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Glucose Effectiveness: The Mouse Trap in the Development of Novel ß-Cell Replacement Therapies
1Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
Background:
Cure of diabetes and normalization of glucose disposal during intravenous glucose tolerance tests (IVGTT) remains critical for stringent evaluation of novel replacement therapies in type 1 diabetes. Glucose disposal during an IVGTT depends on a complex interaction of both insulin-dependent and -independent mechanisms. Glucose effectiveness, that is, the function of glucose per se, independent of insulin, to stimulate its uptake and suppress endogenous glucose production is less recognized.
Methods:
To unravel the relative importance of these pathways, rats were injected with streptozotocin to induce diabetes and implanted subcutaneously with slow-release devices of insulin.
Results:
These animals demonstrated rapid normalization of blood glucose and perfectly normal glucose disposal during an IVGTT with no differences when compared with nondiabetic controls even though no active c-peptide secretion was detected in plasma and almost no remaining insulin-producing cells were present in the pancreas.
Conclusions:
The present study highlights that glucose is the predominant mediator of its own disposal in rodents having only basal and nonglucose-regulated plasma insulin levels. The herein presented results calls for a reassessment how results obtained in the most commonly used experimental models should be interpreted in the development of future replacement therapies in type 1 diabetes.
Insights
Glucose disposal in type 1 diabetes is primarily driven by glucose itself, not just insulin. This finding suggests re-evaluating experimental models for diabetes replacement therapies.
Area of Science:
- Endocrinology
- Metabolic Research
- Diabetes Mellitus Research
Background:
- Type 1 diabetes management requires effective glucose disposal evaluation.
- Glucose disposal involves insulin-dependent and -independent pathways.
- Glucose effectiveness, independent of insulin, is underappreciated.
Purpose of the Study:
- To investigate the role of glucose effectiveness in glucose disposal.
- To determine the relative importance of insulin-dependent versus -independent mechanisms.
- To assess glucose disposal in a type 1 diabetes model with minimal insulin secretion.
Main Methods:
- Streptozotocin-induced diabetes in rats.
- Subcutaneous implantation of slow-release insulin devices.
- Intravenous glucose tolerance tests (IVGTT) for glucose disposal assessment.
Main Results:
- Diabetic rats with insulin devices showed normalized blood glucose levels.
- Glucose disposal during IVGTT was normal in treated rats compared to controls.
- No active C-peptide secretion or significant insulin-producing cells were detected.
Conclusions:
- Glucose is the primary driver of its own disposal in this rodent model.
- Basal, non-glucose-regulated insulin levels are sufficient for normal glucose handling.
- Results necessitate reassessment of experimental models for type 1 diabetes therapies.
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