Springer Nature is making Coronavirus research free. View research | View latest news | Sign up for updates

Partial recovery of insulin secretion and action after combined insulin-sulfonylurea treatment in Type 2 (non-insulin-dependent) diabetic patients with secondary failure to oral agents

  • 91 Accesses


Metabolic control, insulin secretion and insulin action were evaluated in seven Type 2 (non-insulin-dependent) diabetic patients with secondary failure to oral antidiabetic agents before and after two months of combined therapy with supper-time insulin (Ultratard: 0.4 U/kg body weight/day) plus premeal glibenclamide (15 mg/day). Metabolic control was assessed by 24 h plasma glucose, NEFA, and substrate (lactate, alanine, glycerol, ketone bodies) profile. Insulin secretion was evaluated by glucagon stimulation of C-peptide secretion, hyperglycaemic clamp (+7 mmol/l) and 24 h free-insulin and C-peptide profiles. The repeat studies, after two months of combined therapy, were performed at least 72 h after supper-time insulin withdrawal. Combining insulin and sulfonylurea agents resulted in a reduction in fasting plasma glucose (12.9±7 vs 10.4±1.2 mmol/l; p<0.05) and hepaic glucose production (13.9±1.1 vs 11.1±1.1 μmol·kgc-min−1; p<0.05). Mean 24 h plasma glucose was also lower (13.7±1.2 vs 11.1±1.4 mmol/l; p<0.05). Decrements in fasting plasma glucose and mean 24 h profile were correlated (r=0.90; p<0.01). HbA1c also improved (11.8±0.8 vs 8.9±0.5%; p<0.05). Twenty-four hour profile for NEFA, glycerol, and ketone bodies was lower after teatment, while no difference occurred in the blood lactate and alanine profile. Insulin secretion in response to glucagon (C-peptide =+0.53±0.07 vs +0.43±0.07 pmol/ml) and hyperglycaemia (freeinsulin = 13.1±2.0 vs 12.3±2.2 mU/l) did not change. On the contrary, mean 24 h plasma freeinsulin (13.2±2.6 vs 17.5±2.2 mU/l; p<0.01) and C-peptide (0.76±0.10 vs 0.98±0.13 pmol/l; p<0.02) as well as the area under the curve (19.1±4.1 vs 23.6±3.1 U/24 h;p<0.01 and 1.16±0.14 vs 1.38±0.18 μmol/24 h; p<0.02 respectively) were significantly increased. The ratio between glucose infusion (M) and plasma insulin concentration (I) during the hyperglycaemic clamp studies (M/I, an index of insulin sensitivity), was not statistically different (1.40±0.25 vs 1.81±0.40 μmol·kg−1· min−1/mU·l−1). These data suggest that, in Type 2 diabetic patients with secondary failure to oral antidiabetic agents, the combination of supper-time longacting insulin and premeal sulfonylurea agents can improve metabolic control. This positive effect is possibly mediated through an increased secretion of insulin in response to physiologic stimuli.


  1. 1.

    Fabrykant M (1957) Favorable effect of supplemental Orinase in insulin-treated labile diabetes. Metabolism 6: 509–517

  2. 2.

    Lazarus SS, Volk BW (1959) Physiological basis of the effectiveness of combined insulin-tolbutamide. Ann NY Acad Sci 82: 590–602

  3. 3.

    De Fronzo RA (1988) The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 37: 667–687

  4. 4.

    Yalow RS, Black H, Villazon M, Berson SA (1960) Comparison of plasma insulin levels following administration of tolbutamide and glucose. Diabetes 9: 356–362

  5. 5.

    Lebovitz HE, Feinglos MN (1978) Sulfonylurea drugs: Mechanisms of antidiabetic action and therapeutic usefulness. Diabetes Care 1: 189–198

  6. 6.

    Lebovitz HE, Feinglos MN, Bucholtz HK, Lebovitz FL (1977) Potentiation of insulin action: a probable mechanism for the antidiabetic action of sulfonylurea drugs. J Clin Endocrinol Metab 45: 601–604

  7. 7.

    De Fronzo RA, Simonson DC (1984) Oral sulfonylurea agents suppress hepatic glucose production in non-insulin dependent diabetic individuals. Diabetes Care 7 [Suppl 1]: 72–80

  8. 8.

    Scarlett JA, Gray RS, Griffin J, Olefsky JM, Kolterman OG (1982) Insulin treatment reverses the insulin resistance of type II diabetes mellitus. Diabetes Care 5: 353–363

  9. 9.

    Garvey WT, Olefsky JM, Griffin J, Hamman RF, Kolterman OG (1985) The effect of insulin treatment on insulin secretion and insulin action in type II diabetes mellitus. Diabetes 34: 222–234

  10. 10.

