1564-P: Hepatic Lipid Content Associates with Fasting and Prandial Glucagon Secretion in Recent-Onset Type 2 Diabetes

Hyperglycemia in type 2 diabetes (T2D) associates with higher glucagon secretion, which may be further promoted in the presence of metabolic dysfunction-associated steatotic liver disease (MASLD). Thus, we compared fasting and prandial glucagonemia in people with and without recent-onset T2D and MASLD. Participants of the German Diabetes Study (GDS), with T2D (n=50; known duration <1 year) or with normal glucose tolerance (NGT; n=50), underwent mixed meal tolerance tests (MMT; 365 kcal) and hyperinsulinemic-normoglycemic clamps. Early prandial glucose and hormone secretion were quantified by incremental areas under the time curve (iAUC_0-60min) and hepatic lipid content (HCL) by ¹H-magnetic resonance spectroscopy. Associations of HCL (log) and glucagon secretion in people with T2D were assessed by age, sex and BMI-adjusted multiple linear regression. Both groups were similar in age (~53 yrs), sex (~66% male) and BMI (~29 kg/m²)(all p>0.05), whereas T2D featured lower insulin sensitivity (M-value: 7.2±2.7 vs. 9.8±3.1 mg/kg*min, p<0.001), higher Hb_A1c (6.3±0.8 vs. 5.3±0.3 % (43.9±8.3 vs. 34.2±2.9 mmol/mol), p<0.001), HCL (6.6±6.8 vs. 4.0±5.0 %, p=0.008), fasting glucagon (9.4±4.9 vs. 7.2±4.6 pmol/L, p=0.021) and C-peptide (2.53±0.94 vs. 1.78±0.95 ng/mL, p<0.001) and - by trend - more likely MASLD (41% vs. 24%, p=0.056). During MMT, iAUC_0-60min of glucose (100±52 vs. 37±23 mmol/L*min) and of glucagon (538±261 vs. 306±249 pmol/L*min) were greater, while C-peptide iAUC_0-60min (153±69 vs. 235±97 ng/mL*min) was lower than in NGT (all p<0.001). In the regression analyses, an increase in HCL associated with both higher fasting glucagon (β=2.2, p=0.023, model R²= 0.336, p<0.001) and glucagon iAUC_0-60min (β=181.4, p=0.002, model R²= 0.204, p=0.033) in people with T2D.

In conclusion, fasting and prandial glucagon secretion is already elevated in recently-diagnosed and near-normoglycemic T2D, which are further exacerbated with rising liver lipid storage.