This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Suzuki, N. Articles by Hashizume, K. Search for Related Content PubMed PubMed Citation Articles by Suzuki, N. Articles by Hashizume, K.

An Early Insulin Intervention Accelerates Pancreatic ß-Cell Dysfunction in Young Goto-Kakizaki Rats, a Model of Naturally Occurring Noninsulin-Dependent Diabetes¹

Departments of Geriatrics, Endocrinology, and Metabolism (N.S., T.A., N.A., Y.S., M.K., K.Y., K.H.), Laboratory Medicine (H.H.), and Pathology (N.I.), Shinshu University School of Medicine, Matsumoto, Nagano-ken, Japan

Address all correspondence and requests for reprints to: Toru Aizawa, M.D., Department of Geriatrics, Endocrinology, and Metabolism, Shinshu University School of Medicine, 3–1-1 Asahi, Matsumoto, Nagano-ken, Japan.

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
This study was designed to delineate the nature of ß-cell dysfunction in a model of genetically determined nonobese diabetes, the Goto-Kakizaki (GK) rat. Pancreatic ß-cell function was analyzed immediately after weaning and 5 weeks thereafter, comparing animals with or without insulin treatment during the interval. In 3.5-week-old GK rats, fasting plasma glucose was mildly elevated with normoinsulinemia, and the islet insulin content was reduced by 33%. When incubated with 3–30 mM glucose in vitro, the GK rat islets showed reduced glucose sensitivity, i.e. the EC₅₀ values were 19.5 and 15.9 mM, and the Hill constants for the positive cooperativity 2.1 and 4.2, in the islets of GK and the control rats, respectively. On the other hand, the maximum response to glucose was not attenuated when reduced islet insulin content was considered. In 8.5-week-old GK rats, hyperglycemia worsened and glucose-stimulated insulin release by the islets more severely impaired. A daily insulin injection from the 3.5–8.5 weeks of age significantly lowered plasma glucose in the GK rat, accompanied by a marked suppression of both basal (with 3 mM glucose) and glucose (6–30 mM)-stimulated insulin release by the islets. In the GK rat, ß-cell dysfunction develops by the age of 3.5 weeks, and insulin treatment during the subsequent 5 weeks accelerates its progression.

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

 
CLINICAL features of noninsulin-dependent diabetes mellitus (NIDDM) are highly variable in relation to the degree of obesity, age of onset, mode of inheritance, and severity of glucose intolerance (1). Although these phenotypic differences may reflect diverse etiopathogeneses in human NIDDM, a precise disease locus is unknown in the majority of the patients. Nevertheless, early intervention, reversal, and prophylaxis, if possible, of diabetes are highly desirable to obviate the risk of chronic complications (2). In search of effective interventional treatment for each subtype of NIDDM, diabetic model animals are valuable because one can prospectively analyze a homogeneous population with determined diabetes development from the youth. Taking such advantage, we found that diazoxide prevents the development of obesity, glucose intolerance, and ß-cell dysfunction in a genetically determined obese NIDDM model, the OLETF rat (3), which closely resembles obese NIDDM in the human (4).

In the present study we examined another model of genetically determined NIDDM, the Goto-Kakizaki (GK) rat (5, 6). This rat has been evaluated by many investigators, and the following characteristics are established (5, 6, 7, 8, 9): 1) the development of diabetes is virtually 100%; 2) NIDDM in this animal is the nonobese, insulin-deficient type; and 3) although the ß-cell response to glucose is severely impaired, it responds well to nonfuel insulin secretagogues such as arginine despite marked reduction in ß-cell insulin content. All of these findings were obtained in adult GK rats with established diabetes. Accordingly, in the fist part of the study, we analyzed phenotype and ß-cell function in GK rats immediately after weaning to determine whether there is a prediabetic period. Unexpectedly, the young rats were already lean and hyperglycemic, with apparent, albeit mild, ß-cell dysfunction. On the other hand, as in the adult GK rat, islet insulin release in response to a nonfuel secretagogue was normal in the young GK rats in the face of a marked reduction in islet insulin content. On the basis of these facts, we chronically administered insulin to young GK rats in the second part of the study to determine whether the elimination of hyperglycemic overdrive would reverse the ß-cell abnormalities.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion References

