Introduction and Objective: While β cell dysfunction represents a key pathogenetic factor in T2D onset, collecting appropriate pancreatic samples from metabolically profiled donors has proven challenging. In this study, we investigate possible mirroring between in vivo insulin secretion and ex vivo islet function of subjects with and without T2D.Methods: 36 subjects in list for pancreatectomy underwent OGTT and hyperglycemic clamp (HC) and were divided in: non-diabetic (ND n=23) and diabetics (DM n=13). Parameters of β cell function were calculated by C-peptide deconvolution. Islets were isolated from tissues collected during surgery by collagenase P digestion, followed by Lympholyte separation. Islets were stimulated with 3.3 and 16.7 mM glucose (G) and 20 mM arginine (Arg). Insulin levels were assessed by ELISA. SI16.7 was the ratio of insulin at 16.7 and 3.3 mM G stimulation; SIArg was the ratio of insulin at 20 mM Arg and 3.3 G stimulationResults: DM displayed reduced SI16.7 compared to ND (p=0.02). In ND, SIArg was negatively correlated to basal glucose (r=0.45, p=0.03). In DM, SI16.7 was associated with C-peptide AUC during OGTT (r=0.45 p=0.02) and with the following parameters: total and basal insulin secretion rate (tISR, r=0.66 p=0.01; bISR r=0,67 p<0.01), Glucose Sensitivity (r=0.59, p=0.02) and with standardized insulin secretion at 8 mmol/L glucose (r=0.55, p=0.04). Additionally, in DM but not in ND, SI16.7 was positively correlated with HC-derived second phase insulin secretion (ISR2nd r=0.82 p<0.01).Conclusion: In ND, ex vivo stimulation reflects poorly in vivo function, illuminating the role of other players beyond β cells in normal glucose homeostasis. Conversely, in DM, the surprisingly preserved ability to respond to high glucose is closely correlated with functional parameters in vivo, suggesting an heightened β cell autonomous role in metabolic control under T2D conditions, and the extreme heterogeneity in ex vivo functional responses.
G. Di Giuseppe: None. G. Gliozzo: None. E. Di Piazza: None. L. Carciero: None. G. Ciccarelli: None. L. Soldovieri: None. M. Brunetti: None. F. Cinti: None. A. Mari: Consultant; Lilly USA LLC, Novo Nordisk, Sanofi. A. Giaccari: Board Member; Novo Nordisk A/S. Speaker’s Bureau; AstraZeneca, Sanofi. Advisory Panel; Sanofi. Speaker’s Bureau; Guidotti. G. Pani: None. T. Mezza: None.
The Italian Ministry of Education, University, and Research GR-2018-12365577; PRIN 2020SH2ZZA); The Italian Ministry of Health (RF-2019–12369293)
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