Effect of KAD-1229, a Nonsulfonylurea Hypoglycemic Agent, on Plasma Glucose and Insulin in Streptozotocin-Induced Diabetic Dogs

Misawa, Keiko; Ichikawa, Kazuhiko; Ojima, Kazuma; Hamano, Shuichiro; Kitamura, Tasuku; Komatsu, Hidetada

doi:10.1159/000056073

Cited by 9 publications

(6 citation statements)

References 20 publications

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“…There is large variability in the diabetogenic dose among species. In large mammals, doses ranging from 20 (29) to 300 mg/kg (31) have been used. In the dog, the median lethal dose is 1,500 mg/m 2 (50 mg/kg), very close to the diabetogenic dose (2, 32), such that repeated administration of low STZ doses (37), a combination of STZ and alloxan (8), or STZ and pancreatectomy (18) have been used to induce diabetes.…”

Section: Discussionmentioning

confidence: 99%

Novel canine models of obese prediabetes and mild type 2 diabetes

Ionut¹,

Liu²,

Mooradian³

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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(T2DM) is often characterized by obesity-associated insulin resistance (IR) and ␤-cell function deficiency. Development of relevant large animal models to study T2DM is important and timely, because most existing models have dramatic reductions in pancreatic function and no associated obesity and IR, features that resemble more T1DM than T2DM. Our goal was to create a canine model of T2DM in which obesity-associated IR occurs first, followed by moderate reduction in ␤-cell function, leading to mild diabetes or impaired glucose tolerance. Lean dogs (n ϭ 12) received a high-fat diet that increased visceral (52%, P Ͻ 0.001) and subcutaneous (130%, P Ͻ 0.001) fat and resulted in a 31% reduction in insulin sensitivity (S I) (5.8 Ϯ 0.7 ϫ 10 Ϫ4 to 4.1 Ϯ 0.5 ϫ 10 Ϫ4 U ⅐ ml Ϫ1 ⅐ min Ϫ1 , P Ͻ 0.05). Animals then received a single low dose of streptozotocin (STZ; range 30 -15 mg/kg). The decrease in ␤-cell function was dose dependent and resulted in three diabetes models: 1) frank hyperglycemia (high STZ dose); 2) mild T2DM with normal or impaired fasting glucose (FG), 2-h glucose Ͼ200 mg/dl during OGTT and 77-93% AIR g reduction (intermediate dose); and 3) prediabetes with normal FG, normal 2-h glucose during OGTT and 17-74% AIR g reduction (low dose). Twelve weeks after STZ, animals without frank diabetes had 58% more body fat, decreased ␤-cell function (17-93%), and 40% lower S I. We conclude that high-fat feeding and variable-dose STZ in dog result in stable models of obesity, insulin resistance, and 1) overt diabetes, 2) mild T2DM, or 3) impaired glucose tolerance. These models open new avenues for studying the mechanism of compensatory changes that occur in T2DM and for evaluating new therapeutic strategies to prevent progression or to treat overt diabetes.obesity; animal models; streptozotocin; insulin secretion TYPE 2 DIABETES MELLITUS (T2DM) is a highly prevalent disease with an enormous public and individual health impact. According to the Centers for Disease Control National Diabetes Fact Sheet, in 2007 23.6 million people in the US (7.8% of population) had diabetes, and an estimated 57 million people had prediabetes [impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or both] (10). The disease's increasing prevalence requires adequate and strong intervention for prevention of new cases and new or improved therapeutic tools for the existing cases (11). T2DM is characterized by a combination of resistance to insulin action and an inadequate compensatory insulin secretory response and is usually associated with obesity (15). Increased body fat and especially visceral fat accumulation have been shown to be risk factors for the development of IGT or diabetes (14). The mechanisms of the initial alterations in the development of T2DM, related to fat deposition and the associated changes in liver, muscle, and adipocyte, are not fully elucidated. Studying the relationship between insulin resistance and hyperinsulinemic compensation (or failure thereof) and the change from normal glucose tolerance to IGT ...

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Section: Discussionmentioning

confidence: 99%

Novel canine models of obese prediabetes and mild type 2 diabetes

Ionut¹,

Liu²,

Mooradian³

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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“…In vivo studies using nondiabetic Wistar and diabetic GK rats suggested that S 21403 (KAD‐1229) could be a suitable agent for controlling postprandial hyperglycaemia, since it was able to suppress the increase in plasma glucose seen after a meal load up to 5 h after the meal ( Ichikawa et al ., 2002 ). The drug was also effective when administered orally to diabetic dogs ( Misawa et al ., 2001 ).…”

Section: Discussionmentioning

confidence: 99%

Characterization of the action of S 21403 (mitiglinide) on insulin secretion and biosynthesis in normal and diabetic β‐cells

