Abstract
BackgroundQuantitation 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).MethodsInsulin 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.ResultsCompared 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.ConclusionsThe 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.
Highlights
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
Spontaneous obesity, dysmetabolism and diabetes are uncommon in rodents and their natural history and pathogenesis is inconsistent with clinical observations in humans
Intravenous glucose tolerance test In the absence of well-defined criteria to classify diabetes and glucose intolerance in nonhuman primates (NHPs), we used both fasting glucose and insulin as well as the glucose clearance rates obtained from intravenous glucose tolerance test (ivGTT) performed before the graded glucose infusion (GGI) experiments to evaluate the metabolic stages of the monkeys according to an established protocol [17,18]
Summary
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). Loss of glucose-stimulated insulin secretion from pancreatic islet β-cells is one of the fundamental defects in the pathogenesis of type 2 diabetes (T2D) and portends overt diabetes in humans and in nonhuman primates (NHPs). Spontaneous obesity, dysmetabolism (metabolic syndrome) and diabetes are uncommon in rodents and their natural history and pathogenesis is inconsistent with clinical observations in humans. The NHP models have been characterized for their use in quantifying βcell function, and are indispensable preclinical translational models for investigating the pathogenesis of T2D and for testing or profiling novel anti-diabetic agents
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
