80
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lean littermates ;md attributed these findings to an absolute decrease in the number of insulin receptoIS. In their studies, glucagon binding was also somewhat reduced but this may have been more apparent than real, for felsens cited by these investigatoIS. Thus, it is attractive to postulate that the altered stoichiometry of insulin and glucagon concentrations may be due to a major defect in insulin receptor interaction without significant abnormalities in glucagon binding, culminating in a relative increase in glucagon mediated hepatic glucose production in the face of hyperinsulinemia. Glucagon release inappropriate to prevailing glucose levels has also been observed in the perfused ob/ob mouse pancreas (Laube et a1. (974). Similarly glucagon hypersecretion has been noted in the db/db mouse perfused pancreas, an animal wh ich develops hyperglycemia coupled with hyperinsulinemia (Laube et al. 1973). Elevated glucagon levels have been reported in human juvenile diabetics (Unger 1974) and after experimentally-induced diabetes in animals (Katsilambros et al. 19"10, Unger 1974). In our studies, basal IRG levels were higher in the young ob/ob animals than in lean controls, however, in the older group in wh ich hyperglycemia and hyperinsulinemia were more marked, glucagon levels were significanUy lowered. This could be interpreted as an appropriate alpha cell response to hyperglycemia and hyperinsulinemia. Nonetheless, our da ta do not exclude the possibility that alpha cell resistance to insulin may exist with only modest elevations of glucose and insulin in thc ob/ob mouse. Acknowledgements The technical assistance of Mrs. Claudine Nist is gratefully acknowledged. This work was supported in part by USPHS Grants, AM·16008, AM·13457 and H1>-04872 awarded to John W. Ensinck. References
Requests for reprints should be addressed to: Richard J. Mahler, M.D., Eisenhower Medical Center, Probst Professional Building, 39000 Bob Hope Drive, Palm Desert, Calif. 92260
Horm. Metab. Res. 8 (1975) 80-81
© Georg Thieme Verlag Stuttgart Hyperinsulinemia and Fat Cell Glycerokinase Activity in Obese (ob/ob) and Diabetic (db/db) Mice Shirley W. Thenen and J. Mayer Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, U.S.A. Although the primary genetic defects remain obscure, a distinguishing feature between obese-hyperglycemic (ob/ob) and diabetic (db/db) mice is that the former develop a higher and prolonged capacity for secreting insulin through hypertrophy and hyperplasia of the ß-ceUs in thc islets of Langerhans, while the latter develop degenerative changes with diminishing in· sulin secretion (Bray and York 1971). Rccently, Coleman and Hummel (1973) have observed that these differences, essen· tially in the degree of the diabetic-like syndrome, are not the primary defects caused by the ob and db mutations. Since Koschinsky, Gries and Herberg (1971) have established a direct correlation between circulating insulin concentration and fat cell glycerokinase activity (EC 2.7.1.30) in ob/ob mice, we tested whether this same relationship can be observed in db/db mice and in gold thioglucose-induccd obesity (GTG) in mice of the background strain normally carrying the ob mutation. Materials and Methods Groups of approximately five obese and five lean male mice of the obese strain, C57BL/6J-ob, the diabetic strain, C57BL/ KsJ-db, and the genetically-related, background strain, C57BL/6J (Jackson Memorial Laboratory, Bar Harbor, Maine, USA) were used for this study. The times and procedures for induction of obesity with gold thioglucose, epididymal fat cell glycerokinase assay and serum insulin determination were described previously (Thenen and Mayer 1975). Enzyme activity is expressed as nv.unoles glycerophosphate formed/min/mg protein. Rec.: 16 June 1975
Ace.: 6 Oet. 1975
Downloaded by: University of British Columbia. Copyrighted material.
