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Biochemical abnormalities in the chinese hamster (Cricetulus griseus) with spontaneous diabetes
I,,, .I B,r,ihrm Vol 13. ,,,I 41 ,043 6 Per~nmon Prro Ltd ,1)X, Prtnred ,n Great Br,ta,n
MINIREVIEW BIOCHEMICAL ABNORMALITIES IN THE CHINESE HAMSTER (CRICETULUS GRISEUS) WITH SPONTANEOUS DIABETES Diabetes
and Atherosclerosis
A. Y. CHANG Research, The Upjohn Company, (Rrcrired
28 March
INTRODLCTIOU
Snce its discovery by Meier & Yerganian in 1959, considerable data on the biochemistry, epidemiology, genetics, morphology and physiology of the diabetic syndrome in the Chinese hamster have been accumulated. Due to its close resemblance to the disease process in man, the Chinese hamster has become one of the widely used animal models for studies on diabetes n~Jlitus. The purpose of this article is to provide the currently availablle information on the biochemical abnormalities in the Chinese hamster with spontaneous diabetes. IPANCREATIC
ISLET
Abnormally low level of pancreatic insulin in the dtabetic Chinese hamster was one of the early observations in the course of establishing the Upjohn colony (Gerritsen & IDulin. 1967). Continuous inbreeding between siblings using glycosuria and aglycosuria as selection endpoints later yielded highly inbred sublines in the colony; varying degree of pancreatic insulin depletion was also found in the various diabetic sublines (Chang, 197%; Wyse et a/., 1978). The isolated pancreatic islets from the diabetic hamster incorporated [r4C]leucine into insulin at a slower rate than the control islets (Chang, 1970) and they also showed a reduced level of glucose-induced insulin secretion (Malaisse et al., 1967; Chang, 1970). The impaired response to glucose in insulin secretion was later confirmed in perfused pancreas isolated from the diabetic Chinese hamster (Frankel et a[., 1974). In these studies, both the first and the second phases of insulin release were reduced significantly in the diabetics. .4 decreased CAMP response to glucose may be the cause of the impairment of glucose-induced insulin release in the diabetic Chinese hamster islets. Rabinovitch et al. (1979) showed that the islets isolated from the diabetic animals failed to show significant increase in insulin secretion and CAMP accumulation in response to glucose when a phosphodiesterase inhibitor, 3-rsobutyl-I-methylxanthine (IBMX), was present in the medium whereas the control islets did. Two observations made by Siegel et al. (1979) further suggested that a defect in the handling of intracellular Ca2+ may be involved in the impaired insulin release in the diabetic Chinese hamster islets. First, the diabetic ani41
Kalamazoo.
MI 49001. U.S.A
1980)
mal islets showed a lack of stimulated Ca” efflux in response to glucose. Secondly, glucose-induced Ca2’ uptake was normal in the diabetic Chinese hamster islets. Although most of the diabetic animals in the Upjohn colony of Chinese hamsters showed higher pancreatic glucagon content than the nondiabetics (Chang er al., 1977b), the diabetic animals in some sublines showed normal levels of pancreatic glucagon (Chang, 1978~; Wyse et al., 1978). A study of animals in a different colony also showed similar pancreatic glucagon concentrations in both diabetic and nondiabetic Chinese hamsters (Petersson et al., 1977). However, impairment in glucose-dependent suppression of glucagon release was observed in perfused pancreas of the diabetic animals (Frankel et al.. 1974). A decreased content in pancreatic somatostatin also suggests that the diabetic Chinese hamsters may have a subnormal functional activity in the pancreatic D cells (Petersson et al., 1977).
