Dietary Protein Restriction Research Articles

Prescribing pattern of Antihypertensive, Anti-Diabetic, Hypolipidaemic and Anti-Obesity Drugs in Diabetic Nephropathy

Objective: The Purpose of this study is to evaluate prescribing pattern of drugs to prevent progression of nephropathy in patients of diabetes in a tertiary care hospital. Materials and Methods: It was conducted in a tertiary care hospital, written informed consent was taken from those patients, who fulfilled study criteria and study sample included type 2 diabetic nephropathy outdoor patients who aged more than 40 years who were in stage of micro albuminuria (stage 3 diabetic nephropathy), details like sex, duration of illness, on-going treatment concurrent medicines were recorded in predesigned and pretested case record forms, these data were subjected to analysis using descriptive methods, Microsoft excel was used for data entry and descriptive analysis. A total of 100 patients were included in the study. A written permission has been obtained from Institutional Ethics Committee for the conduct of the study. Results: In the present study there were 100 patients, of whom 63 were males and 37 were females, majority of patients have diabetes for more than 20 years, all patients received anti-hypertensive, anti-diabetic and hypolipidaemic drugs. Among antihypertensive drugs, ACE inhibitors are prescribed most followed by diuretics and calcium channel blockers, among ACE inhibitors; Enalapril and Ramipril were prescribed most. Insulin was prescribed in 50% of patients and Glimepiride was the most common sulfonylurea prescribed. Statins were prescribed most among hypolipidaemic drugs; orlistat was prescribed only for 5% of patients. Majority of the patients were advised by physician regarding regular exercise, protein restricted diet, salt restriction, avoidance of cigarette smoking and weight reduction. Conclusion: Our study concluded that prescribing pattern of drugs in diabetic nephropathy was as per current practices and recommendations of guidelines. The pattern of drug use was to achieve better control of all the risk factors which are involved in progression of nephropathy. Further large scale and more detailed study, which includes sample from government setup and private clinics, is recommended to confirm our findings

MO586: Low-Protein Diet Supplemented With Ketoanalogues of Essential Amino Acids in Advanced Diabetic Kidney Disease: Safety Issues in Elderly

Abstract BACKGROUND AND AIMS Lately, studies support the role of dietary protein restriction in the management of patients with chronic kidney disease (CKD). Beneficial effects were noticed in ameliorating metabolic disturbances in advanced CKD and optimizing the blood pressure control, thus postponing kidney replacement therapy. However, nutritional safety of low-protein diets (LPDs) remains debatable, especially in elderly. This prospective unicenter interventional study aimed to assess the effects of LPD in advanced diabetic kidney disease (DKD). We present a sub-analysis of data focusing on the safety in elderly patients. METHOD Ninety-two patients with DKD with stable CKD stage 4+, heavy proteinuria (>3 g/g creatininuria), good nutritional status (Subjective Global Assessment—SGA A) and compliant to protein restriction proved during a 3-month run-in phase (21% of the screened population) were enrolled and received conventional LPD (0.6 g mixed protein/kg-day) supplemented with ketoanalogues of essential amino acids (Ketosteril®, Bad Homburg, Germany), 1 tb/10 kg dry ideal body weight per day (sLPD) for 12 months. Efficacy outcomes were the variation of proteinuria (primary outcome) and the variation of estimated glomerular filtration rate, eGFR (secondary outcome). Safety was assessed throughout the study using anthropometric measures (Body Mass Index, BMI), SGA, serum albumin (SAlb). Inflammatory parameters (C-reactive protein, CRP) and the occurrence of adverse reactions were also recorded. Compliance was evaluated using urinary urea from 24-h urine collection to estimate the protein intake (ePI) and the 3-day food diary for energy intake (EnI). RESULTS Ninety-two patients [61% males, median age 61 (58–67) years, eGFR 11.7 (11.2–12.2) mL/min/1.73 m², proteinuria 4.8 (4.6–5.2) g/g creatininuria] completed the study. For the whole group, proteinuria decreased with 67% from the baseline to the end of study (EOS), and the rate of decline in eGFR was reduced with 80% compared with the period before enrolment. Of the total group, 42% (39 patients) were elderly (≥65 years): median age 75 (71–80) years old, 64% males, median eGFR 12.61 (11.16–13.81) mL/min and median proteinuria 5.14 (4.84–5.25) g/g creatininuria. About 21% (19 patients) were late elderly (≥75 years old). In elderly, proteinuria significantly decreased: 1.51 (0.98–1.75) versus 5.14 (4.84–5.26) g/g creatininuria, i.e. by 70% of the baseline value. eGFR also significantly decreased: 10.73 (9.87–11.68) versus 12.61 (11.16–13.81) mL/min. To note, the rate of decline in kidney function was 0.1 versus 0.5 mL/min-month before enrolment, i.e. 5 times slower. The nutritional status was improved: BMI decreased [25.58 (24.68–26.98) versus 27.08 (25.47–28.11) kg/m² at baseline] and the percentage of overweighted subjects declined (56.4 versus 76.9%), while SGA did not change during the study. SAlb was also stable: 4.19 (4.03–4.30) versus 3.90 (3.86–3.99) mg/dL. The inflammatory status was significantly ameliorated: CRP decreased, 8 (7–9) versus 14 (12–15) at baseline mg/L. Thus, by the EOS the percentage of patients with inflammation (CRP ≥ 10 mg/L) significantly decreased: 23.1 versus 92.3% at baseline. The ePI and EnI were very close to recommendations and remained stable during the study: 0.64 (0.63–0.67) versus 0.68 (0.65–0.69) g/kg-day for ePI and 31.30 (28.50–33.00) versus 31.16 (30.16–32.56) kcal/kg-day for EnI at EOS versus baseline, respectively. In a binary regression analysis, lower levels of CRP were associated with sLPD, lower proteinuria and higher SAlb (P < 0.0001, Negelkerke R Square test 58%, Hosmer & Lemeshow test 0.11). No adverse reactions were noted. CONCLUSION In elderly patients with advanced DKD, low protein diet supplemented with ketoanalogues of essential amino acids seems to be effective in reducing the decline in eGFR and proteinuria, while being also nutritionally safe.