    Andrews WJ, Vasquez B, Nagulesparan M, Klimes I, Foley J, Unger R, Reaven GM (1984) Insulin therapy in obese, non-insulin-dependent diabetes induces improvements in insulin action and secretion that are maintained for two weeks after insulin withdrawal. Diabetes 33: 634–642

  11. 11.

    Del Prato S, Ferrannini E, De Fronzo RA (1986) Evaluation of insulin sensitivity in man. In: Clarke WL, Larner J, Pohl SL (eds) Methods in diabetes research. Clinical methods, vol II. Wiley & Sons, New York, pp 36–76

  12. 12.

    Del Prato S, Nosadini R, Tiengo A, Tessari P, Avogaro A, Trevisan R, Valerio A, Muggeo M, Cobelli C, Toffolo G (1983) Insulin-mediated glucose disposal in type 1 diabetes: evidence for insulin resistance. J Clin Endocrinol Metab 57: 904–910

  13. 13.

    Ferrannini E, Del Prato S, De Fronzo RS (1986) Glucose kinetics. Tracer methods. In: Clarke WL, Larner J, Pohl SL (eds) Methods in diabetes research. Clinical methods, vol II. Wiley & Sons, New York, pp 108–141

  14. 14.

    Shimizu S, Inoue E, Tani Y, Yamada H (1979) Enzymatic microdetermination of serum free fatty acids. Anal Biochem 98: 341–345

  15. 15.

    Groop L, Harno K, Tolppanen E-M (1984) The combination of insulin and sulfonylurea in the treatment of secondary drug failure in patients with type II diabetes. Acta Endocrinol 106: 97–101

  16. 16.

    Bieger WP, Dlugosch R, Rettenmeier A, Holler HD, Bert H, Schwarz W, Fiehn W, Merkt J, Weiker H (1984) Trial of sulfonylurea in combination with insulin in the therapy of diabetes type I and II. Evidence against a primary extrapancreatic effect. Klin Wochenschr 62: 631–639

  17. 17.

    Lardinois CK, Liu GC, Reaven GM (1985) Glyburide in non-insulin-dependent diabetes. Its therapeutic effect in patients with disease poorly controlled by insulin alone. Arch Intern Med 145: 1028–1032

  18. 18.

    Kyllastinen M, Groop L (1985) Combination of insulin and glibenclamide in the treatment of elderly non-insulin dependent (type 2) diabetic patients. Ann Clin Res 17: 100–104

  19. 19.

    Groop L, Harno K, Nikkila EA, Pelkonen R, Tolppanen E-M (1985) Transient effect of the combination of insulin and sulfonylurea (glibenclamide) on glycemic control in non-insulin dependent diabetics poorly controlled with insulin alone. Acta Med Scand 217: 33–39

  20. 20.

    Allen TB, Feinglos TM, Lebovitz HE (1985) Treatment of poorly regulated non-insulin-dependent diabetes mellitus with combination insulin-sulfonylurea. Arch Intern Med 145: 1900–1903

  21. 21.

    Quatraro A, Consoli G, Ceriello A, Giugliano D (1986) Combined insulin and sulfonylurea therapy in non-insulin-dependent diabetics with secondary failure to oral drugs: a one year follow-up. Diabete Metab 12: 315–318

  22. 22.

    Longnecker MP, Elsenhans V, Leiman S, Owen O, Boden G (1986) Insulin and sulfonylurea agent in non-insulin-dependent diabetes mellitus. Arch Intern Med 146: 673–676

  23. 23.

    Mauerhoff T, Ketelslegers JM, Lambert AE (1986) Effect of glibenclamide in insulin-treated diabetic patients with residual insulin secretion. Diabete Metab 12: 34–38

  24. 24.

    Schwartz SL, Fisher JS, Kipnes MS, Boyle M (1987) Effects of short-term insulin therapy upon therapeutic response to glipizide. Am J Med 83 [Suppl 3 A]: 22–30

  25. 25.

    Castillo M, Scheen AJ, Paolisso G, Lefebvre PJ (1987) The addition of glipizide to insulin therapy in Type-II diabetic patients with secondary failure to sulfonylureas is useful only in the presence of a significant residual insulin secretion. Acta Endocrinol 116: 364–372

  26. 26.

    Schade DS, Mitchell WJ, Griego G (1987) Addition of sulfonylurea to insulin treatment in poorly controlled type II diabetes. A double blind, randomized clinical trial. JAMA 257: 2441–2445

  27. 27.

    Simonson DC, Del Prato S, Castellino P, Groop L, De Fronzo RA (1987) Effect of glyburide on glycemic control, insulin requirement, and glucose metabolism in insulin-treated diabetic patients. Diabetes 36: 136–146

  28. 28.

