ABSTRACT
AIMS: The gene SLC2A2 encodes GLUT2, which is found predominantly in pancreas, liver, kidney and intestine. In mice, GLUT2 is the major glucose transporter into pancreatic beta cells, and biallelic Slc2a2 inactivation causes lethal neonatal diabetes. The role of GLUT2 in human beta cells is controversial, and biallelic SLC2A2 mutations cause Fanconi-Bickel syndrome (FBS), with diabetes rarely reported. We investigated the potential role of GLUT2 in the neonatal period by testing whether SLC2A2 mutations can present with neonatal diabetes before the clinical features of FBS appear. METHODS: We studied SLC2A2 in patients with transient neonatal diabetes mellitus (TNDM; n = 25) or permanent neonatal diabetes mellitus (PNDM; n = 79) in whom we had excluded the common genetic causes of neonatal diabetes, using a combined approach of sequencing and homozygosity mapping. RESULTS: Of 104 patients, five (5%) were found to have homozygous SLC2A2 mutations, including four novel mutations (S203R, M376R, c.963+1G>A, F114LfsX16). Four out of five patients with SLC2A2 mutations presented with isolated diabetes and later developed features of FBS. Four out of five patients had TNDM (16% of our TNDM cohort of unknown aetiology). One patient with PNDM remains on insulin at 28 months. CONCLUSIONS: SLC2A2 mutations are an autosomal recessive cause of neonatal diabetes that should be considered in consanguineous families or those with TNDM, after excluding common causes, even in the absence of features of FBS. The finding that patients with homozygous SLC2A2 mutations can have neonatal diabetes supports a role for GLUT2 in the human beta cell.
Subject(s)
Diabetes Mellitus/genetics , Fanconi Syndrome/genetics , Glucose Transporter Type 2/genetics , Insulin/metabolism , Mutation , Base Sequence , Carbohydrate Metabolism, Inborn Errors/genetics , DNA Primers , Diabetes Mellitus/diagnosis , Fanconi Syndrome/diagnosis , Female , Humans , Infant, Newborn , Insulin/genetics , Insulin Secretion , MaleABSTRACT
Fourteen neonatal diabetes mellitus(NDM)patients were recruited. 9 patients were treated with glyburide and the other 5 with insulin. ABCC8, KCNJ11, and INS genes were sequenced in 6 of them. Gene mutations were found in 2, 1, and 1 cases in these genes, respectively. One case with 6q24 hypomethylation and another without known mutation were also found. 8 out of 9 patients treated with glyburide reached euglycemia(88.9%). The other 5 patients with insulin therapy either died or lost contact. The results suggest that glyburide therapy is effective in neonatal diabetes mellitus, while insulin therapy may contribute to poor compliance.
ABSTRACT
Objective To investigate the effect of human growth hormone antagonist (GHA) on diabetic nephropathy in mice. Methods Thirty nine C57BL male mice were divided into five groups: normal control, diabetic control, two GHA diabetic mice groups, human growth hormone (hGH) diabetic group. Diabetic mice were induced with Streptozotocin. hGH, GHA1 〔del(1 4), G120R, K168A, E174A, C182S, del(186 191) Cys 1〕 and GHA2 〔H21A, G120R, E174A〕, were respectively administered subcutaneously to diabetic mice for eleven weeks, the effects of them on body weight, urinary protein excretion and renal morphology in mice of all groups were observed. Results All diabetic mice showed growth retardation including hGH and GH antagonist groups when comparing with their nondiabetic mice. The results of kidney histology showed a significant increase in glomerular area 〔hGH:(4289?798)?m 2, DM:(4226?894)?m 2,GHA1:(3511?717)?m 2, GHA2:(3428?919)?m 2, Normal control:(3399?573)?m 2〕 and cell proliferation (hGH:37.4?5.5, DM:34.5?6.4, GHA1:31.1?6.5, GHA2:29.2?6.5, Normal control:29.0?6.0) in hGH and DM control groups compared with two GH antagonist groups and normal control group, but the expansion of mesangial area with increased extracellualar matrix existed in all diabetic mice, no significant difference was observed among diabetic groups. No statistical difference was found among diabetic groups in urinary protein excretion. Conclusion hGH may aggravate glomerular hypertrophy and mesangial cell proliferation in diabetic mice, and hGH antagonists are effective in preventing diabetic mice glomerular hypertrophy, mesangial cell proliferation and maintaining integrity of kidney normal morphology in diabetic mice.