MO579: The Long-Term Efficacy and Safety of Low-Protein Diets in Non-Diabetic Patients with Advanced CKD: Focus on Elderly

Abstract BACKGROUND AND AIMS Current data suggest the benefits of protein restriction in the management of advanced chronic kidney disease (CKD), improving metabolic abnormalities, optimizing blood pressure control and allowing to postpone kidney replacement therapy (KRT). However, feasibility, safety and even the long-term benefits of low protein diets (LPDs) are questioned, especially in elderly. This study aimed to compare the long-term efficacy and safety of two types of LPDs in elderly non-diabetic patients with advanced CKD. METHOD Long-term follow-up (FU) data from a prospective randomized controlled single-center trial (RCT) on 207 CKD stage 4 + non-diabetic patients are presented. The RCT compared the effects of vegetarian very low protein diet supplemented with keoanalogues of essential amino acids (sVLPD, vegetable proteins 0.3 g/kg-day plus, Ketosteril®, Bad Homburg, Germany, 1 tb/5 kg bw-day) with conventional LPD (mixed proteins 0.6g/kg-day) for 15 months (Garneata L et al. JASN. 2016; doi:10.1681/ASN.2 015 040 369). The composite endpoint was the need of KRT or the patients’ death. The census point was either the occurrence of primary endpoint or 31 July 2018. We are presenting a sub-analysis focusing on elderly patients (>65 years old). Safety was assessed throughout the study by anthropometric measures, Subjective Global Assessment (SGA), serum levels of albumin (SAlb) and C-reactive protein (CRP). Davies Comorbidity score was also registered during the follow-up. RESULTS Two hundred patients who ended the RCT were enrolled in the FU. All of them voluntarily continued the prescribed intervention. Data analysis showed sVLPD to be superior to LPD on long-term with respect to the primary endpoint, preserving the nutritional status (published data). Of the 200 subjects, 36 (18%) were elderly, 15 on LPD and 21 on sVLPD. At 31 July 2018, more than 10 years after the end of RCT, 70% of the elderly patients were alive with no statistically significant difference between groups (81 versus 43.3%, P = 0.08 in sVLPD and LPD, respectively). The median follow-up was significantly higher in the sVLPD group: 116 (106–123) versus 97 (49–115) months. The need for KRT during FU was significantly lower in patients on sVLPD: 43 versus 100%. The time until KRT was similar between groups: 32 (7–54) versus 35 (6–131) months, sVLPD and LPD, respectively. There were no significant differences between sVLPD and LPD at the end of FU (EOFU) in the nutritional status assessed by SGA and SAlb [4.41 (4.14–4.56) versus 4.31 (3.90–4.35) g/dL]. At the EOFU, CRP was significantly lower in the sVLPD group: 7 (4–9) versus 10.5 (7–16) mg/L. Davies Comorbidity Score increased during the FU in both groups, with no difference: 3 (1–3) versus 3 (3–5), sVLPD and LPD, respectively. Kaplan–Meier analysis showed better survival rates in the sVLPD group, both for the patient (10-year survival 78 versus 53% in sVLPD and LPD, respectively) and for kidney (10-year survival 82 versus 20% in sVLPD and LPD, respectively). Cox regression analysis of data showed SGA A and the sVLPD to be associated with better patients’ survival, while only sVLPD was associated with better kidneys’ survival. CONCLUSION Both types of protein-restricted diets proved feasible and safe on long-term in elderly. Vegetarian very low protein diet supplemented with ketoanalogues was associated with better patients and kidneys survival as compared with low protein diet in elderly non-diabetic patients.

