Characteristics of Non-Insulin-Dependent Diabetic Patients With Secondary Failure to Oral Antidiabetic Therapy

Am J Med. 1989 Aug;87(2):183-90. doi: 10.1016/s0002-9343(89)80695-3.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Drug Resistance
  • Energy Metabolism
  • Female
  • Glipizide / therapeutic use
  • Humans
  • Hypoglycemic Agents / therapeutic use*
  • Lipid Metabolism
  • Male
  • Middle Aged
  • Oxidation-Reduction
  • Patient Compliance
  • Proteins / metabolism
  • Sulfonylurea Compounds / therapeutic use*


  • Blood Glucose
  • Hypoglycemic Agents
  • Proteins
  • Sulfonylurea Compounds
  • Glipizide