Immunomodulator FTY720 improves glucose homeostasis and diabetic complications by rejuvenation of β-cell function in nonhuman primate model of diabetes.

Inadequate β-cell mass is essential for the pathogenesis of type 2 diabetes (T2D). Previous report showed that an immunomodulator FTY720, a sphingosine 1-phosphate (S1P) receptor modulator, sustainably normalized hyperglycemia by stimulating β-cell in vivo regeneration in db/db mice. We further examined the effects of FTY720 on glucose homeostasis and diabetic complications in a translational nonhuman primate (NHP) model of spontaneously developed diabetes.

Effects of mixed meal tolerance test on gastric emptying, glucose and lipid homeostasis in obese nonhuman primates.

Meal ingestion elicits a variety of neuronal, physiological and hormonal responses that differ in healthy, obese or diabetic individuals. The mixed meal tolerance test (MMTT) is a well-established method to evaluate pancreatic β-cell reserve and glucose homeostasis in both preclinical and clinical research in response to calorically defined meal. Nonhuman primates (NHPs) are highly valuable for diabetic research as they can naturally develop type 2 diabetes mellitus (T2DM) in a way similar to the onset and progression of human T2DM.

Carbon tetrachloride (CCl) accelerated development of non-alcoholic fatty liver disease (NAFLD)/steatohepatitis (NASH) in MS-NASH mice fed western diet supplemented with fructose (WDF).

Background: Multiple murine models of nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) have been established by using obesogenic diets and/or chemical induction. MS-NASH mouse (formally FATZO) is a spontaneously developed dysmetabolic strain that can progress from hepatosteatosis to moderate fibrosis when fed a western diet supplemented with 5% fructose (WDF). This study aimed to use carbon tetrachloride (CCl) to accelerate and aggravate progression of NAFLD/NASH in MS-NASH mouse.

The FATZO mouse, a next generation model of type 2 diabetes, develops NAFLD and NASH when fed a Western diet supplemented with fructose.

Background: Metabolic disorders such as insulin resistance, obesity, and hyperglycemia are prominent risk factors for the development of non-alcoholic fatty liver disease (NAFLD)/steatohepatitis (NASH). Dietary rodent models employ high fat, high cholesterol, high fructose, methionine/choline deficient diets or combinations of these to induce NAFLD/NASH. The FATZO mice spontaneously develop the above metabolic disorders and type 2 diabetes (T2D) when fed with a normal chow diet.

Comparison of Continuous Glucose Monitoring between Dexcom G4 Platinum and HD-XG Systems in Nonhuman Primates (Macaca Fascicularis).

Timely knowing glucose level helps diabetic patients to manage the disease, including decisions about food, physical activity and medication. This study compared two continuous glucose monitoring systems in conscious and moving-free nonhuman primates (NHPs, Macaca fascicularis). Each normoglycemic or diabetic monkey was implanted with one Dexcom G4 Platinum subcutaneously or one HD-XG glucose sensor arterially for glucose monitoring.

Left ventricular diastolic dysfunction in nonhuman primate model of dysmetabolism and diabetes.

Background: Diabetes is one of the major risk factors for cardiomyopathy and heart failure with reduced ejection fraction (EF) and highly associated with left ventricular (LV) dysfunction in human. This study aimed 1) to noninvasively assess cardiac function using echocardiography; 2) to test the hypothesis that like diabetic human, cardiac function may also be compromised; in spontaneously developed obese, dysmetabolic and diabetic nonhuman primates (NHPs).

Methods: Cardiovascular functions were measured by noninvasive echocardiography in 28 control, 20 dysmetabolic/pre-diabetic and 41 diabetic cynomolgus monkeys based on fasting blood glucose and other metabolic status.

Xylazine-induced reduction of tissue sensitivity to insulin leads to acute hyperglycemia in diabetic and normoglycemic monkeys.

Background: The α2-adrenoceptor agonist xylazine as an anesthetic has been widely used either alone or in combination with other anesthetics, such as ketamine, in veterinary clinic and research. In the last decade xylazine has been used in drug abusers in certain geographic area. This study investigated the effects of xylazine on blood glucose level and insulin secretion in normoglycemic and insulin-dependent diabetic monkeys.

Quantification of β-cell insulin secretory function using a graded glucose infusion with C-peptide deconvolution in dysmetabolic, and diabetic cynomolgus monkeys.

Background: Quantitation of β-cell function is critical in better understanding of the dynamic interactions of insulin secretion, clearance and action at different phases in the progression of diabetes. The present study aimed to quantify β-cell secretory function independently of insulin sensitivity in the context of differential metabolic clearance rates of insulin (MCRI) in nonhuman primates (NHPs).

