Genetic selection for high and low fasting blood glucose levels in mice. I. Fasting blood glucose levels, glucose tolerance and isolated tissue studies

Diabetologia, Aug 1973

R. E. Gleason, P. L. Poffenbarger, R. L. Lavine

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Genetic selection for high and low fasting blood glucose levels in mice. I. Fasting blood glucose levels, glucose tolerance and isolated tissue studies

Genetic Selection for High and Low Fasting Blood Glucose Levels in Mice. I. Fasting Blood Glucose Levels, Glucose Tolerance and Isolated Tissue Studies* R . E . Gleason 0 2 P.L. Poffcnbarger 0 1 2 ~.L. Lavinc 0 2 0 Material and Methods 1 Old Guilford Breeder Pellets, Emery Morse Company , Guilford, Connecticut , USA 2 Elliott P. Joslin Research Laboratory, Department of ~'Iedicine; Harvard Medical School and Peter Bent Brigham Hospital; Joslin Diabetes Foundation, Inc., and New England Deaconess l 3 Supported in part by U.S. P.}LS. Grants AM-11959, AM-09748, 1-FO3-AM-30777, and AM-05077 , and the Upjohn Company , Kalamazoo, Michigan , USA 4 ospital , Boston, Massachnsetts , U.S.A Summary. Swiss-Hauschka mice have been selected for high (HG) and low (LG) fasting blood glucose (FBG) levels for four generations. All rantings were brother to sister. Differences in mean FBG levels have remained relatively constant (20 to 30 rag~ between the two lines since initiation of selection (p < 0.001). Body weights have declined more rapidly with inbreeding in the LG line as compared to the HG line through Fs, but no further decline was noted in the Fa generation. Fasting serum immunoreactivo insulin (It~I) levels were variable and mean levels for the two lines did not differ significantly. A comparison of glucose tolerance data between F 3 }IG and LG line animals showed generally higher mean glucose levels in the HG line in both fasted and randomfed states. Mice; genetic selection; fasting blood glucose; body weight; glucose tolerance; insulin; dietary fat; isolated tissues; randomfed - The study of diabetes in experimental animals and the use of laboratory animals as experimental models for diabetes in humans has recently been enhanced b y the discovery of several species showing spontaneous development of the disease [ 1 ]. Sufficient information has been obtained from these studies, as well as from human studies, to indicate that the development of diabetes is influenced by both heredity and environment. I n previously reported studies from this laboratory [ 2, 3 ], it was noted that mean random blood glucose levels were elevated in randombred Swiss Hanschka mice maintained on a commercial 11% fat diet. 1 Some animals in this study, however, remained n o r m o glycemic, thus suggesting a possible hereditary influence on blood glucose concentration. Early studies by Cammidge and Howard [ 4, 5 ] indicated t h a t hyperglycemia and hypoglycemia in mice were inherited as separate characters, both recessive to normoglycemia. Hypoglycemia was also reported to be recessive to hyperglycemia. Segregation in all cases appeared to be absolute, with no intermediate values reported. These data were subsequently discussed by Dunn and Fisher [6] and by Gruneberg and Haldane [ 7 ]. I n both of these papers, the authors commented on the remarkable agreement of Cammidgc and Howard's observed data with that expected on the basis of simple Mendelian inheritance. 1. Genetic Selection Fifty male and fifty female weanling randombred Swiss Hanschka mice were obtained from a commercial source, 2Males and females were maintained separately, six to ten animals per cage, and all animals received water and the 11% fat commercial diet ad libitum. Body weights were recorded bimonthly. Fasting blood glucose (FBG) levels were measured at 6.5 and 8 months of age following an overnight fast. Five males with FBG levels greater than 80 m g % and eight females with levels greater than 75 mg ~ were selected as parents for a high glucose (HG) line. An additional four males with FBG levels less than 60 m g % and eight females with 2 Charles River Breeding Laboratories, Wilmington, Massachusetts. levels less t h a n 57 r a g % were selected as parents for a low glucose (LG) line. These 25 