Spontaneous glucose intolerance in the progeny of low dose streptozotocin-induced diabetic mice

Diabetologia, Dec 1993

Summary Multiple low doses of streptozotocin (LDS) induce low-incidence diabetes mellitus in Balb/cHan and high-incidence diabetes in CD-1 mice. We studied offspring of diabetic parents in both strains. Group 1 consisted of litters from control mice with no streptozotocin treatment. Group 2 litters had an LDS diabetic mother and a control father, group 3 litters had control mother with LDS diabetic father, and group 4 litters had both, LDS diabetic mother and father. Diabetes was induced by 5×40 mg streptozotocin per kg on five consecutive days. Progeny of diabetic mothers showed a state of reduced glucose tolerance associated with reduced glucose disappearance during intravenous glucose tolerance test and increased insulin secretion of isolated islets of Langerhans. These metabolic abnormalities predominated in the male litters of both strains of mice. Amniotic insulin was increased in diabetic mothers during pregnancy. No histologic abnormalities were observed in group 2 progeny. Pancreases in male offspring of LDS diabetic CD-1 fathers (group 3) were studied for insulitis. Insulitis was found in 40% of mice with normal glucose tolerance. A single subdiabetogenic dose of streptozotocin (40 mg/kg) induced insulitis in 90% of pancreases accompanied by reduced insulin release of isolated islets. By contrast, male Balb/cHan progeny of diabetic fathers failed to develop insulitis. In conclusion, we found (1) parental LDS diabetes was transmitted more often to male offspring, (2) maternal LDS diabetes was associated with hyperinsulin secretion and glucose intolerance in the offspring and (3) paternal LDS diabetes was accompanied by insulitis and insulin secretion deficiency in CD-1 progeny.

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Spontaneous glucose intolerance in the progeny of low dose streptozotocin-induced diabetic mice

Diabetologia Spontaneous glucose intolerance in the progeny of low dose streptozotocin-induced diabetic mice T. Linn 0 E. Loewk 0 K. Schneider 0 K. Federlin 0 0 Medical Clinic III and Policlinic, Department of Internal Medicine, Justus Liebig University , Giessen , Germany Summary. Multiple low doses of streptozotocin (LDS) induce low-incidence diabetes mellitus in Balb/cHan and high-incidence diabetes in CD-1 mice. We studied offspring of diabetic parents in both strains. Group 1 consisted of litters from control mice with no streptozotocin treatment. Group 2 litters had an LDS diabetic mother and a control father, group 3 litters had control mother with LDS diabetic father, and group 4 litters had both, LDS diabetic mother and father. Diabetes was induced by 5 x 40 mg streptozotocin per kg on five consecutive days. Progeny of diabetic mothers showed a state of reduced glucose tolerance associated with reduced glucose disappearance during intravenous glucose tolerance test and increased insulin secretion of isolated islets of Langerhans. These metabolic abnormalities predominated in the male litters of both strains of mice. Amniotic insulin was increased ~n diabetic mothers during pregnancy. No histologic abnormalities were ob- Streptozotocin; offspring; insulitis; islet perifusion 9 Springer-Verlag 1993 D i a b e t e s mellitus can be induced in rodents by diabetogenic drugs, such as streptozotocin (STZ) or alloxan. S T Z interferes with the protective mechanisms of the b e t a cell that normally scavenge endogenously p r o d u c e d free radicals. G i v e n in multiple low doses, S T Z causes insulitis and transient lymphocytic cytotoxicity to pancreatic b e t a cells in susceptible strains of mice [ 1, 2 ]. D i a b e t e s induction is subject to control of the M H C complex and is strain d e p e n d e n t [ 3, 4 ]. N-nitroso c o m p o u n d s can induce insulitis and Type 1 (insulin-dependent) diabetes in mice and m a n [ 1, 5 ]. We studied low dose streptozotocin (LDS) diabetes in two mouse strains, because in this murine m o d e l Type 1 diabetes is induced by a toxic e n v i r o n m e n t a l agent. CD-1 mice are susceptible to L D S diabetes and B a l b / c