Calorie restriction and calorie dilution have different impacts on body fat, metabolism, behavior, and hypothalamic gene expression.

Caloric restriction is a robust intervention to increase lifespan. Giving less food (calorie restriction [CR]) or allowing free access to a diluted diet with indigestible components (calorie dilution [CD]) are two methods to impose restriction. CD does not generate the same lifespan effect as CR. We compare responses of C57BL/6 mice with equivalent levels of CR and CD. The two groups have different responses in fat loss, circulating hormones, and metabolic rate. CR mice are hungrier, as assessed by behavioral assays. Although gene expression of Npy, Agrp, and Pomc do not differ between CR and CD groups, CR mice had a distinctive hypothalamic gene-expression profile with many genes related to starvation upregulated relative to CD. While both result in lower calorie intake, CR and CD are not equivalent procedures. Increased hunger under CR supports the hypothesis that hunger signaling is a key process mediating the benefits of CR.

Protein Restriction in the Peri-Pubertal Period Induces Autonomic Dysfunction and Cardiac and Vascular Structural Changes in Adult Rats.

Perturbations to nutrition during critical periods are associated with changes in embryonic, fetal or postnatal developmental patterns that may render the offspring more likely to develop cardiovascular disease in later life. The aim of this study was to evaluate whether autonomic nervous system imbalance underpins in the long-term hypertension induced by dietary protein restriction during peri-pubertal period. Male Wistar rats were assigned to groups fed with a low protein (4% protein, LP) or control diet (20.5% protein; NP) during peri-puberty, from post-natal day (PN) 30 until PN60, and then all were returned to a normal protein diet until evaluation of cardiovascular and autonomic function at PN120. LP rats showed long-term increased mean arterial pressure (p = 0.002) and sympathetic arousal; increased power of the low frequency (LF) band of the arterial pressure spectral (p = 0.080) compared with NP animals. The depressor response to the ganglion blocker hexamethonium was increased in LP compared with control animals (p = 0.006). Pulse interval variability showed an increase in the LF band and LF/HF ratio (p = 0.062 and p = 0.048) in LP animals. The cardiac response to atenolol and/or methylatropine and the baroreflex sensitivity were similar between groups. LP animals showed ventricular hypertrophy (p = 0.044) and increased interstitial fibrosis (p = 0.028) compared with controls. Reduced protein carbonyls (PC) (p = 0.030) and catalase activity (p = 0.001) were observed in hearts from LP animals compared with control. In the brainstem, the levels of PC (p = 0.002) and the activity of superoxide dismutase and catalase (p = 0.044 and p = 0.012) were reduced in LP animals, while the levels of GSH and total glutathione were higher (p = 0.039 and p = 0.038) compared with NP animals. Protein restriction during peri-pubertal period leads to hypertension later in life accompanied by sustained sympathetic arousal, which may be associated with a disorganization of brain and cardiac redox state and structural cardiac alteration.

Effect of short-term dietary protein restriction before slaughter on meat quality and skeletal muscle metabolomic profile in culled ewes