LIVER
Studies in vitro with liver slices showed that the diabetic Chinese hamsters had accelerated rate of hepatic gluconeogenesis (Chang & Schneider, 1970a). The diabetic animal livers also contained elevated level of phosphoenolpyruvate carboxykinase but the hepatic activities of the other three gluconeogenic enzymes, i.e. glucose-6-phosphatase, fructose- 1,6diphosphatase, and pyruvate carboxylase, were in the normal range (Chang & Schneider, 1970a.b). Only in severely diabetic animals with ketonuria, all four gluconeogenic enzymes were found to be significantly elevated. Likewise, the hepatic glycolytic and pentose phosphate shunt enzymes were not significantly different between the diabetic and nondiabetic Chinese hamsters; but their activities were subnormal in the ketotic animals (Chang & Schneider, 1970b; Chang et ul., 1977b). Lactate dehydrogenase (LDH) activity and its isozyme distribution were studied in the livers of Chinese hamsters selected from the highly inbred sublines in the Upjohn colony (Chang et al., 1977a.). Considerable subline-dependent difference in LDH activity and isozyme pattern was found but no relationship to the state of diabetes could be established. Several acid glycohydrolases were measured in the liver of the Chinese hamsters. The diabetics had
A. Y. CHAW
42
higher levels of N-acetyl-j?-D-hexosaminidase (Chang, 1978b) and a-D-mannosidase (Chang & Perry, 1980) in their livers but they showed similar activities of hepatic r-D-galactosidase and /3-D-galactosidase as the nondiabetics (Chang, 1978a). Two aspects of protein synthesis were also examined in oitro in liver extracts of the Chinese hamster. First, the ability to support polyuridylic acid-dependent polyphenylalanine synthesis from [‘4C]phenylalanine-tRNA was measured in washed liver ribosomes. Secondly, activity in protein synthesis with endogenous mRNAs was followed in the postmitochondrial supernatant fraction after the removal of endogenous amino acid pools by gel filtration. No significant difference in both aspects was found between the diabetic and nondiabetic Chinese hamster (Chang, 1974). These data obtained in vitro were in agreement with a lack of diabetes-dependent difference in hepatic protein content (Chang et al., 1977a). KIDNEY
A lack of diabetes-dependent difference in the rate of protein synthesis was also observed in either washed ribosomes or postmitochondrial supernatant fraction prepared from the Chinese hamster kidney (Chang, 1974). Similar to the results obtained in the liver, the diabetic Chinese hamster showed accelerated rate of renal gluconeogenesis and elevated levels of renal phosphoenolpyruvate carboxykinase (Chang & Schneider, 1970a). While the livers of the diabetic Chinese hamsters showed excessive N-acetyl-/?-D-hexosaminidase and r-D-mannosidase, their kidneys showed significantly depressed level of these enzymes (Chang, 1978~; Chang & Perry, 1980). Furthermore, other acid glycohydrolases such as r-D-galactosidase, fl-D-galactosidase and /?-D-glucuronidase were also present in subnormal quantity in various subcellular fractions of the diabetic Chinese hamster kidney extracts (Chang. 1978a; Chang & Perry, 1979). Although depression of renal acid glycohydrolases generally accompanied or followed the manifestation of diabetes in the Chinese hamster, certain genetic determinants may obliterate their depressions to discernibly abnormal levels (Chang & Greenberg, 1978). PLASMA
Genetic factors also appeared to dictate the diabetes-related changes in plasma acid glycohydrolase activities in the Chinese hamsters (Chang & Perry. 1978). Elevated activities of plasma N-acetyl-P-D-hexusually acosaminidase and @galactosidase companied the emergence of diabetes whereas plasma r-D-glucosidase and rl-D-galactosidase failed to show diabetes-dependent changes. In some diabetic sublines the plasma N-acetyl-P-D-hexosaminidase activity, however, remained exceptionally low although significant correlation to blood sugar levels was still evident. Reciprocal hormonal abnormalities, i.e. excessive glucagon and subnormal insulin levels, were often found in the plasma of the diabetic Chinese hamster (Chang et al., 1977b; Chang, 1978c), in accordance with the bihormonal imbalance in their pancreatic
