title: Insulin reciprocally regulates glucagon secretion in humans.
abstract: OBJECTIVE
  We tested the hypothesis that an increase in insulin per se, i.e., in the absence of zinc, suppresses glucagon secretion during euglycemia and that a decrease in insulin per se stimulates glucagon secretion during hypoglycemia in humans.
  
  
  METHODS
  We measured plasma glucagon concentrations in patients with type 1 diabetes infused with the zinc-free insulin glulisine on three occasions. Glulisine was infused with clamped euglycemia (∼95 mg/dl [5.3 mmol/l]) from 0 to 60 min on all three occasions. Then, glulisine was discontinued with clamped euglycemia or with clamped hypoglycemia (∼55 mg/dl [3.0 mmol/l]) or continued with clamped hypoglycemia from 60 to 180 min.
  
  
  RESULTS
  Plasma glucagon concentrations were suppressed by -13 ± 3, -9 ± 3, and -12 ± 2 pg/ml (-3.7 ± 0.9, -2.6 ± 0.9, and -3.4 ± 0.6 pmol/l), respectively, (all P < 0.01) during zinc-free hyperinsulinemic euglycemia over the first 60 min. Glucagon levels remained suppressed following a decrease in zinc-free insulin with euglycemia (-14 ± 3 pg/ml [-4.0 ± 0.9 pmol/l]) and during sustained hyperinsulinemia with hypoglycemia (-14 ± 2 pg/ml [-4.0 ± 0.6 pmol/l]) but increased to -3 ± 3 pg/ml (-0.9 ± 0.9 pmol/l) (P < 0.01) following a decrease in zinc-free insulin with hypoglycemia over the next 120 min.
  
  
  CONCLUSIONS
  These data indicate that an increase in insulin per se suppresses glucagon secretion and a decrease in insulin per se, in concert with a low glucose concentration, stimulates glucagon secretion. Thus, they document that insulin is a β-cell secretory product that, in concert with glucose and among other signals, reciprocally regulates α-cell glucagon secretion in humans.
authors.affiliation: Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Cooperberg
authors.forename: Philip E
authors.initials: PE
authors.lastname: Cryer
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000097:blood*; D005260:Female; D005934:Glucagon / Q000097:blood / Q000187:drug effects / Q000378:metabolism*; D015309:Glucose Clamp Technique; D006442:Glycated Hemoglobin / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D055815:Young Adult
chemical_list: D005934:Glucagon; D006442:Glycated Hemoglobin; D007328:Insulin
references.citation: J Clin Invest. 1984 Dec;74(6):2296-9
references.pmid: 6392344
references.citation: Diabetes. 1993 Dec;42(12):1791-8
references.pmid: 8243825
references.citation: Diabetes. 2008 Jul;57(7):1905-17
references.pmid: 18390791
references.citation: Diabetes. 2007 Apr;56(4):1107-12
references.pmid: 17317764
references.citation: Diabetes Care. 2009 Dec;32(12):2275-80
references.pmid: 19729529
references.citation: Diabetes Care. 1993 Aug;16(8):1124-30
references.pmid: 8375242
references.citation: Diabetes Technol Ther. 2007 Feb;9(1):109-21
references.pmid: 17316105
references.citation: Pancreas. 2001 Oct;23(3):302-8
references.pmid: 11590327
references.citation: Diabetes. 2009 May;58(5):1175-84
references.pmid: 19228810
references.citation: Diabetes. 2009 Feb;58(2):403-11
references.pmid: 18984743
references.citation: J Endocrinol. 2008 Oct;199(1):5-19
references.pmid: 18669612
references.citation: Diabetes. 2010 Jan;59(1):128-34
references.pmid: 19808893
references.citation: Cell Metab. 2006 Jan;3(1):47-58
references.pmid: 16399504
references.citation: J Biol Chem. 2005 Sep 30;280(39):33487-96
references.pmid: 16027126
references.citation: Science. 1973 Oct 12;182(4108):171-3
references.pmid: 4581053
references.citation: Diabetes Care. 2005 Nov;28(11):2691-6
references.pmid: 16249541
references.citation: Diabetes. 2003 May;52(5):1195-203
references.pmid: 12716752
references.citation: Diabetes. 1984 Aug;33(8):732-7
references.pmid: 6378698
references.citation: N Engl J Med. 1982 Oct 28;307(18):1106-12
references.pmid: 7121528
references.citation: Horm Res. 2001;56(5-6):151-8
references.pmid: 11910200
references.citation: N Engl J Med. 1983 Mar 3;308(9):485-91
references.pmid: 6337335
references.citation: Physiology (Bethesda). 2007 Aug;22:241-51
references.pmid: 17699877
references.citation: Am J Physiol Endocrinol Metab. 2008 Oct;295(4):E751-61
references.pmid: 18647881
references.citation: J Biol Chem. 1964 Jan;239:18-30
references.pmid: 14114842
references.citation: J Biochem. 1981 Jun;89(6):1799-803
references.pmid: 7287653
references.citation: APMIS. 2003 Dec;111(12):1147-54
references.pmid: 14678025
references.citation: Diabetes. 1993 Apr;42(4):550-5
references.pmid: 8454105
references.citation: Trends Endocrinol Metab. 2008 Oct;19(8):277-84
references.pmid: 18771934
references.citation: Endocr Rev. 2007 Feb;28(1):84-116
references.pmid: 17261637
references.citation: Diabetes. 2006 Mar;55(3):659-66
references.pmid: 16505228
references.citation: J Clin Invest. 1993 Mar;91(3):819-28
references.pmid: 8450063
references.citation: Endocr Rev. 2007 May;28(3):253-83
references.pmid: 17409288
references.citation: Diabetes. 2002 Apr;51(4):958-65
references.pmid: 11916913
references.citation: Clin Sci (Lond). 2000 Nov;99(5):351-62
references.pmid: 11052915
references.citation: Physiol Rev. 2007 Oct;87(4):1409-39
references.pmid: 17928588
references.citation: Diabetes. 2005 Jun;54(6):1808-15
references.pmid: 15919803
references.citation: Diabetes. 2005 Mar;54(3):757-64
references.pmid: 15734853
references.citation: J Lab Clin Med. 1985 Dec;106(6):624-9
references.pmid: 4067376
references.citation: Diabetes. 1998 Jul;47(7):995-1005
references.pmid: 9648820
references.citation: Diabetes Care. 2005 May;28(5):1124-31
references.pmid: 15855577
references.citation: Diabetes. 1977 Jan;26(1):22-9
references.pmid: 830562