Insulin and circadian rhythm genes of the Nile rat (Arvicanthis niloticus) are conserved and orthologous to those in the rat, mouse and human.

The African grass or Nile rat (NR) (Arvicanthis niloticus) is a herbivorous diurnal rodent which is used as a biological model for research on type 2 diabetes mellitus (T2DM) and the circadian rhythm. Similar to humans, male NRs develop T2DM with high-carbohydrate diets. The NR thus provides a unique opportunity to identify the nutritional and underlying genetic factors that characterise human T2DM, as well as the effects of potential anti-diabetic phytochemicals such as Water-Soluble Palm Fruit Extract. Whole genome sequencing (WGS) could help identify possible genetic causes why NRs spontaneously develop T2DM in captivity. In this study, we performed WGS on a hepatic deoxyribonucleic acid (DNA) sample isolated from a male NR using PacBio high-fidelity long-read sequencing. The WGS data obtained were then de novo assembled and annotated using PacBio HiFi isoform sequencing (Iso-Seq) data as well as previous Illumina RNA sequencing (RNA-Seq) data. Genes related to insulin and circadian rhythm pathways were present in the NR genome, similar to orthologues in the rat, mouse and human genomes. T2DM development in the NR is thus most likely not attributable to structural differences in these genes when compared to other biological models. Further studies are warranted to gain additional insights on the genetic-environmental factors which underlie the genetic permissiveness of NRs to develop T2DM.

Dietary Carbohydrate as Glycemic Load, Not Fat, Coupled with Genetic Permissiveness Favoring Rapid Growth and Extra Calories, Dictate Metabolic Syndrome and Diabetes Induction in Nile Rats (Arvicanthis niloticus).

Objective: Whether dietary carbohydrate (CHO) or fat is more involved in type 2 diabetes (T2DM) induction uncomplicated by dietary fiber was addressed in a spontaneous diabetic model, the diurnal Nile rat that mimics the human condition. Methods: A total of 138 male Nile rats were fed plant-based and animal-based saturated fat where 10% energy as CHO and fat were exchanged across 5 diets keeping protein constant, from 70:10:20 to 20:60:20 as CHO:fat:protein %energy. Diabetes induction was analyzed by: 1. diet composition, i.e., CHO:fat ratio, to study the impact of diet; 2. quintiles of average caloric intake per day to study the impact of calories; 3. quintiles of diabetes severity to study the epigenetic impact on diabetes resistance. Results: High glycemic load (GLoad) was most problematic if coupled with high caloric consumption. Diabetes severity highlighted rapid growth and caloric intake as likely epigenetic factors distorting glucose metabolism. The largest weanling rats ate more, grew faster, and developed more diabetes when the dietary GLoad exceeded their gene-based metabolic capacity for glucose disposal. Diabetes risk increased for susceptible rats when energy intake exceeded 26 kcal/day and the GLoad was >175/2000 kcal of diet and when the diet provided >57% energy as CHO. Most resistant rats ate <25 kcal/day independent of the CHO:fat diet ratio or the GLoad adjusted to body size. Conclusion: Beyond the CHO:fat ratio and GLoad, neither the type of fat nor the dietary polyunsaturated/saturated fatty acid (P/S) ratio had a significant impact, suggesting genetic permissiveness affecting caloric and glucose intake and glucose disposition were key to modulating Nile rat diabetes. Fat became protective by limiting GLoad when it contributed >40% energy and displaced CHO to <50% energy, thereby decreasing the number of diabetic rats and diabetes severity.

Identification of reference genes for real-time polymerase chain reaction gene expression studies in Nile rats fed Water-Soluble Palm Fruit Extract.