H a n mice are not susceptible. In models of spontaneous diabetes the disease is transmitted to offspring, and it is k n o w n that this occurs also in models of induced diabetes, but it has not b e e n d e m o n s t r a t e d for i m m u n e - m e d i a t e d mechanisms. Consequently, the aims of this study were to determine served in group 2 progeny. Pancreases in male offspring of LDS diabetic CD-1 fathers (group 3) were studied for insulitis. Insulitis was found in 40 % of mice with normal glucose tolerance. A single subdiabetogenic dose of streptozotocin (40 mg/kg) induced insulitis in 90 % of pancreases accompanied by reduced insulin release of isolated islets. By contrast, male Balb/cHan progeny of diabetic fathers failed to develop insulitis. In conclusion, we found (1) parental LDS diabetes was transmitted more often to male offspring, (2) maternal LDS diabetes was associated with hyperinsulin secretion and glucose intolerance in the offspring and (3) paternal LDS diabetes was accompanied by insulitis and insulin secretion deficiency in CD-1 progeny. whether diabetes induced by LDS t r e a t m e n t was transferred to the next generation, and what contribution m a t e r n a l and paternal diabetes m a d e to the transfer. Materials and methods Animals The CD-1 and Balb/c mice used (Versuchstieranstalt, Hannover, Germany) were comparable in terms of physical activity, litter size (4-8 mice), growth after birth and were free from common mouse virus infections. The mice were kept under usual animal housing conditions. STZ (Upjohn Co, Brussels, Belgium) was injected i.p. on 5 consecutive days, 40 mg/kg per day and diabetes was defined by fasting blood glucose greater than 10 mmol/1 on 3 days. Controls were injected with 0.05 mmol/1citrate buffer. Future parents were made diabetic at 6 weeks of age. About 2 weeks after the last injection, mice that had become diabetic were used for breeding. Five parental groups were formed. In group 1, also termed "controls", neither mothers nor fathers were treated with STZ. In group 2, LDS diabetic mothers were After a 12-h fast blood glucose was measured in mmol/1 with a Beckman glucose analyser 14 days after the first STZ injection. Insulitis score is explained in the materials and methods. The number of mice studied is in parentheses. Controls were injected with citrate buffer. Values are given as mean + SEM. " p < 0.01 vs Balb/c male and CD-1 female mated with fathers who had not been treated with STZ. Group 3 progeny had a control mother (no LDS) and an LDS diabetic father, and group 4 litters were born to an LDS diabetic mother and an LDS diabetic father. Group 5 included offspring of group 3 treated with a single subdiabetogenic dose of 40 mg/kg STZ at 4 weeks of age. In all groups offspring were studied for intravenous glucose tolerance, pancreatic histology, and insulin secretion of isolated islets of Langerhans. Amniotic fluid was collected by direct puncture of the fetal cavity on the 20 th day of gestation. Intravenous glucose tolerance test (IVG TT) Litters were subjected to an I V G T F at age 12 weeks. After an overnight fast animals were anaesthetized (sodium pentobarbital 75 mg/kg body weight) and the inferior vena cava was catheterized. Glucose (1 g/kg) was injected through the catheter (24 gauge). During anaesthesia blood samples were withdrawn 0, 2, 4, 6, 10, 20, and 30 min after glucose injection by the catheter. Each blood sample of 50 gl was replaced with an equivalent volume of heparin/NaC1. Haemoglobin before and after the I V G T T dropped from 142_+ 2.1 to 98_+ 1.9 g/1. Blood samples were centrifuged and the plasma was analysed for glucose by a Beckman glucose analyser. Glucose concentrations were plotted against time and the area under the curve ( A U C ) was calculated following the trapezoid rule. Glucose disappearance rate (K-value) was calculated by the least square method and given in % per min (%/min). Islet histology and islet isolation After the I V G T T the pancreas was removed. A b o u t one-third of the pancreatic volume was used for histology and two-thirds were used for islet isolation. For histological examination, pancreas was