Chronic consumption of high saturated-fat diet (HSFD) in animals causes beta-cell dysfunction due to lipotoxicity. Lipotoxicity in vivo in human islets is currently unproven.
AIM: To use “humanised mice” to assess effects of different dietary lipid composition on human islets.
METHODS: Immunodeficient RAG1-null mice (C57Bl/6 background) were studied. Recipients were made diabetic by Streptozotocin. 40 female mice received 2000IEQ human islets from normal glucose tolerant donors. Islets were isolated from research-consented organ donors at Tom Mandel islet transplant program, Melbourne. Mice with functioning grafts (random-fed BGL (rBGL) <10mmol/L, n=33) were then fed chow, high-saturated (HSFD, 45% calories from lipids) or high monounsaturated (MUFD, 45% of calories from lipids). Glucose tolerance tests (GTT) were performed before and during assigned diets. Energy expenditure was measured in metabolic cages.
RESULTS: Mice fed HSFD gained >10% of body-mass by 16 weeks of diet. In contrast, MUFD mice had significantly lower weight-gain which was not different from chow mice. Food intake was not significantly different between MUFD and HSFD mice, nor was voluntary exercise. By mixed model analysis with Tukey’s correction for multiple comparisons, GTT was significantly worse in HSFD mice versus chow (p<0.0001), but not MUFD vs chow.
At cull, HSFD mice had greater adipose tissue mass: inguinal p<0.005 versus MUFD, p<0.005 versus chow, epididymal fat p<0.005 versus MUFD and p<0.0005 vs chow. Mice fed HSFD also had reduced graft final beta-cell volume which was 46% lower than chow and 23% lower than MUFD.
CONCLUSION: HSFD caused weight-gain and detrimental effects on human islets even though 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.