12241 Association Between Brain Glucose And Circulating Glucagon Levels In Response To Acute Hyperglycemia
Authors: Matson Brooke C , Gunawan Felona , Coppoli Anastasia , Jiang Lihong , Rangel Elizabeth Sanchez , Belfort De Aguiar Renata , Rothman Douglas L , Mason Graeme F , Hwang Janice J 
Published: October 2024

Disclosure: B.C. Matson: None. F. Gunawan: None. A. Coppoli: None. L. Jiang: None. E. Sanchez Rangel: None. R. Belfort De Aguiar: None. D.L. Rothman: None. G.F. Mason: None. J.J. Hwang: None.

Recently, there has been renewed interest in glucagon and its role in the pathophysiology of type 2 diabetes and obesity. Glucagon secretion is stimulated in response to hypoglycemia and suppressed in response to hyperglycemia. Fasting and post-prandial hyperglucagonemia are characteristic of type 2 diabetes, although the mechanisms underlying the regulation of glucagon secretion remain incompletely understood. While there is strong data to suggest that glucagon secretion can be modulated in response to central nervous system (CNS) sensing of hypoglycemia, it is unclear whether the CNS plays a role in modulating glucagon secretion under hyperglycemic conditions. In the present abstract, we sought to investigate whether changes in brain glucose during hyperglycemia are associated with changes in glucagon responses to hyperglycemia. Glucagon levels were measured in lean and obese individuals who participated in a previously published study to investigate the effect of obesity on brain glucose metabolism. In that study, participants underwent [1]3C magnetic resonance spectroscopy scanning coupled with a hyperglycemic clamp (target ∼180 mg/dL) using [1-[1]3C] glucose to measure brain glucose uptake and metabolism. Individuals with obesity were observed to have significantly lower brain glucose levels in response to acute hyperglycemia. Here, in an exploratory analysis, we measured plasma glucagon levels at baseline (time 0) and during the hyperglycemic clamp (time 60 min) amongst 6 lean individuals (age 28.5 ± 5.8 years old, BMI 20.5 ± 2.1 kg/m2, A1C 5.4 ± 0.2%) and 4 with obesity (age 30.8 ± 1.9 years old, BMI 31.9 ± 2.0 kg/m2, A1C 5.4 ± 0.2%). While baseline glucagon was not different between groups, glucagon at 60 minutes during the hyperglycemic clamp was higher in obesity (38.2 ± 6.8 pg/mL vs. 25.5 ± 4.6 pg/mL, p=0.01). BMI and glucagon at 60 minutes showed a positive correlation (r=0.74, p=0.01). Moreover, there was a negative correlation between glucagon at 60 minutes and brain glucose levels during the hyperglycemic clamp (r=-0.66, p=0.04), indicating that lower brain glucose levels during hyperglycemia were associated with higher plasma glucagon levels. There were no significant relationships between glucagon and insulin levels or indices of insulin sensitivity including HOMA-IR and Matsuda index calculated from oral glucose tolerance tests. In conclusion, we observe that there is a relationship between reduced change in brain glucose levels during hyperglycemia and higher glucagon levels during hyperglycemia. These data suggest the presence of both central and peripheral impairment in adaptation to hyperglycemia in obesity even in the absence of overt metabolic abnormalities. Whether these changes are cause or consequence of obesity remain unknown.

Presentation: 6/2/2024