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Characteristics of non-insulin-dependent diabetic patients with secondary failure to oral antidiabetic therapy
L Groop1, C Schalin, A Franssila-Kallunki
1Fourth Department of Medicine, Helsinki University Hospital, Finland.
Purpose:
Secondary failure to treatment with oral antidiabetic agents frequently occurs in patients with non-insulin-dependent diabetes mellitus. In the search for causes of such failures, we examined patient- and disease-related factors in nonresponders and in responders to treatment with oral antidiabetic agents.
Patients And Methods:
The study population consisted of three groups: (1) 34 nonresponders to treatment with sulfonylureas; (2) 25 patients who still responded to treatment with sulfonylureas; and (3) 10 age-matched healthy control subjects. In addition to patient-related factors such as adherence to diet and knowledge of diabetes, we examined insulin response to a test meal and hepatic and peripheral insulin sensitivity during a euglycemic insulin clamp in combination with indirect calorimetry and infusion of [3H-3-]glucose.
Results:
Patient-related factors such as daily nutrient intake, activity score, knowledge of diabetes, and "stress level" were similar in both groups. However, nonresponders had a higher rate of basal hepatic glucose production (4.60 +/- 0.14 versus 3.63 +/- 0.26 mg/minute/kg of lean body weight; p less than 0.001), which was less suppressed by euglycemic hyperinsulinemia (about 100 microU/mL) than was that of the responders (p less than 0.001). In addition, total insulin-stimulated glucose metabolism was reduced (5.07 +/- 0.22 versus 7.09 +/- 0.56 mg/kg.LBM.minute; p less than 0.001), and this was mainly accounted for by a reduction in non-oxidative glucose metabolism (glycogen synthesis and anaerobic glycolysis) (1.78 +/- 0.22 versus 3.54 +/- 0.49 mg/kg.LBM.minute; p less than 0.001). The severity of hepatic and peripheral insulin resistance correlated with the plasma glucose concentration but was unrelated to insulin secretion. In a multiple linear regression analysis, glucose overproduction in the liver (26.1%), impaired peripheral glucose metabolism (17.3%), and insulin deficiency (12.6%) could explain only 56% of the causes of secondary drug failure.
Conclusion:
Secondary failure to treatment with oral hypoglycemic agents is determined by the disease itself rather than by patient-related factors. Treatment of secondary drug failure should therefore aim at ameliorating both hepatic and peripheral insulin resistance.
Insights
Secondary failure to oral antidiabetic agents in type 2 diabetes is primarily due to disease factors, not patient behavior. Addressing hepatic and peripheral insulin resistance is key for effective treatment.
Area of Science:
- Endocrinology
- Metabolic Diseases
- Pharmacology
Background:
- Secondary failure to oral antidiabetic agents is common in type 2 diabetes.
- Understanding the causes is crucial for optimizing treatment strategies.
Purpose of the Study:
- To investigate patient-related and disease-related factors contributing to secondary treatment failure in non-insulin-dependent diabetes mellitus.
- To compare responders and nonresponders to oral antidiabetic agents.
Main Methods:
- Study included 34 nonresponders, 25 responders to sulfonylureas, and 10 healthy controls.
- Assessed patient factors (diet, knowledge) and physiological parameters (insulin sensitivity, glucose production) using euglycemic insulin clamp and indirect calorimetry.
Main Results:
- Nonresponders exhibited higher basal hepatic glucose production and reduced suppression by insulin.
- Total insulin-stimulated glucose metabolism and non-oxidative glucose metabolism were significantly lower in nonresponders.
- Hepatic and peripheral insulin resistance correlated with glucose levels but not insulin secretion.
Conclusions:
- Secondary treatment failure in type 2 diabetes is predominantly driven by intrinsic disease processes, specifically insulin resistance.
- Therapeutic strategies should focus on improving both hepatic and peripheral insulin sensitivity to manage secondary drug failure.