mice included approxim a t e l y 10% of the males and 20% of the females from each end of the distribution. Following a third F B G m e a s u r e m e n t at 8.5 months of age, three male and three female H G animals and an equal n u m b e r of LG animals were selected from the group of 25 and mated. These six matings constituted the P1 generation. Selection of parents for subsequent generations was based on three F B G levels measured between 4.5 and 6 months of age. I n general, blood samples were t a k e n at 5, 5.5, and 6 months. The criteria for selection were three relatively constant F B G levels characteristic of the parental line; t h a t is, either high or low. At six months of age blood samples for serum immunoreactive insulin ( I R I ) were obtained. All matings (brother to sister) were made at six months of age and these selected animals changed to a 4 % fat commercial diet. 8 The dietary change was instituted for two reasons. First, the low f a t diet generally caused animals which were hyperglycemic on the 11% f a t diet to become normoglycemic. Second, after several months on the 11% fat diet m o s t of the animals became obese, and changing to the low fat diet decreased the caloric intake, lowered the b o d y weight, and resulted in better breeding performance. Offspring were weaned at three weeks of age and placed on the 11% fat diet. B o d y weights were recorded monthly. All blood samples were obtained from the tail after an overnight fast. Samples for glucose m e a s u r e m e n t consisted of 0.05 ml of blood rapidly transferred into a cup containing 0.95 ml of distilled water and frozen for subsequent analysis b y the AutoAnalyzer 4 using Teehnicon Method N-9 a. F o r serum I g I levels, an additional 0.2 ml of tail blood was collected directly into a small polyethylene tube, allowed to clot overnight at 4~C, then centrifuged, and the serum separated and frozen until assay. Serum II~I levels were determined b y a modification of the double a n t i b o d y method [ 8 ] wherein 0.05 ml of serum was used, and the length of the second incubation period was increased to five days. A purified mouse insulin standard with biological and immunoehemieal p o t e n c y of 25 U/rag was used [ 9 ]. 2. Glucose Tolerance A total of 30 glucose tolerance tests were completed in 21 H G and LG line F 3 mice. Two groups of animals were studied. Group I consisted of four H G and five LG line males of similar body weights and ranging in age from 6.5 to 9 months. A second group (Group I I ) , consisted of four H G and four LG line males on the 4 % fat diet, and four LG males on the 11% fat diet. These animals ranged in age from 10 to 12.5 months, and the 3 Purina Laboratory Chow, l~alston Purina Company, St. Louis, Missouri. 4 Teehnicon Instruments Corporation, Chauneey, New York. mean body weights for the three subgroups were similar. Each animal in Group I had two glucose tolerance tests, one after an overnight fast, and the second one week later in the randomfed state. Group I I animals h a d a single glucose tolerance test in the fed state. Blood samples were obtained from the tail at time 0, and at 0.5, 1, and 2 h after administration of glucose (1 m g / g m b o d y weight of 20% glucose solution, intraperitoneally). Glucose levels were measured b y an ultra-micro glucose oxidase method utilizing 5 ~l of blood [ 10 ]. Eight H G and LG males a p p r o x i m a t e l y 1 year old were used. The animals were sacrified b y decapitation after a 14 h fast; blood was allowed to clot at 4~ for 6 h and the serum from each line was frozen. Nonsuppressible and suppressible insulin-like activity (NSILA, SILA) were determined on each serum pool b y a modification of the bioassay method of Renold (11) using purified mouse insulin as standard. This modification entailed the division of the peripheral aspect of the mouse fat pad into 10-- 12 segments, each weighing 15--20 rag; these segments were then r a n d o m l y distributed into each incubation flask. Mouse epididymal f a t sensitivity to mouse insulin was studied in an identical fashion to the bioassay procedure. Hemidiap h r a g m incubations were performed as outlined b y Ensinck et al. [ 12 ]. Retinae were isolated in