paraffin embedded, cut in 10 sections each separated from the previous one by + 10 slides, and was stained with haematoxylin-eosin. For scoring of insulitis three degrees of insulitis were distinguished: first degree, with lymphocytes present in the periphery of the islet; second degree, with lymphocytes present also inside the islet, without altering its normal architecture; third degree, with massive alterations of its normal architecture. The insulitis score in the 10 sections from each preparation was expressed as the sum of the percentages of islets infiltrated times the degree of infiltration. T. L i n n e t al.: Diabetes in progeny of LDS mice 5 40 mg STZ/kg Blood glucose (mmol/1) Islets were isolated as described previously [ 6 ]. Briefly, the pancreas was distended with Hanks' solution and the tissue was minced and digested with 1.5 mg/ml collagenase for 9-11 min at 37 ~ The tissue was stirred by gentle bubbling with 95 % 02/5 % CO2. Islets were collected with siliconised constriction pipettes under a stereomicroscope. Only islets with a diameter more than 150 ~tm were selected. The average yield was 45 + 21 islets per pancreas. Islet perifusion After a culture period of 12 h in RPMI 1640 medium, batches of 100 islets were transferred to chambers consisting of a plastic filter unit fitted with a nylon filter (15 gm pore size). The basic perifusion medium (Krebs Ringer Bicarbonate) consisted of 119mmol/1 NaC1, 4.7mmol/1 KC1, 2.5mmol/1 CaC12, 1.2mmol/1 MgSO4, 25mmol/1 NaHCO3, 10mmol/1 H E P E S , 3 mmol/I glucose and 0.15 % bovine serum albumin (pH 7.4). Stimulating media consisted of basic medium plus 25 mmol/1 glucose or 10 mmol/1 arginine. The perifusion system has been described previously [ 7 ]. The media were continuously gassed with a mixture of 95 % 02/5 % CO2 with p H kept between 7.35-7.45. The dead space of the system was 2.5 ml and the flow rate was 0.25 ml/min. The effluent was collected once per 10 min, except for the interval between the time points 60 min and 70 rain of every perifusion experiment. During this time the effluent was collected once per min. Samples were stored at -20 ~ Insulin in the effluent and in amniotic fluid was determined by a R I A kit (Behring, Frankfurt, Germany) using rat insulin as standard (kindly provided by Novo Industry A/S, Bagsvaerd, Denmark). Non-specific binding was 6.6 + 0.45 % (n = 10). The detection limit of the R I A was 5 pmol/1. The inter-assay coefficient of variation in the perifusion system was 30% and intra-assay coefficient of variation was 15-20 %. For calculation of first phase insulin response (FPIR) the area under the insulin concentration curve above steady state between 60 and 70 min, for total insulin response (TIR) between 60 and 120 rain was used. Statistical analysis Statistical evaluations were made by Student's t-test for unpaired data. Results were presented as mean + SEM. R e s u l t s Differences between CD-1 and Balb/c mice T a b l e 1 s h o w s t h e d e v e l o p m e n t o f d i a b e t e s in t w o d i f f e r e n t m o u s e s t r a i n s , C D - 1 a n d B a l b / c . W h e n g i v e n in t h e f o r m o f t h e m u l t i p l e i n j e c t i o n r e g i m e n C D - 1 m a l e s d e v e l o p e d f a s t i n g h y p e r g l y c a e m i a (13.4_+2.7 m m o l / 1 ) o n d a y 14 a f t e r t h e first S T Z i n j e c t i o n . B y c o m p a r i s o n , B a l b / c 1".Linn et al.: Diabetes in progeny of LDS mice Data show incremental area under the glucose curve (AUCg~u)and K-values of intravenous glucose tolerance tests performed at 12 weeks of age. Data are given as mean  SEM. p < 0.05, bp < 0.01 VScontrol M e a n l i t t e r sizes w e r e 6.2 _+3.0 f o r n o n - d i a b e t i c m o t h e r ( g r o u p s 1, 3, a n d 5), 5.6 + 3.2 for d i a b e t i c m o t h e r ( g r o u p s 2 a n d 4), a n d 6.4 + 3.1 f o r d i a b e t i c father. T a b l e 2 s h o w s t h a t a m n i o t i c i n s u l i n w a s i n c r e a s e d in d i a b e t i c m o t h e r s of b o t h s t r a i n s i n d i c a t i n g s t i m u l a t i o n of f e t a l b e t a cells. F o u r - w e e k - o l d m a l e C D - 1 o f f s p r i n g of d i a b e t i c m o t h e r s ( g r