E-Poster 63rd Endocrine Society of Australia Annual Scientific Meeting 2020

Obesity is a well-known risk factor for type 2 diabetes. Diet is therefore a critical aspect, but the effect of different diets on human islet function has yet to be determined.

AIM: This research used “humanised mice” which are diabetic mice transplanted with human islets so that human islets control the mouse’s blood glucose levels (BGL). Mice were fed chow or high-fat diet (HFD) to assess effects on human islets.

METHODS: Female immunodeficient RAG1-null mice (C57Bl/6 background) were used as transplant recipients as this avoids the issue of immune-mediated islet rejection. Prior to transplant, diabetes was induced by alloxan. Mice (N=10) each received 2000IEQ human islets under the kidney capsule from human donors with normal glucose tolerance. Donor pancreases did not yield sufficient islets for human transplantation, and the donors were consented for research use of the islets.

Eight weeks after transplantation, 2 mice which did not have post-transplant resolution of diabetes were excluded. Mice with functioning grafts (n=8) were placed on high-fat diet (HFD, 45% of calories from fat) or continued on normal chow (n=2 for each diet for each of 2 human donors). Glucose tolerance testing (GTT) was performed before and 16 weeks after this diet change.

RESULTS: Mice fed HFD gained significant weight (≥3g) and random-fed BGL were higher (2-3mmol/L) than chow-fed mice with transplants from the same human donors . Formal GTT showed that mice fed HFD had deterioration of their glucose tolerance compared to chow-fed animals and to their pre-diet-change GTTs. Deterioration was more pronounced with donor 282 than 281but glucose tolerance deteriorated with HFD for both donor’s islets (p=<0.01 by 2-way ANOVA).
CONCLUSION: Consumption of HFD caused detrimental effects on human islets even though the original human donors had normal glucose tolerance. These results support the lipotoxicity hypothesis for human islets.