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Postreceptor defects causing insulin resistance in normoinsulinemic non-insulin-dependent diabetes mellitus
Abstract:
The mechanisms of the diminished hypoglycemic response to insulin in non-insulin-dependent diabetes mellitus (NIDDM) with normal levels of circulating plasma insulin were investigated. Specific binding of mono-125I (Tyr A14)-insulin to isolated adipocytes and effects of insulin (5--10,000 microunits/ml) on glucose oxidation and lipolysis were determined simultaneously in subcutaneous adipose tissue of seven healthy subjects of normal weight and seven untreated NIDDM patients with normal plasma insulin levels. The two groups were matched for age, sex, and body weight. Insulin binding, measured in terms of receptor number and affinity, was normal in NIDDM, the total number of receptors averaging 350,000 per cell. Neither sensitivity nor the maximum antilipolytic effect of insulin was altered in NIDDM patients as compared with control subjects; the insulin concentration producing half the maximum effect (ED50) was 10 microunits/ml. As regards the effect of insulin on glucose oxidation, for the control subjects ED50 was 30 microunits/ml, whereas in NIDDM patients, insulin exerted no stimulatory effect. The results obtained suggest that the effect of insulin on glucose utilization in normoinsulinemic NIDDM may be diminished in spite of normal insulin binding to receptors. The resistance may be due solely to postreceptor defects, and does not involve antilipolysis.
Insights
In non-insulin-dependent diabetes mellitus (NIDDM), insulin resistance affects glucose utilization but not fat breakdown. This suggests post-receptor defects are key in NIDDM, despite normal insulin binding.
Area of Science:
- Endocrinology
- Metabolic Diseases
- Molecular Biology
Background:
- Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by impaired glucose regulation.
- Understanding insulin resistance mechanisms is crucial for NIDDM management.
- Previous studies suggest defects in insulin signaling pathways.
Purpose of the Study:
- To investigate the mechanisms of diminished insulin response in NIDDM patients with normal insulin levels.
- To differentiate between receptor-level and post-receptor defects in insulin action.
- To assess insulin's effects on glucose oxidation and lipolysis in NIDDM.
Main Methods:
- Isolated adipocytes from healthy subjects and NIDDM patients were used.
- Insulin binding assays were performed to determine receptor number and affinity.
- Effects of varying insulin concentrations on glucose oxidation and lipolysis were measured.
Main Results:
- Insulin binding to adipocyte receptors was normal in NIDDM patients.
- Insulin's antilipolytic effect was preserved in NIDDM patients.
- Insulin failed to stimulate glucose oxidation in NIDDM patients, unlike in control subjects.
Conclusions:
- Insulin resistance in NIDDM with normal insulin levels is primarily due to post-receptor defects affecting glucose utilization.
- The antilipolytic function of insulin remains intact, indicating selective impairment.
- These findings highlight a specific defect in insulin's glucose metabolism pathway in NIDDM.