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Molecular studies of diabetes reported at the Fourth European Congress of endocrinology
1Institute of Experimental Endocrinology, Endocrine Research Center, Russian Academy of Medical Sciences, ul. Moskvorech'e l. Moscow, 115478 Russia.
Abstract:
In his lecture at the Fourth European Congress of Endocrinology, C.R. Kahn considered the effects of knock-out of genes encoding the proteins involved into insulin signal transduction on the development of insulin-resistance and non-insulin-dependent diabetes mellitus. The latter were induced in animals by knockout of genes encoding insulin receptors and intracellular substrate proteins of the insulin receptor. Using special technology, the authors achieved selective knock-out of the insulin receptor gene in muscles and pancreatic beta-cells of mice. Non-insulin-dependent diabetes mellitus developed only after the knock-out of the insulin receptor gene in beta-cells and resulted from the inability of glucose to penetrate into beta-cells and stimulate insulin secretion. The insensitivity of muscles to insulin due to the lack of its receptor did not result in diabetes. In these animals insulin and glucose blood level did not differ from the control values, but blood lipid concentration was increased. For the cases of the reduction in the insulin-dependent penetration of glucose into muscles, these data may indirectly indicate a transition of energy metabolism in muscles from carbohydrate utilization to increased fat consumption as an energy source.
Insights
Knocking out the insulin receptor gene in pancreatic beta-cells caused non-insulin-dependent diabetes mellitus in mice. However, muscle insulin receptor gene knockout did not lead to diabetes, suggesting a key role for beta-cells in glucose regulation.
Area of Science:
- Endocrinology
- Molecular Biology
- Metabolic Diseases
Background:
- Insulin signaling is crucial for glucose homeostasis.
- Insulin resistance and non-insulin-dependent diabetes mellitus (NIDDM) are complex metabolic disorders.
- Gene knockout technologies allow investigation of specific protein functions in vivo.
Framework:
- Investigated the role of insulin receptor (IR) and insulin receptor substrate (IRS) proteins in insulin signaling.
- Utilized selective gene knockout of the IR gene in specific tissues of mice.
- Examined the physiological consequences of disrupted insulin signaling pathways.
Implementation:
- Achieved selective knockout of the insulin receptor gene in pancreatic beta-cells and skeletal muscles of mice.
- Assessed the development of non-insulin-dependent diabetes mellitus (NIDDM) following gene manipulation.
- Monitored blood glucose, insulin, and lipid levels in genetically modified and control mice.
Implications:
- Disruption of the insulin receptor in beta-cells is sufficient to cause NIDDM by impairing glucose-stimulated insulin secretion.
- Insulin insensitivity in muscles due to IR absence does not induce diabetes but alters lipid metabolism.
- Suggests a potential shift in muscle energy metabolism towards fat utilization when glucose uptake is compromised.