The Hypoglycemic Phenotype Is Islet Cell-Autonomous in Short-Chain Hydroxyacyl-CoA Dehydrogenase-Deficient Mice

Abstract

Congenital hyperinsulinism of infancy (CHI) can be caused by inactivating mutations in the gene encoding short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), a ubiquitously expressed enzyme involved in fatty acid oxidation. The hypersecretion of insulin may be explained by a loss of interaction between SCHAD and glutamate dehydrogenase in the pancreatic β-cells. However, there is also a general accumulation of metabolites specific for the enzymatic defect in affected individuals. It remains to be explored whether hypoglycemia in SCHAD CHI can be uncoupled from the systemic effect on fatty acid oxidation. We therefore transplanted islets from global SCHAD knockout (SCHADKO) mice into mice with streptozotocin-induced diabetes. After transplantation, SCHADKO islet recipients exhibited significantly lower random and fasting blood glucose compared with mice transplanted with normal islets or nondiabetic, nontransplanted controls. Furthermore, intraperitoneal glucose tolerance was improved in animals receiving SCHADKO islets compared with those receiving normal islets. Graft β-cell proliferation and apoptosis rates were similar in the two transplantation groups. We conclude that hypoglycemia in SCHAD-CHI is islet cell-autonomous.

Figure 1

Glucose metabolism in male donor mice at age 7–8 weeks, i.e., 3 weeks before transplantation. A: Blood glucose in WT (n = 16) and SCHADKO (n = 16) animals fasted for 24 h. B: Oral glucose tolerance in WT (blue line, n = 7) and SCHADKO (red line, n = 6) animals. C: Serum insulin levels after an overnight fast in WT (n = 7) and SCHADKO (n = 6) animals. *Statistical significance at P = 0.05. ***Statistical significance at P = 0.001.

Figure 2

Effect on random blood glucose (A and B) and body weight (C and D) of transplanting SCHADKO and WT islets into diabetic ICR-SCID mice. A: Measurements of random blood glucose over 11 weeks after transplantation. B: Measurements of random blood glucose after nephrectomy. C: Body weight changes over 11 weeks after transplantation. D: Measurements of body weight after nephrectomy. Time point 0 refers to the date of transplantation (A and C) or nephrectomy (B and D). The red and blue lines represent data from mice that received, respectively, SCHADKO (n = 6) or WT (n = 6) islets and returned to normoglycemia. In panels A and C, the gray line shows measurements in a control group of age-matched, nontransplanted, and euglycemic ICR-SCID mice (n = 8). *Statistical significance at P = 0.05. **Statistical significance at P = 0.01 comparing the SCHADKO and WT transplantation groups.

Figure 3

Glucose metabolism in diabetic mice that received either normal (WT, n = 6; blue) or SCHADKO (n = 6; red) islets and in age-matched, nontransplanted, and euglycemic control ICR-SCID mice (Ctr) (n = 8; gray). A: Fasting blood glucose (24 h). Measurements were done 5 weeks after transplantation. **Statistical significance at P = 0.01. B: Intraperitoneal glucose tolerance at week 10 posttransplantation. *Statistical significance at P = 0.05 comparing the WT group with the controls. C: Serum insulin levels during IPGTT (0, 30, and 90 min after glucose injection).

Figure 4

Immunohistochemistry performed on islet grafts recovered after nephrectomy in the 11th week of the study. Representative sections from the WT and SCHADKO transplantation groups are shown. The dashed white lines indicate outline of the kidney parenchyma. Scale bars are 50 μm. A: Staining performed with fluorescent antibodies against SCHAD (green) and insulin (INS) (red). B: Staining performed with fluorescent antibodies against glucagon (GCG) (green) and insulin (red).