chilled Krebs-Ringer bicarbonate buffer with the aid of a dissecting l a m p ; 2 retinae were incubated for 2 h in 2 ml buffer containing 280 mg/100 ml glucose plus 0.2 fzciaC-g]ucose, a D r y weights were obtained following incubation on preweighed evaporating discs. Glucose concentration in the medium was determined as described above using the ultramicro modified glucose oxidasc method and laCOe t r a p p e d and counted as in the bioassay protocol. Values are presented as izmoles of specifically labeled carbon from glucose recovered as 14C02 and as moles of non-labeled glucose disappearing from the medium, both per milligram of d r y tissue per hour of incubation. Hepatic gluconeogenesis was studied as described b y Krebs, Norton and H e m s [ 13 ] using 10 mM lactic acid as substrate. H e p a t i c glycogen content was determined before and after incubation b y the method of Van I~andel [ 14 ]. Pancreatic insulin was extracted from pooled pancreata b y the method of Davoren [ 9 ] and quantitated b y the modified r a t f a t p a d segment bioassay [ 11 ]. Protein concentration was analyzed b y the colorimetric method of Lowry [ 15 ] using porcine insulin as standard. Between and within line comparisons of mean d a t a were made using paired and unpaired t-tests. Pearson's 5 New England Nuclear, Boston, Massachusetts. Generation n ttG line males F 1 F 2 F 3 F 4 LG line males F 1 F~ F 3 F a 14 42 93 145 19 60 118 93 ~IG line females F 1 F 2 F 3 F 4 17 39 100 137 LG line females F~ F 2 F~ F~ 17 55 110 92 108~_20 99  21 88 19 85 73-~ 16 70-4-17 59 49 9 87~15 82~22 7 7 i 1 5 75~14 664-12 62~15 54~13 49 ~ . E . Gleason eta/. : Genetic Selection for High and Low Fasting Glucose I. Correlations were used to determine the relationship between FBG, fasting I g I and body weight [ 16 ]. R e s u l t s 1. Genetic Selection Mean and standard deviations for FBG levels and body weights for 47 male and 50 female randombred Swiss Hauschka mice at 6.5 months of age were 694-11 and 634-10 mg%, 43.14-5.7 and 43.14-10.6 g, respectively. F B G levels in males were higher than in females (p < 0.01), and were significantly correlated with body weight (p<0.001). I n females, however, FBG and body weight were not significantly correlated. shown a gradual decrease during the first three generations of selection and inbreeding, with little or no further decline in the F~ generation. Mean fasting serum It~I levels (Tab. 1), measured at 6 months of age were much more variable than the corresponding F B G levels, and did not differ significantly between lines. A gradual decline in mean serum I R I levels, similar to that seen in FBG, was also noted during the first three generations of selection. Due to technical problems, the fasting I R I data obtained from the F 4 animals were not usable. Comparison of mean fasted body weights between lines showed significantly higher 6 month weights in F 1, F 3 and F~ HG males and females (p < 0.02 or less). The differences in generation F~ were not significant. Mean randomfed, as well as mean fasting body weights, On the basis of three FBG measured at 6.5, 8, and 8.5 months of age, three pairs of I-IG and three pairs of LG mice were selected and mated. These matings were maintained on the 4% fat diet. Of the three P1 HG line matings only one produced offspring, whereas two of the three P1 LG line matings were fertile. Mean FBG, Ii~I, and body weights for generations F 1 to F~ are shown in Table 1 for both KG and LG line mice. I n general mean FBG levels in H G line males and females have. remained about 30 and 20 mg % higher, respectively, than their LG line counterparts (p < 0.001) throughout the four generation selection period. Also males consistently show significantly higher F B G levels than females in both lines. FBG levels have tended to decrease during the selection period in a manner similar to that observed in FBG and I g I levels. I n the F 1 generation, body weights and FBG at six months of age were not significantly correlated in HG line males, t I G line females, or LG line females, but were (p < 0.025) in LG line males, however. Significant correlations (p < 0.05 or less) were noted in males and females of both lines in all subsequent generations. 