Tenderness is one of the most important meat quality traits. It has been suggested that a short-term dietary protein restriction prior to slaughter could change muscle protein turnover and improve meat tenderness without affecting animal performance. Therefore, the aim of this study was to evaluate the effect of a short-term dietary protein restriction in the end of the finishing phase on skeletal muscle metabolome and meat quality traits of culled ewes. Fourteen crossbred ewes (3 years of age) averaging 39.3 ± 9.4 kg of body weight (BW) were enrolled in this study. Culled ewes were grouped (n = 7) and randomly assigned to one of the following treatments, consisting of: continuously fed the control diet with 13.3% of crude protein (CTRL); fed the control diet to reach the target body weight (45 kg) followed by 14 days feeding a low protein diet (4.33% crude protein; STR). The experiment lasted 46 days. Short-term dietary protein restriction increased meat shear-force at 1 day postmortem (3.67 vs. 3.02 kgf; P = 0.04), which could be partially explained by the higher total collagen content (P = 0.02) in STR compared to CTRL group (2.35 vs. 2.05 mg/g). The protein restriction did not affect final body weight nor carcass weight (P > 0.05), but decreased backfat thickness (3.19 vs. 5.10 mm; P = 0.04). Excreted and retained nitrogen were respectively 80.4% and 70% lower in STR (P < 0.01) than in the CTRL group. A lower abundance of valine (P = 0.02) and asparagine (P = 0.01) was observed in skeletal muscle of STR ewes compared to the CTRL group. Of the muscle metabolites identified, progesterone, succinic acid, and tartronic acid were positively correlated with meat shear-force (toughness), while lysine was negatively correlated (P < 0.05) with the same trait. Collectively, our data shows that despite the changes observed in the skeletal muscle for the abundance of metabolites involved in energy and protein metabolism, the short-term dietary protein restriction near maintenance level prior to slaughter did not improve quality of ewes’ meat quality traits.

Impact of Dietary Protein Restriction on the Immunogenicity and Efficacy of Whole-Sporozoite Malaria Vaccination.

Malaria remains one of the world’s most prevalent infectious diseases. Several vaccination strategies currently under investigation aim at hampering the development of the Plasmodium parasite during the clinically silent liver stage of its life cycle in the mammalian host, preventing the subsequent disease-associated blood stage of infection. Immunization with radiation-attenuated sporozoites (RAS), the liver-infecting parasite forms, can induce sterile protection against malaria. However, the efficacy of vaccine candidates in malaria-naïve individuals in high-income countries is frequently higher than that found in populations where malaria is endemic. Malnutrition has been associated with immune dysfunction and with a delay or impairment of the immune response to some vaccines. Since vaccine efficacy depends on the generation of competent immune responses, and malaria-endemic regions are often associated with malnutrition, we hypothesized that an inadequate host nutritional status, specifically resulting from a reduction in dietary protein, could impact on the establishment of an efficient anti-malarial immune response. We developed a model of RAS immunization under low protein diet to investigate the impact of a reduced host protein intake on the immunogenicity and protective efficacy of this vaccine. Our analysis of the circulating and tissue-associated immune compartments revealed that a reduction in dietary protein intake during immunization resulted in a decrease in the frequency of circulating CD4+ T cells and of hepatic NK cells. Nevertheless, the profile of CD8+ T cells in the blood, liver and spleen was robust and minimally affected by the dietary protein content during RAS immunization, as assessed by supervised and in-depth unsupervised X-shift clustering analysis. Although mice immunized under low protein diet presented higher parasite liver load upon challenge than those immunized under adequate protein intake, the two groups displayed similar levels of protection from disease. Overall, our data indicate that dietary protein reduction may have minimal impact on the immunogenicity and efficacy of RAS-based malaria vaccination. Importantly, this experimental model can be extended to assess the impact of other nutrient imbalances and immunization strategies, towards the refinement of future translational interventions that improve vaccine efficacy in malnourished individuals.

Using complex behavior to understand brain mechanisms in health and disease.

Using complex behavior to understand brain mechanisms in health and disease.

Effects of methionine, leucine, and insulin on circulating concentrations and mammary extraction of energy substrates and amino acids in lactating dairy cows

