Response to Letter to the Editor from Roy et al: "Impaired Suppression of Glucagon in Obese Subjects Parallels Decline in Insulin Sensitivity and Beta-Cell Function".

Roy et al (1) analyzed plasma glucagon levels in relation to insulin sensitivity in Asian Indians with normal glucose tolerance (NGT), impaired fasting glucose (IFG), and impaired glucose tolerance (IGT) and found that their observations are mostly consistent with the results seen in Mexican Americans, particularly in the fasting state (2). Since underlying metabolic abnormalities in pathogenesis of type 2 diabetes mellitus (T2DM) in different populations should be similar, one should not expect to see major differences in results across different ethnicities.

The authors demonstrate a progressive decline in fasting glucagon/insulin ratio from NGT to IGT and with worsening insulin sensitivity, based on quartiles of insulin sensitivity. They did not observe any difference in glucagon/insulin ratio between IFG and IGT individuals. Of note, although we showed a trend in declining glucagon/insulin ratio between IFG and IGT groups, the difference was not statistically significant. The other possibility could be that the number of participants in each category appears too small in their study.

Insulin sensitivity was measured by the Matsuda insulin sensitivity index (MI) during a mixed meal test. Though their observations may be similar, it is not equivalent to MI obtained from an oral glucose tolerance test (OGTT) (3).

The other differences between their observations and our results could be explained by the following. Our study enrolled exclusively obese individuals with a body mass index (BMI) greater than 27, and there was no difference in BMI between the groups (NGT vs IFG/IGT vs T2DM). It is not clear if there was a difference in BMI in their study population. Although plasma glucagon did not differ in relation to BMI, plasma insulin levels are usually higher in obese individuals, which will therefore affect the glucagon/insulin ratio. Roy et al (1) also note that meal-stimulated glucagon responses did not correlate with either insulin sensitivity or insulin secretion. It is well known that glucagon response following OGTT and a mixed meal are different (4). Following an oral glucose load in NGT and IGT patients, there is a progressive decline in glucagon levels whereas following a mixed meal there is usually a transient rise in plasma glucagon followed by a decline, thus the glucagon area under the curve following OGTT and mixed meal cannot be compared.

Overall, there is congruence between plasma glucagon levels and insulin sensitivity in Asian Indians and Mexican Americans, and we agree that future studies with euglycemic insulin clamps at least in a subset of patients will better characterize this relationship. Evaluation of this relationship after interventions such as weight loss will provide further insights into the role of glucagon in pathogenesis of T2DM.