Mechanisms underlying the efficacy of a rodent model of vertical sleeve gastrectomy - A focus on energy expenditure.

OBJECTIVE: Bariatric surgery remains the only effective and durable treatment option for morbid obesity. Vertical Sleeve Gastrectomy (VSG) is currently the most widely performed of these surgeries primarily because of its proven efficacy in generating rapid onset weight loss, improved glucose regulation and reduced mortality compared with other invasive procedures. VSG is associated with reduced appetite, however, the relative importance of energy expenditure to VSG-induced weight loss and changes in glucose regulation, particularly that in brown adipose tissue (BAT), remains unclear. The aim of this study was to investigate the role of BAT thermogenesis in the efficacy of VSG in a rodent model. METHODS: Diet-induced obese male Sprague-Dawley rats were either sham-operated, underwent VSG surgery or were pair-fed to the food consumed by the VSG group. Rats were also implanted with biotelemetry devices between the interscapular lobes of BAT to assess local changes in BAT temperature as a surrogate measure of thermogenic activity. Metabolic parameters including food intake, body weight and changes in body composition were assessed. To further elucidate the contribution of energy expenditure via BAT thermogenesis to VSG-induced weight loss, a separate cohort of chow-fed rats underwent complete excision of the interscapular BAT (iBAT lipectomy) or chemical denervation using 6-hydroxydopamine (6-OHDA). To localize glucose uptake in specific tissues, an oral glucose tolerance test was combined with an intraperitoneal injection of 14C-2-deoxy-d-glucose (14C-2DG). Transneuronal viral tracing was used to identify 1) sensory neurons directed to the stomach or small intestine (H129-RFP) or 2) chains of polysynaptically linked neurons directed to BAT (PRV-GFP) in the same animals. RESULTS: Following VSG, there was a rapid reduction in body weight that was associated with reduced food intake, elevated BAT temperature and improved glucose regulation. Rats that underwent VSG had elevated glucose uptake into BAT compared to sham operated animals as well as elevated gene markers related to increased BAT activity (Ucp1, Dio2, Cpt1b, Cox8b, Ppargc) and markers of increased browning of white fat (Ucp1, Dio2, Cited1, Tbx1, Tnfrs9). Both iBAT lipectomy and 6-OHDA treatment significantly attenuated the impact of VSG on changes in body weight and adiposity in chow-fed animals. In addition, surgical excision of iBAT following VSG significantly reversed VSG-mediated improvements in glucose tolerance, an effect that was independent of circulating insulin levels. Viral tracing studies highlighted a patent neural link between the gut and BAT that included groups of premotor BAT-directed neurons in the dorsal raphe and raphe pallidus. CONCLUSIONS: Collectively, these data support a role for BAT in mediating the metabolic sequelae following VSG surgery, particularly the improvement in glucose regulation, and highlight the need to better understand the contribution from this tissue in human patients.

Effect of tetra-hydroxylated bile acid on size and insulin sensitivity of subcutaneous adipocytes in healthy lean cats.

