Susan B. Stearns and C.A. Benzo
Fujino, M., M. Wakimasu, S. Taketomi, H. fwatsuka: Insulin Rookledge, K.A.: Comparison of some metabolie parameters in the perfused and the incubatcd rat diaphragm museIe like activities and insulin potentiating action of a modified with diaphragm museIe in vivo. Biochem.J. 125: 93-96 insulin B21-26 fragment: ß-Ala-Arg-Gly-Phe-Phe-Tyr-NH 2 . (1971) Endocrinology 101: 360-364 (1977) Gawehn, K., H. U. Bergmeyer: Methods of enzymatic analysis. Reimer, F., G. Löffler, G. Henning, O.H. Wieland: The influence of insulin on glucose and fatty acid metabolism Vol. 3. Bergmeyer, Ed. Academic Press, New York, London (1974), p. 1493-1499 in the isolated perfused rat hind quarter. Hoppe Seyler Kipnis, D.M., CF. Cori: Studies of tissue permeability. Z.PhysioI.Chem. 356: 1055-1066 (1975) Ruderman, N.B., CR.S. Houghton, R. Hems: Evaluation of III. The effect of insulin on pentose uptake by the diaphragm. J.BioI.Chem. 224: 681-693 (1957) the isolated perfused rat hindquarter for the study of musMahler, R.J., O. Szabo, J.C Penhos: Antagonism to insulin ele metabolism. Biochem.J. 124: 639-651 (1971) action on the perfused hind limb of the rat by a reduced Toyota, T., S. Sato, M. Kudo, K. Abe, Y. Goto: Secretory regulation of endocrine pancreas: Cyelic AMP and glucainsulin B-chain-albumin complex. Diabetes 17: 1-7 (1968) Moriwaki, T., B.R. Landau: Fructose and glucose metabolism gon secretion. J.Clin.EndocrinoI.Metab. 41: 81-89 (1975) Toyota, T., A. Kitahara: Glucose metabolism in ageing. in the normal and diabetic rat diaphragm in vitro. Arch. Jap.J.Geriat. 13: lJ6-181 (1976) Biochem. 97: 544-550 (1962) Mortimore, G.E., F. Tietze, D. Sterten: Metabolism of insuWeitzel, G., K. Eiseie, V. Schulz, W. Stock: Further studies lin-p31: Studies in isolated, perfused rat liver and hind on biologically active synthetic fragments of the B-chain. Hoppe Seyler Z.PhysioI.Chem. 354: 321-320 (1973) limb preparations. Diabetes 8: 307-314 (1959) Nakada, H.f.: The metabolism of fructose by isolated rat diaphragms. J.BioI.Chem. 219: 319-326 (1956) Requests for reprints should be addressed to: Dr. T. Toyota, Third Department of Internal Medicine, Tohoku University School of Medicine, Sendai (Japan)
Horm. Metab. Res. 10 (1978) 20-23
© Georg Thieme Verlag Stuttgart
Glucagon and Insulin Relationships in Genetically Diabetic (db/db) and in Streptozotocin-Induced Diabetic Mice* Susan B. Stearns and
c.A. Benzo
Department of Anatomy, State University of New York, Upstate Medical Center, Syracuse, New York, USA
Summary
Introduction
An inappropriate molar ratio of circulating insulin to glucagon is frequently associated with the metabolie alterations accompanying diabetes mellitus. Plasma immunoreactive insulin (IR!) and immunoreactive glucagon (IRG) levels were determined and the IRG:IRI ratio calculated at various intervals in overt diabetes in genetically diabetic (db/db) and in streptozotocin-treated mice. Plasma IRI levels in genetic mutants are elevated at nine weeks of age, but are comparable to values found in lean littermates by 21 weeks. The presence of a prevailing hyperglucagonemia is established for the fust time in the intact db/db mice. Streptozotocin diabetics are found to have characteristically low plasma IRI and high plasma IRG values. The hormonal im balance present in these two experimental animal models is accentuated when the data are expressed as the IRG:IRI ratio, which is seen to increase with the progression of diabetes.
The diabetes exhibited in the genetic mutant mouse C57BL/KsJdb (db/db) and in the streptozotocintreated anima! shows certain characteristics resembling the maturity onset (Hummel, Dickie and Coleman 1966, Coleman and Hummel 1967, Coleman and Hummel 1969) and the juvenile onset forms of the human disease, respectively. While plasma insulin values in the db/db mouse are initially elevated (Coleman and Hummel 1967, Ma/aisse, Ma/aisse-Lagae and Coleman 1968, Wyse and Dulin 1970) they fall to approximate those found in control anima!s during the overt stage of the syndrome. However, the prevailing hyperglycemia accompanied by elevated gluconeogenie enzyme activities (Coleman and Hummel 1967, Chang and Schneider 1970, Chan, Young, Hutson, Brumley and Exton 1975) are indicative of the insulin resistance of these animals.