 
GK rats and the control Wistar rats were obtained from Takeda Pharmaceutical Co. (Osaka, Japan), where the original colonies of the GK and the control Wistar rat have been strictly maintained. First, GK rats and control Wistar rats (5, 6) were compared at the age of 3.5 weeks, which is 4 days after weaning. Second, GK rats were examined at 8.5 weeks of age with or without a daily injection of long acting human insulin (Novolin U, Nova Nordisk A/S, Bagsvaerd, Denmark) during the preceding 5 weeks. Animals were kept under controlled light (0900–2100 h), and insulin was injected sc at 2000 h. The insulin doses were 1 and 2 U/rat during the initial 3.5 weeks and the following 1.5 weeks of the 5-week treatment period, respectively. The dose was increased because of the rapid weight gain of the animals during this period (see Table 1).

In the second part of the study, insulin treatment was initiated at 3.5 weeks of age in GK rats, and insulin-treated and untreated GK rats were used for experiments at 8.5 weeks of age. Random blood samples were obtained at 1000 h by decapitation without anesthesia; this was 14 h after the final insulin injection in insulin-treated group. Fasting blood samples were obtained only in untreated GK rats after 6 h of fasting by decapitation without anesthesia.

In all cases, pancreatic islets were obtained by collagenase dispersion from freely fed rats, and insulin release by the islets was determined in batch incubation experiments using five size-matched islets per tube in Krebs-Ringer bicarbonate (KRB) buffer as previously described (3, 11, 12, 13, 14). In brief, the islets were incubated in KRB buffer containing 3 mM glucose for 30 min (preincubation). During the subsequent 30 min, the islets were incubated in fresh KRB buffer with the test substance (experimental incubation). For the determination of ATP-sensitive K⁺ (K⁺-ATP) channel-independent glucose action, KRB buffer containing 150 µM diazoxide was used, and the experimental incubation was carried out in the presence of 25 mM K⁺ as previously described (11, 14).

The pancreata of some animals were fixed with 10% formalin, and histological examination was performed with hematoxylin-eosin staining and immnostaining with an anti-insulin antibody. In 3.5-week-old rats, the number of islets was counted through the entire pancreatic section using three sections from each rat in the two groups. The average islet diameter was determined by measuring the diameter of all islets in each analyzed section. For this purpose, the pancreas was removed with a portion of the spleen and the duodenum attached to it, and the section through the splenic hilus to the head of the pancreas was obtained.

Islets from the same batch used for the insulin release experiment were stored at -20 C for later extraction of insulin. The extraction was performed by adding 0.5 ml acid-ethanol to the tube containing five islets (15). Separated plasma was kept at -20 C for later determination of PG by the hexokinase method and immunoreactive insulin (IRI) by RIA. The insulin RIA does not discriminate between rat and human insulin, so plasma IRI in insulin-treated rats is the sum of endogenous and exogenous insulin. IRI was determined with rat insulin as a standard as previously described (3, 11, 12, 13, 14, 15). Statistical analysis was performed by one-way ANOVA with Fisher’s protected least significance different test or Wilcoxon’s rank sum test using Statview (Apple Computer, Cupertino, CA). P < 0.05 was considered statistically significant. Data are expressed as the mean ± SE.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
Phenotypic characteristics of GK rats and the effects of insulin treatment (Table 1)
The GK rats were slightly lean and mildly hyperglycemic but normoinsulinemic at the age of 3.5 weeks compared to the age-matched control rats. Hyperglycemia in the GK rats was more severe at the age of 8.5 weeks. Insulin treatment from 3.5–8.5 weeks of age in GK rats significantly lowered PG, determined at the age of 8.5 weeks, without affecting body weight. Because the blood samples were obtained 14 h after the injection of long-acting insulin, PG in the insulin-treated rats was at the nadir. Plasma IRI levels were not significantly different between untreated and insulin-treated GK rats.

