Dietary Protein Restriction Research Articles

Impaired placental hemodynamics and function in a non-human primate model of gestational protein restriction

Maternal malnutrition increases fetal and neonatal morbidity, partly by affecting placental function and morphology, but its impact on placental hemodynamics are unknown. Our objective was to define the impact of maternal malnutrition on placental oxygen reserve and perfusion in vivo in a rhesus macaque model of protein restriction (PR) using advanced imaging. Animals were fed control (CON, 26% protein), 33% PR diet (17% protein), or a 50% PR diet (13% protein, n = 8/group) preconception and throughout pregnancy. Animals underwent Doppler ultrasound and fetal biometry followed by MRI at gestational days 85 (G85) and 135 (G135; term is G168). Pregnancy loss rates were 0/8 in CON, 1/8 in 33% PR, and 3/8 in 50% PR animals. Fetuses of animals fed a 50% PR diet had a smaller abdominal circumference (G135, p < 0.01). On MRI, placental blood flow was decreased at G135 (p < 0.05) and placental oxygen reserve was reduced (G85, p = 0.05; G135, p = 0.01) in animals fed a 50% PR diet vs. CON. These data demonstrate that a 50% PR diet reduces maternal placental perfusion, decreases fetal oxygen availability, and increases fetal mortality. These alterations in placental hemodynamics may partly explain human growth restriction and stillbirth seen with severe PR diets in the developing world.

Maternal Protein Restriction in Rats Alters Postnatal Growth and Brain Lipid Sensing in Female Offspring.

Perinatal nutrition is a key player in the susceptibility to developing metabolic diseases in adulthood, leading to the concept of "metabolic programming". The aim of this study was to assess the impact of maternal protein restriction during gestation and lactation on glucose homeostasis and eating behaviour in female offspring. Pregnant rats were fed a normal or protein-restricted (PR) diet and followed throughout gestation and lactation. Body weight, glucose homeostasis, and eating behaviour were evaluated in offspring, especially in females. Body weight gain was lower in PR dams during lactation only, despite different food and water intakes throughout gestation and lactation. Plasma concentration of leptin, adiponectin and triglycerides increased drastically before delivery in PR dams in relation to fat deposits. Although all pups had identical birth body weight, PR offspring body weight differed from control offspring around postnatal day 10 and remained lower until adulthood. Offspring glucose homeostasis was mildly impacted by maternal PR, although insulin secretion was reduced for PR rats at adulthood. Food intake, satiety response, and cerebral activation were examined after a lipid preload and demonstrated some differences between the two groups of rats. Maternal PR during gestation and lactation does induce extrauterine growth restriction, accompanied by alterations in maternal plasma leptin and adiponectin levels, which may be involved in programming the alterations in eating behaviour observed in females at adulthood.

Protein restriction during lactation causes transgenerational metabolic dysfunction in adult rat offspring.

Protein restriction during lactation can induce metabolic dysfunctions and has a huge impact on the offspring's phenotype later in its life. We tested whether the effects of a maternal low-protein diet (LP) in rats can be transmitted to the F2 generation and increase their vulnerability to dietary insults in adulthood. Female Wistar rats (F0) were fed either a low-protein diet (LP; 4% protein) during the first 2 weeks of lactation or a normal-protein diet (NP; 23% protein). The female offspring (F1 generation) were maintained on a standard diet throughout the experiment. Once adulthood was reached, female F1 offspring from both groups (i.e., NP-F1 and LP-F1) were bred to proven males, outside the experiment, to produce the F2 generation. Male F2 offspring from both groups (NP-F2 and LP-F2 groups) received a standard diet until 60 days old, at which point they received either a normal fat (NF; 4.5% fat) or a high fat diet (HF; 35% fat) for 30 days. At 90 days old, LPNF-F2 offspring had increased lipogenesis and fasting insulinemia compared to NPNF-F2, without alteration in insulin sensitivity. HF diet caused increased gluconeogenesis and displayed glucose intolerance in LPHF-F2 offspring compared to LPNF-F2 offspring. Additionally, the HF diet led to damage to lipid metabolism (such as steatosis grade 3), higher body weight, fat pad stores, and hepatic lipid content. We concluded that an F0 maternal protein restricted diet during lactation can induce a transgenerational effect on glucose and liver metabolism in the F2 generation, making the offspring's liver more vulnerable to nutritional injury later in life.