Bray, G.A., D.A. York: Physiol. Rev. 51: 598-646 (1971). - Elliott, J., D.A. Hems, A. Beloff·Chain: Biochem.J. 125: 773· 780 (1971). - Ensinck, J., C. Shepard, R.J. Dudl, R.H. Willillms: J.Oin.Endocr.Metab. 35: 463-467 (1972). - Ex ton , J.H., C.R. Park: Pharmaco1. Rev. 18: 181-188 (1966). - Haies, C.N., P.J. Randle: Biochem.J. 88: 137·145 (1963). - Kahn, C.R., D.M. Neville, Jr., J. Roth: J.BioI.Chem. 248: 244-250 (1973). - Katsilambros, N., Y. Abdel Rahman, M. Hinz, R.D. Fuss· gänger, K.E. Schröder, K. Straub, E.F. Pfeiffer: Horm.Metab.Res. 2: 268-270 (1970). - Lane, P. W.: Endocrinology 65: 863·868 (1959). - Laube, H., R.D. Fussgänger, V. Maier, E.F. Pfeiffer: Diabetologia 9: 400-402 (1973). - Laube, H., R.D. Fussgänger, E.F. Pfeiffer: Horm.Metab.Res. 6: 426 (1974). - Mackrell, D.J., J.E. Sokal: Diabetes 18: 724-732 (1969). Parrilla, R., M.N. Goodman, C.J. Toews: Diabetes 23: 725-731 (1974). - Seidman, I., A.A. Horland, G. W. Teebor: Diabetologia 6: 313·316 (1970). - Shull, K.H., J. Mayer: J.BioI.Chem. 218: 885-896 (1956). -- Unger, R.H.: Metabolism 23: 581593 (1974). - Westman, S.: Diabetologia 4: 141-149 (1968). -
81
Short Communications
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Figure. a) Bars represent mean ± SEM for glycerokinase activity in homogenates of epididymal fat cells. b) Correlation between serum insulin and glycerokinase activity in fat cells from ob/ob (x), db/db (0), GTG (ß) obese mice and all lean control (e) mice. Results and DiliCussion (see Figure)
Short Communications
lean littermates ;md attributed these findings to an absolute decrease in the number of insulin receptoIS. In their studies, glucagon binding was also somewhat reduced but this may have been more apparent than real, for felsens cited by these investigatoIS. Thus, it is attractive to postulate that the altered stoichiometry of insulin and glucagon concentrations may be due to a major defect in insulin receptor interaction without significant abnormalities in glucagon binding, culminating in a relative increase in glucagon mediated hepatic glucose production in the face of hyperinsulinemia. Glucagon release inappropriate to prevailing glucose levels has also been observed in the perfused ob/ob mouse pancreas (Laube et a1. (974). Similarly glucagon hypersecretion has been noted in the db/db mouse perfused pancreas, an animal wh ich develops hyperglycemia coupled with hyperinsulinemia (Laube et al. 1973). Elevated glucagon levels have been reported in human juvenile diabetics (Unger 1974) and after experimentally-induced diabetes in animals (Katsilambros et al. 19"10, Unger 1974). In our studies, basal IRG levels were higher in the young ob/ob animals than in lean controls, however, in the older group in wh ich hyperglycemia and hyperinsulinemia were more marked, glucagon levels were significanUy lowered. This could be interpreted as an appropriate alpha cell response to hyperglycemia and hyperinsulinemia. Nonetheless, our da ta do not exclude the possibility that alpha cell resistance to insulin may exist with only modest elevations of glucose and insulin in thc ob/ob mouse. Acknowledgements The technical assistance of Mrs. Claudine Nist is gratefully acknowledged. This work was supported in part by USPHS Grants, AM·16008, AM·13457 and H1>-04872 awarded to John W. Ensinck. References
Requests for reprints should be addressed to: Richard J. Mahler, M.D., Eisenhower Medical Center, Probst Professional Building, 39000 Bob Hope Drive, Palm Desert, Calif. 92260
