255-LB: Defining Functional Phenotype in Human Islets across Endocrine Cell Composition, Donor Age, Sex, and Ancestry

Abstract

The Integrated Islet Distribution Program (IIDP) is currently the largest source of human islets for research in the U.S. The IIDP Human Islet Phenotyping Program (HIPP) provides standardized islet assessment and makes these data available to researchers. Since 2016, HIPP has phenotyped 337 islet samples from nondiabetic organ donors (40%F / 60%M, 45±12 years, BMI 29.0±5.4; 52% European, 26% Latino, 8% African, 3% Asian, and 11% other ancestry) . To define the islet structure-function relationships, we integrated physiological profiling of hormone secretion with islet cell composition measured by immunohistochemistry­. We found that % β cells varied significantly (range 34 - 92%; CV 21%) and had a strong negative correlation with % α (range 3 - 59%; CV 33%; r -0.95; p<1.78E-163) and % δ cells (range 1 - 19%; CV 44%; r -0.32, p=2.69E-09) . This variation did not impact basal insulin secretion at 5.6 mM glucose, but insulin secretory responses stimulated by high 16.7 mM glucose, cAMP-evoked potentiation, and KCl-mediated depolarization, were all negatively correlated with % α and δ cells. By contrast, glucagon response to basal 5.6 mM glucose had the strongest negative correlation with % β cells (r -0.31, p=4.25E-09) , but not % δ cells (r 0.03, p=0.63) . Furthermore, the β cell composition did not correlate with age or BMI, but was higher in males vs. females (59.1±12.2% vs. 55.7±11.0%, p=0.0107) and in islets from donors of Asian ancestry (71.2±14.7%, p<0.01) . Finally, we noted that insulin response to KCl-mediated depolarization was significantly lower in islets from donors of African vs. European or Asian ancestry (8.3±4.0 vs. 16.5±8.8 and 13.0±7.0ng/IEQ; p<0.01) . Thus, these data highlight the importance of endocrine cell composition in islet hormone secretion possibly influencing β-α cell paracrine interactions and setpoint of glucagon secretion in response to low glucose. In addition, they suggest that β cell composition and insulin secretion are influenced by sex and ancestry. Disclosure M. Brissova: None. G. Poffenberger: None. D. C. Saunders: None. A. C. Powers: None. J. C. Niland: None. C. Evans-molina: Advisory Panel; Avotres Inc., DiogenX, Isla Technologies, MaiCell Therapeutics, Provention Bio, Inc., Other Relationship; Astellas Pharma Inc., Dompé, Lilly, Research Support; BMS, Nimbus Therapeutics. H. H. Durai: None. S. Mei: None. A. Coldren: None. C. Davis: None. C. Reihsmann: None. A. L. Hopkirk: None. D. Gibson: None. R. Aramandla: None.