Obesity leads to insulin resistance and is a major risk factor for the development of diabetes mellitus in cats. Prevention of obesity and obesity-induced insulin resistance is difficult, and reliable long-term strategies are currently lacking. Retinoid-related orphan receptor gamma (RORγ) was recently identified as an important transcription factor in the development of large insulin-resistant adipocytes in mice and humans. RORγ negatively affects adipocyte differentiation through expression of its target gene matrix metalloproteinase 3 (MMP3) and promotes the development of large insulin-resistant adipocytes. Preliminary studies in mice showed that RORγ can be inhibited by its ligand tetra-hydroxylated bile acid (THBA). In the present study, serum THBA levels were determined in healthy and diabetic cats. Moreover, potential side effects and the effects of THBA supplementation on adipocyte size, mRNA expression of RORγ, MMP3, interleukin 6, tumor necrosis factor α, adiponectin and leptin in feline subcutaneous adipocytes and insulin sensitivity were investigated in healthy normal weight cats. Thirteen healthy and 13 diabetic cats were used for determination of serum THBA level, and six healthy normal-weight cats were included in a feeding trial. Similar THBA levels were determined in serum of healthy and diabetic cats. Supplementation of 5 mg/kg THBA for 8 wk did not cause any negative effect on feeding behavior, general condition and blood parameters of tested cats. It significantly reduced adipocyte size and mRNA expression of MMP3, interleukin 6, and tumor necrosis factor α in adipocytes, while mRNA expression of adiponectin significantly increased and mRNA expression of RORγ and leptin remained unchanged. Administration of THBA did not influence fasting blood glucose levels or the response of cats to acute insulin administration. Based on these results, THBA is palatable and is considered safe for use in cats. It reduces expression of MMP3 and promotes the development of small adipocytes with increased expression of adiponectin and reduced expression of interleukin 6 and tumor necrosis factor α. Further studies are recommended to evaluate the effect of THBA on adipocyte size and insulin sensitivity in obese cats.

A once-monthly GLP-1 receptor agonist for treatment of diabetic cats.

There is growing evidence that peptidic glucagon-like peptide-1 receptor agonists (GLP-1RA), such as exenatide, may provide useful therapeutic options for treatment of feline diabetes. However, because such drugs are administered subcutaneously, it is desirable that they be long-acting and not require frequent injections. We have developed a chemically controlled delivery system to support half-life extension of peptidic therapeutics. Here, the peptide is covalently attached to hydrogel microspheres by a self-cleaving ß-eliminative linker; after subcutaneous injection of the microspheres, the peptide is slowly released from the depot to the systemic circulation. Using this technology, we developed a delivery system that supports once-monthly administration of a stable exenatide analog, [Gln28]exenatide, in rodents (Schneider, et al, ACS Chem Biol 12, 2107 to 2116, 2017). The purposes of the present study were a) to demonstrate pharmacokinetic and pharmacodynamic similarities of the deamidation-sensitive GLP-1RA exenatide and the closely related, more stable [Gln28]exenatide and b) to develop a long-acting GLP-1RA in cats. The results show that exenatide and [Gln28]exenatide injected intravenously or subcutaneously at 10 µg/kg have nearly identical pharmacokinetics in the cat-both having elimination half-lives of ∼40 min-but subcutaneously administered [Gln28]exenatide has superior bioavailability-93% for [Gln28]exenatide vs 52% for exenatide. The results also show that exenatide and [Gln28]exenatide have similar insulinotropic activities in the cat during a high-dose intravenous glucose tolerance test; they increased the area under the curve (AUC) for insulin to a similar extent but had no effect on glucose AUC. Finally, subcutaneous injection of a microsphere-[Gln28]exenatide conjugate containing an appropriate self-cleaving linker in the cat provides plasma [Gln28]exenatide with a half-life of about 40 d vs 40 min with the injected free peptide. Hence, the large body of information available for exenatide can be used to facilitate clinical development of [Gln28]exenatide as a treatment for feline diabetes, and the microsphere-[Gln28]exenatide conjugate is quite suitable for once-monthly subcutaneous administration of the peptide in the cat.

Establishment of a protocol for the isolation of feline pancreatic islets.

Diabetes mellitus is a common endocrinopathy in cats that is associated with pancreatic islets lesions. Research on isolated islets contributed to the understanding of the pathophysiology of human diabetes. Therefore, by improving the existing methods of isolation in cats, we aimed at increasing islet yield, purity and viability of feline isolated islets. Islet isolation was accomplished by pancreas perfusion with 80ml of Collagenase type IV through the pancreatic duct at the site of the major papilla. The enzymatic digestion was combined with mechanical disruption and controlled by dithizone staining. Purification was performed by filtration and handpicking. Purified islets were plated on extracellular matrix pre-coated plates and cultured for 48h. Feline islets with a high degree of viability and purity were isolated and cultured for the first time. Although the percentage of islet free from the acinar tissue relative to the total number of isolated islets was low compared to other species, the suggested protocol represents a promising progress in the procedure of islet isolation in cats.

