitus. Up to now, insulin has been used to treat these patients. Some of the monogenic forms of diabetes respond preferentially to sulphonylurea preparations. The aim of the current study was to elucidate whether exenatide, a GLP-1 receptor agonist, and glipizide, a sulphonylurea, are effective in a mouse model of Wolfram syndrome 1. Wolframin-deficient mice were used to test the effect of insulin secretagogues. Wolframin-deficient mice had nearly normal fasting glucose levels but developed hyperglycaemia after glucose challenge. Exenatide in a dose of 10 μg/kg lowered the blood glucose level in both wild-type and wolframin-deficient mice when administered during a nonfasted state and during the intraperitoneal glucose tolerance test. Glipizide (0.6 or 2 mg/kg) was not able to reduce the glucose level in wolframin-deficient animals. In contrast to other groups, wolframin-deficient mice had a lower insulin-to-glucose ratio during the intraperitoneal glucose tolerance test, indicating impaired insulin secretion. Exenatide increased the insulin-to-glucose ratio irrespective of genotype, demonstrating the ability to correct the impaired insulin secretion caused by wolframin deficiency. We conclude that GLP-1 agonists may have potential in the treatment of Wolfram syndrome-related diabetes.
Insights
Glucagon-like peptide-1 (GLP-1) agonists like exenatide show promise for treating Wolfram syndrome 1 diabetes. These drugs improved glucose levels and insulin secretion in a mouse model, unlike sulfonylureas.
Area of Science:
- Endocrinology
- Genetics
- Metabolic Disorders
Background:
- Wolfram syndrome 1 is a rare monogenic disorder causing diabetes mellitus.
- Current treatments for Wolfram syndrome 1 diabetes primarily involve insulin.
- Some monogenic diabetes types respond better to sulfonylureas.
Purpose of the Study:
- To evaluate the efficacy of exenatide (a GLP-1 receptor agonist) and glipizide (a sulfonylurea) in a mouse model of Wolfram syndrome 1.
- To investigate the impact of these drugs on glucose metabolism and insulin secretion in wolframin-deficient mice.
Main Methods:
- Utilized wolframin-deficient mice as a model for Wolfram syndrome 1.
- Administered exenatide and glipizide to assess their effects on blood glucose levels.
- Conducted intraperitoneal glucose tolerance tests to evaluate glucose and insulin responses.
- Measured insulin-to-glucose ratios to assess insulin secretion capacity.
Main Results:
- Exenatide effectively lowered blood glucose in both wild-type and wolframin-deficient mice.
- Glipizide did not significantly reduce glucose levels in wolframin-deficient mice.
- Wolframin-deficient mice exhibited impaired insulin secretion, indicated by a lower insulin-to-glucose ratio.
- Exenatide improved the insulin-to-glucose ratio, correcting the impaired secretion.
Conclusions:
- GLP-1 receptor agonists, such as exenatide, demonstrate potential therapeutic value for Wolfram syndrome 1-related diabetes.
- Exenatide's ability to enhance insulin secretion suggests it could be a viable treatment option.
- Sulfonylureas like glipizide appear less effective in this specific model of monogenic diabetes.