The Nile rat (Arvicanthis niloticus) is a novel diurnal carbohydrate-sensitive rodent useful for studies on type 2 diabetes mellitus (T2DM) and the metabolic syndrome. Hepatic responses to T2DM and any interventions thereof can be evaluated via transcriptomic gene expression analysis. However, the study of gene expression via real-time reverse transcription quantitative polymerase chain reaction (RT-qPCR) requires identification of stably expressed reference genes for accurate normalisation. This study describes the evaluation and identification of stable reference genes in the livers from Control Nile rats as well as those supplemented with Water-Soluble Palm Fruit Extract, which has been previously shown to attenuate T2DM in this animal model. Seven genes identified as having stable expression in RNA-Sequencing transcriptome analysis were chosen for verification using real-time RT-qPCR. Six commonly used reference genes from previous literature and two genes from a previous microarray gene expression study in Nile rats were also evaluated. The expression data of these 15 candidate reference genes were analysed using the RefFinder software which incorporated analyses performed by various algorithms. The Hpd, Pnpla6 and Vpp2 genes were identified as the most stable across the 36 samples tested. Their applicability was demonstrated through the normalisation of the gene expression profiles of two target genes, Cela1 and Lepr. In conclusion, three novel reference genes which can be used for robust normalisation of real-time RT-qPCR data were identified, thereby facilitating future hepatic gene expression studies in the Nile rat.

Publisher Correction: Palm Fruit Bioactives augment expression of Tyrosine Hydroxylase in the Nile Grass Rat basal ganglia and alter the colonic microbiome.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Palm Fruit Bioactives augment expression of Tyrosine Hydroxylase in the Nile Grass Rat basal ganglia and alter the colonic microbiome.

Tyrosine hydroxylase (TH) catalyzes the hydroxylation of L-tyrosine to L-DOPA. This is the rate-limiting step in the biosynthesis of the catecholamines - dopamine (DA), norepinephrine (NE), and epinephrine (EP). Catecholamines (CA) play a key role as neurotransmitters and hormones. Aberrant levels of CA are associated with multiple medical conditions, including Parkinson's disease. Palm Fruit Bioactives (PFB) significantly increased the levels of tyrosine hydroxylase in the brain of the Nile Grass rat (NGR), a novel and potentially significant finding, unique to PFB among known botanical sources. Increases were most pronounced in the basal ganglia, including the caudate-putamen, striatum and substantia nigra. The NGR represents an animal model of diet-induced Type 2 Diabetes Mellitus (T2DM), exhibiting hyperglycemia, hyperinsulinemia, and insulin resistance associated with hyperphagia and accelerated postweaning weight gain induced by a high-carbohydrate diet (hiCHO). The PFB-induced increase of TH in the basal ganglia of the NGR was documented by immuno-histochemical staining (IHC). This increase in TH occurred equally in both diabetes-susceptible and diabetes-resistant NGR fed a hiCHO. PFB also stimulated growth of the colon microbiota evidenced by an increase in cecal weight and altered microbiome.  The metabolites of colon microbiota, e.g. short-chain fatty acids, may influence the brain and behavior significantly.

Genetic Permissiveness and Dietary Glycemic Load Interact to Predict Type-II Diabetes in the Nile rat (Arvicanthis niloticus).