Use of an implantable pump for controlled subcutaneous insulin delivery in healthy cats.

The aim of this study was to examine the safety and reliability of a research-grade implantable pump for controlled delivery of insulin glargine in cats. For this purpose, a small telemetrically controlled drug delivery pump with a refillable reservoir was implanted into the subcutaneous tissues of the dorsal neck in 10 clinically healthy cats. The reservoir was filled with insulin glargine, and the pump was programmed to deliver four boluses of 0.25 IU/kg, 2-3 weeks apart. As a control, insulin glargine (0.25 IU/kg) was injected SC. Blood glucose and plasma insulin glargine concentrations were measured before each bolus and SC injection and for 8 h afterward. Cats were monitored for signs of discomfort. Pumps were easily implanted and well tolerated by all cats. The experiment was completed in five of 10 cats. In four, the pump failed because of technical reasons; another cat developed severe hypoglycaemia attributable to insulin leakage. Overall, plasma insulin glargine increased after six of eight (75%) initial boluses and after one of 16 (6%) successive boluses. Glucose decreased after seven of eight (88%) initial boluses and after four of 16 (25%) successive boluses. Only the first bolus significantly increased plasma insulin glargine (P = 0.008) and decreased glucose (P = 0.008). Of 20 SC injections, 10 (50%) increased plasma insulin glargine (P <0.001) and 12 (60%) decreased glucose (P <0.001). The pump did not cause discomfort in cats, but life-threatening hypoglycaemia occurred in one. Frequent device problems suggest that the pump needs improvements. Because successive boluses did not increase plasma insulin glargine, this type of insulin may not be appropriate with the pump.

Influence of Roux-en-Y gastric bypass on plasma bile acid profiles: a comparative study between rats, pigs and humans.

BACKGROUND: Roux-en-Y gastric bypass (RYGBP) is the most widely used bariatric surgery procedure, which induces profound metabolic and physiological effects, such as substantial improvements in obesity, type 2 diabetes and their comorbidities. Increasing evidence identifies bile acids (BAs) as signaling molecules that contribute to the metabolic improvement after RYGBP. However, how and to what extent BAs mediate the metabolic effects of RYGBP still remains unclear and requires mechanism of action studies using preclinical models. In this study, we compared plasma BA profiles before and after RYGBP in two animal models, rats and pigs, with humans to evaluate their translational potential. METHODS: Plasma BAs were profiled in rats, pigs and humans by liquid chromatography coupled with tandem mass spectrometry before and after RYGBP. RESULTS: RYGBP increased baseline plasma total BA concentrations in humans and in the two animal models to a similar extent (∼3-fold increase), despite differences in presurgery BA levels and profiles between the models. However, qualitatively, RYGBP differently affected individual plasma BA species, with similar increases in some free species (cholic acid (CA), chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA)), different increases in glyco-conjugated species depending on the model and globally no increase in tauro-conjugated species whatever the model. CONCLUSIONS: The tested animal models share similar quantitative RYGBP-induced increases in peripheral blood BAs as humans, which render them useful for mechanistic studies. However, they also present qualitative differences in BA profiles, which may result in different signaling responses. Such differences need to be taken into account when translating results to humans.

Alterations in energy expenditure in Roux-en-Y gastric bypass rats persist at thermoneutrality.