Characteristics of pancreatic islets (Table 2)
The morphology of the islets was normal in GK rats at the age of 3.5 and 8.5 weeks, and insulin treatment did not cause morphological changes in the islet. The number of islets and islet diameter were similar in 3.5-week-old GK rats and age-matched control rats; islet numbers per mm² pancreas section were 2.4 ± 0.2 (n = 3) and 1.9 ± 0.2 (n = 3), and islet diameters (microns) were 57.8 ± 2.1 (n = 475) and 65.6 ± 2.6 (n = 305) in GK and control rats, respectively.

Insulin release by the islets
At the age of 3.5 weeks, insulin release in the presence of a substimulatory concentration (3 mM) of glucose was similar in the islets of GK and control rats (Fig. 1). However, the following abnormalities were found in the concentration dependency curve of glucose-induced insulin release by GK rat islets, indicating reduced glucose sensitivity. First, the EC₅₀ was elevated; the values were 19.5 and 15.9 mM in the islets of GK and control rats, respectively (Fig. 1). Second, the calculated Hill constant at the EC₅₀, an index of positive cooperativity, was reduced: the values were 2.1 and 4.2 in the former and the latter, respectively (Fig. 1). The positive cooperativity occurs due to positive regulation of the ß-cell glucokinase by glucose and other yet unidentified glucose actions (16), and it is regarded as an index of ß-cell glucose sensitivity. On the other hand, the maximum insulin release by the islets in response to a high concentration of glucose was reduced approximately in proportion to the reduced islet insulin content in GK rats (Fig. 1 and Table 2).

View larger version (15K): [in this window] [in a new window]   Figure 1. Glucose-induced insulin release by the isolated islets. After preincubation in KRB buffer containing 3 mM glucose for 30 min, the islets were incubated with fresh buffer containing 3, 6, 12, 18, 24, or 30 mM glucose for 30 min. Islets were obtained from Wistar rats at the age of 3.5 weeks (), GK rats at the age of 3.5 weeks (), GK rats at the age of 8.5 weeks (), and insulin-treated GK rats at the age of 8.5 weeks (). Insulin release from the islets of the insulin-treated GK rats () was significantly (P < 0.05 and P < 0.01) reduced compared to that from islets in the other groups (, , and ) at all glucose concentrations. The differences between 3.5-week-old Wistar rats () and 3.5-week-old GK rats () were significant (P < 0.05 and P < 0.01) at 12 mM or higher concentrations of glucose. The differences between 3.5-week-old () and 8.5-week-old () GK rats were significant (P < 0.05) at 12, 24 and 30 mM. There were 8–10 determinations for each point. The conversion factor for IRI to Systeme International units is 0.174 (nanograms to picomoles).

Insulin release by the islets from insulin-treated 8.5-week-old GK rats was further reduced compared to release by islets from age-matched untreated GK rats; the differences between the two groups of islets were significant for all concentrations of glucose tested (Fig. 1). The concentration dependency curve in the islets from insulin-treated GK rats was almost flat, and high concentrations of glucose up to 18 mM failed to significantly increase insulin release (Fig. 1).

