Arginine is preferred to glucagon for stimulation testing of β-cell function

Abstract

A key aspect of research into the prevention and treatment of type 2 diabetes is the availability of reproducible clinical research methodology to assess β-cell function. One commonly used method employs nonglycemic secretagogues like arginine (arg) or glucagon (glgn). This study was designed to quantify the insulin response to arg and glgn and determine test repeatability and tolerability. Obese overnight-fasted subjects with normal glucose tolerance were studied on 4 separate days: twice using arg (5 g iv) and twice with glgn (1 mg iv). Pre- and postinfusion samples for plasma glucose, insulin, and C-peptide were acquired. Arg and glgn challenges were repeated in the last 10 min of a 60-min glucose (900 mg/min) infusion. Insulin and C-peptide secretory responses were estimated under baseline fasting glucose conditions (AIRarg and AIRglgn) and hyperglycemic (AIRargMAX AIRglgnMAX) states. Relative repeatability was estimated by intraclass correlation coefficient (ICC). Twenty-three (12 men and 11 women) subjects were studied (age: 42.4 ± 8.3 yr; BMI: 31.4 ± 2.8 kg/m²). Geometric means (95% CI) for baseline-adjusted values AIRarg and AIRglgn were 84 (75-95) and 102 (90-115) μU/ml, respectively. After the glucose infusion, AIRargMAX and AIRglgnMAX were 395 (335-466) and 483 (355-658) μU/ml, respectively. ICC values were >0.90 for AIRarg andAIRargMAX. Glucagon ICCs were 0.83, 0.34, and 0.36, respectively, although the exclusion of one outlier increased the latter two values (to 0.84 and 0.86). Both glgn and arg induced mild adverse events that were transient. Glucagon, but not arginine, induced moderate adverse events due to nausea. Taken together, arginine is preferred to glucagon for assessment of β-cell function.

Keywords: arginine; glucagon; insulin secretion; β-cell function.

Fig. 1.

Plasma glucose levels during arginine-induced insulin secretion and glucagon-induced insulin secretion studies. Left: the first intravenous pulse of arginine (5 g) was given at time 0; the continuous glucose infusion was started at 20 min, and at 80 min the second pulse of arginine was given. Right: glucagon (1 mg) was given instead of arginine. In both cases the target glucose level of ∼300 mg/dl was reached in 60 min, although the values were slightly higher after the glucagon pulses.

Fig. 2.

Plasma insulin levels during arginine-induced insulin secretion and glucagon-induced insulin secretion stimulation tests. Both arginine (left) and glucagon (right) elicited acute insulin responses (AIRarg and AIRglgn) before the glucose infusions that were potentiated by the glucose infusions (AIRargMAX and AIRglgnMAX).

Fig. 3.

Plasma C-peptide levels during arginine-induced C-peptide secretion and glucagon-induced C-peptide secretion stimulation tests. Both arginine (left) and glucagon (right) elicited acute C-peptide responses (ACRarg and ACRglgn) before the glucose infusions that were potentiated by the glucose infusions (ACRargMAX and ACRglgnMAX).

Fig. 4.

Plasma glucagon concentrations during arginine-induced insulin secretion. Arginine-stimulated glucagon responses both in the baseline normoglycemic state and during hyperglycemia. These responses were lower during hyperglycemia, which is consistent with the known ability of hyperglycemia to dampen glucagon secretion.