BACKGROUND: The compensatory decrease in energy expenditure (EE) in response to body weight loss is attenuated by Roux-en-Y gastric bypass (RYGB) surgery in rats. The thermoneutral zone (TNZ) is at higher temperatures in rodents than in humans. Consequently, rodents may be under moderate cold stress if EE is measured at room temperature, leading to increased EE due to adaptive thermogenesis. We speculated that the reported alterations in EE of RYGB rats at room temperature are caused by higher adaptive thermogenesis and are therefore not present at thermoneutrality. METHODS: Male Wistar rats were randomized for RYGB or sham surgery. Some sham rats were body weight matched (BWM) to the RYGB rats by food restriction, the others received ad libitum access to food (AL). EE, body temperature, physical activity and food intake were measured at ambient temperatures between 22 and 32 °C to determine the TNZ. Adaptive thermogenesis requires ß3-adrenergic receptor-mediated uncoupling protein-1 (UCP-1) expression in brown adipose tissue (BAT). The in vivo thermogenic capacity of BAT was determined by administering the ß3-adrenergic agonist CL316,243, and UCP-1 protein expression was measured at room temperature. RESULTS: The TNZ was between 28 and 30 °C for AL and RYGB and between 30 and 32 °C for BWM rats, respectively. In contrast to AL and BWM rats, EE was not significantly higher at room temperature than at thermoneutrality in RYGB rats, reflecting a lack of adaptive thermogenesis. Consistently, both the thermogenic capacity of BAT and UCP-1 expression were decreased in RYGB compared with AL rats at room temperature. CONCLUSIONS: Our data confirm that the decrease in EE after body weight loss is attenuated by RYGB surgery and show that this effect persists at thermoneutrality. Contrary to our hypothesis, we found that adaptive thermogenesis at room temperature is reduced in RYGB rats.

Gut hormones such as amylin and GLP-1 in the control of eating and energy expenditure.

The control of meal size is the best studied aspect of the control of energy balance, and manipulation of this system constitutes a promising target to treat obesity. A major part of this control system is based on gastrointestinal hormones such as glucagon-like peptide-1 (GLP-1) or amylin, which are released in response to a meal and which limit the size of an ongoing meal. Both amylin and GLP-1 have also been shown to increase energy expenditure in experimental rodents, but mechanistically we know much less how this effect may be mediated, which brain sites may be involved, and what the physiological relevance of these findings may be. Most studies indicate that the effect of peripheral amylin is centrally mediated via the area postrema, but other brain areas, such as the ventral tegmental area, may also be involved. GLP-1's effect on eating seems to be mainly mediated by vagal afferents projecting to the caudal hindbrain. Chronic exposure to amylin, GLP-1 or their analogs decrease food intake and body weight gain. Next to the induction of satiation, amylin may also constitute an adiposity signal and in fact interact with the adiposity signal leptin. Amylin analogs are under clinical consideration for their effect to reduce food intake and body weight in humans, and similar to rodents, amylin analogs seem to be particularly active when combined with leptin analogs.

Endocrine Pancreas in Cats With Diabetes Mellitus.

Pancreatic amyloidosis and loss of α and ß cells have been shown to occur in cats with diabetes mellitus, although the number of studies currently available is very limited. Furthermore, it is not known whether pancreatic islet inflammation is a common feature. The aims of the present study were to characterize islet lesions and to investigate whether diabetic cats have inflammation of the pancreatic islets. Samples of pancreas were collected postmortem from 37 diabetic and 20 control cats matched for age, sex, breed, and body weight. Histologic sections were stained with hematoxylin and eosin and Congo red; double labeled for insulin/CD3, insulin/CD20, insulin/myeloperoxidase, insulin/proliferating cell nuclear antigen, and glucagon/Ki67; and single labeled for amylin and Iba1. Mean insulin-positive cross-sectional area was approximately 65% lower in diabetic than control cats (P = .009), while that of amylin and glucagon was similar. Surprisingly, amyloid deposition was similar between groups (P = .408). Proliferation of insulin- and glucagon-positive cells and the number of neutrophils, macrophages, and T (CD3) and B (CD20) lymphocytes in the islets did not differ. The presence of T and B lymphocytes combined tended to be more frequent in diabetic cats (n = 8 of 37; 21.6%) than control cats (n = 1 of 20; 5.0%). The results confirm previous observations that loss of ß cells but not α cells occurs in diabetic cats. Islet amyloidosis was present in diabetic cats but was not greater than in controls. A subset of diabetic cats had lymphocytic infiltration of the islets, which might be associated with ß-cell loss.