OBJECTIVE: The Nile rat (Arvicanthis niloticus) is a superior model for Type-II Diabetes Mellitus (T2DM) induced by diets with a high glycemic index (GI) and glycemic load (GLoad). To better define the age and gender attributes of diabetes in early stages of progression, weanling rats were fed a high carbohydrate (hiCHO) diet for between 2 to 10 weeks. Methods. Data from four experiments compared two diabetogenic semipurified diets (Diet 133 (60:20:20, as % energy from CHO, fat, protein with a high glycemic load (GLoad) of 224 per 2000 kcal) versus Diets 73MBS or 73MB (70:10:20 with or without sucrose and higher GLoads of 259 or 295, respectively). An epidemiological technique was used to stratify the diabetes into quintiles of blood glucose (Q1 to Q5), after 2-10 weeks of dietary induction in 654 rats. The related metagenetic physiological growth and metabolic outcomes were related to the degree of diabetes based on fasting blood glucose (FBG), random blood glucose (RBG), and oral glucose tolerance test (OGTT) at 30 minutes and 60 minutes. Results. Experiment 1 (Diet 73MBS) demonstrated that the diabetes begins aggressively in weanlings during the first 2 weeks of a hiCHO challenge, linking genetic permissiveness to diabetes susceptibility or resistance from an early age. In Experiment 2, ninety male Nile rats fed Diet 133 (60:20:20) for 10 weeks identified two quintiles of resistant rats (Q1,Q2) that lowered their RBG between 6 weeks and 10 weeks on diet, whereas Q3-Q5 became progressively more diabetic, suggesting an ongoing struggle for control over glucose metabolism, which either stabilized or not, depending on genetic permissiveness. Experiment 3 (32 males fed 70:10:20) and Experiment 4 (30 females fed 60:20:20) lasted 8 weeks and 3 weeks respectively, for gender and time comparisons. The most telling link between a quintile rank and diabetes risk was telegraphed by energy intake (kcal/day) that established the cumulative GLoad per rat for the entire trial, which was apparent from the first week of feeding. This genetic permissiveness associated with hyperphagia across quintiles was maintained throughout the study and was mirrored in body weight gain without appreciable differences in feed efficiency. This suggests that appetite and greater growth rate linked to a fiber-free high GLoad diet were the dominant factors driving the diabetes. Male rats fed the highest GLoad diet (Diet 73MB 70:10:20, GLoad 295 per 2000 kcal for 8 weeks in Experiment 3], ate more calories and developed diabetes even more aggressively, again emphasizing the Cumulative GLoad as a primary stressor for expressing the genetic permissiveness underlying the diabetes. Conclusion: Thus, the Nile rat model, unlike other rodents but similar to humans, represents a superior model for high GLoad, low-fiber diets that induce diabetes from an early age in a manner similar to the dietary paradigm underlying T2DM in humans, most likely originating in childhood.

In contrast to Western diet, a plant-based, high-fat, low-sugar diet does not exacerbate retinal endothelial injury in streptozotocin-induced diabetes.

Controversy remains about how diet affects the vascular endothelial dysfunction associated with disordered insulin-glucose homeostasis. It is postulated that the type and level of certain macronutrients contribute to endothelial dysfunction in vascular diabetes complications. However, it is not well understood how specific macronutrients affect the molecular inflammatory response under conditions of hyperglycemia. Here, we examined retinal microvascular endothelial injury in streptozotocin (STZ)-diabetic rats fed a laboratory Western diet (WD). WD, characterized by its high content of saturated fat, cholesterol, and sugar, significantly increased retinal leukocyte accumulation and endothelial injury in the STZ-diabetic rats. Suppression of endothelial NF-κB signaling in the STZ model reduced the WD-induced increase in leukocyte accumulation. To isolate the effect of dietary fat, we generated high-fat diets with varying fatty acid balance and type. These diets contained moderate amounts of carbohydrates but no sugar. We found that neither high levels of saturated or unsaturated fats per se increased retinal leukocyte accumulation and endothelial injury in the STZ-diabetic rat model but that the combination of high levels of dietary cholesterol with specific saturated fatty acids that are abundant in WD exacerbated leukocyte accumulation and endothelial injury in the retinas of STZ-diabetic rats.-Barakat, A., Nakao, S., Zandi, S., Sun, D., Schmidt-Ullrich, R., Hayes, K. C., Hafezi-Moghadam, A. In contrast to Western diet, a plant-based, high-fat, low-sugar diet does not exacerbate retinal endothelial injury in streptozotocin-induced diabetes.

Drosophila larvae fed palm fruit juice (PFJ) delay pupation via expression regulation of hormetic stress response genes linked to ageing and longevity.

