Heart rate variability as a measure of autonomic regulation of cardiac activity for assessing stress and welfare in farm animals -- a review.

Among the most widely used animal models in obesity-induced type 2 diabetes mellitus (T2DM) research are the congenital leptin- and leptin receptor-deficient rodent models. These include the leptin-deficient ob/ob mice and the leptin receptor-deficient db/db mice, Zucker fatty rats, Zucker diabetic fatty rats, SHR/N-cp rats, and JCR:LA-cp rats. After decades of mechanistic and therapeutic research schemes with these animal models, many species differences have been uncovered, but researchers continue to overlook these differences, leading to untranslatable research. The purpose of this review is to analyze and comprehensively recapitulate the most common leptin/leptin receptor-based animal models with respect to their relevance and translatability to human T2DM. Our analysis revealed that, although these rodents develop obesity due to hyperphagia caused by abnormal leptin/leptin receptor signaling with the subsequent appearance of T2DM-like manifestations, these are in fact secondary to genetic mutations that do not reflect disease etiology in humans, for whom leptin or leptin receptor deficiency is not an important contributor to T2DM. A detailed comparison of the roles of genetic susceptibility, obesity, hyperglycemia, hyperinsulinemia, insulin resistance, and diabetic complications as well as leptin expression, signaling, and other factors that confound translation are presented here. There are substantial differences between these animal models and human T2DM that limit reliable, reproducible, and translatable insight into human T2DM. Therefore, it is imperative that researchers recognize and acknowledge the limitations of the leptin/leptin receptor-based rodent models and invest in research methods that would be directly and reliably applicable to humans in order to advance T2DM management.

Leptin- and leptin receptor-deficient rodent models: relevance for human type 2 diabetes.

A resist composition is provided comprising a silicone resin, a photoacid generator, a nitrogen-containing organic compound, and a solvent. The silicone resin is obtained through cohydrolytic condensation of a mixture of three silane monomers containing an organic group having a hydroxyl group and having at least 3 fluorine atoms, in total, on a proximate carbon atom, an organic group having a carboxyl group protected with an acid labile group, and a lactone ring-bearing organic group, respectively. The resist composition has satisfactory resolution and overcomes the problem of a low selective etching ratio between resist film and organic film during oxygen reactive etching.

Resist composition and patterning process

Animal models of type 1 diabetes remain essential tools for investigation of the etiology and pathogenesis of the disease and, importantly, for the development of effective new treatments. Although a range of well-characterized and widely used models of type 1 diabetes in rodents are currently available, large animal models are a valuable complement to rodent models for both physiological and practical reasons. The pig is very useful in many aspects as a model for human physiology and pathophysiology because many organ systems of this species, as well as physiological and pathophysiological responses, resemble those of the human. The Gottingen minipig is particularly suitable for long-term studies because of its inherent small size and ease of handling, even at full maturity. Of particular relevance to the field of type 1 diabetes are the many similarities evident between humans and pigs with regard to pharmacokinetics of compounds after subcutaneous administration, structure and function of the gastrointestinal tract, morphology of the pancreas, and the overall metabolic status of the two species. Because spontaneous type 1-like diabetes is very rare in pigs, a model of the condition must be induced experimentally, either surgically or chemically. This process is discussed, and the use of the pig as a model in islet transplantation and diabetic complications is briefly summarized.

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Use of the Göttingen minipig as a model of diabetes, with special focus on type 1 diabetes research.

In humans, diabetes mellitus (DM) is considered a heterogeneous metabolic disorder. Swine have been used as a model for many human conditions including type 1 (insulindeficient) and type 2 (insulin-resistant) DM research because of their phenotypic similarities to humans including: cardiovascular anatomy and function, metabolism, lipoprotein profile, size, tendency to obesity, and omnivorous habits. There is phenotypic overlap between the two types of DM and pig models show characteristics and complications of both. Streptozotocin and alloxan have been used to create insulin deficient diabetes in pigs. One of the most unique and useful phenotypes is that these insulin-deficient pigs develop more severe coronary atherosclerosis than nondiabetic controls. It is not fully understood why patients with either type 1 or type 2 DM have increased severity and diffuseness of atherosclerosis compared with nondiabetic patients. The current human epidemic of type 2 DM and its attendant cardiovascular complications underscore the unmet need for creating a useful, readily available animal model of type 2 insulin resistant DM that also develops coronary artery atherosclerosis. The phenotypic susceptibility to coronary atherosclerosis makes pigs an attractive species to identify causative mechanisms. Suggested criteria for validation of an animal model of humanoid type 2 DM are described. The goal would be to develop a useful animal model for mechanistic studies as well as to develop and test novel therapeutics both for type 2 DM as well as its cardiovascular complications.

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Swine models of type 2 diabetes mellitus: insulin resistance, glucose tolerance, and cardiovascular complications.