The aim of this experiment was to test whether insulin potentiates the effects of two abomasally infused amino acids (AA), leucine and methionine (LM), on mammary extraction efficiency of energetic and nitrogenous nutrients. Six lactating Holstein cows (155 ± 9 DIM) were ruminally-cannulated and had the right carotid artery subcutaneously transposed. Cows were fed a 20% metabolizable protein-restricted diet and abomasally infused with water (8 L/d) or AA (Met 26 g/d, Leu 70 g/d) for 8 h/d, for 7 days. On the last day of each period, cows were intravenously infused with saline (0.9% NaCl, 110 mL/h) or subjected to 8 h hyperinsulinemic clamp (IC) alongside abomasal infusions. For IC, insulin was infused at 1 µg/kg/h. Normoglycemia was maintained by varying glucose (50% w/v in water) infusion rate based on coccygeal vein glucose concentration. Carotid arterial and subcutaneous abdominal (mammary) vein blood samples were collected at 0, 1, 2, 4, and 6 h from the start of infusions. Milk weights and samples for baseline measurements of production were taken on day 5 PM, day 6 AM and PM, and day 7 AM of the experimental period. A final milk weight and sample was taken immediately after abomasal and intravenous infusions on day 7 PM for assessing the interaction between insulin and the infused AA. The experiment had an incompletely replicated Latin square design with a 2 × 2 factorial arrangement of treatments (abomasal and intravenous infusion). Baseline milk production when cows were only receiving abomasal infusions was largely unaffected by LM, but milk protein yield tended to be decreased. On day 7, LM tended to positively increase milk fat and de novo fatty acid content, and IC tended to decrease milk protein content. Both milk urea nitrogen and plasma urea nitrogen were decreased by IC. Circulating AA concentrations in plasma were decreased by both LM and IC, but mammary extraction efficiency was affected by neither. Infusion of LM had no effect on any energy metabolite analyzed. Circulating non-esterified fatty acid concentration was decreased by IC, with no effect on mammary extraction efficiency. Mammary extraction efficiency of both acetate and β-hydroxybutyrate were decreased by IC. Overall, while both circulating concentrations of energy metabolites and amino acids were decreased in response to treatments, this was not due to improved mammary extraction efficiency.

Protein restriction during pregnancy affects lung development and promotes oxidative stress and inflammation in C57 BL/6 mice offspring

ObjectivesThe present study aimed to evaluate the effects of maternal protein restriction during pregnancy on the lungs of 1-d and 31-d old offspring of C57BL/6 mice. MethodsThe C57BL/6 mice (8–10 wk) were used for breeding. After pregnancy confirmation, female mice were randomly divided into a control group (CG) receiving a standard diet (22% protein) and a protein-restriction group (PRG) receiving a low-protein diet (6% protein). In the low-protein diet, protein was replaced by carbohydrate. After parturition, female mice that received the low-protein diet were fed the standard diet. Male offspring were euthanized 1 d and 31 d after birth for subsequent analysis. We evaluated the effects of a protein-restricted diet during gestation in pulmonary organogenesis, lung oxidative stress, and pulmonary inflammatory response of the offspring. ResultsPRG mice 1 d after birth showed lower body and lung mass, length, relative mass, lung density, and erythrocyte count compared with CG mice. There was an increase in alveolar airspace density and a higher mean linear intercept (Lm), greater oxidative damage, and inflammation in PRG mice compared with CG mice. At 31 d after birth, PRG mice had lower body mass, length, and lung mass values compared with CG mice. PRG mice showed greater recruitment of inflammatory cells to the airways. In addition, there was increased collagen deposition in the lungs, altered inflammatory mediators, and greater oxidative damage compared with CG mice. ConclusionsProtein restriction during pregnancy reduces the body weight of offspring and promotes inflammation and oxidative stress, resulting in a simplification of the lung structure.

FGF21 is required for protein restriction to extend lifespan and improve metabolic health in male mice

Dietary protein restriction is increasingly recognized as a unique approach to improve metabolic health, and there is increasing interest in the mechanisms underlying this beneficial effect. Recent work indicates that the hormone FGF21 mediates the metabolic effects of protein restriction in young mice. Here we demonstrate that protein restriction increases lifespan, reduces frailty, lowers body weight and adiposity, improves physical performance, improves glucose tolerance, and alters various metabolic markers within the serum, liver, and adipose tissue of wildtype male mice. Conversely, mice lacking FGF21 fail to exhibit metabolic responses to protein restriction in early life, and in later life exhibit early onset of age-related weight loss, reduced physical performance, increased frailty, and reduced lifespan. These data demonstrate that protein restriction in aging male mice exerts marked beneficial effects on lifespan and metabolic health and that a single metabolic hormone, FGF21, is essential for the anti-aging effect of this dietary intervention.