2. Glucose Tolerance Tests Group I consisted of four t I G and five LG line males on the 11% fat diet with similar body weights (means  S D : 48.5 4- 5.7 and 47.8  5.5 g, respectively), 65 41  32 35 -60 40 42~39 -84~57 45~49 35~:31 -83~38 394-33 41 -(10)a ( 1 3 ) ( 5 4 ) ( 1 0 ) (4) ( 5 0 ) ( 1 0 6 ) Body Weight (g) 50.8 47.4 ~ 6.8 44.8i4.7 44.2 48.8~5.3 45.6~6.3 39.2~5.6 37.2 ~4.4 53.0 43.3q-9.3 40.9q-6.8 42.7-4-7.3 43.44-6.3 40.24-7.1 33.5 33.04-5.5 ranging in age from 6.5 to 9 months. Each animal received two glucose tolerance tests, one after an overnight fast, and the second one week later in the fed state. The results are shown in Fig. 1. Because of individual variation, m e a n fasting levels (Fig. 1 a) were not significantly different between the two lines. All mice reached peak glucose levels a t 30 min, with m e a n levels and standard deviations of 228 ~ 37 and 161  40 mg~o for H G and LG lines, respectively (p <0.05). When the m e a n changes in glucose were compared in the two lines, it was noted t h a t t I G line animals had a significantly greater rise to 30 rain (p < 0.05), and a more rapid drop in the second half hour (p < 0.02) t h a n the LG line mice. I n the randomfed state (Fig. 1 b),,the tI.G line animals had significantly higher mean glucose levels during the early phase of the test t h a n LG line mice. The m e a n change in glucose levels however, did not differ significantly between the two lines at a n y time during the test. XI L .I N.S. between the two lines. Comparison of LG line mice on 4 % and 11% fat diets (Fig. 2b) showed t h a t mean changes in glucose level were significantly greater for LG line mice on the 110/0 fat diet during the second 30 min of the test (p <0.01). This was due to the fact t h a t all four LG mice on the low fat diet had peal( glucose levels at 60 rain, whereas all L G mice on the high fat diet reached m a x i m u m levels at 30 rain following the glucose load. During the final hour of the test, the LG animals on the 4 ~ fat diet showed a sIightly greater change in glucose t h a n those on the 11~ fat diet ( p < 0 . 1 ) . I t was noted t h a t the H G males on the 4 % fat diet performed almost identieMly to LG males fed an 110/0 fat diet following a glucose load (Fig. 2 e). 0ie__~t HG m = 4 % Fat (n = 4 ) L6 o - - - - o 4 % F a t ( n - - 4 ) Diet LG o . - - - - o 4 % For ( n = 4 ) LG o , , o 1 1 % F o t ( n = 4 ) ,D!,et HG ; ~ 4 % For {n =4) LG o - - - - O l l % For ( n = 4 ) Z kO tO o r O O m 150 50 150 50 150 50 B C I n order to define the dietary influence on glucose tolerance more precisely, a second group of animals consisting of four t I G and four LG line males on the 4 ~ fat, diet since six months of age, and four LG males on the I 1o/0 fat diet were studied. These animals ranged in age from 10 to 12.5 months, and their mean b o d y weights were similar (means-t-SD: H G 4 % fat, 48.8 :~ 2.8; LG 4 % fat, 47.4:~2.8; and LG 11~ fat, 44.6~: 5.4 g). Each Group I I animal received a single glucose tolerance test in the randomfed state and the results are shown in Fig. 2. Comparison of H G and L G aninaMs on the 4 % fat diet (Fig. 2a) showed no significant differences in the m e a n delta glucose levels l%.E. Gleason et al. : Genetic Selection for High and Low Fasting Glucose I. H G ; 3 8 . 3 ~ : 2 7 . 8 LG) d i d n o t differ significantly bet w e e n t h e two lines. F a t tissue from H G a n i m a l s e x h i b i t e d g r e a t e r glucose o x i d a t i o n a t insulin concent r a t i o n s of t3 ~U ( p < 0 . 0 1 ) a n d 63 ~U ( p < 0 . 0 5 ) , b u t n o t at t h e higher c o n c e n t r a t i o n s , t h a n L G mice. N o differences were f o u n d in i s o l a t e d r e t i n a l m e t a b o l i s m , h e p a t i c glycogen, gluconeogenesis, or p a n c r e a t i c insulin b e t w e e n t h e two lines. This p a p e r s u m m a r i z e s t h e results of t h e first four g e n e r a t i o n s of selection a n d i n b r e e d i n g of Swiss H a u s e h k a mice on t h e basis of F B G only. I t is of i n t e r e s t t h a t t h e difference in F B G b e t w e e n t h e lines has r e m a i n e d a l m o s t c o n s t a n t f r o m F 1 t h r o u g h F~. This fact w o u l d t e n d to s