Endocrine Abstracts

Impaired glucagon suppression is an overlooked contributor to the transition of prediabetes to type 2 diabetes. We used Graded Glucose Infusion (GGI) to examine the relationship of ISR and Glucagon Secretion Rate (GSR) with rising glucose. We studied 39 non-diabetic, weight-stable individuals (53±2 yrs, 30±1 Kg/M²) categorized by fasting and glucose tolerance status following a 75g OGTT at the time of screening. After an overnight fast, at 07:00 a variable insulin infusion was used to maintain glucose at ~4.4 mmol/l (until 08:30) enabling the subsequent measurement of ISR and GSR in response to rising glucose concentrations. At 09:00 GGI commenced, starting at 1 mg/kg/min and doubling every 60 min until 13:00. GSR and ISR were calculated by nonparametric deconvolution from plasma concentrations of glucagon and c-peptide respectively. GSR exhibited an exponential relationship with glucose, that could be characterized by τ – the change in glucose necessary to suppress GSR by 50%. τ was increased in people with impaired fasting glucose (IFG) compared to those with normal fasting glucose (NFG) regardless of the presence or absence of impaired or normal glucose tolerance (IGT or NGT – 1.4±0.2 vs. 1.5±0.2 vs. 2.0±0.2 vs. 2.5±0.3 mmol/l, P <0.01, NFG/NGT vs. NFG/IGT vs. IFG/NGT vs. IFG/IGT respectively). The glycemic threshold for stimulation of ISR was lower in subjects with IGT, regardless of the presence or absence of IFG (4.7±0.1 vs. 4.4±0.1 vs. 4.9±0.1 vs. 4.4±0.1 mmol/l, P <0.01, NFG/NGT vs. NFG/IGT vs. IFG/NGT vs. IFG/IGT respectively). These data show that in non-diabetic humans, both α-cell and β-cell dysfunction contribute differentially to the subtypes of prediabetes. This may have implications for the design of targeted interventions for prediabetes.