Key-Words: Diabetic Mouse - Insulin - Glucagon - Glu· cagon:Insulin Ratio - Streptozotocin Diabetes *This work was supported by an NIH Training Grant 5TOIGM-326-16 (l1-944P) to S.B.S. and by Grants RR0542 01E043C; ll-EI04D) from USPHS General Research Support Branch and from the Research Foundation of State University ofNew York (I 1-71 24A) to C.A.B. Received: 16 Febr. 1977 Accepted: 23 May 1977 0018-5043/78
0132-0020
$ 05.00
©
lt has been recently hypothesized that diabetes mellitus may be the result of a bihormonal abnormality
1978 Georg Thieme Publishers
Downloaded by: University of Pennsylvania Libraries. Copyrighted material.
20
21
Glucagon and Insulin in Genetically Diabetic and in Streptozotocin-Induced Diabetic Mice Table I. Blood glucose, IRG and IRI values in diabetic mice and lean littermates Age and group
No. Animals
IRI (uU/ml)
Blood glucose (mg/dl)
IRG (pg/ml)
11 9 6 6
212.7 ± 8.6 89.1 b 933.3 236 aa ' 459.0 37:8 ab ' 637.5
127.5 240.0 221.0 219.3
30.1 43 b 6'O cd ' 8: I cd'
10 9 6 7
198.5 879.0 331.0 379.0
23.3 172 a 39:5 ca ' 27.8 aa '
98.3 249.3 157.5 251.0
18 11 6 5
168.0 1055.0 416.3 466.0
0.8 125.1 b , 50.0 aa 26.6 aa '
136.0 346.7 140.0 317.5
Molar ratio (IRG/IRI)
9 Week Lean db/db Lean; 2 wk post-injection Lean; 4 wk post-injection
42.6 123.6 6.3 6.3
7.6 12. I b 0.6 ba ' 1.3 ba'
0.12 0.08 1.50 1.48
7.6 15.0 a 42.6 16.1 a
25.4 45.5 7.3 4.8
1.I 6.l d 2.2 aa ' 1.I ab'
0.17 0.24 0.94 2.22
17.5 68 I d 6:0 c' 67.7 d
25.0 33.5 15.8 10.1
4.1 8.6 3.6 1.I cd'
0.22 0.45 0.40 1.34
12 Wttek Lean db/db Lean; 2 wk post-injection Lean; 4 wk post-injection
Lean db/db Lean; 2 wk post-injection Lean; 4 wk post-injection
Values are presented as mean ± SEM of (N) determinations. When injected animals were compared with lean Iittermates or with db/db animals (indicated by superscript) significance was obtained at the following levels, a. p .001 b. P .05, utilizing the Student's t-test. .01 c. P .025 d. P
Fujino, M., M. Wakimasu, S. Taketomi, H. fwatsuka: Insulin Rookledge, K.A.: Comparison of some metabolie parameters in the perfused and the incubatcd rat diaphragm museIe like activities and insulin potentiating action of a modified with diaphragm museIe in vivo. Biochem.J. 125: 93-96 insulin B21-26 fragment: ß-Ala-Arg-Gly-Phe-Phe-Tyr-NH 2 . (1971) Endocrinology 101: 360-364 (1977) Gawehn, K., H. U. Bergmeyer: Methods of enzymatic analysis. Reimer, F., G. Löffler, G. Henning, O.H. Wieland: The influence of insulin on glucose and fatty acid metabolism Vol. 3. Bergmeyer, Ed. Academic Press, New York, London (1974), p. 1493-1499 in the isolated perfused rat hind quarter. Hoppe Seyler Kipnis, D.M., CF. Cori: Studies of tissue permeability. Z.PhysioI.Chem. 356: 1055-1066 (1975) Ruderman, N.B., CR.S. Houghton, R. Hems: Evaluation of III. The effect of insulin on pentose uptake by the diaphragm. J.BioI.Chem. 224: 681-693 (1957) the isolated perfused rat hindquarter for the study of musMahler, R.J., O. Szabo, J.C Penhos: Antagonism to insulin ele metabolism. Biochem.J. 124: 639-651 (1971) action on the perfused hind limb of the rat by a reduced Toyota, T., S. Sato, M. Kudo, K. Abe, Y. Goto: Secretory regulation of endocrine pancreas: Cyelic AMP and glucainsulin B-chain-albumin complex. Diabetes 17: 1-7 (1968) Moriwaki, T., B.R. Landau: Fructose and glucose metabolism gon secretion. J.Clin.EndocrinoI.Metab. 41: 81-89 (1975) Toyota, T., A. Kitahara: Glucose metabolism in ageing. in the normal and diabetic rat diaphragm in vitro. Arch. Jap.J.Geriat. 13: lJ6-181 (1976) Biochem. 97: 544-550 (1962) Mortimore, G.E., F. Tietze, D. Sterten: Metabolism of insuWeitzel, G., K. Eiseie, V. Schulz, W. Stock: Further studies lin-p31: Studies in isolated, perfused rat liver and hind on biologically active synthetic fragments of the B-chain. Hoppe Seyler Z.PhysioI.Chem. 354: 321-320 (1973) limb preparations. Diabetes 8: 307-314 (1959) Nakada, H.f.: The metabolism of fructose by isolated rat diaphragms. J.BioI.Chem. 219: 319-326 (1956) Requests for reprints should be addressed to: Dr. T. Toyota, Third Department of Internal Medicine, Tohoku University School of Medicine, Sendai (Japan)
Horm. Metab. Res. 10 (1978) 20-23
© Georg Thieme Verlag Stuttgart
Glucagon and Insulin Relationships in Genetically Diabetic (db/db) and in Streptozotocin-Induced Diabetic Mice* Susan B. Stearns and
c.A. Benzo
Department of Anatomy, State University of New York, Upstate Medical Center, Syracuse, New York, USA
Summary
Introduction
An inappropriate molar ratio of circulating insulin to glucagon is frequently associated with the metabolie alterations accompanying diabetes mellitus. Plasma immunoreactive insulin (IR!) and immunoreactive glucagon (IRG) levels were determined and the IRG:IRI ratio calculated at various intervals in overt diabetes in genetically diabetic (db/db) and in streptozotocin-treated mice. Plasma IRI levels in genetic mutants are elevated at nine weeks of age, but are comparable to values found in lean littermates by 21 weeks. The presence of a prevailing hyperglucagonemia is established for the fust time in the intact db/db mice. Streptozotocin diabetics are found to have characteristically low plasma IRI and high plasma IRG values. The hormonal im balance present in these two experimental animal models is accentuated when the data are expressed as the IRG:IRI ratio, which is seen to increase with the progression of diabetes.
