title: Quantification of β-cell insulin secretory function using a graded glucose infusion with C-peptide deconvolution in dysmetabolic, and diabetic cynomolgus monkeys.
abstract: BACKGROUND
  Quantitation of β-cell function is critical in better understanding of the dynamic interactions of insulin secretion, clearance and action at different phases in the progression of diabetes. The present study aimed to quantify β-cell secretory function independently of insulin sensitivity in the context of differential metabolic clearance rates of insulin (MCRI) in nonhuman primates (NHPs).
  
  
  METHODS
  Insulin secretion rate (ISR) was derived from deconvolution of serial C-peptide concentrations measured during a 5 stage graded glucose infusion (GGI) in 12 nondiabetic (N), 8 prediabetic or dysmetabolic (DYS) and 4 overtly diabetic (DM) cynomolgus monkeys. The characterization of the monkeys was based on the fasting glucose and insulin concentrations, glucose clearance rate measured by intravenous glucose tolerance test, and insulin resistance indices measured in separate experiments. The molar ratio of C-peptide/insulin (C/I) was used as a surrogate index of hepatic MCRI.
  
  
  RESULTS
  Compared to the N monkeys, the DYS with normal glycemia and hyperinsulinemia had significantly higher basal and GGI-induced elevation of insulin and C-peptide concentrations and lower C/I, however, each unit of glucose-stimulated ISR increment was not significantly different from that in the N monkeys. In contrast, the DM monkeys with β-cell failure and hyperglycemia had a depressed GGI-stimulated ISR response and elevated C/I.
  
  
  CONCLUSIONS
  The present data demonstrated that in addition to β-cell hypersecretion of insulin, reduced hepatic MCRI may also contribute to the development of hyperinsulinemia in the DYS monkeys. On the other hand, hyperinsulinemia may cause the saturation of hepatic insulin extraction capacity, which in turn reduced MCRI in the DYS monkeys. The differential contribution of ISR and MCRI in causing hyperinsulinemia provides a new insight into the trajectory of β-cell dysfunction in the development of diabetes. The present study was the first to use the GGI and C-peptide deconvolution method to quantify the β-cell function in NHPs.
authors.affiliation: Cardiovascular and Metabolic Diseases Research, Crown Bioscience Inc,, 6 Beijing West Road, Science & Technology Park, Taicang Economic Development Area, Taicang, Jiangsu Province 215400, P,R, China. yxwang@crownbio.com.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wang
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Hansen
authors.forename: Da
authors.initials: D
authors.lastname: Shi
authors.forename: Yupeng
authors.initials: Y
authors.lastname: Fang
authors.forename: Fenglai
authors.initials: F
authors.lastname: Du
authors.forename: Bingdi
authors.initials: B
authors.lastname: Wang
authors.forename: Yaxiong Michael
authors.initials: YM
authors.lastname: Chen
authors.forename: Francine M
authors.initials: FM
authors.lastname: Gregoire
authors.forename: Yi-Xin Jim
authors.initials: YX
authors.lastname: Wang