Palm fruit juice (PFJ) containing oil palm phenolics is obtained as a by-product from oil palm (Elaeis guineensis) fruit milling. It contains shikimic acid, soluble fibre and various phenolic acids including p-hydroxybenzoic acid and three caffeoylshikimic acid isomers. PFJ has also demonstrated beneficial health properties in various biological models. Increasing concentrations of PFJ and different PFJ fractions were used to assess growth dynamics and possible anti-ageing properties in fruit flies (Drosophila melanogaster) genotype w1118. Microarray gene expression analysis was performed on whole fruit fly larvae and their fat bodies, after the larvae were fed a control Standard Brandeis Diet (SBD) with or without PFJ. Transcripts from Affymetrix GeneChips were utilised to identify the possible mechanisms involved, with genes having fold changes > |1.30| and p < 0.05 considered differentially expressed. PFJ dose-dependently delayed larval growth and pupation, but not percent eclosion from pupae. Eclosed male fruit flies fed PFJ or its fractions during the larval stage tended to have 20-40% improved survival ratings over controls when allowed to age on the control diet (SBD). Microarray analysis of whole fruit fly larvae revealed that 127 genes were up-regulated, while 67 were down-regulated by PFJ. Functional analysis revealed transport and metabolic processes were up-regulated, while development and morphogenesis processes, including the nutrient-sensing Tor gene, were down-regulated by PFJ, whereas microarray analysis of larval fat bodies found 161 genes were up-regulated, while 84 genes were down-regulated. Genes involved in defence response and determination of adult lifespan, including those encoding various heat shock proteins and the antioxidant enzyme Sod2, were up-regulated, while cell cycle and growth genes were down-regulated. Thus, PFJ supplementation lengthened the growth stages in fruit fly larvae that was reflected in extended ageing of adult flies, suggesting that larval expression of hormetic stress response genes was linked to subsequent ageing and longevity.

The Nile Rat (Arvicanthis niloticus) as a Superior Carbohydrate-Sensitive Model for Type 2 Diabetes Mellitus (T2DM).

Type II diabetes mellitus (T2DM) is a multifactorial disease involving complex genetic and environmental interactions. No single animal model has so far mirrored all the characteristics or complications of diabetes in humans. Since this disease represents a chronic nutritional insult based on a diet bearing a high glycemic load, the ideal model should recapitulate the underlying dietary issues. Most rodent models have three shortcomings: (1) they are genetically or chemically modified to produce diabetes; (2) unlike humans, most require high-fat feeding; (3) and they take too long to develop diabetes. By contrast, Nile rats develop diabetes rapidly (8-10 weeks) with high-carbohydrate (hiCHO) diets, similar to humans, and are protected by high fat (with low glycemic load) intake. This review describes diabetes progression in the Nile rat, including various aspects of breeding, feeding, and handling for best experimental outcomes. The diabetes is characterized by a striking genetic permissiveness influencing hyperphagia and hyperinsulinemia; random blood glucose is the best index of disease progression; and kidney failure with chronic morbidity and death are outcomes, all of which mimic uncontrolled T2DM in humans. Non-alcoholic fatty liver disease (NAFLD), also described in diabetic humans, results from hepatic triglyceride and cholesterol accumulation associated with rising blood glucose. Protection is afforded by low glycemic load diets rich in certain fibers or polyphenols. Accordingly, the Nile rat provides a unique opportunity to identify the nutritional factors and underlying genetic and molecular mechanisms that characterize human T2DM.

Low glycemic load diets protect against metabolic syndrome and Type 2 diabetes mellitus in the male Nile rat.

BACKGROUND: Dietary modification helps prevent and manage Metabolic Syndrome (MetS) and Type 2 Diabetes Mellitus (T2DM) in humans and Nile rats. Specifically fibrous legumes, like lentils, benefit humans, but whether this reflects a specific change in the Glycemic Load (GLoad) remains controversial. Accordingly, low-GLoad foods were tested in the glucose-sensitive Nile rat. METHODS: 131 male Nile rats aged 3 weeks to 15 months were challenged during four experiments with 15 dietary exposures that varied Glycemic Index (GI, 36-88), GLoad (102-305/2000 kcal), and cumulative GLoad (Cum GLoad=days×GLoad, 181-537g total glucose). RESULTS: Lentil diets with low GLoads (102, 202) prevented, delayed, reduced, even reversed the progress of MetS and T2DM as measured by blood glucose (fasting, random, and oral glucose tolerance test) and plasma lipid parameters (plasma cholesterol and triglycerides) plus necropsy findings (liver and kidney pathology plus adipose reserves). The benefit from lentils exceeded dietary factors such as macronutrient composition (%Energy from carbohydrate:fat:protein, between 70:10:20 to 40:40:20), total fiber (0-24%), or dietary caloric density (2.9-4.7 kcal/g). The benefit of a low GLoad applied equally to rats inherently susceptible or resistant to T2DM, based on random glucose above or below 75 mg/dl, respectively, during interventions of 7-17 weeks. CONCLUSIONS: Measuring total food intake and the novel concept of Cum GLoad during growth generated strong correlations (up to r=0.93) between Cum GLoad and parameters of MetS and T2DM, especially during sexual maturation. The present experiments confirm the applicability of male Nile rats to diet-induced human T2DM, and suggest dietary compositions to deter MetS and T2DM in humans.