Dietary Isoleucine and Valine: Effects on Lipid Metabolism and Ureagenesis in Pigs Fed with Protein Restricted Diets.

A mixture of valine (Val) and isoleucine (Ile) not only decreases the negative impact of very low protein (VLP) diets on the growth of pigs, but also influences the nitrogen (N) balance and lipid metabolism; however, the underlying pathways are not well understood. This study aimed to investigate the effect of dietary Val and Ile on lipogenesis, lipolysis, and ureagenesis under protein restriction. After one week of acclimation, forty three-week-old pigs were randomly assigned to following dietary treatments (n = 8/group) for 5 weeks: positive control (PC): normal protein diet; negative control (NC): VLP diet; HV: NC supplemented with Val; HI: NC supplemented with Ile; and HVI: NC supplemented with both Val and Ile. HVI partially improved the body weight and completely recovered the feed intake (FI) of pigs fed with NC. HVI increased thermal radiation and improved the glucose clearance. HVI had a lower blood triglyceride than PC and blood urea N than NC. NC and HV promoted lipogenesis by increasing the transcript of fatty acid synthase (FAS) in the liver and lipoprotein lipase (LPL) in adipose tissue but reducing hormone-sensitive lipase (HSL) in the liver. HVI reduced the increased rate of lipogenesis induced by the NC group through normalizing the mRNA abundance of hepatic FAS, sterol regulatory element binding transcription factor 1, and HSL and LPL in adipose tissue. NC, HV, HI, and HVI reduced the ureagenesis by decreasing the protein abundance of carbamoyl phosphate synthetase I, ornithine transcarboxylase, and arginosuccinate lyase in the liver. Overall, HVI improved the growth, FI, and glucose clearance, and decreased the rate of lipogenesis induced by VLP diets.

Protein restriction for diabetic kidney disease.

Diabetic kidney disease (DKD) continues to be the leading cause of kidney failure across the world. For decades dietary protein restriction has been proposed for patients with DKD with the aim to retard the progression of chronic kidney disease (CKD) towards kidney failure. However, the relative benefits and harms of dietary protein restriction for slowing the progression of DKD have not been addressed. To determine the efficacy and safety of low protein diets (LPD) (0.6 to 0.8 g/kg/day) in preventing the progression of CKD towards kidney failure and in reducing the incidence of kidney failure and death (any cause) in adult patients with DKD. Moreover, the effect of LPD on adverse events (e.g. malnutrition, hyperglycaemic events, or health-related quality of life (HRQoL)) and compliance were also evaluated. We searched the Cochrane Kidney and Transplant Register of Studies up to 17 November 2022 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. We included randomised controlled trials (RCTs) or quasi-RCTs in which adults with DKD not on dialysis were randomised to receive either a LPD (0.6 to 0.8 g/kg/day) or a usual or unrestricted protein diet (UPD) (≥ 1.0 g/kg/day) for at least 12 months. Two authors independently selected studies and extracted data. Summary estimates of effect were obtained using a random-effects model. Results were summarised as risk ratios (RR) with 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) or standardised MD (SMD) with 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We identified eight studies involving 486 participants with DKD. The prescribed protein intake in the intervention groups ranged from 0.6 to 0.8 g/kg/day. The prescribed protein intake in the control groups was ≥ 1.0 g/kg/day, or a calculated protein intake ≥ 1.0 g/kg/day if data on prescribed protein intake were not provided. The mean duration of the interventions was two years (ranging from one to five years). Risks of bias in most of the included studies were high or unclear, most notably for allocation concealment, performance and detection bias. All studies were considered to be at high risk for performance bias due to the nature of the interventions. Most studies were not designed to examine death or kidney failure. In low certainty evidence, a LPD may have little or no effect on death (5 studies, 358 participants: RR 0.38, 95% CI 0.10 to 1.44; I² = 0%), and the number of participants who reached kidney failure (4 studies, 287 participants: RR 1.16, 95% CI 0.38 to 3.59; I² = 0%). Compared to a usual or unrestricted protein intake, it remains uncertain whether a LPD slows the decline of glomerular filtration rate over time (7 studies, 367 participants: MD -0.73 mL/min/1.73 m²/year, 95% CI -2.3 to 0.83; I² = 53%; very low certainty evidence). It is also uncertain whether the restriction of dietary protein intake impacts on the annual decline in creatinine clearance (3 studies, 203 participants: MD -2.39 mL/min/year, 95% CI -5.87 to 1.08; I² = 53%). There was only one study reporting 24-hour urinary protein excretion. In very low certainty evidence, a LPD had uncertain effects on the annual change in proteinuria (1 study, 80 participants: MD 0.90 g/24 hours, 95% CI 0.49 to 1.31). There was no evidence of malnutrition in seven studies, while one study noted this condition in the LPD group. Participant compliance with a LPD was unsatisfactory in nearly half of the studies. One study reported LPD had no effect on HRQoL. No studies reported hyperglycaemic events. Dietary protein restriction has uncertain effects on changes in kidney function over time. However, it may make little difference to the risk of death and kidney failure. Questions remain about protein intake levels and compliance with protein-restricted diets. There are limited data on HRQoL and adverse effects such as nutritional measures and hyperglycaemic events. Large-scale pragmatic RCTs with sufficient follow-up are required for different stages of CKD.