    Reich A, Abraira C, Lawrence AM (1987) Combined glyburide and insulin therapy in type II diabetes. Diab Res 6: 99–104

  29. 29.

    Holman RR, Steemson J, Turner RC (1987) Sulphonylurea failure in type 2 diabetes: treatment with basal insulin supplement. Diabetic Med 4: 457–462

  30. 30.

    Gutniak M, Karlander S-V, Efendic S (1987) Glyburide decreases insulin requirement, increases Beta-cell response to mixed meal, and does not affect insulin sensitivity: effects of shortand long-term combined treatment in secondary failure to sulfonylurea. Diabetes Care 10: 545–554

  31. 31.

    Lins P-E, Lundblad S, Persson-Trotzig E, Adamson U (1988) Glibenclamide improves the response to insulin treatment in non-insulin-dependent diabetics with secondary failure to sulfonylurea therapy. Acta Med Scand 223: 171–179

  32. 32.

    Stenman S, Groop P-H, Saloranta C, Totterman KJ, Fyhrqvist F, Groop L (1988) Effects of the combination of insulin and glibenclamide in Type 2 (non-inslulin-dependent) diabetic patients with secondary failure to oral hypoglycaemic agents. Diabetologia 31: 206–213

  33. 33.

    Iavicoli M, Cucinotta D, De Mattia G, Lunetta M, Morsiani M, Pontiroli AE, Pozza G (1988) Blood glucose control and insulin secretion improved with combined therapy in type 2 diabetic patients with secondary failure to oral hypoglycemic agents. Diabetes Med 5: 849–855

  34. 34.

    Clarke WL, Haymond M, Santiago J (1980) Overnight basal insulin requirements in fasting insulin-dependent diabetics. Diabetes 29: 78–80

  35. 35.

    Bolli GB, Gerich JE (1984) The “dawn phenomenon”: a common occurrence in both non-insulin-dependent and insulin-dependent diabetes mellitus. N Engl J Med 300: 746–750

  36. 36.

    Hamelbeck H, Lein W, Zoltobrocki M, Schoffling K (1982) Glibenclamid-Insulin-Kombinationsbehandlung beim Sekundarversagen der Sulfonylharnstoff-Therapie. Dtsch Med Wochenschr 107: 1581–1583

  37. 37.

    Eaton RP, Allen RC (1981) Tolbutamide reverses insulin-resistant diabetes. Diabetes Care 4: 299–304

  38. 38.

    De Fronzo RA, Binder C, Wahren J, Felig P, Ferrannini E, Faber OK (1981) Sensitivity of insulin secretion to feedback inhibition by hyperinsulinaemia. Acta Endocrinol 98: 81–85

  39. 39.

    Meglasson MD, Matschinsky FM (1986) Pancreatic islet glucose metabolism and regulation of insulin secretion. Diabet Metab Res 2: 163–214

  40. 40.

    Leahy JL, Bonner Weir S, Weir GC (1984) Abnormal glucose regulation of insulin secretion in models of reduced B-cell mass Diabetes 33: 667–673

  41. 41.

    Groop L, Bonadonna R, Del Prato S, Ratheiser K, Zyck K, Ferrannini E, De Fronzo RA (1989) Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus: evidence for multiple sites of insulin resistance. J Clin Invest 84: 205–213

  42. 42.

    Ferrannini E, Barret E, Bevilacqua S, De Fronzo RA (1983) Effect of fatty acids on glucose production and utilization in man. J Clin Invest 72: 1737–1747

  43. 43.

    Blumenthal SA (1983) Stimulation of gluconeogenesis by palmitic acid in rat hepatocytes: evidence that this effect can be dissociated from provision of reducing equivalents. Metabolism 32: 971–976

  44. 44.

    Taskinen M-R, Sane T, Helve E, Karonen S-L, Nikkila EA, Yki-Jarvinen H (1989) Bedtime insulin for suppression of overnight free-fatty acid, blood glucose, and glucose production in NIDDM. Diabetes 38: 580–588

  45. 45.

    Riddle MC (1985) New tactics for type 2 diabetes: regimens based on intermediate-long acting insulin taken at bed time. Lancet 1: 192–195

Download references

Author information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Del Prato, S., de Kreutzenberg, S.V., Riccio, A. et al. Partial recovery of insulin secretion and action after combined insulin-sulfonylurea treatment in Type 2 (non-insulin-dependent) diabetic patients with secondary failure to oral agents. Diabetologia 33, 688–695 (1990).

Download citation

Key words

  • insulin
  • sulfonylurea
  • combined therapy
  • insulin action
  • insulin secretion
  • metabolic control