o u p s 2, 4) s h o w e d s i g n i f i c a n t l y (p < 0.05) l o w e r b o d y w e i g h t s c o m p a r e d to m a l e o f f s p r i n g o f d i a b e t i c f a t h e r s ( g r o u p s 3, 5) as d e p i c t e d in F i g u r e 1. I n f e m a l e p r o g e n y o f C D - 1 d i a b e t i c m o t h e r s , b o d y w e i g h t L & 20 22 24 20 17.7 +_5.2 4.69 + 3.1 13.9  3.9 4.f +1.5 12.8  4.4 2.57 _+0.19 13.9_+4.1 2.5  0.9 22 20 20 22 22.9 +_5.0a 3.44 +_1.9 17.2 +_4.2 4.0_+3.4 16.7  3.8 1.42 + 1.19 13.7_+4.0 2.6 _+0.9 33.7 _+5.0~ 0.91 +_1.08u 23 20 20 19 17.8  4.7 4.0_+3.9 14.2 i 2.4 2.49 + 1.9 12.8+3.0 2.9  1.0 of islets from progeny of LDS diabetic CD-1 or Control l LDS female 2 Parents Groups CD-1 Maleoffspring 70 min) and TIR (Total insulinrelease, 60-120 min) are presented in nmol. 1-~9100 islets- ~.min- ~as incrementalarea under the curve. p < 0.001, bp < 0.02 vs control For every pancreas a single insulitisscore was calculated as described in the materials and methods section. Data are mean score values with number of pancreases in parentheses. ap < 0.001, bp < 0.05 VScontrol; cp < 0.05 VSgroup 3 male offspring was n o t significantly different f r o m controls. By contrast, Balb/c diabetic m o t h e r s h a d o v e r w e i g h t m a l e a n d f e m a l e progeny. Glucose tolerance, insulin secretion and frequency of insulitis in male offspring of adult age Diabetic mother Male offspring of diabetic m o t h e r s were glucose intolerant in b o t h strains. CD-1 m a l e offspring of diabetic m o t h ers h a d 8.5 + 2.4 mmol/1 n o n - f a s t i n g glucose at 12 weeks of age while Balb/c m a l e offspring had 7.6 + 1.9 mmol/1 (p < 0.05). Table 3 shows that AUCg~u was significantly higher in g r o u p 2 (p < 0.01) a n d 4 (p < 0.05) c o m p a r e d to controls. K - v a l u e of g r o u p 2 was significantly (p < 0.05) lower t h a n in controls. T h e insulin secretion p a t t e r n of isolated islets of L a n g e r h a n s in group 2 a n d 4 of p r o g e n y is d e p i c t e d in F i g u r e 1 B a n d F i g u r e 1 D, respectively. D a t a of F P I R a n d T I R are given in Table 4. F o r the CD-1 strain G r o u p 3 offspring of b o t h strains a n d of b o t h sexes had n o r m a l n o n - f a s t i n g b l o o d glucose values with n o statistical differences c o m p a r e d to controls. AUCg~u a n d K - v a l u e were n o r m a l in m a l e offspring with a diabetic father o n l y ,O 60 A I 24O I 240 E I 240 o~ oo c A non-fasting blood glucose level of 8.2 + 1.7 mmol/1 was measured in CD-1 group 2 females (vs control 6.0+1.6mmol/1, p < 0 . 0 5 , and vs Balb/c group 2 7.33 + 1.9 mmol/1, p < 0.05). Glucose intolerance was found by IVGTT in this group (Table 3) while TIR and FPIR were not impaired (Table 4). Female offspring with diabetic mother and diabetic father (group 4) did not show any abnormalities. Balb/c female progeny had normal glucose tolerance in all groups. TIR to glucose was slightly, but significantly increased (p < 0.05) in Balb/c group 2 and group 4. T. Linn et al.:Diabetes in progeny of LDS mice 3mmol/I GIc I 25mmol/I GIc 3mmol/l GIc 10 mmol/i Arg 3 mmol/I GIc 25 mmol/I GIc 3mmoi/I GIc L 10mmol/I Arg 120 Time (rain) 120 Time (min) 120 Time (rain) __ 180 180 180 3mmol/I Grc 25 mmol/I GIc 3 mmel/I GIc 10mmol/I Arg Fig,2A-E. Insulin secretory response (IRI) to glucose (Glc) and arginine (Arg) by perifused islets of Langerhans isolated from 12-week-old male offspring (CD-1) of LDS parents. A-E correspond to Groups 1-5, respectively. (See Materials and methods section) (group 3, Table 3) in both strains. Isolated islets showed normal insulin responses (Table 4, Fig.2C). However, when a single subdiabetogenic dose of STZ was injected to CD-1 mice (group 5) K-values were markedly reduced (p < 0.01) and AUCg~u was increased (p < 0.05). Islets isolated from group 5 male CD-1 offspring released significantly less insulin in response to a glucose challenge than group i (control) islets (Table 4). Figure 1E depicts that arginine-stimulated insulin secretion was not decreased. By contrast, glucose tolerance and insulin secretion pattern of islets remained unaltered in group 5 of the Balb/c mice. 60 60 o _ 