islets (Chang, 1978~; Wyse rt (11.. 1978). Electrophoretic analysis of serum proteins in the Chinese hamsters failed to show any correlation in r-2 serum protein pattern to the manifestation of diabetes (Gerritsen & Dulin. 1966). OTHER TISSUES
The sciatic nerves and lenses from the diabetic Chinese hamster showed excessive levels of glucose, fructose, and polyols which. on the other hand, were present in normal quantities in the spinal cords and gastrocnemius muscles (Holcomb cat rrl.. 1974). Studies in oitro with intima-media segments of aorta showed significantly reduced rate of total glucose utilization and conversion of glucose to lactic acid. COz, lipid, glycogen and protein in the diabetics (Chobanian et al.. 1974a). The rates of exchange of cholesterol between plasma and various tissues were not different in diabetic and nondiabetic Chinese hamsters. The hypercholesterolemic diabetic Chinese hamsters showed significantly increased cholesterol content in liver, intestine. aorta and adipose tissue but the normocholesterolemic diabetic Chinese hamsters showed normal cholesterol levels in most of these tissues (Chobanian rt ul., 1974b). No significant difference in the activities of epididymal fat pad hexokinase, pyruvate kinase, glucose-6phosphate dehydrogenase. 6-phosphogluconate dehydrogenase, malate dehydrogenase, malic enzyme, isocitrate dehydrogenase and LDH was found between the diabetic and nondiabetic Chinese hamsters (Chang rf al., 1977b). Highly divergent sublinedependent variations in LDH isozyme pattern was present in the epididymal fat pad of the Chinese hamster. The difference. however, arose from genetic factor(s) unrelated to diabetes. The onset of hyperglycemia, nevertheless, further affected the distribution of epididymal fat pad LDH isozymes leading to a decrease in isozymes rich in LDH-A (Chang ct (II.. 1977a). The diabetic Chinese hamster did not show significantly different activities of acid glycohydrolases in its spleen, hind leg muscle, cheek pouch or spinal cord as compared to the nondiabetic control (Chang, 1978a,b). The diabetic Chinese hamster, however, showed excessively high glucagon-like immunoreactivity in its stomach (Chang et al.. 1977b; Chang, 1978~) and subnormal content of somatostatin in its stomach and hypothalamus (Petersson et al.. 1977). REFERENCES
CHANG A. Y. (1970) Insulin synthesis and secretion bv isolated islets of spontaneously diabetic Chinese hamsters. Wenner-Gren Svmrmsium No. 16 (Edited bv FALKMER S.. HELLMAN B. 8~~TALICDAL I. B.) pp. 5 15 i26. Pergamon Press, Oxford. CHANG A. Y. (1974) Hepatic and renal protein synthesis in normal. diabetic and ketotlc Chinese hamsters. Diahetoloyiu
(Suppl) IO. 555 5%.
CHAF~G A. Y. (197Xa) Acid glycohydrolase in Chmese hamster with spontaneous diabetes. I. Depressed levels of renal z-galactosidase rind p-galactosidase. Biochim hiophys. Acra 522, 49 I -SW CHANG A. Y. (1978b) Acid glycohydrolase in Chlncse hamster with spontaneous diabetes. Il. ,~-Acetvl-/j-t,-helo-
Diabetic hamsters saminidase in olasma and tissues. Biochim. biophys. Acru 522, 503-514. CHANG A. Y. (197&z) Spontaneous diabetes in animals. Gen. Pharmac. 9, rM7-450. CHANGA. Y. & GREENBERG H. S. (1978) Acid glycohydrolase in Chinese hamster with spontaneous diabetes. III. Line-dependent variance. Biochim. biophys. Acta 525, 134-141. CHANG A. Y.. NOBLE R. E. & GREENBERG H. S. (1977a) Variance in LDH isozyme patterns in a Chinese hamster ICricefulus yriseus) colony. Camp. Biochem. Physiol. 58B. 119-123. CIIANC; A. Y., NOBLE R. E. & WYSE B. M. (1977b) Comparison of highly inbred diabetic and nondiabetic lines in the Upjohn colony of Chinese hamsters. Diabetes 26, 1063. 1071.