We did not examine the islets from 8.5-week-old Wistar rats in the present study because insulin release by the islets from young adult (7–12 weeks of age) Wistar rats are well characterized in the past. Namely, in the islets from young adult Wistar rats (17, 18), glucose-induced insulin release per islet is approximately 1.5 times greater than that in islets from 3-week-old (17) or 3.5-week-old (present study) Wistar rats, which may be in part due to an age-related increase in the islet insulin content. The concentration dependency of glucose-induced insulin release in the islets from 7-week-old (18) or 8-week-old (8) Wistar rats is similar to that in the islets from 3.5-week-old Wistar rats (present study); the EC₅₀ occurred at 9.5–11 mM, and the maximum effect was obtained at approximately 20 mM (8, 18). The mean fasting PG in 2-month-old Wistar rats is reportedly 4.1 mM (8), which is not higher than that in 3.5-week-old Wistar rats (present study). Thus, changes in ß-cell function in GK rats at 3.5 and 8.5 weeks of age, which consist of reduced glucose sensitivity and glucose responsiveness, are clearly distinct from the age-related changes in normal Wistar rats. The changes in GK rats are, therefore, pathological features of the ß-cell in this model.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
This is the first study in which ß-cell structure and function has been systematically analyzed during evolution of naturally occurring diabetes with and without insulin treatment. We examined the GK rat, a widely used model of NIDDM (5, 6, 7, 8, 9), immediately after weaning. The rats used in the present study are the original GK rats and the control Wistar rats (5, 6). The use of appropriately matched control rats, which was not the case in many of the previous studies on the GK rats (7, 8, 9, 19, 20, 21), is especially important for study such as ours, in which animals are evaluated during a rapidly growing period when minor strain differences may produce false positive or negative results.

In the previous studies, the following important questions were left unanswered. First, the onset of hyperglycemia and/or ß-cell dysfunction in the GK rat was not well established. Second, it was unknown whether the ß-cell dysfunction was due to glucose toxicity, or conversely, the dysfunction was the cause of the diabetes. Third, it was not known why the ß-cell of the GK rat displays a poor response to glucose but a normal response to arginine despite a profound decrease in islet insulin content (7, 8, 9). Fourth and most importantly, it is completely unknown whether any treatment can retard or prevent the worsening of ß-cell function in this animal model. Nevertheless, impaired glucose action at the level of K⁺-ATP channels (22) and abnormal glucose metabolism by the ß-cell (8) were considered possible mechanisms of ß-cell dysfunction in adult GK rats.

We found that the GK rat ß-cell is already abnormal at the age of 3.5 weeks, and insulin treatment from 3.5–8.5 weeks of age does not prevent, but accelerates, subsequent progression of ß-cell dysfunction in GK rats. Failure of an early insulin intervention to prevent the deterioration of ß-cell function in GK rats strongly indicates that hyperglycemia is not the cause of ß-cell dysfunction in the GK rat. Conversely, impaired insulin secretion is most likely an etiological abnormality in this animal model. Abdel-Halim et al. (19) reached a similar conclusion using islets from F₁ hybrids of GK-Wistar rats, which were transplanted to the normoglycemic nude mice. More recently, it was reported that restoration of normoglycemia in adult GK rats normalizes reduced islet mitochondrial glycerol phosphate dehydrogenase activity (20), a key enzyme of the glycerol-phosphate shuttle. Although insulin release by the islets was not determined in the study (20), the fact that insulin treatment does not restore, but further suppresses, insulin release by the islets from the GK rats (present study) strongly indicates that the glycerol-phosphate shuttle activity is not the rate-limiting step of glucose-induced insulin release in the ß-cell of GK rats.

In adult GK rats, insulin release by the islets was so severely impaired that a concentration dependency curve of glucose-induced insulin release was not obtainable (7, 8, 9). Using young GK rats, we established that a salient feature of the concentration dependency of glucose-induced insulin release in the GK rat ß-cell is reduced glucose sensitivity. Interestingly, ß-cell glucose sensitivity is reduced not only in the young GK rats, but also in other animals with genetically determined diabetes, e.g. the OLETF rat (3, 23), a model of obese NIDDM (4), and in the heterozygous mouse with targeted disruption of pancreatic ß-cell-specific glucokinase gene (24) (Aizawa, T., N. Asanuma, Y. Terauchi, N. Suzuki, M. Komatsu, N. Itoh, T. Nakabayashi, H. Hidaka, H. Ohnota, K. Yamauchi, K. Yasuda, Y. Yazaki, T. Kodawaki, K. Hashizume, unpublished observation), a newly generated model of insulin-deficient NIDDM. Therefore, we consider it is likely that reduced ß-cell sensitivity is causally related to the development of NIDDM at large.