Methods: Insulin secretion rate (ISR) was derived from deconvolution of serial C-peptide concentrations measured during a 5 stage graded glucose infusion (GGI) in 12 nondiabetic (N), 8 prediabetic or dysmetabolic (DYS) and 4 overtly diabetic (DM) cynomolgus monkeys.

1-(1-acetyl-piperidin-4-yl)-3-adamantan-1-yl-urea (AR9281) as a potent, selective, and orally available soluble epoxide hydrolase inhibitor with efficacy in rodent models of hypertension and dysglycemia.

1-(1-Acetyl-piperidin-4-yl)-3-adamantan-1-yl-urea 14a (AR9281), a potent and selective soluble epoxide hydrolase inhibitor, was recently tested in a phase 2a clinical setting for its effectiveness in reducing blood pressure and improving insulin resistance in pre-diabetic patients. In a mouse model of diet induced obesity, AR9281 attenuated the enhanced glucose excursion following an intraperitoneal glucose tolerance test. AR9281 also attenuated the increase in blood pressure in angiotensin-II-induced hypertension in rats.

Inhibition of soluble epoxide hydrolase attenuates endothelial dysfunction in animal models of diabetes, obesity and hypertension.

Endothelial dysfunction is a hallmark of, and plays a pivotal role in the pathogenesis of cardiometabolic diseases, including type II diabetes, obesity, and hypertension. It has been well established that epoxyeicosatrienoic acids (EETs) act as an endothelial derived hyperpolarization factor (EDHF). Soluble epoxide hydrolase (s-EH) rapidly hydrolyses certain epoxylipids (e.

Soluble epoxide hydrolase in atherosclerosis.

Like many eicosanoids, epoxyeicosatrienoic acids (EETs) have multiple biological functions, including reduction of blood pressure, inflammation, and atherosclerosis in multiple species. Hydration of EETs by the soluble epoxide hydrolase (sEH) is the major route of their degradation to the less bioactive diols. Inhibition of the sEH stabilizes EETs, thus, enhancing the beneficial effects of EETs.

Inhibition of soluble epoxide hydrolase attenuated atherosclerosis, abdominal aortic aneurysm formation, and dyslipidemia.

Objective: Epoxyeicosatrienoic acids (EETs) have been shown to have antiinflammatory effects and therefore may play a role in preventing vascular inflammatory and atherosclerotic diseases. Soluble epoxide hydrolase (s-EH) converts EETs into less bioactive dihydroxyeicosatrienoic acids. Thus, inhibition of s-EH can prevent degradation of EETs and prolong their effects.

Gait analysis in a murine model of collagen-induced arthritis.

Murine collagen-induced arthritis (CIA) has become a valuable animal model for elucidating pathogenic mechanisms and evaluating therapeutic effects for rheumatoid arthritis. Recent advances in digital imaging and computer technology have enabled gait analysis to develop into a powerful tool for objectively detecting functional deficits in human and animal models. The present study explored the use of non-invasive video-capture gait analysis in the evaluation of a murine CIA model.

Do measures of vascular compliance correlate with endothelial function?

Accumulating evidence demonstrates that measures of vascular compliance correlate with endothelial function in animal models and patients with cardiovascular, metabolic, and kidney diseases. Nitric oxide modulates not only endothelial function, but also vascular compliance. Disruption of normal endothelial function may, at least partially, be responsible for reduced vascular compliance.

Monocyte chemoattractant protein-1 or macrophage inflammatory protein-1alpha deficiency does not affect angiotensin II-induced intimal hyperplasia in carotid artery ligation model.

Background: Angiotensin II (Ang II) promotes atherosclerotic vascular diseases, in which proinflammatory and proliferative effects play a major pathogenic role. Ang II up-regulates chemokines, such as monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory protein (MIP)-1alpha, which are important pro-inflammatory factors mediating infiltration of inflammatory cells into atherosclerotic lesion. The aim of the present study was to determine whether the presence of MCP-1 or MIP-1alpha is essential in Ang II-induced intimal hyperplasia in the carotid artery ligation model.

Angiotensin II induces histomorphologic features of unstable plaque in a murine model of accelerated atherosclerosis.

Background: We explored the role of angiotensin II in determining the histomorphometric features of plaque stability in apolipoprotein E-deficient mice submitted to ligation of the carotid artery.

Methods: Six-month-old apolipoprotein E-deficient mice underwent ligation of the common left carotid artery and were immediately assigned to receive either angiotensin II (1.4 mg .

Enalapril attenuates angiotensin II-induced atherosclerosis and vascular inflammation.

Angiotensin converting enzyme (ACE) inhibitors prevent a wide variety of key events underlying atherogenesis. Whether these actions depend solely on reduction of angiotensin II (Ang II) generation is still to be determined. This study was undertaken to determine whether enalapril, an ACE inhibitor, prevents atherosclerosis and vascular inflammation induced by Ang II in apolipoprotein E-deficient (apoE-KO) mice.