Exocrine Pancreas in Cats With Diabetes Mellitus.

Pancreatitis has been described in cats with diabetes mellitus, although the number of studies currently available is very limited. In addition, ketoacidosis has been hypothesized to be associated with pancreatitis in diabetic cats. The aims of the present study were to investigate whether diabetic cats have pancreatitis and to determine if pancreatitis is more frequent with ketoacidosis. Samples of pancreas were collected postmortem from 37 diabetic cats, including 15 with ketoacidosis, and 20 control cats matched for age, sex, breed, and body weight. Sections were stained with hematoxylin and eosin, double-labeled for insulin/CD3, insulin/CD20, insulin/myeloperoxidase, insulin/PCNA, and glucagon/Ki67, and single-labeled for Iba1. A previously proposed semiquantitative score was used to characterize pancreatitis, along with counts of inflammatory cells. Scores of pancreatitis and the number of neutrophils, macrophages, and lymphocytes in the exocrine pancreas did not differ between diabetic and control cats or between diabetic cats with and without ketoacidosis. Of note, PCNA-positive acinar cells were increased (P = .002) in diabetic cats, particularly near islets (P < .001). Ki67-positive acinar cells were increased only near islets (P = .038). Ketoacidosis was not linked to proliferation. The results suggest that histopathologic evidence of pancreatitis may not be more frequent in diabetic cats and that ketoacidosis may not be associated with it at the time of death. Augmented PCNA-positive acinar cells might indicate increased proliferation due to chronic pancreatitis. The reason behind the prevalent proliferation of acinar cells surrounding pancreatic islets deserves further investigation.

Effect of the Glucagon-like Peptide-1 Analogue Exenatide Extended Release in Cats with Newly Diagnosed Diabetes Mellitus.

BACKGROUND: Exenatide extended release (ER) is a glucagon-like peptide-1 analogue that increases insulin secretion, inhibits glucagon secretion and induces satiation in humans with type 2 diabetes mellitus. The use of exenatide ER is safe and stimulates insulin secretion in healthy cats. OBJECTIVES: The objective of this study is to assess the safety of exenatide ER and its effect on body weight, remission and metabolic control in newly diagnosed diabetic cats receiving insulin and a low-carbohydrate diet. ANIMALS: Thirty client-owned cats. METHODS: Prospective placebo-controlled clinical trial. Cats were treated with exenatide ER or 0.9% saline, administered SC, once weekly. Both groups received insulin glargine and a low-carbohydrate diet. Exenatide ER was administered for 16 weeks, or in cats that achieved remission it was given for 4 weeks after discontinuing insulin treatment. Nonparametric tests were used for statistical analysis. RESULTS: Cats in the exenatide ER and placebo groups had transient adverse signs including decreased appetite (60% vs. 20%, respectively, P = .06) and vomiting (53% vs. 40%, respectively, P = .715). Body weight increased significantly in the placebo group (P = .002), but not in cats receiving exenatide ER. Cats on exenatide ER achieved remission or good metabolic control in 40% or 89%, respectively, whereas in control cats percentages were 20% or 58% (P = .427 and P = .178, respectively). CONCLUSION AND CLINICAL IMPORTANCE: Exenatide ER is safe in diabetic cats and does not result in weight gain. Our pilot study suggests that, should there be an additional clinically relevant beneficial effect of exenatide ER in insulin-treated cats on rate of remission and good metabolic control, it would likely approximate 20% and 30%, respectively.

Longitudinal evaluation of serum pancreatic enzymes and ultrasonographic findings in diabetic cats without clinically relevant pancreatitis at diagnosis.