Hepatic transcriptome implications for palm fruit juice deterrence of type 2 diabetes mellitus in young male Nile rats.

BACKGROUND: The Nile rat (NR, Arvicanthis niloticus) is a model of carbohydrate-induced type 2 diabetes mellitus (T2DM) and the metabolic syndrome. A previous study found that palm fruit juice (PFJ) delayed or prevented diabetes and in some cases even reversed its early stages in young NRs. However, the molecular mechanisms by which PFJ exerts these anti-diabetic effects are unknown. In this study, the transcriptomic effects of PFJ were studied in young male NRs, using microarray gene expression analysis. METHODS: Three-week-old weanling NRs were fed either a high-carbohydrate diet (%En from carbohydrate/fat/protein = 70:10:20, 16.7 kJ/g; n = 8) or the same high-carbohydrate diet supplemented with PFJ (415 ml of 13,000-ppm gallic acid equivalent (GAE) for a final concentration of 5.4 g GAE per kg diet or 2.7 g per 2000 kcal; n = 8). Livers were obtained from these NRs for microarray gene expression analysis using Illumina MouseRef-8 Version 2 Expression BeadChips. Microarray data were analysed along with the physiological parameters of diabetes. RESULTS: Compared to the control group, 71 genes were up-regulated while 108 were down-regulated in the group supplemented with PFJ. Among hepatic genes up-regulated were apolipoproteins related to high-density lipoproteins (HDL) and genes involved in hepatic detoxification, while those down-regulated were related to insulin signalling and fibrosis. CONCLUSION: The results obtained suggest that the anti-diabetic effects of PFJ may be due to mechanisms other than an increase in insulin secretion.

The Increasing Use of Interesterified Lipids in the Food Supply and Their Effects on Health Parameters.

A variety of modified fats that provide different functionalities are used in processed foods to optimize product characteristics and nutrient composition. Partial hydrogenation results in the formation of trans FAs (TFAs) and was one of the most widely used modification processes of fats and oils. However, the negative effects of commercially produced TFAs on serum lipoproteins and risk for cardiovascular disease resulted in the Institute of Medicine and the 2010 US Dietary Guidelines for Americans both recommending that TFA intake be as low as possible. After its tentative 2013 determination that use of partially hydrogenated oils is not generally regarded as safe, the FDA released its final determination of the same in 2015. Many food technologists have turned to interesterified fat as a replacement. Interesterification rearranges FAs within and between a triglyceride molecule by use of either a chemical catalyst or an enzyme. Although there is clear utility of interesterified fats for retaining functional properties of food, the nutrition and health implications of long-term interesterified fat consumption are less well understood. The Technical Committee on Dietary Lipids of the North American Branch of the International Life Sciences Institute sponsored a workshop to discuss the health effects of interesterified fats, identify research needs, and outline considerations for the design of future studies. The consensus was that although interesterified fat production is a feasible and economically viable solution for replacing dietary TFAs, outstanding questions must be answered regarding the effects of interesterification on modifying certain aspects of lipid and glucose metabolism, inflammatory responses, hemostatic parameters, and satiety.

Phenotypic transformation of intimal and adventitial lymphatics in atherosclerosis: a regulatory role for soluble VEGF receptor 2.