A high concentration of glucose exerts diverse effects on the ß-cell, other than acute stimulation of insulin release. It is well known that high glucose potentiates the ß-cell so that subsequent stimuli elicit larger insulin release, i.e. glucose priming (21). On the other hand, chronic infusion of a large amount of glucose into the normal animal causes an impaired ß-cell response, which is called glucose toxicity (25). Contrary to our expectation, early insulin intervention did not prevent, but further accelerated, deterioration of ß-cell function in young GK rats. Accordingly, we speculate that hyperglycemia is acting as a stimulus for the ß-cell, although the drive is insufficient to completely offset the genetic ß-cell abnormalities in this model. In other words, the GK rat may be a model of glucose priming (26) rather than glucose toxicity (25). Then, insulin treatment, which attenuates the priming by lowering PG, would suppress insulin synthesis and accelerate impaired insulin secretion.

The following facts indirectly support such a hypothesis. First, the ß-cell of adult GK rats retains normal responsiveness to nonfuel secretagogues (7, 8, 9). This was also the case in 3.5-week-old GK rats. Namely, K⁺ depolarization-induced insulin release by the islets was not reduced in the GK rat. Because the islet insulin content is clearly reduced in GK rats, a quantitatively normal response implies an exaggerated response; this paradoxical overresponse in the GK rat ß-cell has attracted little attention in the past, and the reason for it remained obscure. This is well explained if the GK rat ß-cell is primed with a high concentration of PG. Second, glucose-induced closure of the K⁺-ATP channels is impaired in the GK rat ß-cell (22); this glucose action is a required step for its toxicity to occur (27). On the other hand, glucose priming of the ß-cell is mostly, if not completely, mediated by the K⁺-ATP channel-independent glucose actions (14, 28), and this branch of glucose signaling remains intact in the young GK rat ß-cell. Thus, it is conceivable that glucose exerts predominantly a priming, but not a toxicity, effect on the ß-cell in the GK rat. Further studies are needed to substantiate this hypothesis.

Overinsulinization in the rat suppresses insulin synthesis and/or insulin secretion, provided the treatment causes sustained hypoglycemia (29, 30); the ß-cell suppression is due to hypoglycemia, but not to hyperinsulinemia (31), under this setting. As indicated, insulin treatment in the present study was by no means an overinsulinization.

Finally, the GK rat and the patients with the common type of NIDDM are different in the following aspects. Although hyperglycemia is "infant onset" in the GK rat, it is "maturity onset" in the patients. The ß-cell function deteriorates after a small degree of PG lowering in the GK rat; however, it usually improves after insulin treatment in the patients (32, 33). Therefore, it may be unwise to assume the GK rat as a model of the common type of NIDDM in humans.

	Acknowledgments

 
The authors thank Dr. Monte A. Greer for editorial assistance, and Takeda Pharmaceutical Co. and Novonordisk for the generous gifts of the rats and Novolin U, respectively. The technical assistance of Ms. Tomoko Nishizawa is greatly appreciated.

	Footnotes

 
¹ This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education Science and Culture, Japan.

Received September 18, 1996.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

