title: Insulin dose-response studies in severely insulin-resistant type 2 diabetes--evidence for effectiveness of very high insulin doses.
abstract: OBJECTIVE
  To combat diabetic complications strict glycaemic control is desirable in type 2 diabetes, but some patients are severely insulin resistant and it is not known whether high doses of insulin are effective. This study was designed to determine the acute dose-response effects of insulin in patients with type 2 diabetes and severe insulin resistance.
  
  
  METHODS
  We included eight insulin-resistant (mean insulin dose: 186 IU/day; body mass index: 35) subjects with type 2 diabetes in a single-blinded, randomized crossover study. Each subject was studied on two occasions. On each occasion, subjects underwent two 3-h hyperinsulinaemic euglycaemic clamps. The subjects were randomized to two low-dose insulin infusions (0.5 and 1.5 mU/kg/min in random order) on one occasion and to two high-dose insulin infusions (3.0 and 5.0 mU/kg/min in random order) on another occasion.
  
  
  RESULTS
  On all occasions, steady-state glucose infusion rates (SSGIRs) were accomplished and we observed a clear dose-response relationship with GIR values of 0.4 ± 0.2 (s.e.), 2.6 ± 0.6, 3.7 ± 0.8 and 4.9 ± 0.9 mg/kg/min during the 0.5, 1.5, 3.0 and 5.0 mU/kg/min insulin infusions, respectively (p < 0.001). Likewise, there was a dose-dependent suppression of endogenous glucose production (EGP) (p < 0.009), plasma free fatty acids (FFAs) (p < 0.001) and plasma glucagon (p = 0.001).
  
  
  CONCLUSIONS
  Our results show that the insulin dose response in terms of GIR and EGP is preserved for insulin doses corresponding to >800 IU/day, suggesting effectiveness of very high insulin doses in severely insulin-resistant subjects.
authors.affiliation: Department of Endocrinology and Internal Medicine, NBG/THG, Aarhus University Hospital, Aarhus, Denmark. ulla@opstrup.dk
authors.forename: U
authors.initials: U
authors.lastname: Kampmann
authors.forename: P
authors.initials: P
authors.lastname: Hoeyem
authors.forename: A
authors.initials: A
authors.lastname: Mengel
authors.forename: O
authors.initials: O
authors.lastname: Schmitz
authors.forename: J
authors.initials: J
authors.lastname: Rungby
authors.forename: L
authors.initials: L
authors.lastname: Orskov
authors.forename: N
authors.initials: N
authors.lastname: Møller
mesh_terms: D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D019317:Evidence-Based Medicine; D005260:Female; D006801:Humans; D006946:Hyperinsulinism / Q000097:blood / Q000188:drug therapy* / Q000517:prevention & control; D007328:Insulin / Q000008:administration & dosage* / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index
chemical_list: D007328:Insulin