A defect late in stimulus-secretion coupling impairs insulin secretion in Goto-Kakizaki diabetic rats.

Metz, Stewart A.; Meredith, Melissa; Vadakekalam, Jacob; Rabaglia, Mary E.; Kowluru, Anjaneyulu

doi:10.2337/diabetes.48.9.1754

Cited by 55 publications

(53 citation statements)

References 53 publications

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“…These phenotypic data are in agreement with those published by Cohen et al (27) in earlier studies, in which they showed in CDs rats that were fed HSD for Ͼ2 months a moderate fasting hyperinsulinemia and a subsequent agedependent reduction in their ability to secrete insulin in response to glucose stimulation. A similar impaired insulin response also has been described in GK rats (7,28). A possible explanation for these findings is prolonged exposure to hyperglycemia per se, which exhausts the insulinsecreting ability of the pancreas (13,17,18,28 -31).…”

Section: Discussionmentioning

confidence: 61%

“…Its most outstanding and distinctive feature is that it expresses genetic susceptibility (sensitivity and resistance) to a carbohydrate-rich diet, a central feature of type 2 diabetes in humans (1,2,4,5) that is not present in other major genetically inbred rat strains that simulate type 2 diabetes in humans. The other major rat models of type 2 diabetes, the Goto-Kakizaki (GK) (6,7), the Otsuka Long-Evens Tokushima Fatty (OLETF) (8 -10), and the Zucker diabetic fatty (ZDF) rats (11,12) develop diabetes spontaneously, without any important relationship to the composition of diet. Another central feature of the Cohen model is that it consists of two genetically derived contrasting strains, originating from the same parent strain, which is useful for genetic and physiological studies.…”

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confidence: 99%

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The Newly Inbred Cohen Diabetic Rat

et al. 2001

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The newly inbred Cohen diabetic rat is an exceptional experimental model of diet-induced type 2 diabetes mellitus that is the result of secondary inbreeding nearly 30 years after it originally had been established. Animals from the original colony were selectively inbred by stringent criteria for 10 additional generations, bringing overall inbreeding to >50 generations. The metabolic phenotypes of the resulting contrasting strains, designated as the Cohen diabetic-sensitive (CDs) and -resistant (CDr) rats, were characterized. The phenotype of the CDs strain that was fed a regular diet consisted of fasting normoglycemia, normal glucose tolerance to intraperitoneal glucose loading, normal fasting insulin levels, and a normal insulin response to glucose loading. In contrast, CDs rats that were fed a custom-prepared high-sucrose low-copper diabetogenic diet became overtly diabetic: fasting glucose levels were normal or elevated, and the blood glucose insulin response to glucose loading was markedly abnormal. CDr rats that were fed a regular or diabetogenic diet did not develop diabetes and maintained normal glucose tolerance and insulin secretion. A striking sex difference was observed in CDs rats that were fed a diabetogenic diet: males had a lower growth rate and a more severe glucose intolerance pattern than females. Gonadectomy shortly after weaning did not prevent the development of the diabetic phenotype in its early phase in either sex but markedly attenuated its expression in males at a later phase, abolishing the sex differences. Alternate-day feeding, as opposed to daily feeding, also attenuated the metabolic phenotype in males. The development of the diabetic phenotype in CDs rats that were fed a diabetogenic diet was not accompanied by obesity or hyperlipidemia. The genetic profile of the strains was established using 550 microsatellite markers evenly distributed throughout the rat genome. The rate of homozygosity within strain was >96%. The rate of polymorphism between the contrasting strains was 43%. We conclude that the metabolic phenotypes of the rebred colony of CDs and CDr rats and their genetic makeup render the Cohen diabetic rat a useful experimental model that is highly suitable for studying the interaction between nutritional-metabolic environmental factors and genetic susceptibility (sensitivity and resistance) for the development of type 2 diabetes. The model is also distinctively useful for investigating the effect of sex on the expression of the diabetic phenotype.

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Section: Discussionmentioning

confidence: 61%

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confidence: 99%

The Newly Inbred Cohen Diabetic Rat

et al. 2001

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“…However, in previous investigations involving 8-week-old Wistar, GK and hybrid rats from the Stockholm colony, a majority of the islets appeared histologically normal and only a few starfishshaped islets were found (Abdel-Halim et al 1994, Guenifi et al 1995. In other studies, no differences in islet -cell density or insulin content were seen between GK rats and Wistar rats at 12 weeks of age (Ohneda et al 1993, Höög et al 1996, Metz et al 1999. The animals studied in the present experiments were 14 weeks old, and were thus not expected to show significant aberrations in islet architecture or -cell mass.…”

Section: Discussionmentioning

confidence: 92%

Lack of compensatory increase in islet blood flow and islet mass in GK rats following 60% partial pancreatectomy

