Long-term consumption of high saturated-fat diet (HSFD) in animals causes β-cell deterioration due to lipotoxicity. Lipotoxicity in vivo in human islets is currently unproven.
AIM: To use “humanised mice” to examine effects of different dietary lipid composition on human islets in vivo.
METHODS: Immunodeficient RAG1-null mice (C57Bl/6 background) were studied. Recipient mice were made diabetic by Streptozotocin. 45 female mice received 2000IEQ human islets from 8 normal glucose tolerant donors. Mice with functioning grafts (random-fed BGL (rBGL) <10mmol/L, n=36) were then fed chow, high-saturated (HSFD, 45% calories from lipids) or high monounsaturated fat diets (MUFD, 45% of calories from lipids). Glucose tolerance tests (GTT) were performed before and during assigned diets.
RESULTS: Mice fed HSFD gained >10% of body-mass, rBGL were also increased by 16 weeks of diet. In contrast, MUFD mice had significantly lower weight-gain and rBGL which did not differ from chow mice.
By mixed model analysis with Tukey’s correction for multiple comparisons, GTT was significantly worsen in HSFD mice versus chow (p<0.0001), but not MUFD vs chow. Comparing all transplants by mixed model with repeated measures, there was a significant difference between islet preparations, (p<0.0001), and diets (p<0.001) as well as a significant diet-donor-preparation interaction (p=0.001).
HSFD grafts had reduced final β-cell volume which was 46% lower than chow and 23% lower than MUFD. There was also an increase in glucagon staining (alpha-cells) and dual glucagon and insulin positive cells in HSFD grafts, indicated potential β-cell dedifferentiation or β to α cells trans-differentiation.
CONCLUSION: HSFD caused weight-gain and deteriorations on human islets despite all human islet-donors had normal glucose tolerance. Thus far, every human donor shows significant deterioration in GTT with HSFD. MUFD did not cause these deleterious effects. This work has important implications for diet after pancreas- or islet-transplantation and in people with diabetes.