1791-P: The Threshold for Fasting Insulin Secretion Is Independent of the Beta-Cell Secretory Response to Glucose in Nondiabetic Humans

The transition from normal fasting glucose (NFG) and normal glucose tolerance (NGT) to type 2 diabetes is characterized by impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). Graded Glucose Infusion (GGI) has been used to measure β-cell function in response to glucose and to extrapolate the β-cell threshold for insulin secretion. However, this assumes a linear relationship between fasting insulin secretion and the response to a GGI. This may not be the case in e.g., humans with IFG/NGT who have normal β-cell function despite IFG. As part of a series of experiments examining the pathogenesis of prediabetes, we examined the relationship of fasting insulin secretion with the subsequent β-cell response to GGI. To do so, we studied nondiabetic, weight-stable individuals (53 ± 2 yrs, BMI 27.5 ± 1.2 kg/m2). At the time of screening, subjects underwent a 75 g oral glucose tolerance test. On the study day, after an overnight fast, at 0700 (-120 min) a variable insulin infusion was used to maintain glucose at ∼80 mg/dL (until 0845). At 0900, GGI commenced (0-240 min total, starting at 1 mg/kg/min and doubling every 60 min). Insulin Secretion Rate (ISR) was estimated by deconvolution of frequently sampled peripheral C-peptide concentrations. The rate of change of ISR in response to increasing glucose concentrations was used to calculate β-cell responsivity to glucose and the set-point of insulin secretion. As expected, ISR rose throughout the study (0.07 ± 0.01, 0.21 ± 0.05, 0.30 ± 0.07, 0.55 ± 0.13, 0.94 ± 0.15 nmol/min; 0, 60, 120, 180, and 240 min respectively). The individual glucose threshold for insulin secretion (4.8 ± 0.1 mmol/l) was independent of β-cell function during the screening glucose tolerance test (R2 = 0.07, p = 0.67) and during the GGI (R2 = 0.06, p = 0.68). These data imply that the glucose threshold for insulin secretion is independent of β-cell function. Disclosure J.D. Kohlenberg: None. M.C. Laurenti: None. A.M. Egan: None. C. Dalla Man: Research Support; Self; Sanofi-Aventis Deutschland GmbH. R.A. Rizza: None. C. Cobelli: None. A. Vella: Advisory Panel; Self; vTv Therapeutics, Zealand Pharma A/S. Research Support; Self; Novo Nordisk A/S, Xeris Pharmaceuticals, Inc. Funding Endocrine Fellows Foundation; National Institutes of Health (R01DK78646, R01DK116231)