CHANc A. Y. & PERRY C. S. (1978) Acid glycohydrolase in Chinese hamster with spontaneous diabetes. IV. Diabetes- and line-dependent variation in plasma enzyme activity. Diabetologia 15, 423429. O~ANG A. Y. & PERRY C. S. (1979) Acid glycohydrolase in Chinese hamster with spontaneous diabetes. V. Subcellular distribution in the kidney. Comp. Biochem. Physiol. b2B, 557-561. Ct(ANc A. Y. & PERRY C. S. (1980) Acid glycohydrolase in Chinese hamster with spontaneous diabetes. VI. Diabe-
[es-dependent dilkrence of a-D-mannosidase
in plasma,
liver and kidney. Camp. Biochem. Physiol. 65B. 489495. CIIANG A. Y. & SCHNEIDER D. I. (197Oa) Rate of gluconeogenesis and levels of gluconeogenic enzymes in-liver and kidney of diabetic and normal Chinese hamster. Biochim. hiophys.
Acta 222, 587-592.
C~IANG A. Y. & SCHNEIDER D. I. (1970b) Metabolic abnormalities in the pancreatic islets and livers of the diabetic Chinese hams&. Diabetologia 6. 180-l 85. CHOBANIAN A. V.. GERRITSEN G. C.. BRECHER P. I. & KESSLER M. (1974a) Cholesterol metabolism in the diabetic Chinese hamster. Diabetologia (Suppl) 10, 595-600. CHOBANIAN A. V., GERRITSEN G. C., BRECHER P. I. & MCCOMBS L. (1974b) Aortic glucose metabolism in the diabetic Chinese hamster. Diabetologia (Suppl) 10, i89-594.
43
FRANKEL B. J., GERICH J. E., HAGURA R., FANSKA R. E.. GERRITSEN G. C. & GRODSKY G. M. (1974) Abnormal secretion of insulin and glucagon by the in oitro perfused pancreas of the genetically diabetic Chinese hamster. J. c/in. Invest. 53, 1637-1646. GERRITSEN G. C. & DULIN W. E. (1966) Serum proteins of Chinese hamsters and response of diabetics to tolbutamide and insulin. Diabetes IS, 33 I-335. GERRITSEN G. C. & DULIN W. E. (1967) Characterization of diabetes in the Chinese hamster. Diabetologia 3. 74-84. HOLCOMB G. N., KLEMM L. A. & DULIN W. E. (1974) The polyol pathway for glucose metabolism in tissues from normal. diabetic and ketotic Chinese hamsters. Diabetologia (Suppl) 10. 549-554. MALAISSE W.. MALAISSE-LAGAE F., GERRITSEN G. C., DULIN W. E. & WRIGHT P. H. (1967) Insulin secretion in Gtro by the pancreas of the Chinese hamster. Diabetologia 3, 109-I
14.
MEIER H. & YERGANIAN (1959) Spontaneous diabetes mellitus in the Chinese hamster (Crrcerulus yriseus). 1. Pathological Findings. Proc. Sac. exp. Biol. 100. 810-815. PETERSON B., ELDE R.. EFENDIC S., HOKFELT T., JOHANSSON O., LUFT R., CERASI E. & HELLERS~ROM C. (1977) Somatostatin in the pancreas, stomach and hypothalamus of the diabetic Chinese hamster. Diahetologiu 13. 463466. RABINOVITCH A., RENOLD A. E. & CERASI E. (1976) Decreased cyclic AMP and insulin responses to glucose in pancreatic islets of diabetic Chinese hamsters. Diubetologia 12, 581-587.
SIEGEL E. G., WOLLHEIM C. B., SHARP G. W. G., HERBERG L. 8~ RENOLD A. E. (1979). Defective calcium handling and insulin release in islets from diabetic Chinese hamsters. Biochem. J. 180, 233-236. WYSE B. M., CHANG A. Y. & GREENBERG H. S. (1978) Glucose, insulin and glucagon levels in nondiabetic and spontaneously diabetic Chinese hamsters. Diabetes 27 (Suppl 1). 514.