The Association Between Total Protein Intake and All-Cause Mortality in Middle Aged and Older Korean Adults With Chronic Kidney Disease

Background and AimsOver the past decades, the optimum protein intake for patients with chronic kidney disease (CKD) has been an important, controversial issue. Dietary protein restriction has been commonly recommended for patients with CKD for preserving kidney function. However, evidence of the associations between long-term protein intake and mortality is not consistent in patients with CKD. Therefore, we aimed to examine the associations between total protein intake and all-cause mortality in Korean adults with CKD.MethodsFrom three sub-cohorts of the Korean Genome and Epidemiology Study (KoGES) starting from 2001, total 3,892 participants with eGFR < 60 mL/min/1.73 m2 (CKD stage 3–5) were included in this study. Dietary data were collected using food-frequency questionnaires at baseline. Deaths were followed from 2001 to 2019. Cox proportional hazards regression model was used to evaluate the association between protein intake and all-cause mortality.ResultsDuring a median follow-up (min-max) of 11.1 years (0.3–15.1), 602 deaths due to all causes of mortality were documented. After adjustment for covariates, higher total protein intake was not associated with all-cause mortality [highest vs. lowest quintile of total protein intake (g/kg/day) and proportion (%) (Q5 vs. Q1), HR = 1.14 (0.75–1.72), and HR = 0.87 (0.67–1.13)] in CKD stage 3–5 patients.ConclusionDietary protein intake was not associated with mortality from all causes in patients with CKD. Further research is needed to establish optimal protein intake levels and examine the impact of the dietary source of protein on various health outcomes and mortality in CKD.

Short-Term Ketogenic Diet Induces a Molecular Response That Is Distinct From Dietary Protein Restriction.

There is increasing interest in utilizing short-term dietary interventions in the contexts of cancer, surgical stress and metabolic disease. These short-term diets may be more feasible than extended interventions and may be designed to complement existing therapies. In particular, the high-fat, low-carbohydrate ketogenic diet (KD), traditionally used to treat epilepsy, has gained popularity as a potential strategy for weight loss and improved metabolic health. In mice, long-term KD improves insulin sensitivity and may extend lifespan and healthspan. Dietary protein restriction (PR) causes increased energy expenditure, weight loss and improved glucose homeostasis. Since KD is inherently a low-protein diet (10% of calories from protein vs. >18% in control diet), here we evaluated the potential for mechanistic overlap between PR and KD via activation of a PR response. Mice were fed control, protein-free (PF), or one of four ketogenic diets with varying protein content for 8 days. PF and KD both decreased body weight, fat mass, and liver weights, and reduced fasting glucose and insulin levels, compared to mice fed the control diet. However, PF-fed animals had significantly improved insulin tolerance compared to KD. Furthermore, contrary to the PF-fed mice, mice fed ketogenic diets containing more than 5% of energy from protein did not increase hepatic Fgf21 or brown adipose Ucp1 expression. Interestingly, mice fed KD lacking protein demonstrated greater elevations in hepatic Fgf21 than mice fed a low-fat PF diet. To further elucidate potential mechanistic differences between PF and KD and the interplay between dietary protein and carbohydrate restriction, we conducted RNA-seq analysis on livers from mice fed each of the six diets and identified distinct gene sets which respond to dietary protein content, dietary fat content, and ketogenesis. We conclude that KD with 10% of energy from protein does not induce a protein restriction response, and that the overlapping metabolic benefits of KD and PF diets may occur via distinct underlying mechanisms.

Natural history of arginase 1 deficiency and the unmet needs of patients: A systematic review of case reports.

BackgroundArginase 1 deficiency (ARG1‐D) is a rare, progressive and debilitating urea cycle disorder characterized by clinical manifestations including spasticity, seizures, developmental delay, and intellectual disability. The aim of this systematic review was to identify and summarize the natural history of ARG1‐D and the unmet needs of patients.MethodsA comprehensive search of published case reports was undertaken to identify patients with ARG1‐D regardless of interventions, comparisons, or outcomes. MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and other evidence‐based medicine literature databases were searched on 20 April 2020. Quality was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist. (PROSPERO registration: CRD42020212142.)ResultsOne hundred and fifty seven ARG1‐D patients were included from 111 publications (good overall quality based on JBI's Checklist); 84 (53.5%) were males. Motor deficits (including spasticity), intellectual disability, and seizures were reported in >50% of the cases. Mean age (SD) at diagnosis was 6.4 years and the laboratory findings most commonly reported to support diagnosis included elevated plasma arginine (81.5%), mutation in ARG1 gene through genetic testing (60%), and absence/reduction of red blood cell arginase activity (51%). Reported management approaches mainly included dietary protein restriction (68%), nitrogen scavengers (45%), and essential amino acid supplements (21%). Author‐reported clinical improvement was documented for 26% of patients, 15% deteriorated, and 19% had limited or no change; notably, no indication of clinical outcome was reported for 40% cases.ConclusionThis review illustrates a significant burden of disease and highlights a considerable unmet need for clinically effective treatment options for patients with ARG1‐D.

