Decreased blood glucose excursion by nateglinide ameliorated neuropathic changes in Goto-Kakizaki rats, an animal model of non-obese type 2 diabetes

Kitahara, Yoshiro; Miura, Kyoko; Takesue, Kaori; Mine, Tomoyuki; Wada, Ryuichi; Uchida, Yoshiaki; Ito, Satoru; Yagihashi, Soroku

doi:10.1053/meta.2002.35195

Cited by 28 publications

(25 citation statements)

References 27 publications

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“…It has been shown that these animals retain Ͼ40% of their total ␤-cell mass (a number similar to human type 2 diabetes) but have impaired glucose-induced insulin release (23)(24)(25). 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).…”

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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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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“…Nateglinide is a short-acting insulin secretagogue with a rapid effect, which restores early-phase insulin secretion in patients with type 2 diabetes by rapidly binding to SUR1 [26][27][28][29][30] and thus suppresses postprandial hyperglycemia. It has been unclear whether or not GLP-1 is involved in these effects of nateglinide.…”

Section: )mentioning

confidence: 99%

Nateglinide Stimulates Glucagon-Like Peptide-1 Release by Human Intestinal L Cells via a KATP Channel-Independent Mechanism

Kitahara

Miura

Yasuda

et al. 2011

Biological & Pharmaceutical Bulletin

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The incretin effect is markedly reduced in patients with type 2 diabetes, mainly due to defective glucagon-like peptide-1 (GLP-1) secretion from the intestinal L cells in response to stimulation by various nutrients. 1,2) This leads to impairment of early-phase insulin secretion after food intake and consequently results in postprandial hyperglycemia and hyperlipidemia. [3][4][5][6] GLP-1 is an incretin hormone that is released by intestinal L cells following their stimulation by nutrients, 7,8) and it promotes glucose-stimulated insulin secretion by pancreatic bcells. GLP-1 has also been reported to have various other beneficial effects, such as promoting b-cell proliferation, 9) suppressing glucagon release, 10) suppressing food intake, 11,12) slowing gastric emptying, 13,14) and cardiovascular protection.15) Therefore, restoration of GLP-1 secretion by intestinal L cells could be an important new therapeutic option for the management of metabolic syndrome. Although the exact mechanism of GLP-1 secretion by intestinal L cells remains to be elucidated, the sulfonylurea receptor 1 (SUR1)/K ATP channel, 16,17) Na ϩ /glucose co-transporter 1 (SGLT1), 18) glucose transporter 2 (GLUT2), 19) sweet taste receptor, 20)TGR5 21) and G-protein coupled receptors (GPRs) [22][23][24][25] have all been reported to be involved in this process. In the present study, we investigated the effect of nateglinide on GLP-1 secretion by human intestinal L cells.Nateglinide is a short-acting insulin secretagogue with a rapid effect, which restores early-phase insulin secretion in patients with type 2 diabetes by rapidly binding to SUR1 [26][27][28][29][30] and thus suppresses postprandial hyperglycemia. It has been unclear whether or not GLP-1 is involved in these effects of nateglinide. Recently, Duffy et al. reported that nateglinide increases the plasma GLP-1 level by inhibiting dipeptidyl peptidase IV (DPP IV), 31) but the influence of nateglinide on GLP-1 secretion is still unknown. Therefore, we investigated the effect of nateglinide on GLP-1 secretion in vivo by monitoring GLP-1 levels in the portal venous blood after oral administration of nateglinide to normal Wistar rats. We also conducted an in vitro study to assess the direct effect of nateglinide on GLP-1 secretion by human intestinal L cells (NCI-H716). MATERIALS AND METHODSAnimals Male Goto-Kakizaki (GK) rats and male Wistar rats (6 weeks old) were purchased from Japan SLC Inc. (Hamamatsu, Japan). The animals were housed in individual polycarbonate cages with woodchip bedding, and were provided with food and water ad libitum. The animal room was maintained on a 12-h light/dark cycle (7 a.m.-7 p.m.: dark; 7 p.m.-7 a.m.: light), with a temperature range of 22Ϯ1°C and a relative humidity of 55Ϯ5%, throughout the experimental period. These animal experiments were performed in accordance with the Guiding Principles for the care and use of laboratory animals approved by the Japanese Pharmacological Society. In addition, this study was approved by the Animal Care and Use Committ...