120 Time (rain) 120 Time (min) 180 180 Diabetic father Female offspring of CD-1 and Balb/c LDS diabetic fathers were not glucose intolerant at 12 weeks of age (Table 3). A single subdiabetogenic dose of STZ did not impair glucose tolerance or insulin secretion of islets in group 5. Insulitis scores in female offspring of diabetic fathers were lower than in male offspring (Table 5). Significant scores were found in CD-1 mice only. Discussion Low body weight at young age was associated with glucose intolerance and increased insulin responses in adult offspring of LDS diabetic mothers of the high-incidence strain (CD-1). These abnormalities were predominantly observed in CD-1 males. Balb/c youngsters of diabetic mothers and of both sexes were overweight. At adult age they had lower postprandial blood glucose compared to CD-1 mice of the same age and sex, but nevertheless Balb/c mice had reduced tolerance to an intravenous glucose load, and increased TIR, too. In male offspring of LDS diabetic fathers we observed spontaneous insulitis and normal glucose tolerance. Although the insulin release profile from progeny of diabetic fathers was indistinguishable from the control group, a single subdiabetogenic dose of STZ induced a general blunting of the secretory response to glucose. Histologically, this phenomenon was accompanied by a dramatically increased incidence of insulitis. Both, insulitis and reduced insulin response to glucose are characteristics of autoimmune prediabetes [ 8 ]. Increased Type 1 diabetes susceptibility in children of diabetic fathers has also been reported in man [ 9 ]. LDS diabetes in the mother and the father partly protected male CD-1 offspring from insulitis, but not from glucose intolerance. Balb/c offspring failed to develop insulitis and glucose intolerance. Steele [ 10 ] tested the effect of parental exposure to STZ. He described a single spontaneously hyperglycaemic CBA/H mouse among the litters from the cross of LDS male with non-treated female. Spergel et al. [ 11 ] reported, that alloxan-induced latent diabetes in the rat could be transmitted to offspring either through the male or female parent with increasing glucose intolerance through the generations. There have been several reports on STZ and other N-nitroso compounds on pancreatic beta cell function after prenatal exposure [ 3, 12, 13 ]. Pancreatic insulin stores were decreased and insulin secretion was impaired in response to glucose and arginine in the offspring of STZ treated pregnant rats. In our experimental design, exposure to STZ was not during pregnancy, because mice were mated after the onset of manifest LDS diabetes. We observed reduced insulin response to glucose, but normal insulin secretion to arginine. This implies, that STZ leaves the fetal beta cell non-responsive to different secretagogues, while hyperglycaemia, on one hand, and insulitis, on the other hand, impair insulin secretion selectively to glucose in the progeny. STZ may act on germ cells, both in females and males. No chromosome damage was found in the testes isolated from T. Linnet al.:Diabetesin progenyof LDS mice male mice directly after LDS treatment (unpublished observation). STZ-induced deficits in testosterone production in rats have been reported, but it is not clear whether this is an effect of STZ itself or of hyperglycaemia [ 14 ]. During pregnancy of a diabetic mother fetal beta cells are chronically stimulated by hyperglycaemia to produce insulin. As a result, we measured increased concentra: tions of insulin in the amniotic fluid of pregnant LDS mice. Chronic hyperglycaemia leads to compensatory growth of fetal islet tissue. In our study maternal diabetes during pregnancy resulted in increased probability in the offspring to develop diabetes without significant insulitis. This effect is not immunologically mediated, but is attributable to intrauterine hyperglycaemia as previously described [ 15, 16 ]. We observed insulitis predominantly in the progeny of diabetic fathers. Recently, it was reported that prevention of autoimmune diabetes can be achieved by neonatal stimulation of beta cells with glucose [17]. In this study, insulitis in pancreases