MINIREVIEW BIOCHEMICAL ABNORMALITIES IN THE CHINESE HAMSTER (CRICETULUS GRISEUS) WITH SPONTANEOUS DIABETES Diabetes
and Atherosclerosis
A. Y. CHANG Research, The Upjohn Company, (Rrcrired
28 March
INTRODLCTIOU
Snce its discovery by Meier & Yerganian in 1959, considerable data on the biochemistry, epidemiology, genetics, morphology and physiology of the diabetic syndrome in the Chinese hamster have been accumulated. Due to its close resemblance to the disease process in man, the Chinese hamster has become one of the widely used animal models for studies on diabetes n~Jlitus. The purpose of this article is to provide the currently availablle information on the biochemical abnormalities in the Chinese hamster with spontaneous diabetes. IPANCREATIC
ISLET
Abnormally low level of pancreatic insulin in the dtabetic Chinese hamster was one of the early observations in the course of establishing the Upjohn colony (Gerritsen & IDulin. 1967). Continuous inbreeding between siblings using glycosuria and aglycosuria as selection endpoints later yielded highly inbred sublines in the colony; varying degree of pancreatic insulin depletion was also found in the various diabetic sublines (Chang, 197%; Wyse et a/., 1978). The isolated pancreatic islets from the diabetic hamster incorporated [r4C]leucine into insulin at a slower rate than the control islets (Chang, 1970) and they also showed a reduced level of glucose-induced insulin secretion (Malaisse et al., 1967; Chang, 1970). The impaired response to glucose in insulin secretion was later confirmed in perfused pancreas isolated from the diabetic Chinese hamster (Frankel et a[., 1974). In these studies, both the first and the second phases of insulin release were reduced significantly in the diabetics. .4 decreased CAMP response to glucose may be the cause of the impairment of glucose-induced insulin release in the diabetic Chinese hamster islets. Rabinovitch et al. (1979) showed that the islets isolated from the diabetic animals failed to show significant increase in insulin secretion and CAMP accumulation in response to glucose when a phosphodiesterase inhibitor, 3-rsobutyl-I-methylxanthine (IBMX), was present in the medium whereas the control islets did. Two observations made by Siegel et al. (1979) further suggested that a defect in the handling of intracellular Ca2+ may be involved in the impaired insulin release in the diabetic Chinese hamster islets. First, the diabetic ani41
Kalamazoo.
MI 49001. U.S.A
1980)
mal islets showed a lack of stimulated Ca” efflux in response to glucose. Secondly, glucose-induced Ca2’ uptake was normal in the diabetic Chinese hamster islets. Although most of the diabetic animals in the Upjohn colony of Chinese hamsters showed higher pancreatic glucagon content than the nondiabetics (Chang er al., 1977b), the diabetic animals in some sublines showed normal levels of pancreatic glucagon (Chang, 1978~; Wyse et al., 1978). A study of animals in a different colony also showed similar pancreatic glucagon concentrations in both diabetic and nondiabetic Chinese hamsters (Petersson et al., 1977). However, impairment in glucose-dependent suppression of glucagon release was observed in perfused pancreas of the diabetic animals (Frankel et al.. 1974). A decreased content in pancreatic somatostatin also suggests that the diabetic Chinese hamsters may have a subnormal functional activity in the pancreatic D cells (Petersson et al., 1977).