The role of lymphatics in atherosclerosis is not yet understood. Here, we investigate lymphatic growth dynamics and marker expression in atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice. The prolymphangiogenic growth factor, VEGF-C, was elevated in atherosclerotic aortic walls. Despite increased VEGF-C, we found that adventitial lymphatics regress during the course of formation of atherosclerosis (P < 0.01). Similar to lymphatic regression, the number of lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1(+)) macrophages decreased in the aortic adventitia of apoE(-/-) mice with atherosclerosis (P < 0.01). Intimal lymphatics in the atherosclerotic lesions exhibited an atypical phenotype, with the expression of podoplanin and VEGF receptor 3 (VEGFR-3) but not of LYVE-1 and prospero homeobox protein 1. In the aortas of atherosclerotic animals, we found markedly increased soluble VEGFR-2. We hypothesized that the elevated soluble VEGFR-2 that was found in the aortas of apoE(-/-) mice with atherosclerosis binds to and diminishes the activity of VEGF-C. This trapping mechanism explains, despite increased VEGF-C in the atherosclerotic aortas, how adventitial lymphatics regress. Lymphatic regression impedes the drainage of lipids, growth factors, inflammatory cytokines, and immune cells. Insufficient lymphatic drainage could thus exacerbate atherosclerosis formation. Our study contributes new insights to previously unknown dynamic changes of adventitial lymphatics. Targeting soluble VEGFR-2 in atherosclerosis may provide a new strategy for the liberation of endogenous VEGF-C and the prevention of lymphatic regression.-Taher, M., Nakao, S., Zandi, S., Melhorn, M. I., Hayes, K. C., Hafezi-Moghadam, A. Phenotypic transformation of intimal and adventitial lymphatics in atherosclerosis: a regulatory role for soluble VEGF receptor 2.

Anti-diabetic effects of palm fruit juice in the Nile rat (Arvicanthis niloticus).

With the increasing incidence of metabolic diseases, numerous bioactive phytochemicals have been proffered in the dietary prevention of these conditions. Palm fruit juice (PFJ) possesses bioactive phenolic compounds (referred to as oil palm phenolics; OPP) that may deter diabetes. The objective of the present experiments was to document the degree to which PFJ reduces diabetes symptoms in a variety of circumstances in the Nile rat (Arvicanthis niloticus), a novel model for carbohydrate-induced type 2 diabetes (type 2 diabetes mellitus; T2DM) and the metabolic syndrome. Wild-type male Nile rats (n 100) were fed laboratory chow or semi-purified diabetogenic diets in five experiments lasting 4-36 weeks. PFJ was provided as a drink or mixed into the diet to provide OPP intakes from 170 to 720 mg gallic acid equivalents/kg body weight per d. Body weight and random and fasting blood glucose were assessed at different time points, and were analysed along with terminal fasting organ weights, insulin, plasma and liver lipids as measures of diabetes progression. PFJ proved to be anti-hyperglycaemic and anti-lipaemic in all experiments relative to untreated controls, delaying T2DM onset and even reversing advancing diabetes. Protection by PFJ was directly related to its OPP content, and no negative effects on energy intake or growth were observed. PFJ was effective both as a drink and mixed into the diet. Results suggest that PFJ may slow the rate of glucose absorption, reduce insulin resistance and/or enhance insulin secretion.

Retinopathy in a novel model of metabolic syndrome and type 2 diabetes: new insight on the inflammatory paradigm.

The pathogenesis of diabetic retinopathy (DR) in metabolic syndrome (MetS) and type 2 diabetes (T2D) is not well studied, partly because an appropriate model has not been developed. Recently, we introduced a novel model of spontaneous T2D and MetS that replicates the relevant features of the human disease. In the current study, we investigated the retinal vascular changes in these animals. Experimental DR in streptozotocin (STZ)-injected rodents is described as an inflammatory disease, in which intercellular adhesion molecule 1 (ICAM-1) plays a key role. In comparison, advanced diabetes (HbA1c>10%) in the Nile grass rat (NGR) was associated with lower ICAM-1 protein expression when compared with that in normal or moderately diabetic animals. Vascular cell adhesion molecule 1 (VCAM-1) expression, however, was unaffected by the disease state. As opposed to the STZ-induced model of DR, in diabetic NGRs, most leukocytes accumulated in the retinal arteries. Consistent with the ICAM-1 reduction, leukocyte accumulation was significantly reduced in advanced disease. Similarly, leukocyte adhesions were significantly lower, with elevated plasma triglycerides (>200 mg/dl), and cholesterol (>240 mg/dl). However, these adhesions were significantly higher in animals with higher plasma insulin (>5 µIU/ml) and leptin (>20 ng/ml), suggesting a role for these hormones in diabetic retinal leukostasis. Diabetic NGRs showed substantial retinal endothelial injury, primarily in the microvessels, including vascular tortuosity, obliterated acellular capillaries, and pericyte ghosts. The NGR provides a convenient and realistic model for investigation of retinal changes in MetS/T2D with convincing advantages over the commonly used STZ-induced T1D.

