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Abstract
Background
Leprechaunism, which is caused by insulin receptor defect, is clinically characterized by hyperinsulinemia, stunted growth, dysmorphic somatic abnormalities, lipodystrophy and early death around 2-3 years of age.
Methods
In this study we describe 2 cases of Korean leprechaunism patients. In addition, the disturbed insulin induced effects such as glucose uptake, insulin binding assay, thymidine uptake and PDGF stimulated phosphorylation change were investigated using the fibroblasts from 1 Korean patient and those from 4 foreign leprechaunism patients.
Figures and Tables
Fig. 2
Phase contrast microscopy of cultured fibroblasts, a) from a normal control and b) from a patient with leprechaunism.
Fig. 3
Stimulation of glucose uptake by insulin in normal controls and patients fibroblasts. Glucose uptake was measured as described in the Materials Method. Data are represented mean (± S.D. Significant differences in insulin-stimulated glucose uptake were not noted between all leprechaunism patient fibroblasts (Normal: P < 0.05, Patient: P < 0.001). Statistical comparisons between the means were made with t-test.
Fig. 4
Insulin stimulation of thymidine incorporation in the fibroblasts derived from patients and normal control. Cells were growth-arrested by incubating the cells in serum-free DMEM for 48 h. The cells were incubated with increasing concentrations of insulin. After 16 h of incubation, cells were labeled with 0.5 µCi/ml of [3H]thymidine for another 4h. The radioactivity was counted using a scintillation counter. Data are expressed as mean ± SEM. Statistical comparisons between the means were made with Mann-Whitney test.
Fig. 5
Receptor binding assay. a, c) Binding of 125I-IGF-1; b, d) binding of 125I-insulin. In receptor binding assay, the cell extracts were incubated with increasing concentrations (a, 0-10000ng/ml, c, 0-5000ng/ml) of 125I-IGF-I and 125I-insulin (b, 0-10000ng/ml, d, 0-5000ng/ml). Data are represented mean ± S.D. Statistical comparisons between the means were made with Mann-Whitney test.
References
1. Cohen P, Nimmo HG, Proud CG. How does insulin stimulate glycogen synthesis? Biochem Soc Symp. 1978. 43:69–95.
2. Olefsky JM, Ciaraldi TP, Kolterman OG. Mechanisms of insulin resistance in non-insulin-dependent (type II) diabetes. Am J Med. 1985. 79:12–22.
3. Lyen KR. The insulin receptor. Ann Acad Med Singapore. 1985. 14:364–373.
4. Tan MH, Bonen A. Insulin receptors: their roles in the pathogenesis and management of type II diabetes mellitus. Ann Acad Med Singapore. 1985. 14:360–363.
5. Takahashi Y, Tobe K, Kadowaki H, Katsumata D, Fukushima Y, Yazaki Y, Akanuma Y, Kadowaki T. Roles of insulin receptor substrate-1 and Shc on insulin-like growth factor I receptor signaling in early passages of cultured human fibroblasts. Endocrinology. 1997. 138:741–750.
6. Tsujino G, Yoshinaga T. A case of leprechaunism and an analysis of some clinical manifestations of this syndrome. Z Kinderheilk. 1975. 118:347–445.
7. Longo N, Wang Y, Smith SA, Langley SD, DiMeglio LA, Giannella-Neto D. Genotype-phenotype correlation in inherited severe insulin resistance. Hum Mol Genet. 2002. 11:1465–1475.
8. Accili D, Drago J, Lee EJ, Johnson MD, Cool MH, Salvatore P, Asico LD, Jose PA, Taylor SI, Westphal H. Early neonatal death in mice homozygous for a null allele of the insulin receptor gene. Nat genet. 1996. 12:106–109.
9. Michael MD, Kulkarni RN, Postic C, Previs SF, Shulman GI, Magnuson MA, Kahn CR. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol Cell. 2000. 6:87–97.
10. Yamauchi T, Tobe K, Tamemoto H, Ueki K, Kaburagi Y, Yamamoto-Honda R, Takahashi Y, Yoshizawa F, Aizawa S, Akanuma Y, Sonenberg N, Yazaki Y, Kadowaki T. Insulin signaling and insulin actions in the muscles and livers of insulin-resistant, insulin receptor substrate 1 deficient mice. Mol Cell Biol. 1996. 16:3074–3084.
11. Bruning JC, Winnay J, Bonner-Weir S, Taylor SI, Accili D, Kahn CR. Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles. Cell. 1997. 88:561–572.
12. Katz EB, Stenbit AE, Hatton K, DePinho R, Charron MJ. Cardiac and adipose tissue abnormalities but not diabetes in mice deficient in GLUT4. Nature. 1995. 377:151–155.
13. Bruning JC, Michael MD, Winnay JN, Hayashi T, Horsch D, Accili D, Goodyear LJ, Kahn CR. A muscle specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. Mol Cell. 1998. 2:559–569.
14. Garg A, Wilson R, Barnes R, Arioglu E, Zaidi Z, Gurakan F, Kocak N, O'Rahilly S, Taylor SI, Patel SB, Bowcock AM. A gene for congenital general lipodystrophy maps to human chromosome 9q34. J Clin Endocrinol Metab. 1999. 84:3390–3394.
15. Nakae J, Kato M, Murashita M, Shinohara N, Tajima T, Fujieda K. Long-term effect of recombinant human insulin-like growth factor I on metabolic and growth control in a patient with leprechaunism. J Clin Endocrinol Metab. 1998. 83:542–549.
16. Takahashi Y, Tobe K, Kadowaki H, Katsumata D, Fukushima Y, Yazaki Y, Akanuma Y, Kadowaki T. Roles of insulin receptor substrate-1 and Shc on insulin-like growth factor I receptor signaling in early passages of cultured human fibroblasts. Endocrinology. 1997. 138:741–750.
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