of offspring of diabetic fathers was partially compensated when both mother and father were diabetic. This supports the hypothesis that perinatal hyperglycaemia sensitizes fetal islets to glucose at an early stage in life and therewith protects them from future immune-mediated impairment of glucose-induced insulin secretion. In accordance with publications dealing with prenatal STZ exposure we observed defects of insulin release primarily in male litters of LDS diabetic parents. On intraperitoneal challenge with STZ, progeny of group 3 mice responded with insulitis in an enhanced mode. This finding should be considered in the context of the significance of nitrosamine compounds in the pathogenesis of human Type i diabetes. Analyses of population-based registries of childhood diabetes have revealed an influence of nutrients, among them nitrosamines [ 18, 19 ]. Why do male LDS mice transmit the tendency to develop insulitis to the next generation. ? Obviously, this cannot result from hyperglycaemia during fetal development, but must occur genetically. It is known that STZ induces strand breaks in different cell types including beta cells [20] and that it can also activate oncogenes, such as H-ras oncogene [ 21 ]. STZ can induce tumour growth in islets, kidney, liver, and mammary gland [ 22, 23 ]. Complex effects of STZ including DNA damage on beta cells have been extensively reported. LDS treatment has been shown to result in the expression of retrovirus in beta cells associated with insulitis [ 24 ]. Oncogenes or protooncogenes may be activated by STZ directly or by activation of virus oncogenes in susceptible mice. Since males are more susceptible to LDS induced insulitis than females, this could indicate that activation of oncogenes may be modulated by hormones. This mechanism could explain increased susceptibility to STZ in offspring of LDS diabetic fathers [ 10, 11 ]. In addition, STZ may also have direct effects on the level of the immune system, because it stimulates T cells and induces the secretion of lymphokines, such as interferon [ 25 ]. There is also evidence that subcutaneous STZ injection is followed by lymphoproliferation without diabetes [ 26 ]. STZ could use either one or more of these p a t h w a y s t o t r a n s m i t d i a b e t e s w i t h i n s u l i t i s in t h e p r o g e n y o f L D S d i a b e t i c f a t h e r s . I n c o n c l u s i o n , this p a p e r r e p r e s e n t s a s y s t e m a t i c s t u d y o n s e x - d e p e n d e n t t r a n s m i s s i o n o f d i a b e t e s u n d e r t h e c o n d i t i o n s o f this m u r i n e m o d e l . U s i n g i n s u l i t i s as a n ind i c a t o r o f i m m u n e m e c h a n i s m s w e f o u n d t h a t p a t e r n a l d i a b e t e s is a s s o c i a t e d w i t h i n c r e a s e d i n c i d e n c e o f insulitis in t h e o f f s p r i n g as a r i s k f a c t o r f o r d e v e l o p i n g i n s u l i n - d e f i c i e n t d i a b e t e s . D i a b e t i c f a t h e r s t e n d t o t r a n s m i t insulitis to t h e i r m a l e p r o g e n y w h i l e d i a b e t i c m o t h e r s t r a n s m i t gluc o s e i n t o l e r a n c e , b u t n o t i n s u l i t i s t o t h e i r m a l e o f f s p r i n g . I n m a t e r n a l d i a b e t e s , t h e i n f l u e n c e o f u t e r i n e e n v i r o n m e n t is m o r e i m p o r t a n t for t h e o u t c o m e o f t h e i r p r o g e n y t h a n in i n f l a m m a t o r y p r o c e s s e s w h i c h a r e p o t e n t i a l l y d e s t r u c t i v e f o r t h e islets o f L a n g e r h a n s . Acknowledgements. This work is a part of the thesis of K. S. who is granted by Friedrich-Ebert-Stiftung. This work was supported by grants from Deutsche Gesellschaft for Innere Medizin (1991), Projektf6rderuug der Deutschen Diabetesgesellschaft(1992) and Deutsche Forschungsgemeinschaft Li 353/7-1. We thank Dr. B.Hering ~br using his perifusion apparatus. 1. 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T. Linn, E. Loewk, K. Schneider, K. Federlin. Spontaneous glucose intolerance in the progeny of low dose streptozotocin-induced diabetic mice, Diabetologia, 1993, 1245-1251, DOI: 10.1007/BF00400801