Dietary carbohydrate dictates development of Type 2 diabetes in the Nile rat.

Amount and type of dietary carbohydrate (CHO), as well as the CHO:fat ratio, are thought to be critical for both the rate of development and severity of Type 2 diabetes mellitus. Thus, these nutritional considerations were examined in the previously described "spontaneous" model of diabetes and metabolic syndrome, the Nile rat. Weanling male Nile rats (n=92) were fed semipurified diets, modifying glycemic index and load by changing the amount of fiber or altering the CHO:fat ratio. Random and fasting blood glucose and body weight were assessed, and diabetes was characterized in terms of blood glucose, relevant plasma and liver parameters, food and water intake and terminal organ weights. Nile rats fed with hiCHO became more hyperglycemic than rats fed with modCHO (P<.05), while loCHO and hiCHO+hiFiber rats remained essentially normoglycemic. Liver lipid and glycogen accumulation was associated with severe hyperlipemia in diabetic rats, analogous to metabolic syndrome in humans. Advanced diabetes was linked to liver and kidney damage and elevated blood urea nitrogen with weight loss. Dispersing dietary CHO by fiber or replacing it by moderate fat (reducing the glycemic index and load) delayed the onset of diabetes but did not prevent signs of insulin resistance. A very low content of dietary CHO (high fat) seemed to prevent even these early indicators of insulin resistance. Thus, the Nile rat represents a novel CHO-sensitive model for study of Type 2 diabetes that reliably follows the course of disease in humans.

Triglyceride recrystallized phytosterols in fat-free milk improve lipoprotein profiles more than unmodified free phytosterols in hypercholesterolemic men and women.

OBJECTIVE: Foods incorporating plant sterols (PS) consistently decrease serum low-density lipoprotein cholesterol (LDL-C), although results vary depending on the PS form and food matrix. The objective was to study the effect of a novel triglyceride-recrystallized phystosterol (TRP) incorporated into fat-free milk on markers of cardiovascular risk compared to unmodified free sterols alone in the same fat-free milk. METHODS: Hypercholesterolemic men and women (n = 13 males/7 females; 56 ± 10 years; body mass index 27.3 ± 5.9 kg/m(2)) participated in 3 sequential 4-week phases of 480 mL milk consumption. During phase 1 (control) all subjects consumed 2% milk containing no PS, followed by phase 2 with fat-free milk containing free PS (2 g/d fPS) and phase 3 with fat-free milk with TRP (2 g/d). After each phase, determinations of lipoprotein cholesterol distribution, particle concentration via nuclear magnetic resonance (NMR), apolipoproteins, inflammatory markers, and fat-soluble dietary antioxidants were made. RESULTS: Body mass, body composition, dietary energy and macronutrients, and physical activity were unaffected throughout the study. Compared to the control 2% milk, LDL-C was significantly (p < 0.05) decreased by fPS (-9.1%) and was further decreased by TRP (-15.4%); reductions with TRP were significantly greater. Total LDL particle concentration was decreased to a greater extent after TRP (-8.8%) than fPS (-4.8%; p < 0.05). Only TRP significantly decreased serum levels of apolipoprotein B (apoB; -6%), interleukin-8 (IL-8; -11%) and monocyte chemotactic protein-1 (MCP-1; -19%). Plasma α- and γ-tocopherols and carotenoids, normalized to cholesterol, remained unchanged throughout the study with the exception that ß-carotene was lowered by 18%. CONCLUSION: In summary, TRP in fat-free milk may provide cardiovascular benefits beyond that of fPS by inducing more substantial decreases in LDL cholesterol and particle concentration, associated with declines in markers of vascular inflammation.

The development of evidence-informed physical activity guidelines for adults with spinal cord injury.