LIVER
Studies in vitro with liver slices showed that the diabetic Chinese hamsters had accelerated rate of hepatic gluconeogenesis (Chang & Schneider, 1970a). The diabetic animal livers also contained elevated level of phosphoenolpyruvate carboxykinase but the hepatic activities of the other three gluconeogenic enzymes, i.e. glucose-6-phosphatase, fructose- 1,6diphosphatase, and pyruvate carboxylase, were in the normal range (Chang & Schneider, 1970a.b). Only in severely diabetic animals with ketonuria, all four gluconeogenic enzymes were found to be significantly elevated. Likewise, the hepatic glycolytic and pentose phosphate shunt enzymes were not significantly different between the diabetic and nondiabetic Chinese hamsters; but their activities were subnormal in the ketotic animals (Chang & Schneider, 1970b; Chang et ul., 1977b). Lactate dehydrogenase (LDH) activity and its isozyme distribution were studied in the livers of Chinese hamsters selected from the highly inbred sublines in the Upjohn colony (Chang et al., 1977a.). Considerable subline-dependent difference in LDH activity and isozyme pattern was found but no relationship to the state of diabetes could be established. Several acid glycohydrolases were measured in the liver of the Chinese hamsters. The diabetics had
A. Y. CHAW
42
higher levels of N-acetyl-j?-D-hexosaminidase (Chang, 1978b) and a-D-mannosidase (Chang & Perry, 1980) in their livers but they showed similar activities of hepatic r-D-galactosidase and /3-D-galactosidase as the nondiabetics (Chang, 1978a). Two aspects of protein synthesis were also examined in oitro in liver extracts of the Chinese hamster. First, the ability to support polyuridylic acid-dependent polyphenylalanine synthesis from [‘4C]phenylalanine-tRNA was measured in washed liver ribosomes. Secondly, activity in protein synthesis with endogenous mRNAs was followed in the postmitochondrial supernatant fraction after the removal of endogenous amino acid pools by gel filtration. No significant difference in both aspects was found between the diabetic and nondiabetic Chinese hamster (Chang, 1974). These data obtained in vitro were in agreement with a lack of diabetes-dependent difference in hepatic protein content (Chang et al., 1977a). KIDNEY
A lack of diabetes-dependent difference in the rate of protein synthesis was also observed in either washed ribosomes or postmitochondrial supernatant fraction prepared from the Chinese hamster kidney (Chang, 1974). Similar to the results obtained in the liver, the diabetic Chinese hamster showed accelerated rate of renal gluconeogenesis and elevated levels of renal phosphoenolpyruvate carboxykinase (Chang & Schneider, 1970a). While the livers of the diabetic Chinese hamsters showed excessive N-acetyl-/?-D-hexosaminidase and r-D-mannosidase, their kidneys showed significantly depressed level of these enzymes (Chang, 1978~; Chang & Perry, 1980). Furthermore, other acid glycohydrolases such as r-D-galactosidase, fl-D-galactosidase and /?-D-glucuronidase were also present in subnormal quantity in various subcellular fractions of the diabetic Chinese hamster kidney extracts (Chang. 1978a; Chang & Perry, 1979). Although depression of renal acid glycohydrolases generally accompanied or followed the manifestation of diabetes in the Chinese hamster, certain genetic determinants may obliterate their depressions to discernibly abnormal levels (Chang & Greenberg, 1978). PLASMA
Genetic factors also appeared to dictate the diabetes-related changes in plasma acid glycohydrolase activities in the Chinese hamsters (Chang & Perry. 1978). Elevated activities of plasma N-acetyl-P-D-hexusually acosaminidase and @galactosidase companied the emergence of diabetes whereas plasma r-D-glucosidase and rl-D-galactosidase failed to show diabetes-dependent changes. In some diabetic sublines the plasma N-acetyl-P-D-hexosaminidase activity, however, remained exceptionally low although significant correlation to blood sugar levels was still evident. Reciprocal hormonal abnormalities, i.e. excessive glucagon and subnormal insulin levels, were often found in the plasma of the diabetic Chinese hamster (Chang et al., 1977b; Chang, 1978c), in accordance with the bihormonal imbalance in their pancreatic