u p p o r t t h e single a u t o s o m a l gene m o d e of i n h e r i t a n c e p r o p o s e d b y C a m m i d g e a n d H o w a r d . The a m o u n t of v a r i a t i o n w i t h i n t h e two lines, 1 Mice were matched for age and body weight; n = 8 for each line except where indicated. For significance levels see text. 2 D a t a recorded as ~ moles uptake/g d r y wt/h. 3 D a t a recorded as m~ moles 14CO2/g wet wt/h. 4 Values expressed as ~t moles 1~CO2 per rag/h, and as ~ moles glucose uptake/ mg/h. 5 Percent d r y weight at time of sacrifice, i>"~:"~ ~, 6 D a t a recorded as ~zmoles glucose produeed/g/h from lactic acid s u b s t r a t e . 7 Units/g pancreas (pooled panereata). 8 Results of bioassay of pooled serum diluted (1 : 5) ~U/ml. Discussion 1. Genetic Selection E a r l y studies b y C a m m i d g e a n d H o w a r d [ 4, 5 ] concluded t h a t F B G levels in mice were d e t e r m i n e d b y c o m b i n a t i o n s of t h r e e alleles a t a single a u t o s o m a l locus. I-Iyperglycemia a n d h y p o g l y c e m i a were b o t h recessive to n o r m o g l y c e m i a a n d h y p o g l y c e m i a was r e p o r t e d to be recessive to h y p e r g l y c e m i a . More recently, C h a r l e w o r t h [17] s t u d i e d t h e i n h e r i t a n c e of b l o o d glucose levels in five strains of mice including t h e Swiss mouse being u t i l i z e d in this i n v e s t i g a t i o n . A f t e r m a k i n g crosses b e t w e e n t h e s t r a i n s a n d s u b j e c t i n g the d a t a to analysis of variance, she concluded t h a t , a l t h o u g h t h e differences b e t w e e n t h e s t r a i n s were small, t h e y were i n h e r i t e d . N o m e n t i o n was m a d e , however, as to w h e t h er t h e b l o o d glucose m e a s u r e m e n t s were m a d e in t h e f a s t e d or r a n d o m f e d state. on t h e o t h e r h a n d , i n d i c a t e s t h a t F B G levels in mice are p r o b a b l y also influenced b y o t h e r genetic a n d / o r physiologic factors. B o d y weight which were quite s i m i l a r in t h e P1 g e n e r a t i o n of t h e H G a n d L G lines, differed b y 2 to 3 g in t h e F~, a n d f r o m 7 to 10 g in t h e F 4 g e n e r a t i o n ; t h e I-IG line a n i m a l s b e c o m i n g h e a v i e r t h a n L G line a n i m a l s of t h e s a m e age. The r e a s o n for this change is n o t known. 2. Glucose Tolerance Test I n general, glucose t o l e r a n c e t e s t s p e r f o r m e d in H G a n d L G line mice r e s u l t e d in n e a r l y p a r a l l e l curves (Fig. 1), H G line a n i m a l s showing t h e poorer glucose tolerance. Glucose t o l e r a n c e results in H G a n d L G line mice fed different diets i n d i c a t e d a definite d i e t a r y influence on this response. I t a p p e a r e d t h a t line differences ]~.E. Gleason et al. : Genetic Selection for High and Low Fasting Glucose I. persisted when b o t h t I G and L G mice were fed the same diet (Fig. 2a). L G line mice performed differently when animals on different diets were c o m p a r e d (Fig. 2b), b u t differences between the lines were n o t apparent when IKG line mice received the low fat diet and L G mice received the high fat diet (Fig. 2c). A series of studies b y Cole et al. describe two strains of rats differing in glucose tolerance which show striking similarities to H G a n d L G line mice such as nearly parallel glucose tolerance test curves differing b y a b o u t 30 m g % at each point, a n d a more rapid g r o w t h rate in the strain with higher glucose levels [ 18 ]. The authors concluded t h a t decreased glucose tolerance is p r o b a b l y the result of one principal gene plus modifiers with the principal gene tending to be incompletely recessive [ 19 ]. 