BACKGROUND: Cats with diabetes mellitus can have subclinical pancreatitis but prospective studies to confirm this are lacking. Metabolic control of diabetic cats with pancreatitis is difficult. HYPOTHESIS: Subclinical pancreatitis occurs in diabetic cats at the time diabetes is diagnosed or might develop during the follow-up period, hampering diabetic remission. ANIMALS: Thirty cats with newly diagnosed diabetes without clinical signs of pancreatitis on admission. METHODS: Prospective study. On admission and 2 and 6 months later, serum Spec fPL and DGGR-lipase were measured and the pancreas underwent ultrasonographic examination. Pancreatitis was suspected if serum markers were increased or ≥2 ultrasonographic abnormalities were detected. Cats were treated with insulin glargine and diabetic remission was defined as euglycemia ≥4 weeks after discontinuation of insulin. Nonparametric statistical tests were used for analysis. RESULTS: Subclinical pancreatitis at the time of diagnosis was suspected in 33, 50, and 31% of cats based on Spec fPL, DGGR-lipase and ultrasonography, respectively; and in 60% when diagnostic criteria were combined. During the follow-up period, suspected pancreatitis developed in additional 17-30% cats. Only 1 cat had transient clinical signs compatible with pancreatitis. Seventeen of the 30 cats (57%) achieved remission. Frequency of abnormal Spec fPL and DGGR-lipase and abnormal ultrasonographic findings did not differ in cats achieving remission and those who did not. Cats achieving remission had significantly lower Spec fPL at 2 months (P < .001). CONCLUSIONS AND CLINICAL IMPORTANCE: Based on laboratory and ultrasonographic measurements, many cats with diabetes might have pancreatitis, although without clinical signs. Cats with high Spec fPL might have a reduced chance of diabetic remission; however, this topic needs further studies in large cohorts of diabetic cats.

Effects of the glucagon-like peptide-1 (GLP-1) analogues exenatide, exenatide extended-release, and of the dipeptidylpeptidase-4 (DPP-4) inhibitor sitagliptin on glucose metabolism in healthy cats.

Incretin analogues and inhibitors of the breakdown of endogenous incretins are antidiabetic drugs that increase ß-cell proliferation and glucose-stimulated insulin secretion in rodents and humans. Objectives were to test whether exenatide, exenatide extended-release, and sitagliptin can be safely used in cats, to identify the most effective drug, and to test the effects of prolonged exenatide extended-release administration. Three cats each were given exenatide (0.2-2 µg/kg, q12h, subcutaneously, 5 days), exenatide extended-release (40-400 µg/kg, subcutaneously, once), and sitagliptin (1-10 mg/kg, q24h, orally, 5 days). Before and after treatment, glucose, insulin and glucagon areas under the curve (AUC) were assessed by meal response tests (MRT). Exenatide increased insulin AUC by 224%, 258%, 331% and 93%, exenatide extended-release by 127%, 169%, 178% and 95%, and sitagliptin by 32%, 69%, 62%, and 43%, respectively. The tested drugs are safe to use in cats and enhance insulin secretion. Incretin-based therapy may be beneficial in cats with diabetes mellitus.

Intensive intravenous infusion of insulin in diabetic cats.