Mouse Model of Small for Gestational Age Offspring with Catch-up Growth Failure and Dysregulated Glucose Metabolism in Adulthood.

BackgroundWe aimed to build mouse models of small for gestational age (SGA), recapitulating failure of catch-up growth and dysregulated metabolic outcomes in adulthood.MethodsPregnant C57BL/6 mice were given a protein-restricted diet (PRD; 6% kcal from protein) during pregnancy without (model 1) or with cross-fostering (model 2). Model 3 extended the PRD to the end of the lactation period. Model 4 changed to a 9% PRD without cross-fostering.ResultsModel 1 yielded a reduced size of offspring with a poor survival rate. Model 2 improved survival but offspring showed early catch-up growth. Model 3 maintained a reduced size of offspring after weaning with a higher body mass index and blood glucose levels in adult stages. Model 4 increased the survival of the offspring while maintaining a reduced size and dysregulated glucose metabolism.ConclusionModels 3 and 4 are suitable for studying SGA accompanying adulthood short stature and metabolic disorders.

Dynamic effects of dietary protein restriction on body weights, food consumption, and protein preference in C57BL/6J and Fgf21-KO mice.

Single-case experimental designs (SCEDs) are rarely used in behavioral neuroscience despite their potential benefits. The current study used a SCED to evaluate the effects of dietary protein restriction in C57BL/6J and Fgf21-knockout (KO) mice on body weight, food consumption, and protein preference and changes in those outcome measures were quantified using multilevel linear models. In C57BL/6J mice, rate of weight gain was lower and food consumption and protein preference higher during periods of low (4% kcal) protein diet feeding compared to periods of normal (18% kcal) protein diet feeding. In Fgf21-KO mice, who do not produce the liver-derived hormone FGF21, rate of weight gain and protein preference were not substantially affected by diet although food consumption was slightly higher during periods of low protein diet than periods of normal protein diet. These results demonstrate that protein restriction dynamically regulates physiological and behavioral responses at the individual mouse level and that FGF21 is necessary for those responses. Further, the current results demonstrate how a SCED can be used in behavioral neuroscience research, which entails both scientific and practical benefits.

Personalized Nutrition in Patients with Type 2 Diabetes and Chronic Kidney Disease: The Two-Edged Sword of Dietary Protein Intake.

In type 2 diabetes (T2D), there is a general and strong focus on carbohydrate restriction. However, this may have unwarranted consequences for those with concomitant chronic kidney disease (CKD) since decreasing intake of carbohydrates implies a higher proportion of dietary protein, which is of critical debate in patients with CKD due to its ambiguous implications in maintaining either kidney function or nutritional status. We evaluated adherence to the protein recommendations, taking into account the nutritional status of patients with T2D with or without CKD. Patients were divided in three groups according to their estimated Glomerular Filtration Rate (eGFR): mild to no CKD (eGFR > 60 mL/min/1.73 m2), moderate CKD (eGFR 30–60 mL/min/1.73 m2), or advanced CKD (eGFR < 30 mL/min/1.73 m2). Regarding adherence to the protein recommendations, 17% of the patients without advanced CKD consumed < 0.8 g/kg/day, 29% of the patients with moderate CKD consumed > 1.3 g/kg/day, and 60% of the patients with advanced CKD consumed > 1.0 g/kg/day. In addition, patients with moderate- or advanced CKD tend to have a lower muscle mass, normalized by height, compared to patients with mild to no CKD (p < 0.001), while body mass index was not significantly different between patients with or without CKD (p = 0.44). We found that although dietary protein restriction has not been indicated in either of the CKD stages, approximately 10% had a dietary protein intake < 0.8 g/kg/day, with accompanying risks of malnourishment and sarcopenia. Our main advice is to maintain a dietary protein intake of at least 0.8 g/kg/day in order to prevent patients from becoming malnourished and sarcopenic.

