Impact of lack of suppression of glucagon on glucose tolerance in humans

People with type 2 diabetes have defects in both alpha- and beta-cell funct ion. To determine whether lack of suppression of glucagon causes hyperglyce mia when insulin secretion is impaired but not when insulin secretion is in tact, twenty nondiabetic subjects were studied on two occasions. On both oc casions, a "prandial" glucose infusion was given over 5 h while endogenous hormone secretion was inhibited. Insulin was infused so as to mimic either a nondiabetic (n = 10) or diabetic (n = 10) postprandial profile. Glucagon was infused at a rate of 1.25 ng.kg(-1).min(-1), beginning either at time z ero to prevent a fall in glucagon (nonsuppressed study day) or at 2 h to cr eate a transient fall in glucagon (suppressed study day). During the "diabe tic insulin profile, lack of glucagon suppression resulted in a marked incr ease (P < 0.002) in both the peak glucose concentration (11.9 +/- 0.4 vs. 8 .9 +/- 9.4 mmol/l) and the area above basal of glucose (927 +/- 77 vs. 546 +/- 112 mmol.l(-1).6 h) because of impaired (P < 0.001) suppression of gluc ose production. In contrast, during the "nondiabetic" insulin profile, lack of suppression of glucagon resulted in only a slight increase (P < 0.02) i n the peak glucose concentration (9.1 +/- 0.4 vs. 8.4 +/- 0.3 mmol/l) and t he area above basal of glucose (654 +/- 146 vs. 488 +/- 118 mmol.l(-1).6 h) . Of interest, when glucagon was suppressed, glucose concentrations differe d only minimally during the nondiabetic and diabetic insulin profiles. Thes e data indicate that lack of suppression of glucagon can cause substantial hyperglycemia when insulin availability is limited, therefore implying that inhibitors of glucagon secretion and/or glucagon action are likely to be u seful therapeutic agents in such individuals.