3. Isolated Tissue Studies The results of several H G and L G line comparisons with respect to isolated tissues revealed no statistically significant differences. I n general, however, the importance of these early results in F a animals must await further analysis of subsequent generations, but they presently suggest the possibility t h a t enhanced glucose oxidation occurs in H G tissues. I t is generally t h o u g h t t h a t insulin occupies the central role in regulation of glucose homeostasis a n d m o d u l a t i o n of hepatic glueoneogenesis and glucose disposition. I t is therefore s o m e w h a t suprising t h a t no differences were f o u n d in basal I R I or basal I L A . The agreement between I R I values a n d suppressible I L A , however, suggests t h a t m o s t of the circulating i m m u n e reactive insulin is biologically active, at least on isolated adipose tissue. I n contrast, the failure to identify a significant line difference in serum nonsuppressible I L A is n o t surprising since few studies have demons t r a t e d a physiological role for this a c t i v i t y in glucose homeostasis. Acknowledgements. The authors gratefully acknowledge the technical assistance of the following : Mr. Arvids Klavins, Mrs. Marta Grinbergs, Mrs. Daisy Shcn, Mrs. Maija Grinbush, and Mr. Alex Cirulis. 1. Brook lodge workshop on spontaneous diabetes in laboratory animals. Diabetologia 3 , 63 -- 286 ( 1967 ). 2. Gleason , R.E. , Lauris , V. , Soeldner , J. S. : Studies on experimental diabetes in the Wellesley hybrid mouse I I I . Dietary effects and similar changes in a commercial Swiss-Hausehka strain . Diabetologia 3 , 1 7 5 - i78 ( 1967 ). 3. Kramer , M.W. , Liberman , D.F. , Soeldner , J.S. , Gleason , R.E. : Dissociation of hyperglycemia and obesity in mice fed high fat diets . Diabetologia 5 , 353 -- 355 ( 1969 ). 4. Cammidge , P.J. , Howard , H . A . H . : Hyperglycemia as a mendelian recessive character in mice . J. Genet . 16 , 387 -- 392 ( 1926 ). 5. Cammidge , P.J. , Howard , H.A.H.- The hereditary transmission of hypoglycemia in mice . Prec. roy. See. Med . 23 , 1341 -- 1343 ( 1930 ). 6. Dunn , L. C. , Fisher , R. A. : A new series of allelomorphs in mice . Nature (Lend.) 129 , 130 ( 1932 ). 7. Gruneberg , H. Haldane , J.B.S.: Congenital hyperglycemia in mice . Nature (Lend,) 145 , 704 -- 705 ( 1940 ). 8. Soeldner , J.S. , Slone , D. : Critical variables in the radioimmunoassay of serum insulin using the double antibody technic . Diabetes 14 , 771 -- 779 ( 1965 ). 9. Davoren , P.R. : The isolation of insulin from a single cat pancreas . Biochcm. biophys. Aeta 63 , 150 -- 153 ( 1962 ). 10. Chick , W.L. , Lavine , R.L. , Like , A.A. : Studies in the diabetic m u t a n t mouse: V. Glucose tolerance in mice homozygous and heterozygous for the diabetes (db) gene . Diabetologia 16 , 257 -- 262 ( 1970 ). 11. Renold , A.E. , Martin , D.B. , Dagenais , Y.M. , Steinke , J. , Nickerson , R.J. , Sheps , M.C. : Measurement of small quantities of insulin-like activity using rat adipose tissue. I. A proposed procedure . J. olin. Invest . 39 , 1487 -- 1497 ( 1960 ). 12. Ensinck , J . W . , Poffenbarger , P.L. , Hogan , R.A. , Williams , R . H . : Studies of insulin antagonism. I. An artificial antagonist to insulin and plasma nonsuppressible insulin-like activity occurring in preparation of "albumin" . Diabetes 16 , 289 -- 301 ( 1967 ). 13. Krebs , H.A. , Norton , B.M. , g e m s , R. : Gluconeogenesis in mouse liver slices . Biochem. J . 191 , 607 -- 617 ( 1966 ). 14. Van Handel , E. : Estimation of glycogen in small amounts of tissue . Anal. Biochem . 11 , 256 -- 265 ( 1965 ). 15. Lowry , O.H. , Rosebrough , N.J. , Farr , A.L. , Randell , R . J . : Protein measurement with the Folin phenol reagent . J. biol. Chem . 193 , 265 -- 275 ( 1951 ). 16. Steel , R.G.D. , Torrie , J . H . : Principles and procedures of statistics, p. 73 and 183 . New Y o r k : Me Graw-tIill 1960 . 17. Charlesworth , D. : Small, inherited differences in blood glucose levels in mice . Genet. Res . 14 , 1 -- 7 ( i969 ). 18. Cole , V.V. , Earned , B.K. : Diabetic traits in a strain of rats . Endocrinology 23 , 318 -- 326 ( 1938 ). 19. Cole , V.V. , Harned , B.K. , Keeler , C.E. : Inheritance of glucose tolerance . Endocrinology 28 , 25 -- 32 ( 1941 ). Senior Investigator Elliott P. Joslin Research Laboratory 170 Pilgrim Road Boston, Mass. 02215 USA

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R. E. Gleason, P. L. Poffenbarger, R. L. Lavine. Genetic selection for high and low fasting blood glucose levels in mice. I. Fasting blood glucose levels, glucose tolerance and isolated tissue studies, Diabetologia, 1973, 268-273, DOI: 10.1007/BF01221853