The diabetes exhibited in the genetic mutant mouse C57BL/KsJdb (db/db) and in the streptozotocintreated anima! shows certain characteristics resembling the maturity onset (Hummel, Dickie and Coleman 1966, Coleman and Hummel 1967, Coleman and Hummel 1969) and the juvenile onset forms of the human disease, respectively. While plasma insulin values in the db/db mouse are initially elevated (Coleman and Hummel 1967, Ma/aisse, Ma/aisse-Lagae and Coleman 1968, Wyse and Dulin 1970) they fall to approximate those found in control anima!s during the overt stage of the syndrome. However, the prevailing hyperglycemia accompanied by elevated gluconeogenie enzyme activities (Coleman and Hummel 1967, Chang and Schneider 1970, Chan, Young, Hutson, Brumley and Exton 1975) are indicative of the insulin resistance of these animals.
Key-Words: Diabetic Mouse - Insulin - Glucagon - Glu· cagon:Insulin Ratio - Streptozotocin Diabetes *This work was supported by an NIH Training Grant 5TOIGM-326-16 (l1-944P) to S.B.S. and by Grants RR0542 01E043C; ll-EI04D) from USPHS General Research Support Branch and from the Research Foundation of State University ofNew York (I 1-71 24A) to C.A.B. Received: 16 Febr. 1977 Accepted: 23 May 1977 0018-5043/78
0132-0020
$ 05.00
©
lt has been recently hypothesized that diabetes mellitus may be the result of a bihormonal abnormality
1978 Georg Thieme Publishers
Downloaded by: University of Pennsylvania Libraries. Copyrighted material.
20
21
Glucagon and Insulin in Genetically Diabetic and in Streptozotocin-Induced Diabetic Mice Table I. Blood glucose, IRG and IRI values in diabetic mice and lean littermates Age and group
No. Animals
IRI (uU/ml)
Blood glucose (mg/dl)
IRG (pg/ml)
11 9 6 6
212.7 ± 8.6 89.1 b 933.3 236 aa ' 459.0 37:8 ab ' 637.5
127.5 240.0 221.0 219.3
30.1 43 b 6'O cd ' 8: I cd'
10 9 6 7
198.5 879.0 331.0 379.0
23.3 172 a 39:5 ca ' 27.8 aa '
98.3 249.3 157.5 251.0
18 11 6 5
168.0 1055.0 416.3 466.0
0.8 125.1 b , 50.0 aa 26.6 aa '
136.0 346.7 140.0 317.5
Molar ratio (IRG/IRI)
9 Week Lean db/db Lean; 2 wk post-injection Lean; 4 wk post-injection
42.6 123.6 6.3 6.3
7.6 12. I b 0.6 ba ' 1.3 ba'
0.12 0.08 1.50 1.48
7.6 15.0 a 42.6 16.1 a
25.4 45.5 7.3 4.8
1.I 6.l d 2.2 aa ' 1.I ab'
0.17 0.24 0.94 2.22
17.5 68 I d 6:0 c' 67.7 d
25.0 33.5 15.8 10.1
4.1 8.6 3.6 1.I cd'
0.22 0.45 0.40 1.34
12 Wttek Lean db/db Lean; 2 wk post-injection Lean; 4 wk post-injection
Lean db/db Lean; 2 wk post-injection Lean; 4 wk post-injection
Values are presented as mean ± SEM of (N) determinations. When injected animals were compared with lean Iittermates or with db/db animals (indicated by superscript) significance was obtained at the following levels, a. p .001 b. P .05, utilizing the Student's t-test. .01 c. P .025 d. P