Horm. Metab. Res. 8 (1975) 80-81
© Georg Thieme Verlag Stuttgart Hyperinsulinemia and Fat Cell Glycerokinase Activity in Obese (ob/ob) and Diabetic (db/db) Mice Shirley W. Thenen and J. Mayer Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, U.S.A. Although the primary genetic defects remain obscure, a distinguishing feature between obese-hyperglycemic (ob/ob) and diabetic (db/db) mice is that the former develop a higher and prolonged capacity for secreting insulin through hypertrophy and hyperplasia of the ß-ceUs in thc islets of Langerhans, while the latter develop degenerative changes with diminishing in· sulin secretion (Bray and York 1971). Rccently, Coleman and Hummel (1973) have observed that these differences, essen· tially in the degree of the diabetic-like syndrome, are not the primary defects caused by the ob and db mutations. Since Koschinsky, Gries and Herberg (1971) have established a direct correlation between circulating insulin concentration and fat cell glycerokinase activity (EC 2.7.1.30) in ob/ob mice, we tested whether this same relationship can be observed in db/db mice and in gold thioglucose-induccd obesity (GTG) in mice of the background strain normally carrying the ob mutation. Materials and Methods Groups of approximately five obese and five lean male mice of the obese strain, C57BL/6J-ob, the diabetic strain, C57BL/ KsJ-db, and the genetically-related, background strain, C57BL/6J (Jackson Memorial Laboratory, Bar Harbor, Maine, USA) were used for this study. The times and procedures for induction of obesity with gold thioglucose, epididymal fat cell glycerokinase assay and serum insulin determination were described previously (Thenen and Mayer 1975). Enzyme activity is expressed as nv.unoles glycerophosphate formed/min/mg protein. Rec.: 16 June 1975
Ace.: 6 Oet. 1975
Downloaded by: University of British Columbia. Copyrighted material.
Bray, G.A., D.A. York: Physiol. Rev. 51: 598-646 (1971). - Elliott, J., D.A. Hems, A. Beloff·Chain: Biochem.J. 125: 773· 780 (1971). - Ensinck, J., C. Shepard, R.J. Dudl, R.H. Willillms: J.Oin.Endocr.Metab. 35: 463-467 (1972). - Ex ton , J.H., C.R. Park: Pharmaco1. Rev. 18: 181-188 (1966). - Haies, C.N., P.J. Randle: Biochem.J. 88: 137·145 (1963). - Kahn, C.R., D.M. Neville, Jr., J. Roth: J.BioI.Chem. 248: 244-250 (1973). - Katsilambros, N., Y. Abdel Rahman, M. Hinz, R.D. Fuss· gänger, K.E. Schröder, K. Straub, E.F. Pfeiffer: Horm.Metab.Res. 2: 268-270 (1970). - Lane, P. W.: Endocrinology 65: 863·868 (1959). - Laube, H., R.D. Fussgänger, V. Maier, E.F. Pfeiffer: Diabetologia 9: 400-402 (1973). - Laube, H., R.D. Fussgänger, E.F. Pfeiffer: Horm.Metab.Res. 6: 426 (1974). - Mackrell, D.J., J.E. Sokal: Diabetes 18: 724-732 (1969). Parrilla, R., M.N. Goodman, C.J. Toews: Diabetes 23: 725-731 (1974). - Seidman, I., A.A. Horland, G. W. Teebor: Diabetologia 6: 313·316 (1970). - Shull, K.H., J. Mayer: J.BioI.Chem. 218: 885-896 (1956). -- Unger, R.H.: Metabolism 23: 581593 (1974). - Westman, S.: Diabetologia 4: 141-149 (1968). -
81
Short Communications
.15
b
1.25
a
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• O~----~IOO~-----2~O~O------3~O-O------4·0-0----~500
OllES[
CII11LIIJ
microunit. in.ulin/ml serum
Figure. a) Bars represent mean ± SEM for glycerokinase activity in homogenates of epididymal fat cells. b) Correlation between serum insulin and glycerokinase activity in fat cells from ob/ob (x), db/db (0), GTG (ß) obese mice and all lean control (e) mice. Results and DiliCussion (see Figure)