A protein restricted diet induces a stable increased fat storage phenotype in flies.

Scientific evidence has revealed possible confounders in diet induced obesity models of Drosophila melanogaster. High Sugar Diet (HSD) induction of obesity in flies has been associated with fly hyperosmolarity and glucotoxicity, while High Fat Diet (HFD) induction has been associated with lipotoxicity. The objective of this study was to assess for a healthy obesity phenotype by comparison of fly survival, physio-chemical and biochemical changes associated with HSD, HFD and Protein Restricted Diet (PRD) obesity induction models of male Drosophila melanogaster. Here, we provide information on a PRD as the plausible option in obesity research not involving cancer, diabetes, glucotoxicity and lipotoxicity studies. Obesity was induced by exposing Drosophila melanogaster white mutant w1118 to four experimental diets for four weeks. Group 1 was fed regular food (control), group 2 was fed a 0.5% less yeast than in regular feed (PRD), group 3 was fed a 30% w/v sucrose to regular cornmeal food (HSD) and group 4 was fed a 10% w/v food-grade coconut oil to regular cornmeal food (HFD). Peristaltic waves were measured on 3rd instar larvae of all experimental groups. Negative geotaxis, fly survival, body mass, catalase activity, triglycerides (TG/TP), sterol, and total protein were measured in adult Drosophila melanogaster after four weeks. Triglycerides (TG/TP) and total protein levels were significantly higher in HSD phenotype. Sterols were higher in HFD phenotype. Though catalase enzyme activity was highest in PRD phenotype, this activity was not statistically significant when compared to that of HSD and HFD phenotypes. However, PRD phenotype had the lowest mass, highest survival rate and the highest negative geotaxis, thus demonstrating a balanced, stable and more viable metabolic status in the experimental model. A protein restricted diet induces a stable increased fat storage phenotype in Drosophila melanogaster.

PS-C23-12: DIETARY INTERVENTION WITH THE PROCESSED LOW PROTEIN GENMAI (BROWN RICE) AGAINST CHRONIC KIDNEY DISEASE.

Background: Although protein-restricted diets have shown to preserve the renal function, there are a couple of challenges such as (1) the intake of vegetable protein, which is useful for maintaining renal function, is insufficient due to potassium restriction, and (2) caloric intake tends to be inadequate. Therefore, we investigated the effects of diets that may solve these problems with maintaining the current dietary restrictions and may also be additional effects on renal protection. Another study also has shown that patients with CKD are under a chronic inflammatory state and those uremic toxins produced by the gut microbiota are the causes of increased inflammatory cytokine production. We sought to intervene in renal function via modulating this kidney-gut axis in CKD. We thus focused on the processed low protein genmai (brown rice) (PLPG), marketed since 2018 by Follica Foods, Inc. as a candidate food that retains the fiber and GABA characteristic of brown rice, reduces protein to less than 20% of conventional rice, and also limits potassium and phosphorus. Methods: The study was conducted in a before-and-after trial. Thirty patients with eGFR of 59 or less were recruited. PLPG was a retort pack of 150 g for one meal. The patients ate provided with about 10 servings of PLPG per week for 3 months. Results: One patient withdrew due to poor health after participation, and a final total of 29 patients were analyzed. The median age of the participants was 73 years, the mean eGFR was 35.41 ml/min/1.73 m2. The median in BMI decreased by -0.31 (P = 0.037). The median change in the Constipation scoring system score improved by -1.00 (P = 0.032). The change in eGFRcreat decreased with a mean value of -1.241 ml/min/1.73 m2. (P = 0.044), but the monthly eGFRcreat slope was not significantly different. Indoxyl sulfate did not differ significantly, but it showed a decreasing trend with a median change of -0.20 (P = 0.050). The median change in IL-6 was 0.300 pg/mL (P = 0.004). Among short-chain fatty acids, only acetic acid showed an increase with a median change of 7.401 μmol/g (P = 0.010). Conclusion: Participants’ protein intake did not decrease. Therefore, it was thought that the effects of PLPG itself was observed, independent of the effect of low protein. The increase in acetic acid may have contributed to this change. The decrease in e-GFR along with the decrease in urinary protein levels indicated an initial dip due to correction of glomerular hypertension. Long-term follow-up is plausible to establish the novel dietary treatment.