Svensson

Östenson²,

Bodin³

et al. 2005

Journal of Endocrinology

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The effects of a 60% partial pancreatectomy were studied in hyperglycemic GK (Goto-Kakizaki) rats. Partial pancreatectomy or a sham operation was performed on 12-weekold female Wistar rats, GK rats or hybrids between male GK rats and female Wistar rats. Measurements of pancreatic blood flow and islet blood flow were performed by a microsphere technique 2 weeks after surgery. Glucose tolerance was decreased in hybrid compared with Wistar rats, and in GK rats compared with both hybrid and Wistar rats before surgery. Partial pancreatectomy induced minor changes in glucose tolerance. Wistar rats had a decreased islet mass following partial pancreatectomy. Both hybrid and GK rats showed a significant decrease in relative islet volume, but only GK rats in total islet mass, compared with Wistar rats 2 weeks after surgery. Pancreatic blood flow and islet blood flow did not significantly differ between sham-operated Wistar, hybrid or GK rats. After partial pancreatectomy, islet blood flow in relation to islet mass increased 3-fold in Wistar rats and 2-fold in hybrid rats. In contrast, GK rats showed no increase in islet blood flow following partial pancreatectomy. It is concluded that compensatory mechanisms after partial pancreatectomy are operating less efficiently in hybrid and GK rats.

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“…In addition, treatment of GK rats with nateglinide, an insulin secretagogue, reduces postprandial hyperglycemia and elicits early-phase insulin secretion, a phenomenon not observed in type 1 diabetes (26,27). Insulin resistance and hyperlipidemia often accompany type 2 diabetes, and the presence of these risk factors in GK rats has been controversial (22,28,29). Thus, we specifically assessed the presence of these risk factors in our colony.…”

Section: Discussionmentioning

confidence: 99%

Type 2 Diabetes Causes Remodeling of Cerebrovasculature via Differential Regulation of Matrix Metalloproteinases and Collagen Synthesis

et al. 2005

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The risk of cerebrovascular disease is four-to sixfold higher in patients with diabetes. Vascular remodeling, characterized by extracellular matrix deposition and an increased media-to-lumen ratio, occurs in diabetes and contributes to the development of complications. However, diabetes-induced changes in the cerebrovascular structure remain unknown. Endothelin-1 (ET-1), a potent vasoconstrictor with profibrotic properties, is chronically elevated in diabetes. To determine diabetesmediated changes in the cerebrovasculature and the role of ET-1 in this process, type 2 diabetic GotoKakizaki (GK) rats were administered an ET A receptor antagonist for 4 weeks. Middle cerebral arteries were harvested and studies were performed to determine vascular structure. Tissue and plasma ET-1 levels were increased in GK rats compared with controls. Significant medial hypertrophy and collagen deposition resulted in an increased wall-to-lumen ratio in diabetic rats that was reduced by ET A receptor antagonism. Vascular matrix metalloproteinase (MMP)-2 activity was higher, but MMP-1 levels were significantly reduced in GK rats, and MMP levels were restored to control levels by ET A receptor antagonism. We conclude that ET-1 promotes cerebrovascular remodeling in type 2 diabetes through differential regulation of MMPs. Augmented cerebrovascular remodeling may contribute to an increased risk of stroke in diabetes, and ET A receptor antagonism may offer a novel therapeutic target. Diabetes 54:2638 -2644, 2005 T ype 2 diabetes, a disease that affects more than 17 million Americans, holds a two-to sixfold increased risk for cerebrovascular disease and stroke (1,2), and 70% of patients with a recent stroke have overt diabetes or pre-diabetes characterized by impaired fasting glucose or impaired glucose tolerance (3). However, the underlying basis of this predisposition remains unclear. Diabetic vascular complications are associated with remodeling of the vessel wall in the retinal, renal, and mesenteric circulations. However, diabetesinduced structural changes in the cerebral microvessels are unknown.The endothelium is an early target in diabetes, and dysfunction of vascular endothelial cells has a role in the diabetic vascular disease process (4). For example, the release of vasodilator and antiproliferative mediators such as nitric oxide and prostaglandin-I 2 is decreased, whereas production of endothelin-1 (ET-1) is increased (5). A significant correlation has been observed between plasma ET-1 levels and diabetes complications. In addition to being vasoconstrictive, ET-1 is also mitogenic. In streptozotocin-induced diabetes, nonselective ET receptor antagonism prevents extracellular matrix deposition in the retina as well as in the mesenteric arteries, providing evidence for a causal relationship (6,7). Nonselective blockade of ET receptors also prevents increased myogenic tone of cerebral vessels in diabetes (8), but the effect on vascular structure and the underlying mechanisms remain to be identified.The matrix metalloproteinases ...

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A defect late in stimulus-secretion coupling impairs insulin secretion in Goto-Kakizaki diabetic rats.

Cited by 55 publications

References 53 publications

The Newly Inbred Cohen Diabetic Rat

The Newly Inbred Cohen Diabetic Rat

Lack of compensatory increase in islet blood flow and islet mass in GK rats following 60% partial pancreatectomy

Type 2 Diabetes Causes Remodeling of Cerebrovasculature via Differential Regulation of Matrix Metalloproteinases and Collagen Synthesis

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