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“…Spontaneously or inducedly, several animal models are widely used for type 2 diabetes mellitus. Spontaneous, models such as Zucker diabetic fatty (ZDF) rat [1] and Goto-Kakizaki (GK) rat [2] are subject to the resources of the animal with the major factor being genetic predisposition. Induced, models use relatively high dosages of streptozotocin (STZ) (more than 50 mg/kg) [3] to reduce the synthesis and secretion of insulin in β cells and tend to manifest type 1 diabetes, even in combinations of 50 mg/kg STZ and fat fed diets [4].…”

Section: Introductionmentioning

confidence: 99%

The Rat Model of Type 2 Diabetic Mellitus and Its Glycometabolism Characters

Zhang

et al. 2003

Exp. Anim.

132

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Abstract:To develop a rat model of type 2 diabetic mellitus that simulated the common manifestation of the metabolic abnormalities and resembled the natural history of a certain type 2 diabetes in human population, male Sprague-Dawley rats (4 months old) were injected with low-dose (15 mg/kg) STZ after high fat diet (30% of calories as fat) for two months (L-STZ/2HF). The functional and histochemical changes in the pancreatic islets were examined. Insulin-glucose tolerance test, islet immunohistochemistry and other corresponding tests were performed and the data in L-STZ/2HF group were compared with that of other groups, such as the model of type 1 diabetes (given 50 mg/kg STZ) and the model of obesity (high fat diet). The body weight of rats in the group of rats given 15 mg/kg STZ after high fat diet for two months increased significantly more than that of rats in the group of rats given 50 mg/kg STZ (the model of type 1 diabetes) (595 ± 33 g vs. 352 ± 32 g, p<0.05). Fast blood glucose levels for L-STZ/2HF group were 16.92 ± 1.68 mmol/l, versus 5.17 ± 0.55 mmol/l in normal control and 5.59 ± 0.61 mmol/l in rats given high fat diet only. Corresponding values for fast serum insulin were 0.66 ± 0.15 ng/ml, 0.52 ± 0.13 ng/ml, 0.29 ± 0.11 ng/ml, respectively. Rats of type 2 diabetes (L-STZ/2HF) had elevated levels of triglyceride (TG, 3.82 ± 0.88 mmol/l), and cholesterol(Ch, 2.38 ± 0.55 mmol/l) compared with control (0.95 ± 0.15 mmol/l and 1.31 ± 0.3 mmol/l, respectively) (p<0.05). The islet morphology as examined by immunocytochemistry using insulin antibodies in the L-STZ/2HF group was affected and quantitative analysis showed the islet insulin content was higher than that of rats with type 1 diabetes (P<0.05). We concluded that the new rat model of type 2 diabetes established with conjunctive treatment of low dose of STZ and high fat diet was characterized by hyperglycemia and light impaired insulin secretion function accompanied by insulin resistance, which resembles the clinical manifestation of type 2 diabetes. Such a model, easily attainable and inexpensive, would help further elucidation of the underlying mechanisms of diabetes and its complications.

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Decreased blood glucose excursion by nateglinide ameliorated neuropathic changes in Goto-Kakizaki rats, an animal model of non-obese type 2 diabetes

Cited by 28 publications

References 27 publications

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

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

Nateglinide Stimulates Glucagon-Like Peptide-1 Release by Human Intestinal L Cells via a KATP Channel-Independent Mechanism

The Rat Model of Type 2 Diabetic Mellitus and Its Glycometabolism Characters

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