islets (Chang, 1978~; Wyse rt (11.. 1978). Electrophoretic analysis of serum proteins in the Chinese hamsters failed to show any correlation in r-2 serum protein pattern to the manifestation of diabetes (Gerritsen & Dulin. 1966). OTHER TISSUES
The sciatic nerves and lenses from the diabetic Chinese hamster showed excessive levels of glucose, fructose, and polyols which. on the other hand, were present in normal quantities in the spinal cords and gastrocnemius muscles (Holcomb cat rrl.. 1974). Studies in oitro with intima-media segments of aorta showed significantly reduced rate of total glucose utilization and conversion of glucose to lactic acid. COz, lipid, glycogen and protein in the diabetics (Chobanian et al.. 1974a). The rates of exchange of cholesterol between plasma and various tissues were not different in diabetic and nondiabetic Chinese hamsters. The hypercholesterolemic diabetic Chinese hamsters showed significantly increased cholesterol content in liver, intestine. aorta and adipose tissue but the normocholesterolemic diabetic Chinese hamsters showed normal cholesterol levels in most of these tissues (Chobanian rt ul., 1974b). No significant difference in the activities of epididymal fat pad hexokinase, pyruvate kinase, glucose-6phosphate dehydrogenase. 6-phosphogluconate dehydrogenase, malate dehydrogenase, malic enzyme, isocitrate dehydrogenase and LDH was found between the diabetic and nondiabetic Chinese hamsters (Chang rf al., 1977b). Highly divergent sublinedependent variations in LDH isozyme pattern was present in the epididymal fat pad of the Chinese hamster. The difference. however, arose from genetic factor(s) unrelated to diabetes. The onset of hyperglycemia, nevertheless, further affected the distribution of epididymal fat pad LDH isozymes leading to a decrease in isozymes rich in LDH-A (Chang ct (II.. 1977a). The diabetic Chinese hamster did not show significantly different activities of acid glycohydrolases in its spleen, hind leg muscle, cheek pouch or spinal cord as compared to the nondiabetic control (Chang, 1978a,b). The diabetic Chinese hamster, however, showed excessively high glucagon-like immunoreactivity in its stomach (Chang et al.. 1977b; Chang, 1978~) and subnormal content of somatostatin in its stomach and hypothalamus (Petersson et al.. 1977). REFERENCES
CHANG A. Y. (1970) Insulin synthesis and secretion bv isolated islets of spontaneously diabetic Chinese hamsters. Wenner-Gren Svmrmsium No. 16 (Edited bv FALKMER S.. HELLMAN B. 8~~TALICDAL I. B.) pp. 5 15 i26. Pergamon Press, Oxford. CHANG A. Y. (1974) Hepatic and renal protein synthesis in normal. diabetic and ketotlc Chinese hamsters. Diahetoloyiu
(Suppl) IO. 555 5%.
CHAF~G A. Y. (197Xa) Acid glycohydrolase in Chmese hamster with spontaneous diabetes. I. Depressed levels of renal z-galactosidase rind p-galactosidase. Biochim hiophys. Acra 522, 49 I -SW CHANG A. Y. (1978b) Acid glycohydrolase in Chlncse hamster with spontaneous diabetes. Il. ,~-Acetvl-/j-t,-helo-
Diabetic hamsters saminidase in olasma and tissues. Biochim. biophys. Acru 522, 503-514. CHANG A. Y. (197&z) Spontaneous diabetes in animals. Gen. Pharmac. 9, rM7-450. CHANGA. Y. & GREENBERG H. S. (1978) Acid glycohydrolase in Chinese hamster with spontaneous diabetes. III. Line-dependent variance. Biochim. biophys. Acta 525, 134-141. CHANG A. Y.. NOBLE R. E. & GREENBERG H. S. (1977a) Variance in LDH isozyme patterns in a Chinese hamster ICricefulus yriseus) colony. Camp. Biochem. Physiol. 58B. 119-123. CIIANC; A. Y., NOBLE R. E. & WYSE B. M. (1977b) Comparison of highly inbred diabetic and nondiabetic lines in the Upjohn colony of Chinese hamsters. Diabetes 26, 1063. 1071.
