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Major insulin gene transcription factors, such as PDX-1 or NeuroD1, have equally important roles in pancreatic development and the differentiation of pancreatic endocrine cells. Previously, we identified and cloned another critical insulin gene transcription factor MafA (RIPE3b1) and reported that other Maf factors were expressed in pancreatic endocrine cells. Maf factors are important regulators of cellular differentiation; to understand their role in differentiation of pancreatic endocrine cells, we analyzed the expression pattern of large-Maf factors in the pancreas of embryonic and adult mice. Ectopically expressed large-Maf factors, MafA, MafB, or cMaf, induced expression from insulin and glucagon reporter constructs, demonstrating a redundancy in their function. Yet in adult pancreas, cMaf was expressed in both alpha- and beta-cells, and MafA and MafB showed selective expression in the beta- and alpha-cells, respectively. Interestingly, during embryonic development, a significant proportion of MafB-expressing cells also expressed insulin. In embryos, MafB is expressed before MafA, and our results suggest that the differentiation of beta-cells proceeds through a MafB+ MafA- Ins+ intermediate cell to MafB- MafA+ Ins+ cells. Furthermore, the MafB to MafA transition follows induction of PDX-1 expression (Pdx-1(high)) in MafB+ Ins+ cells. We suggest that MafB may have a dual role in regulating embryonic differentiation of both beta- and alpha-cells while MafA may regulate replication/survival and function of beta-cells after birth. Thus, this redundancy in the function and expression of the large-Maf factors may explain the normal islet morphology observed in the MafA knockout mice at birth.

Twenty-one patients with pituitary dwarfism were treated with methionine-free hGH (r-hGH) for 6 months with a dosage of 0.5 IU/kg/week. The height of newly treated patients (N = 14), increased from 2.4 to 5.0 cm during treatment, which corresponded to from 4.8 to 10.0 cm with a mean of 8.1 +/- 0.5 cm/year. In switched patients (N = 7), height increased from 2.2 to 3.8 cm during the treatment, which corresponded to 4.4-7.6 cm with a mean of 6.1 +/- 0.5 cm/year, which was similar to that observed in previous treatment with pituitary extracted hGH (p-hGH). Anti-hGH antibody was observed in two patients (9.5%) at the end of 6 months of treatment with a titer of 10. These data indicate that r-hGH has a growth promoting effect and low antigenicity.

Ten patients with idiopathic pituitary dwarfism were treated with methionyl human growth hormone (met-hGH) produced by recombinant DNA technology. They were given 0.5 IU/kg/week of met-hGH for three months. There were no significant changes in physical, blood, urine examinations. Their height increased between 1.5 and 2.7 cm during the 3 months of treatment, which was calculated to be equivalent 6.0 and 10.8 cm per year with a mean increase of 8.7 cm. Anti-hGH antibody was observed in all patients between one and two months of treatment with a titer between 10(1)X and 10(4)X. In spite of the formation of antibodies, the growth rate did not decrease in 7 of the 10 cases.

Sixty-two patients with pituitary dwarfism were treated with three different preparations of methionyl hGH (m-hGH) for 3 to 14 months. They were given 0.5 IU/kg/week intramuscularly. The growth rate during treatment with the three different preparations was the same for each and increased from 3.5 +/- 0.9 to 8.2 +/- 1.7 cm/year. A high incidence of hGH antibody formation was observed following the treatment, but the titer of antibody was decreased according to the purity of m-hGH preparations. At the end of 12 month treatment with a highly purified preparation (Somatonorm III), 76.2% of the patients had hGH antibody. However, the presence of antibodies did not affect the growth rate except in one patient. No clinical or laboratory side-effects were observed following the treatment with m-hGH. Thus, m-hGH was considered to be useful for the treatment of GH deficient children.