1. Zimmet PZ 1995 The pathogenesis and prevention of diabetes in adults. Genes, autoimmunity, and demography. Diabetes Care 18:1050–1064[Medline]
2. The Diabetes Control and Complications Trial Research Group 1993 The effect of intensive treatment of diabetes on the development of and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986[Abstract/Free Full Text]
3. Aizawa T, Taguchi N, Sato Y, Nakabayashi T, Kobuchi H, Hidaka H, Nagasawa T, Ishihara F, Itoh N, Hashizume K 1995 Prophylaxis of generically determined diabetes by diazoxide: a study in a rat model of naturally occurring obese diabetes. J Pharmacol Exp Ther 275:194–199[Abstract/Free Full Text]
4. Kawano K, Hirashima T, Mori S, Saitoh Y, Kurosumi M Natori T 1992 Spontaneous long-term hyperglycemic rats with diabetic complications. Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes 41:1422–1428[Abstract]
5. Goto Y, Kakizaki M, Masaki N 1975 Spontaneous diabetes produced by selective breeding of normal Wistar rats. Proc Jpn Acad 51:80–85
6. Suzuki K-I, Goto Y, Toyota T 1993 Spontaneously diabetic GK (Goto-Kakizaki) rats. In: Shafrir E (ed) Lessons from Animal Diabetes IV. Smith-Gordon, London, pp 107–116
7. Giroix M-H, Vesco L, Portha B 1993 Functional and metabolic perturbation in isolated pancreatic islets from the GK rat, a genetic model of noninsulin-dependent diabetes. Endocrinology 132:815–822[Abstract]
8. Östenson C-G, Khan A, Abdel-Halim SM, Guenifi A, Suzuki K, Goto Y, Efendic S 1993 Abnormal insulin secretion and glucose metabolism in pancreatic islets from the spontaneously diabetic GK rat. Diabetologia 36:3–8[Medline]
9. Portha B, Serradas P, Bailbe D, Suzuki K, Goto Y, Giroix M-H 1991 ß-Cell insensitivity to glucose in the GK rat, spontaneous nonobese model for type II diabetes. Diabetes 40:486–491[Abstract]
10. Aizawa T, Greer MA 1981 Delineation of the hypothalamic area controlling thyrotropin secretion in the rat. Endocrinology 109:1731–1738[Abstract]
11. Aizawa T, Sato Y, Ishihara F, Taguchi N, Komatsu M, Suzuki N, Hashizume K, Yamada T 1994 ATP-sensitive K⁺ channel-independent glucose action in rat pancreatic ß-cell. Am J Physiol 266:C622–C627
12. Komatsu M, Yokokawa N, Takeda T, Nagasawa Y, Aizawa T, Yamada T 1989 Pharmacological characterization of the voltage-dependent calcium channel of pancreatic B-cell. Endocrinology 125:2008–2014[Abstract]
13. Komatsu M, Aizawa T, Yokokawa N, Sato Y, Okada N, Takasu N, Yamada T 1992 Mastoparan-induced hormone release from rat pancreatic islets. Endocrinology 130:221–228[Abstract]
14. Taguchi N, Aizawa T, Sato Y, Ishihara F, Hashizume K 1995 Mechanism of glucose-induced biphasic insulin release by pancreatic B-cell: physiological role of ATP-sensitive K⁺ channel-independent glucose action. Endocrinology 136:3942–3948[Abstract]
15. Ishihara F, Aizawa T, Taguchi N, Sato Y, Hashizume K 1994 Differential metabolic requirement for initiation and augmentation of insulin release by glucose: a study with rat pancreatic islets. J Endocrinol 143:497–503[Abstract]
16. Meglasson MD, Matschinsky FM 1986 Pancreatic islet glucose metabolism and regulation of insulin secretion. Diabetes Metab Rev 2:163–214[Medline]
17. Bliss CR, Sharp GWG 1992 Glucose-induced insulin release in islets of young rats: time-dependent potentiation and effects of 2-bromostearate. Am J Physiol 263:E890–E896
18. Komatsu M, Yokokawa N, Nagasawa Y, Komiya I, Aizawa T, Takasu N, Yamada T 1991 Gradual delay in glucose-induced first phase insulin secretion by the pancreatic islets of 7 w-, 6 mo- and 1 y-old rats. J Gerontology 46:B59–B64