Cardiac autonomic neuropathy is a common complication in insulin dependent diabetes mellitus. Nevertheless, little is known about when this impairment occurs during the time course of the disease. Analysis of blood pressure (BP) and heart rate (HR) variability could be used to detect early signs of autonomic alteration. To test this proposal, twelve sexually mature male Yucatan miniature pigs were equipped with an arterial catheter for telemetric BP analysis, and with a venous access. BP and HR were recorded together with respiratory movements while the animals were resting in a sling. After the first recording session performed when the pigs were 5 months old, streptozotocin (STZ) was used to induce diabetes in seven pigs, while the five others were controls. BP and HR were measured 3 and 6 months after the onset of diabetes and at a similar age in the controls. BP and HR oscillated at the respiratory range (0.19 Hz). Spectral analysis showed this respiratory component was the main determinant of the short-term variability of BP and HR. Atropine increased HR and BP and markedly diminished the respiratory sinus arrhythmia. Propranolol diminished HR and the respiratory peak of HR. A reduced respiratory oscillation of BP paralleled the diminution of the respiratory peak of HR. Baroreceptor-HR reflex was estimated using injections of phenylephrine and nitroprusside, and by cross-spectral analysis between BP and HR. Atropine shifted the curve to higher HR values, while propranolol reduced the level of the upper plateau. Atropine decreased both the coherence and gain of the cross-spectral analysis. STZ injection resulted in a type 1 diabetes. At 3 months, diabetic pigs exhibited low levels of BP and a reduced overall variability of HR and BP. Spectral analysis indicated the respiratory sinus arrhythmia was markedly reduced. In addition, the sensitivity of the baroreceptor-HR reflex was reduced. At a latter stage of diabetes these alterations were marked and the level of the resting HR was increased. These data demonstrate the dual (vagal and sympathetic) control of HR in pigs and the dominant role of respiration in the genesis of HR and BP fluctuations. The spectral and cross-spectral analysis of BP and HR were altered after 3 months of diabetes and could be proposed as early detectors of cardiac autonomic neuropathy.

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Early detection of cardiovascular autonomic neuropathy in diabetic pigs using blood pressure and heart rate variability.

. The invention concerns compounds of general formula (I) wherein: R1, R2, R3, R4, R5 and R6 are as defined in Claim 1. Said compounds are useful in the treatment of pathologies related to the insulin-resistance syndrome.

Dihydro-1,3,5-triazine amine derivatives and their therapeutic uses

Objective: Rats with ventromedial hypothalamic lesion (VMH) are massively obese with endogenous hyperinsulinemia, insulin resistance, low sympathetic activity, and high parasympathetic activity, which are likely to induce hypertension. The goal was to follow in this model the long-term hemodynamic changes and to investigate the role of autonomic nervous system and insulin resistance in these changes.



Research Metho ds and Procedures: Heart rate and blood pressure were monitored for 12 weeks after operation using a telemetric system in VMH and sham rats. Plasma catecholamines and heart β-adrenoceptors were measured. Glucose tolerance was studied after an intravenous glucose injection and insulin sensitivity during a euglycemic hyperinsulinemic clamp test.



Results: A marked bradycardia and only a mild increase in blood pressure occurred in VMH rats compared with sham animals. Response to autonomic-acting drugs showed an increase in heart vagal tone and responsiveness to a β-agonist drug. Plasma catecholamine levels were markedly increased, and the density and affinity of heart β-adrenoceptors were similar in VMH, sham, and control rats. Muscle glucose use was reduced by 1 week after operation in VMH animals.



Discussion: These results show the following in this model of massively obese rats with sympathetic impairment: 1) adrenal medulla secretion is increased, probably as a result of hyperinsulinemia and increased vagal activity; 2) cardiac responsiveness to β-agonist stimulation is increased; and 3) despite these changes and suspected resistance to the vasodilative effect of insulin, blood pressure does not increase. We conclude that high vagal activity may be protective against hypertension associated with obesity.

Cardiovascular Vagosympathetic Activity in Rats with Ventromedial Hypothalamic Obesity

The invention relates to the field of chemistry and more particularly to that of therapeutic chemistry. The invention more precisely features novel 5-phenoxyalkyl 2,4-thiazolidinediketones of general formula (I): in which A represents one linear or branched alkylene group comprising 2 to 16 carbon atoms D represents one monocyclic, bycyclic or tricyclic, homocarbonaceous or heterocarbonaceous aromatic structure capable of enclosing one or several heteroatoms X represents the aromatic structure substituent and is as defined in claim 1 n is one integer ranging from 1 to 3 with the restriction that if A represents one butyl radical, (a) does not represent the 4-chlorophenyl group. The invention also disclosed tautomer, enantiomer, diastereoisomer and epimer forms of general formula (I) compounds, in free or salified form. The invention also discloses methods for obtaining general formula (I) compounds, their use as antidiabetic agents, and in the insulin resistance metabolic syndrome, as well as in the pharmaceutical compositions that contain general formula (I) compounds.

Didier Mesangeau

Papers

Early detection of cardiovascular autonomic neuropathy in diabetic pigs using blood pressure and heart rate variability.

Dihydro-1,3,5-triazine amine derivatives and their therapeutic uses

Cardiovascular Vagosympathetic Activity in Rats with Ventromedial Hypothalamic Obesity

Novel thiazolidone-2 derivatives, 4-diketone substituted, method for obtaining them and pharmaceutical compositions containing same

Arterial stiffness and the autonomic nervous system during the development of Zucker diabetic fatty rats.