title: The disposition index does not reflect β-cell function in IGT subjects treated with pioglitazone.
abstract: OBJECTIVE
  The insulin secretion/insulin resistance (IR) (disposition) index (ΔI/ΔG ÷ IR, where Δ is change from baseline, I is insulin, and G is glucose) is commonly used as a measure of β-cell function. This relationship is curvilinear and becomes linear when log transformed. ΔI is determined by 2 variables: insulin secretion rate (ISR) and metabolic clearance of insulin. We postulated that the characteristic curvilinear relationship would be lost if Δ plasma C-peptide (ΔCP) (instead of Δ plasma insulin) was plotted against insulin sensitivity.
  
  
  METHODS
  A total of 441 individuals with impaired glucose tolerance (IGT) from ACT NOW received an oral glucose tolerance test and were randomized to pioglitazone or placebo for 2.4 years.
  
  
  RESULTS
  Pioglitazone reduced IGT conversion to diabetes by 72% (P < .0001). ΔI/ΔG vs the Matsuda index of insulin sensitivity showed the characteristic curvilinear relationship. However, when ΔCP/ΔG or ΔISR/ΔG was plotted against the Matsuda index, the curvilinear relationship was completely lost. This discordance was explained by 2 distinct physiologic effects that altered plasma insulin response in opposite directions: 1) increased ISR and 2) augmented metabolic clearance of insulin. The net result was a decline in the plasma insulin response to hyperglycemia during the oral glucose tolerance test. These findings demonstrate a physiologic control mechanism wherein the increase in ISR ensures adequate insulin delivery into the portal circulation to suppress hepatic glucose production while delivering a reduced but sufficient amount of insulin to peripheral tissues to maintain the pioglitazone-mediated improvement in insulin sensitivity without excessive hyperinsulinemia.
  
  
  CONCLUSIONS
  These results demonstrate the validity of the disposition index when relating the plasma insulin response to insulin sensitivity but underscore the pitfall of this index when drawing conclusions about β-cell function, because insulin secretion declined despite an increase in the plasma insulin response.
authors.affiliation: Texas Diabetes Institute and University of Texas Health Science Center at San Antonio (R.A.D., D.T., M.A.-G., N.M., A.G.), South Texas Veterans Health Care System Audie Murphy Division (R.A.D., D.T.), San Antonio, Texas 78229; and Cardiometabolic Risk Unit, Institute of Clinical Physiology (A.G.), 56124 Pisa, Italy.
authors.forename: Ralph A
authors.initials: RA
authors.lastname: DeFronzo
authors.forename: Devjit
authors.initials: D
authors.lastname: Tripathy
authors.forename: Muhammad
authors.initials: M
authors.lastname: Abdul-Ghani
authors.forename: Nicolas
authors.initials: N
authors.lastname: Musi
authors.forename: Amalia
authors.initials: A
authors.lastname: Gastaldelli
mesh_terms: D001786:Blood Glucose / Q000187:drug effects; D015992:Body Mass Index; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D005500:Follow-Up Studies; D018149:Glucose Intolerance / Q000188:drug therapy* / Q000378:metabolism; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D000077205:Pioglitazone; D010919:Placebos; D045162:Thiazolidinediones / Q000627:therapeutic use*
chemical_list: D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D000077205:Pioglitazone; D010919:Placebos; D045162:Thiazolidinediones; C517652:hemoglobin A1c protein, human