BACKGROUND: Remission occurs in 10-50% of cats with diabetes mellitus (DM). It is assumed that intensive treatment improves ß-cell function and increases remission rates. HYPOTHESIS: Initial intravenous infusion of insulin that achieves tight glycemic control decreases subsequent insulin requirements and increases remission rate in diabetic cats. ANIMALS: Thirty cats with newly diagnosed DM. METHODS: Prospective study. Cats were randomly assigned to one of 2 groups. Cats in group 1 (n = 15) received intravenous infusion of insulin with the goal of maintaining blood glucose concentrations at 90-180 mg/dL, for 6 days. Cats in group 2 (n = 15) received subcutaneous injections of insulin glargine (cats ≤4 kg: 0.5-1.0 IU, q12h; >4 kg 1.5-2.0 IU, q12h), for 6 days. Thereafter, all cats were treated with subcutaneous injections of insulin glargine and followed up for 6 months. Cats were considered in remission when euglycemia occurred for ≥4 weeks without the administration of insulin. Nonparametric tests were used for statistical analysis. RESULTS: In groups 1 and 2, remission was achieved in 10/15 and in 7/14 cats (P = .46), and good metabolic control was achieved in 3/5 and in 1/7 cats (P = .22), respectively. Overall, good metabolic control or remission occurred in 13/15 cats of group 1 and in 8/14 cats of group 2. In group 1, the median insulin dosage given during the 6-month follow-up was significantly lower than in group 2 (group 1: 0.32 IU/kg/day, group 2: 0.51 IU/kg/day; P = .013). CONCLUSIONS AND CLINICAL IMPORTANCE: Initial intravenous infusion of insulin for tight glycemic control in cats with DM decreases insulin requirements during the subsequent 6 months.

L-lysine dose dependently delays gastric emptying and increases intestinal fluid volume in humans and rats.

BACKGROUND: Novel sensory inputs for the control of food intake and gastrointestinal (GI) function are of increasing interest due to the rapid increase in nutrition-related diseases. The essential amino acid L-lysine was demonstrated to have a selective impact on food intake, gastric emptying, and intestinal transit in rats, thus indicating a potential novel direct sensory input to assess dietary protein content and quality. The aim of this study was to assess translational aspects of this finding and to investigate the dose-dependent effect of L-lysine on human and rat GI function. METHODS: L-lysine doses from 0-800 mg in rats and 0.5-7.5 g in humans were analyzed for their effect on gastric emptying and GI secretion. Human GI function was assessed non-invasively using magnetic resonance imaging (MRI), rat data were acquired using standard lethal measurement methods. L-lysine dose dependently delayed gastric emptying and stimulated GI secretion in rats as reflected by residual phenol red content and increased gastric wet weight. KEY RESULTS: The dose-dependent delay in gastric emptying observed in rats was confirmed in humans with an increase in halftime of gastric emptying of 4 min/g L-lysine, p < 0.01. Moreover, a dose-dependent increase in intestinal fluid accumulation was observed (0.4 mL/min/g L-lysine, p < 0.0001). No effect on alkaline tide, glucose concentration, hematocrit, or visceral sensations was detected. CONCLUSIONS & INFERENCES: This translational study demonstrates comparable dose-dependent effects of intragastric L-lysine on GI function in humans and rats and suggests a broader role for individual amino acids in the control of GI motility and secretion in vivo.

High dietary fat intake influences the activation of specific hindbrain and hypothalamic nuclei by the satiety factor oleoylethanolamide.

Chronic exposure to a diet rich in fats changes the gastrointestinal milieu and alters responses to several signals involved in the control of food intake. Oleoylethanolamide (OEA) is a gut-derived satiety signal released from enterocytes upon the ingestion of dietary fats. The anorexigenic effect of OEA, which requires intestinal PPAR-alpha receptors and is supposedly mediated by vagal afferents, is associated with the induction of c-fos in several brain areas involved in the control of food intake, such as the nucleus of the solitary tract (NST) and the hypothalamic paraventricular (PVN) and supraoptic nuclei (SON). In the present study we investigated whether the exposure to a high fat diet (HFD) alters the hindbrain and hypothalamic responses to OEA. To this purpose we evaluated the effects of OEA at a dose that reliably inhibits eating (10mg/kg i.p.) on the induction of c-fos in the NST, area postrema (AP), PVN and SON in rats maintained either on standard chow or a HFD. We performed a detailed analysis of the different NST subnuclei activated by i.p. OEA and found that peripheral OEA strongly activates c-fos expression in the AP, NST and in the hypothalamus of both chow and HFD fed rats. The extent of c-fos expression was, however, markedly different between the two groups of rats, with a weaker activation of selected NST subnuclei and stronger activation of the PVN in HFD-fed than in chow-fed rats. HFD-fed rats were also more sensitive to the immediate hypophagic action of OEA than chow-fed rats. These effects may be due to a decreased sensitivity of vagal afferent fibers that might mediate OEA's actions on the brain and/or an altered sensitivity of brain structures to OEA.