CHANc A. Y. & PERRY C. S. (1978) Acid glycohydrolase in Chinese hamster with spontaneous diabetes. IV. Diabetes- and line-dependent variation in plasma enzyme activity. Diabetologia 15, 423429. O~ANG A. Y. & PERRY C. S. (1979) Acid glycohydrolase in Chinese hamster with spontaneous diabetes. V. Subcellular distribution in the kidney. Comp. Biochem. Physiol. b2B, 557-561. Ct(ANc A. Y. & PERRY C. S. (1980) Acid glycohydrolase in Chinese hamster with spontaneous diabetes. VI. Diabe-
[es-dependent dilkrence of a-D-mannosidase
in plasma,
liver and kidney. Camp. Biochem. Physiol. 65B. 489495. CIIANG A. Y. & SCHNEIDER D. I. (197Oa) Rate of gluconeogenesis and levels of gluconeogenic enzymes in-liver and kidney of diabetic and normal Chinese hamster. Biochim. hiophys.
Acta 222, 587-592.
C~IANG A. Y. & SCHNEIDER D. I. (1970b) Metabolic abnormalities in the pancreatic islets and livers of the diabetic Chinese hams&. Diabetologia 6. 180-l 85. CHOBANIAN A. V.. GERRITSEN G. C.. BRECHER P. I. & KESSLER M. (1974a) Cholesterol metabolism in the diabetic Chinese hamster. Diabetologia (Suppl) 10, 595-600. CHOBANIAN A. V., GERRITSEN G. C., BRECHER P. I. & MCCOMBS L. (1974b) Aortic glucose metabolism in the diabetic Chinese hamster. Diabetologia (Suppl) 10, i89-594.
43
FRANKEL B. J., GERICH J. E., HAGURA R., FANSKA R. E.. GERRITSEN G. C. & GRODSKY G. M. (1974) Abnormal secretion of insulin and glucagon by the in oitro perfused pancreas of the genetically diabetic Chinese hamster. J. c/in. Invest. 53, 1637-1646. GERRITSEN G. C. & DULIN W. E. (1966) Serum proteins of Chinese hamsters and response of diabetics to tolbutamide and insulin. Diabetes IS, 33 I-335. GERRITSEN G. C. & DULIN W. E. (1967) Characterization of diabetes in the Chinese hamster. Diabetologia 3. 74-84. HOLCOMB G. N., KLEMM L. A. & DULIN W. E. (1974) The polyol pathway for glucose metabolism in tissues from normal. diabetic and ketotic Chinese hamsters. Diabetologia (Suppl) 10. 549-554. MALAISSE W.. MALAISSE-LAGAE F., GERRITSEN G. C., DULIN W. E. & WRIGHT P. H. (1967) Insulin secretion in Gtro by the pancreas of the Chinese hamster. Diabetologia 3, 109-I
14.
MEIER H. & YERGANIAN (1959) Spontaneous diabetes mellitus in the Chinese hamster (Crrcerulus yriseus). 1. Pathological Findings. Proc. Sac. exp. Biol. 100. 810-815. PETERSON B., ELDE R.. EFENDIC S., HOKFELT T., JOHANSSON O., LUFT R., CERASI E. & HELLERS~ROM C. (1977) Somatostatin in the pancreas, stomach and hypothalamus of the diabetic Chinese hamster. Diahetologiu 13. 463466. RABINOVITCH A., RENOLD A. E. & CERASI E. (1976) Decreased cyclic AMP and insulin responses to glucose in pancreatic islets of diabetic Chinese hamsters. Diubetologia 12, 581-587.
SIEGEL E. G., WOLLHEIM C. B., SHARP G. W. G., HERBERG L. 8~ RENOLD A. E. (1979). Defective calcium handling and insulin release in islets from diabetic Chinese hamsters. Biochem. J. 180, 233-236. WYSE B. M., CHANG A. Y. & GREENBERG H. S. (1978) Glucose, insulin and glucagon levels in nondiabetic and spontaneously diabetic Chinese hamsters. Diabetes 27 (Suppl 1). 514.