A second mutant insulin, identified as [SerB24]-insulin, has a highly hydrophilic character. To determine the biologic activity and the degradation of this mutant insulin, human [SerB24]- and [SerB25]-insulin analogues were semisynthesized from porcine insulin by an enzyme-assisted coupling method. All of the following studies on isolated rat adipocytes were performed at 37°C to directly correlate the binding potency and the biologic activity. The ability of these insulins to displace 125I-porcine insulin bound to adipocytes was 0.5–2% and 1–4%, respectively, of porcine insulin. When the ability of these insulins to stimulate glucose transport and glucose oxidation was measured, both analogues had full activity at high concentrations (250 ng/ml). However, ED50 of the porcine, [SerB24]-, and [SerB25]-insulins tostimulate glucose transport was 0.37 ± 0.05, 46.3 ± 5.4, and 23.3 ± 5.5 ng/ml, respectively. Similarly, for glucose oxidation, ED50 was 0.38 ± 0.06, 33.8 ± 3.6, and 16.6 ± 3.4 ng/ml, respectively. Thus, the biologic activity of [SerB24]- and [SerB25]-insulins was reduced to 0.5–2% and 1–4% of that of porcine insulin, which was compatible with our previous studies under different conditions. No antagonistic effects were observed for either analogue. Degradation of 125I-labeled [SerB24]- and [SerB25]-insulins was also decreased to 62.8% and 55.8%, respectively, of 125I-porcine insulin. These results confirm the importance of the hydrophobic residues at B24 and B25 in the biologic activity of insulin; the patient having this hydrophilic insulin was considered to be in an insulinopenic state despite the hyperinsulinemia due to decreased degradation of the mutant insulin.
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Original Contribution|
June 01 1985
Decreased Biologic Activity and Degradation of Human [SerB24]-Insulin, a Second Mutant Insulin
Masakazu Haneda;
Masakazu Haneda
1
Shionogi Research Laboratories, Shionogi and Co., Ltd.
Osaka, Japan
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Masashi Kobayashi;
Masashi Kobayashi
1
Shionogi Research Laboratories, Shionogi and Co., Ltd.
Osaka, Japan
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Hiroshi Maegawa;
Hiroshi Maegawa
1
Shionogi Research Laboratories, Shionogi and Co., Ltd.
Osaka, Japan
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Nobuaki Watanabe;
Nobuaki Watanabe
1
Shionogi Research Laboratories, Shionogi and Co., Ltd.
Osaka, Japan
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Yasumitsu Takata;
Yasumitsu Takata
1
Shionogi Research Laboratories, Shionogi and Co., Ltd.
Osaka, Japan
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Osamu Ishibashi;
Osamu Ishibashi
1
Shionogi Research Laboratories, Shionogi and Co., Ltd.
Osaka, Japan
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Yukio Shigeta;
Yukio Shigeta
1
Shionogi Research Laboratories, Shionogi and Co., Ltd.
Osaka, Japan
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Ken Inouye
Ken Inouye
2
Department of Medicine, Shiga University of Medical Science
Otsu, Japan
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Address reprint requests to Dr. Masakazu Haneda, Third Department of Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga 520–21, Japan.
Diabetes 1985;34(6):568–573
Article history
Received:
June 18 1984
Revision Received:
November 29 1984
Citation
Masakazu Haneda, Masashi Kobayashi, Hiroshi Maegawa, Nobuaki Watanabe, Yasumitsu Takata, Osamu Ishibashi, Yukio Shigeta, Ken Inouye; Decreased Biologic Activity and Degradation of Human [SerB24]-Insulin, a Second Mutant Insulin. Diabetes 1 June 1985; 34 (6): 568–573. https://doi.org/10.2337/diab.34.6.568
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