Kaiser

Нешер

Oprescu

et al. 2005

British J Pharmacology

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1 S 21403 (mitiglinide) is a new drug for type 2 diabetes mellitus (T2DM). Its action on insulin release and biosynthesis was investigated in several experimental systems utilizing pancreas from normal and T2DM animals. 2 At high concentrations (10 mM), S 21403, like classical sulphonylurea, induced insulin release in the absence of glucose. In contrast, at therapeutic (0.1-1.0 mM) concentrations, S 21403 amplified insulin secretion glucose dose-dependently and with similar magnitude in normal and diabetic GK rat islets. 3 In perfused GK rat pancreas, S 21403 induced normal kinetics of insulin secretion including firstphase response. 4 The effect of S 21403 was strongly modulated by physiological factors. Thus, 0.1 mM adrenaline inhibited S 21403-induced insulin release. There was marked synergism between S 21403 and arginine in GK rat islets, combination of the two normalizing insulin secretion. 5 In primary islet cultures from normal rats or prediabetic Psammomys obesus, prolonged exposure to S 21403 did not induce further depletion of insulin stores under normal or 'glucotoxic' conditions. 6 Proinsulin biosynthesis was not affected by 2-h exposure of rat or prediabetic P. obesus islets to 1 mM S 21403. Yet, 24-h exposure of rat islets to S 21403 resulted in 30% increase in proinsulin biosynthesis at 8.3 mM glucose. 7 Amplification by S 21403 of glucose-induced insulin secretion in diabetic GK b-cells with restoration of first-phase response, a strong synergistic interaction with arginine and marked inhibition by adrenaline, make it a prime candidate for successful oral antidiabetic agent.

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“…Experimentally, injection of streptozotocin (STZ) into animals can damage pancreatic β-cells providing researchers with diabetic animal models for further study (Like et al 1978). Adjustment of STZ dose, in dogs can result in either insulin dependent or noninsulin dependent diabetic animals (Misawa et al 2001;Sebbag et al 1994;Tobin and Finegood 1993) which exhibit similar symptoms to Type 2 diabetes in humans. However, Type 2 diabetes has yet to be unequivocally shown to exist in dogs (Hoenig 2002;Rand et al 2004).…”

Section: Introductionmentioning

confidence: 99%

“…However, Type 2 diabetes has yet to be unequivocally shown to exist in dogs (Hoenig 2002;Rand et al 2004). STZ-induced diabetic dogs have been previously used for evaluating new types of insulin and/or oral hypoglycemic drug treatments (Misawa et al 2001;Mori et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Supplementing transglucosidase with a high-fiber diet for prevention of postprandial hyperglycemia in streptozotocin-induced diabetic dogs

et al. 2010

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Indigestible oligosaccharides have been shown to normalize blood glucose and insulin concentration thereby promoting good health and preventing diseases, such as diabetes. Transglucosidase (TG, alpha-glucosidase, enzyme code (EC) 3.2.1.20) is an enzyme capable of converting starch to oligosaccharides, such as iso-malto-oligosaccharides from maltose, via the action of amylase. The aim of this study was to evaluate whether oral administration of TG with maltose or dextrin is capable of reducing post-prandial serum glucose concentration in experimentally streptozotocin (STZ)-induced diabetic dogs fed on a high-fiber diet. Five healthy and five STZ-induced diabetic dogs were employed in this study. TG supplementation with dextrin or maltose had no detrimental effect in healthy dogs. In fact, TG and dextrin exhibited a flatlined serum glucose pattern, while reducing mean post-prandial serum insulin and glucose concentration as compared to control diet alone. When TG supplementation was tested in STZ-induced diabetic dogs under the context of a high fiber diet, a 13.8% and 23.9% reduction in mean glucose concentration for TG with maltose and dextrin, respectively was observed. Moreover, TG with dextrin resulted in a 13% lower mean post-prandial glucose concentration than TG with maltose, suggesting that dextrin may be a more efficient substrate than maltose when used at the same concentration (1 g/kg). Our results indicate that TG supplementation with diet can lead to lower postprandial glucose levels versus diet alone. However, the efficacy of TG supplementation may depend on the type of diet it is supplemented with. As such, TG administration may be useful for preventing the progression of diabetes mellitus and in its management in dogs.

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Effect of KAD-1229, a Nonsulfonylurea Hypoglycemic Agent, on Plasma Glucose and Insulin in Streptozotocin-Induced Diabetic Dogs

Cited by 9 publications

References 20 publications

Novel canine models of obese prediabetes and mild type 2 diabetes

Novel canine models of obese prediabetes and mild type 2 diabetes

Characterization of the action of S 21403 (mitiglinide) on insulin secretion and biosynthesis in normal and diabetic β‐cells

Supplementing transglucosidase with a high-fiber diet for prevention of postprandial hyperglycemia in streptozotocin-induced diabetic dogs

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