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The insulin receptor concept and its relation to the treatment of diabetes
Abstract:
The initial step in insulin action is binding to specific receptors. Two covalent receptor modifications possibly involved in producing pharmacodynamic effects as a result of insulin receptor binding are autophosphorylation and disulphide insulin binding. Insulin receptor numbers are 'down regulated' by insulin, but this effect may be minimised by pulsatile insulin secretion. Insulin receptor affinity is modulated rapidly by fasting, exercise and dietary composition. In non-insulin-dependent diabetes coupling of receptor binding to bioeffects is impaired. Binding is also reduced in those subjects with hyperinsulinaemia and non-insulin-dependent diabetes. Insulin-dependent diabetics have reduced insulin sensitivity, which is only partially reversed by conventional insulin therapy. 'Post-binding defects' in some diabetics could be related to defective covalent receptor modifications resulting from genetic receptor defects. High carbohydrate diets improve diabetes control through effects on the binding and coupling defects. In addition to stimulating insulin secretion, oral hypoglycaemics stimulate post-binding insulin action in vivo and in vitro. Insulin therapy in diabetes also tends to reverse post-binding defects. Pulsatile insulin delivery is more effective in lowering blood sugar than continuous administration, and produces less 'down regulation' of receptors. Combined insulin and sulphonylurea drugs reduce insulin requirements only in insulin-dependent diabetics with some endogenous insulin secretion, whereas metformin reduces insulin requirement in C-peptide negative insulin-dependent diabetes mellitus.
Insights
Insulin resistance in diabetes involves impaired insulin receptor binding and post-binding defects. Optimizing insulin delivery and utilizing specific oral hypoglycemics can improve insulin action and diabetes control.
Area of Science:
- Endocrinology and Metabolism
- Molecular Biology
- Pharmacology
Background:
- Insulin action initiates with insulin receptor binding, a process crucial for glucose homeostasis.
- Receptor modifications like autophosphorylation and disulphide binding are implicated in insulin's pharmacodynamic effects.
- Insulin receptor regulation involves 'down regulation' and affinity modulation influenced by physiological states and diet.
Purpose of the Study:
- To investigate the role of insulin receptor binding and post-binding events in insulin resistance.
- To explore defects in insulin receptor function in various diabetic conditions.
- To evaluate the impact of different therapeutic strategies on insulin action and receptor dynamics.
Main Methods:
- Analysis of insulin receptor binding affinity and number.
- Assessment of covalent receptor modifications (autophosphorylation, disulphide binding).
- Evaluation of bioeffects following receptor binding in diabetic models and human subjects.
- Comparison of therapeutic interventions including pulsatile insulin delivery, oral hypoglycemics, and drug combinations.
Main Results:
- Impaired coupling of receptor binding to bioeffects observed in non-insulin-dependent diabetes and hyperinsulinaemia.
- Reduced insulin sensitivity in insulin-dependent diabetes partially reversed by conventional therapy.
- Potential 'post-binding defects' linked to genetic receptor abnormalities and impaired covalent modifications.
- High carbohydrate diets improve diabetes control by addressing binding and coupling defects.
- Oral hypoglycemics and insulin therapy demonstrate capacity to reverse post-binding defects.
- Pulsatile insulin delivery shows superior glycemic control and reduced receptor 'down regulation' compared to continuous administration.
- Metformin effectively reduces insulin requirements in C-peptide negative insulin-dependent diabetes mellitus.
Conclusions:
- Insulin resistance involves complex defects at the insulin receptor binding and post-binding levels.
- Therapeutic strategies targeting receptor function, such as pulsatile insulin delivery and specific oral agents, offer improved glycemic control.
- Understanding receptor modifications and defects is key to developing more effective diabetes treatments.