Impact of moderate dietary protein restriction on glucose homeostasis in a model of estrogen deficiency

The need to consume adequate dietary protein to preserve physical function during ageing is well recognized. However, the effect of protein intakes on glucose metabolism is still intensively debated. During age-related estrogen withdrawal at the time of the menopause, it is known that glucose homeostasis may be impaired but the influence of dietary protein levels in this context is unknown. The aim of the present study is to elucidate the individual and interactive effects of estrogen deficiency and suboptimal protein intake on glucose homeostasis in a preclinical model involving ovariectomy (OVX) and a 13 week period of a moderately reduced protein intake in 7 month-old ageing rats. To investigate mechanisms of action acting via the pancreas-liver-muscle axis, fasting circulating levels of insulin, glucagon, IGF-1, FGF21 and glycemia were measured. The hepatic lipid infiltration and the protein expression of GLUT4 in the gastrocnemius were analyzed. The gene expression of some hepatokines, myokines and lipid storage/oxidation related transcription factors were quantified in the liver and the gastrocnemius. We show that, regardless of the estrogen status, moderate dietary protein restriction increases fasting glycemia without modifying insulinemia, body weight gain and composition. This fasting hyperglycemia is associated with estrogen status-specific metabolic alterations in the muscle and liver. In estrogen-replete (SHAM) rats, GLUT4 was down-regulated in skeletal muscle while in estrogen-deficient (OVX) rats, hepatic stress-associated hyperglucagonemia and high serum FGF21 were observed. These findings highlight the importance of meeting dietary protein needs to avoid disturbances in glucose homeostasis in ageing female rats with or without estrogen withdrawal.

Effect of nighttime light exposure on glucose metabolism in protein-restricted mice.

Disruption of biological rhythms due to exposure to artificial light at night (ALAN) has emerged as a new risk factor for metabolic diseases. However, the effects of ALAN exposure on energy metabolism with concomitant misalignment in the circadian system caused by nutritional imbalance remain largely unexplored. Here, we evaluate whether a low-protein (LP) diet could enhance the effects induced by exposure to ALAN on the energy metabolism and consequently predispose to metabolic disorders. Male C57BL6/J mice were weaned on a normal protein (NP) or a LP diet and housed on 12 h light:12 h darkness (LD) cycle. After 6 weeks, mice maintained on their respective diets were subdivided into normal light/darkness cycle (NP/LD; LP/LD) or exposed to ALAN (NP/LL; LP/LL) for 8 weeks. We observed that exposure to ALAN concomitant to LP diet disrupts the behavioral rhythms, without shifting the timing of food intake. Furthermore, exposure to ALAN leads to increased body and fat pad weights, higher levels of fast and fed glycemia and glucose intolerance independent of the diet consumed. Importantly, the effects of ALAN on circadian regulation of insulin sensitivity were diet-dependent with LP/LL mice showing insulin resistance in an opposite time of day than NP/LL. At the molecular level, exposure to ALAN concurrent with LP diet increased the expression of phosphoenolpyruvate carboxykinase 1 in both periods analyzed and inverted the pattern of fibroblast growth factor 21 (Fgf21) expression in the liver. Our data suggest that dietary protein restriction modulates the effects induced by nighttime light exposure on glucose metabolism, which could be partially related with the dysregulation of hepatic Fgf21 expression.

Balanced branched-chain amino acids modulate meat quality by adjusting muscle fiber type conversion and intramuscular fat deposition in finishing pigs.

Pork is an important food for humans and improving the quality of pork is closely related to human health. This study was designed to investigate the effects of balanced branched-chain amino acid (BCAA)-supplemented protein-restricted diets on meat quality, muscle fiber types, and intramuscular fat (IMF) in finishing pigs. The results showed that, compared with the normal protein diet (160 g kg-1 crude protein), the reduced-protein diet (120 g kg-1 crude protein) supplemented with BCAAs to the ratio of 2:1:2 not only had higher average daily gain (P < 0.05) and carcass weight (P < 0.05) but also improved meat tenderness and juiciness by decreasing shear force (P < 0.05) and increasing water-holding capacity (P < 0.05). In particular, this treatment showed higher (P < 0.05) levels of phospho-acetyl-CoA carboxylase (P-ACC) and peroxisome proliferation-activated receptor-γ (PPARγ), and lower (P < 0.05) levels of P-adenosine 5'-monophosphate (AMP)-activated protein kinase (P-AMPK), increasing the composition of IMF and MyHC I (P < 0.05) in the longissimus dorsi muscle (LDM). In terms of health, this group increased eicosapentaenoic acid (EPA) (P < 0.01) and desirable hypocholesterolemic fatty acids (DHFA) (P < 0.05), and decreased atherogenicity (AI) (P < 0.01) and hypercholesterolemic saturated fatty acids (HSFA) (P < 0.05). Our findings suggest a novel role for a balanced BCAA-supplemented restricted protein (RP) diet in the epigenetic regulation of more tender and healthier pork by increasing IMF deposition and fiber type conversion, providing a cross-regulatory molecular basis for revealing the nutritional regulation network of meat quality. © 2021 Society of Chemical Industry.