OBJECTIVES: To systematically develop evidence-informed physical activity guidelines to improve physical fitness in people with spinal cord injury (SCI). SETTING: This study was conducted in Canada. METHODS: The Appraisal of Guidelines, Research and Evaluation II guideline development protocol was used to develop exercise guidelines to improve physical capacity and muscular strength. The evidence base for the guideline development process consisted of a systematic review and quality appraisal of research examining the effects of exercise on physical fitness among people with SCI. A multidisciplinary expert panel deliberated the evidence and generated the guidelines. Pilot testing led to refinement of the wording and presentation of the guidelines. RESULTS: The expert panel generated the following guidelines: for important fitness benefits, adults with a SCI should engage in (a) at least 20 min of moderate to vigorous intensity aerobic activity two times per week and (b) strength training exercises two times per week, consisting of three sets of 8-10 repetitions of each exercise for each major muscle group. CONCLUSION: People with SCI, clinicians, researchers and fitness programmers are encouraged to adopt these rigorously developed guidelines.

Replacing trans fat: the argument for palm oil with a cautionary note on interesterification.

To replace dietary trans fatty acids (TFA), two practical options exist: revert to a natural saturated fat without cholesterol (most likely palm oil or its fractions) or move to a newer model of modified fat hardened by interesterification (IE). This review summarizes the relative risks for cardiovascular disease inherent in these options. Interestingly, both types of fat have been the subject of nutritional scrutiny for approximately the last 40 years, and both have positive and negative attributes. Only during that period has palm oil production developed to the point where it has become the major edible oil in world markets, making clinical studies of it an important objective. On the other hand, approximately 25 human studies have fed interesterified fat in one form or another over this period, some for weeks, some as a single meal. Two types of diet designs exist. Several fed a small amount of interesterified fat, usually incorporated within a margarine, and stayed below the radar of biological detection of any abnormal metabolism. A few fed interesterified fat that incorporated stearic acid, as interesterified 18:0 (IE-18:0), even comparing it to trans fat and saturated fat, as a major part of total daily calories to assess its metabolic impact per se. These latter 5 to 6 studies clearly reveal negative biological effects on lipoproteins, blood glucose, insulin, immune function, or liver enzymes when relatively high intake of IE-18:0 or palmitic acid (IE-16:0) were fed in fats with sn2-saturated fatty acids. High intake of 18:0 in natural fats can depress total lipoproteins, while IE-18:0 and IE-16:0 at high levels adversely affect lipoprotein metabolism. Still other studies have supplied interesterified fat as a single meal or fed such fat daily only in a single snack, as opposed to incorporating the fat into the entire fat pool consumed at all meals in association with most foods (which is the more physiological approach and more apt to elicit effects). Even in meal studies, IE-18:0 typically delayed fat absorption postprandially, indicating its effect on fat metabolism originating, in part, in the intestine. Mainly 2 saturated fatty acids (18:0 or 16:0) have been interesterified to harden oils, using the 16:0 from fully hydrogenated palm oil or 18:0 from fully hydrogenated soybean oil as the source material. It is not clear that IE-16:0 is as problematic as IE-18:0, but IE-16:0 has been studied less. Levels between 8% energy (%E) and 12%E from 18:0 as interesterified fat (the typical diet provides about 2%E-4%E as 18:0 from natural fats) show the most effect. Detection of adverse effects would seem to start around 7%E-8%E as IE-18:0, but one can assume that effects are initiated, even if undetected, at a lower intake, similar to the situation with TFA. Thus, although an intake of 1%E to 4%E from IE-18:0 does not appear to influence lipoproteins, it is not necessarily the only system affected. The negative effects of IE-18:0 may be alleviated or masked by dilution with other fats, especially by adding 18:2-rich polyunsaturated oils to the diet. This is similar to the trans fat story, i.e., if a limited intake of TFA is heavily diluted with other oils, the consumption of TFA fails to be detected as an adverse effect. Accordingly, more research is warranted to determine the appropriateness of interesterified fat consumption, particularly before it becomes insidiously embedded in the food supply similar to TFA and intake levels are achieved that compromise long-term health.