The microsomal triglyceride transfer protein (MTP) takes part in the mobilization and secretion of triglyceride-rich lipoproteins from enterocytes and hepatocytes. In this study, we investigated the effects of diethyl-2-({3-dimethylcarbamoyl-4-[(4Ј-trifluoromethylbiphenyl-2-carbonyl) amino] phenyl}acetyloxymethyl)-2-phenylmalonate (JTT-130), a novel intestine-specific MTP inhibitor, on food intake, gastric emptying, and gut peptides using Sprague-Dawley rats fed 3.1% fat, 13% fat, or 35% fat diets. JTT-130 treatment suppressed cumulative food intake and gastric emptying in rats fed a 35% fat diet, but not a 3.1% fat diet. In rats fed a 13% fat diet, JTT-130 treatment decreased cumulative food intake but not gastric emptying. In addition, treatment with orlistat, a lipase inhibitor, completely abolished the reduction of food intake and gastric emptying by JTT-130 in rats fed a 35% fat diet. On the other hand, JTT-130 treatment increased the plasma concentrations of gut peptides, peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) but not cholecystokinin, in the portal vein in rats fed a 35% fat diet. These elevations in PYY and GLP-1 were also abolished by treatment with orlistat. Furthermore, JTT-130 treatment in rats fed a 35% fat diet increased the contents of triglycerides and free fatty acids in the intestinal lumen, which might contribute to the elevation of PYY and GLP-1 levels. The present findings indicate that JTT-130 causes satiety responses, decreased food intake, and gastric emptying in a dietary fat-dependent manner, with enhanced production of gut peptides such as PYY and GLP-1 from the intestine.

ABSTRACT. Spontaneously Diabetic Torii (SDT) rat is a hereditary model of diabetes. Although the SDT rat shows severe diabetic complications, the onset of hyperglycemia is late. SDT fatty rat, established by introducing the fa allele of the Zucker fatty rat to SDT rat, develops diabetes much faster than SDT rat. In the present study, diabetic peripheral neuropathy (DPN) was evaluated to show the further usefulness of this animal model. Motor nerve conduction velocity (MNCV) was delayed, and the number of sural nerve fibers was decreased in SDT fatty rat. Treatment of pioglitazone lowered blood glucose level and prevented delay of MNCV in SDT fatty rats. SDT fatty rat is a useful animal model for studies of DPN in type 2 diabetes. KEY WORDS: diabetes, diabetic peripheral neuropathy, nerve conduction velocity, SDT fatty rat.doi: 10.1292/jvms.12-0149; J. Vet. Med. Sci. 74(12): 1669-1673, 2012 Diabetes mellitus (DM) is a major metabolic disease, and the number of diabetics worldwide is estimated at approximately 350 million [5]. More than half of all DM patients have one or more diabetic microvascular complications such as diabetic retinopathy, diabetic nephropathy, or diabetic peripheral neuropathy (DPN). DPN is the most frequent complication, and nearly half of all diabetics suffer some type of nerve damages or symptoms [1]. Moreover, DPN causes foot ulceration, amputation, and chronic pain that reduce quality of life. Large clinical trials have proven that strict control of blood glucose level can delay the onset and progression of diabetic complications, including DPN [16,26].To clarify the pathophysiology of DPN, many diabetic animal models have been reported [2,14,30]. Spontaneously Diabetic Torii (SDT) rat is a model for non-obese type 2 diabetes [24,25] showing pronounced hypoinsulinemia and hyperglycemia due to pancreatic β-cell degeneration from around 20 weeks of age [11]. SDT rat shows all three major diabetic complications in kidneys [17], nerves [21,27], and especially in eyes [19,22,24,25]. Although the SDT rat is a useful model to study diabetic complications, a late onset of hyperglycemia brings disadvantage for laboratory experiments not infrequently. To solve this problem, the SDT fatty rat was established by introducing the fa allele of the Zucker fatty rat into the SDT rat genome [10]. This animal model develops diabetes from 5-6 weeks of age, and the time for progression is much earlier than that of original SDT rat (13-24 weeks, Table 1). The SDT fatty rats showed hyperinsulinemia at early stage of diabetes (4-8 weeks), but the insulin levels decreased to normal levels after 16 weeks of age. Plasma triglyceride (TG) and total cholesterol (TC) levels in SDT fatty rats were significantly higher than those in original SDT rats. These properties mitigate evaluation of diabetic complications. Although the eye and kidney complications in this animal model have been reported previously [12], nerve complications have not been examined. Therefore, in the present study, we evaluated the DPN in SDT fatty...

The discovery and optimization of a series of acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) inhibitors based on a pyrimido[4,5-b][1,4]oxazine scaffold is described. The SAR of a moderately potent HTS hit was investigated resulting in the discovery of phenylcyclohexylacetic acid 1, which displayed good DGAT1 inhibitory activity, selectivity, and PK properties. During preclinical toxicity studies a metabolite of 1 was observed that was responsible for elevating the levels of liver enzymes ALT and AST. Subsequently, analogues were synthesized to preclude the formation of the toxic metabolite. This effort resulted in the discovery of spiroindane 42, which displayed significantly improved DGAT1 inhibition compared to 1. Spiroindane 42 was well tolerated in rodents in vivo, demonstrated efficacy in an oral triglyceride uptake study in mice, and had an acceptable safety profile in preclinical toxicity studies.

Type 2 diabetes mellitus (T2DM) arises primarily due to lifestyle factors and genetics. A number of lifestyle factors are known to be important in the development of T2DM, including obesity. JTT-553, a novel Acyl CoA:diacylglycerol acyltransferase 1 inhibitor, reduced body weight depending on dietary fat in diet-induced obesity (DIO) rats in our previous study. Here, the effect of JTT-553 on glucose metabolism was evaluated using body weight reduction in T2DM mice. JTT-553 was repeatedly administered to DIO and KK-A(y) mice. JTT-553 reduced body weight gain and fat weight in both mouse models. In DIO mice, JTT-553 decreased insulin, non-esterified fatty acid (NEFA), total cholesterol (TC), and liver triglyceride (TG) plasma concentrations in non-fasting conditions. JTT-553 also improved insulin-dependent glucose uptake in adipose tissues and glucose intolerance in DIO mice. In KK-A(y) mice, JTT-553 decreased glucose, NEFA, TC and liver TG plasma concentrations in non-fasting conditions. JTT-553 also decreased glucose, insulin, and TC plasma concentrations in fasting conditions. In addition, JTT-553 decreased TNF-α mRNA levels and increased GLUT4 mRNA levels in adipose tissues in KK-A(y) mice. These results suggest that JTT-553 improves insulin resistance in adipose tissues and systemic glucose metabolism through reductions in body weight.

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