19. Abdel-Halim SM, Östenson C-G, Andersson A, Jansson L, Efendic S 1995 A defective stimulus-secretion coupling rather than glucotoxicity mediates the impaired insulin secretion in the mildly diabetic F₁ hybrids of GK-Wistar rats. Diabetes 44:1280–1284[Abstract]
20. MacDonald MJ, Efendic S, Östensen C-G 1996 Normalization by insulin treatment of low mitochondrial glycerol phosphate dehydrogenase and pyruvate carboxylase in pancreatic islets of the GK rat. Diabetes 45:886–890[Abstract]
21. Serradas P, Giroix M-H, Sauliner C, Gangnerau M-N, Borg LAH, Welsh M, Portha B, Welsh N 1995 Mitochondrial deoxyribonucleic acid content is specifically decreased in adult, but not in fetal, pancreatic islets of the Goto-Kakizaki rat, a genetic model of noninsulin-dependent diabetes. Endocrinology 136:5623–5631[Abstract]
22. Tsuura Y, Ishida H, Okamoto Y, Kato S, Sakamoto K, Horie M, Ikeda H, Okada Y, Seino Y 1993 Glucose sensitivity of ATP-sensitive K⁺ channels is impaired in ß-cells of the GK rat. A new genetic model of NIDDM. Diabetes 42:1446–1453[Abstract]
23. Sato Y, Aizawa T, Taguchi N, Ishihara F, Hashizume K 1995 Glucose-induced insulin release by pancreatic islets is enhanced in rats with naturally occurring obese non-insulin-dependent diabetes. Horm Metab Res 7:299–301
24. Terauchi Y, Sakura H, Yasuda K, Iwamoto K, Takahashi N, Ito K, Kasai H, Suzuki H, Ueda O, Kamada N, Jishage K, Komeda K, Noda M, Kanazawa Y, Taniguchi S, Miwa I, Akanuma Y, Kodama T, Yazaki Y, Kadowaki T 1995 Pancreatic ß-cell-specific targeted disruption of glucokinase gene. Diabetes mellitus due to defective inulin secretion to glucose. J Biol Chem 270:30253–30256[Abstract/Free Full Text]
25. Simonson DC, Rosseti L, Giaccari A, DeFronzo RA 1992 Glucose toxicity. In: Alberti KGMM, DeFronzo RA, Keen H, Zimmet P (eds) International Textbook of Diabetes Mellitus. Wiley and Sons, Chichester, vol 1:635–667
26. Grodsky GM 1972 A threshold distribution hypothesis for packet storage of insulin and its mathematical modeling. J Clin Invest 52:2047–2059
27. Sako Y, Grill VE 1990 Coupling of B-cell desensitization by hyperglycemia to excessive stimulation and circulating insulin in glucose-infused rats. Diabetes 39:1580–1583[Abstract]
28. Grill V, Adamson U, Rundfeldt M, Andersson S, Cerasi E 1979 Glucose memory of pancreatic B and A2 cells. J Clin Invest 64:700–707
29. Kruszynska YT, Villa-Komaroff L, Halban PA 1988 Islet B-cell dysfunction and the time course of recovery following chronic overinsulinization of normal rats. Diabetologia 31:621–626[CrossRef][Medline]
30. Ping CC, Goodner CJ 1968 Lack of functional suppression of pancreatic beta cells during chronic insulin replacement in the rat. Endocrinology 82:296–302[Medline]
31. Appel MC, Kislauskis EH 1984 Effects of glucose infusion in rats with a functional insulinoma. Diabetes [Suppl 1] 33:82A (Abstract)
32. Kosaka K, Kuzuya T, Akanuma Y, Hagura R 1980 Increase in insulin response after treatment of overt maturity-onset diabetes is independent of the mode of treatment. Diabetologia 18:23–28[CrossRef][Medline]
33. Aizawa T, Katakura M, Taguchi N, Kobayashi H, Aoyagi E, Hashizume K, Yoshizawa K 1995 Ketoacidosis-onset noninsulin dependent diabetes in Japanese subjects. Am J Med Sci 310:198–201[Medline]

This article has been cited by other articles:

				F. C. Howarth, M. Shafiullah, and M. A. Qureshi Heart/Cardiac Muscle: Chronic effects of type 2 diabetes mellitus on cardiac muscle contraction in the Goto-Kakizaki rat Exp Physiol, November 1, 2007; 92(6): 1029 - 1036. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Suzuki, N. Articles by Hashizume, K. Search for Related Content PubMed PubMed Citation Articles by Suzuki, N. Articles by Hashizume, K.