Renal morphology in cats with diabetes mellitus.

In humans, diabetes mellitus (DM) is an important cause of renal damage, with glomerular lesions being predominant. In cats, although diabetes is a common endocrinopathy, it is yet unknown whether it leads to renal damage. The aim of the study was to compare renal histologic features and parameters of renal function in diabetic cats against a control population matched for age, gender, breed, and body weight. Thirty-two diabetic and 20 control cats were included. Kidney sections from paraffin-embedded kidney samples were stained and examined with optical microscopy to identify glomerular, tubulointerstitial, and vascular lesions and to assess their frequency and severity. Serum creatinine and urea concentrations were also compared. Glomerular lesions were observed in 29 cats overall, with mesangial matrix increase being more common (19 cats). Tubulointerstitial lesions were observed in 42 cats, including lymphocytic infiltration (29), fibrosis (22), or tubular necrosis (21). Vascular lesions were observed in 5 cases. The frequency and severity of histologic lesions did not differ between diabetic and control cats; however, among diabetics, those that survived longer after diagnosis had more glomerular and vascular lesions. Serum creatinine and urea concentrations were similar between groups; in diabetic cats median creatinine was 109 µmol/l (range, 51-1200) and urea was 12 mmol/l (range, 4-63), and in controls creatinine was 126 µmol/l (range, 50-875) and urea 11 mmol/l (range, 3-80). The results suggest that DM in cats does not lead to microscopically detectable kidney lesions or clinically relevant renal dysfunction. The authors hypothesize that the short life expectancy of diabetic cats may be the main reason for the difference from human diabetics.

The interaction of amylin with other hormones in the control of eating.

Twenty years of research established amylin as an important control of energy homeostasis. Amylin controls nutrient and energy fluxes by reducing energy intake, by modulating nutrient utilization via an inhibition of postprandial glucagon secretion and by increasing energy disposal via a prevention of compensatory decreases of energy expenditure in weight reduced individuals. Like many other gastrointestinal hormones, amylin is secreted in response to meals and it reduces eating by promoting meal-ending satiation. Not surprisingly, amylin interacts with many of these hormones to control eating. These interactions seem to occur at different levels because amylin seems to mediate the eating inhibitory effect of some of these gastrointestinal hormones, and the combination of some of these hormones seems to lead to a stronger reduction in eating than single hormones alone. Amylin's effect on eating is thought to be mediated by a stimulation of specific amylin receptors in the area postrema. Secondary brain sites that were defined to mediate amylin action - and hence potential additional sites of interaction with other hormones - include the nucleus of the solitary tract, the lateral parabrachial nucleus, the lateral hypothalamic area and other hypothalamic nuclei. The focus of this review is to summarize the current knowledge of amylin interactions in the control of eating. In most cases, these interactions have only been studied at a descriptive rather than a mechanistic level and despite the clear knowledge on primary sites of amylin action, the interaction sites between amylin and other hormones are often unknown.

Diabetes from humans to cats.

Diabetes mellitus is a common endocrinopathy in humans and in cats. The general prevalence of diabetes mellitus, and in particular of type 2 diabetes, has risen dramatically in recent years. This increase has often been linked to the rise in the obesity pandemic because obesity and the ensuing metabolic consequences constitute major risk factors for human type 2 and for feline diabetes. Feline diabetes shares many features of human type 2 diabetes in respect to its pathophysiology, underlying risk factors and treatment strategies. This review will briefly summarize major characteristics in the human and the feline disease and where available, point out the current knowledge on similarities and differences.