title: Role of the decrement in intraislet insulin for the glucagon response to hypoglycemia in humans.
abstract: OBJECTIVE
  Animal and in vitro studies indicate that a decrease in beta-cell insulin secretion, and thus a decrease in tonic alpha-cell inhibition by intraislet insulin, may be an important factor for the increase in glucagon secretion during hypoglycemia. However, in humans this role of decreased intraislet insulin is still unclear.
  
  
  METHODS
  We studied glucagon responses to hypoglycemia in 14 nondiabetic subjects on two separate occasions. On both occasions, insulin was infused from 0 to 120 min to induce hypoglycemia. On one occasion, somatostatin was infused from -60 to 60 min to suppress insulin secretion, so that the decrement in intraislet insulin during the final 60 min of hypoglycemia would be reduced. On the other occasion, subjects received an infusion of normal saline instead of the somatostatin.
  
  
  RESULTS
  During the 2nd h of the insulin infusion, when somatostatin or saline was no longer being infused, plasma glucose ( approximately 2.6 mmol/l) and insulin levels ( approximately 570 pmol/l) were comparable in both sets of experiments (both P > 0.4). In the saline experiments, insulin secretion remained unchanged from baseline (-90 to -60 min) before insulin infusion and decreased from 1.20 +/- 0.12 to 0.16 +/- 0.04 pmol . kg(-1) . min(-1) during insulin infusion (P < 0.001). However, in the somatostatin experiments, insulin secretion decreased from 1.18 +/- 0.12 pmol . kg(-1) . min(-1) at baseline to 0.25 +/- 0.09 pmol . kg(-1) . min(-1) before insulin infusion so that it did not decrease further during insulin infusion (-0.12 +/- 0.10 pmol . kg(-1) . min(-1), P = 0.26) indicating the complete lack of a decrement in intraislet insulin during hypoglycemia. This was associated with approximately 30% lower plasma glucagon concentrations (109 +/- 7 vs. 136 +/- 9 pg/ml, P < 0.006) and increments in plasma glucagon above baseline (41 +/- 8 vs. 67 +/- 11 pg/ml, P < 0.008) during the last 15 min of the hypoglycemic clamp. In contrast, increases in plasma growth hormone were approximately 70% greater during hypoglycemia after somatostatin infusion (P < 0.007), suggesting that to some extent the increases in plasma glucagon might have reflected a rebound in glucagon secretion.
  
  
  CONCLUSIONS
  These results provide direct support for the intraislet insulin hypothesis in humans. However, the exact extent to which a decrement in intraislet insulin accounts for the glucagon responses to hypoglycemia remains to be established.
authors.affiliation: Carl T. Hayden VA Medical Center, 650 E. Indian School Road, Phoenix, AZ 85012, USA. christian.meyer@med.va.gov
authors.forename: Niyaz R
authors.initials: NR
authors.lastname: Gosmanov
authors.forename: Ervin
authors.initials: E
authors.lastname: Szoke
authors.forename: Zarmen
authors.initials: Z
authors.lastname: Israelian
authors.forename: Tamar
authors.initials: T
authors.lastname: Smith
authors.forename: Philip E
authors.initials: PE
authors.lastname: Cryer
authors.forename: John E
authors.initials: JE
authors.lastname: Gerich
authors.forename: Christian
authors.initials: C
authors.lastname: Meyer
mesh_terms: D000328:Adult; D001786:Blood Glucose; D002096:C-Peptide / Q000097:blood; D004837:Epinephrine / Q000097:blood; D005260:Female; D005934:Glucagon / Q000097:blood* / Q000378:metabolism; D019382:Human Growth Hormone / Q000097:blood; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007003:Hypoglycemia / Q000139:chemically induced / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood*; D007328:Insulin / Q000008:administration & dosage / Q000097:blood* / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D013004:Somatostatin / Q000008:administration & dosage
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D007004:Hypoglycemic Agents; D007328:Insulin; D019382:Human Growth Hormone; D013004:Somatostatin; D005934:Glucagon; D006854:Hydrocortisone; D004837:Epinephrine