Dietary leucine deficiency alters performance, body composition, intestine microbiota, and immune response of female Cobb broilers

Context Leucine (Leu) is one of the branched-chain amino acids that is necessary for muscle protein synthesis. Basically, poultry feed ingredients contain abundant amounts of Leu. But little is known about dietary Leu deficiency in performance and health-attributing parameters of female broiler chickens, which may occur in crude protein-restricted diets. Aims This study evaluates the effect of Leu deficiency in diets on the growth performance, body composition, immunity, and caecum microbiota of female broilers. Methods Female broiler chicks (Cobb 500; 8 days old; n = 540) were randomly divided into six groups with six replicates (15 birds in each replicate) in a completely randomised design. The experimental diets included six concentrations of Leu (80%, 84%, 88%, 92%, 96%, and 100%) fed for 14 days. A basal Leu-deficient diet was formulated at the 80% recommended level, and the experimental diets were created by gradual replacing of crystalline L-glutamic acid with crystalline L-Leu. Average daily intake (ADI), average daily gain (ADG), feed efficiency (gain:feed), body composition, cutaneous basophil hypersensitivity (CBH) test to phytohaemagglutinin-P (PHA-P), antibody response to sheep red blood cell (SRBC) and caecum microbiota were investigated. Key results The birds receiving the lowest Leu application level had the lowest ADI (P &lt; 0.05) and a 20% higher fat content (P &lt; 0.01) than did the birds fed 96% Leu. The population of Escherichia coli and coliform bacteria count was increased (P &lt; 0.001; by 36% and 10.3% compared with the birds fed 100% Leu in the diet respectively), and Lactobacillus (but not Enterococcus) count was decreased (P &lt; 0.001; by 26.4% compared with the birds fed 100% Leu in the diet) with decreasing concentrations of dietary Leu. Average daily gain, feed efficiency, carcass dry matter, protein and ash percentages, and immunity were not affected markedly by dietary treatments with different Leu concentrations. Conclusions The Leu deficiency influenced the broiler performance, body composition, and caecum microbiota, but not the immune response. Implications This study points to the importance of Leu supplementation in the diet of broilers to improve their growth performance, fat content, and intestine health.

Effects of Dietary Protein Restriction on Colonic Microbiota of Finishing Pigs.

This study is aimed at the effects of low-protein diets with four amino acids balanced on serum biochemical parameters and colonic microflora of finishing pigs. Fifty-four healthy (Duroc × Landrace × Yorkshire) hybrid barrows with an average body weight of 70.12 ± 4.03 kg were randomly assigned to one of three dietary treatments with three barrows per pen and six pens per treatment. The barrows were fed a normal protein diet (NP), a low-protein diet (LP), and a very low-protein diet (VLP). Compared with the NP diet, reduced dietary protein did not influence serum biochemical parameters (p > 0.05). The valeric acid was significantly increased with the VLP diet (p < 0.05). Compared with the NP diets, the abundance of Terrisporobacter (13.37%) Clostridium_sensu_stricto_1 (23.37%) and Turicibacter (2.57%) increased to 21.04, 33.42 and 13.68% in LP diets and 16.72, 43.71 and 14.61% in VLP diets, while the abundance of Lactobacillus (9.30%) and Streptococcus (25.26%) decreased to 3.57 and 14.50% in LP diets and 1.86 and 4.07% in VLP diets. Turicibacter and Clostridium_sensu_stricto_6 had a powerful negative correlation with the content of valeric acid (p < 0.01), while Peptococcus and Clostridia_UCG-014 had a very solid positive correlation (p < 0.01). In conclusion, reducing dietary protein level can improve colon microbiota composition, especially reducing the abundance of bacteria related to nitrogen metabolism, but has no significant effect on SCFA except valeric acid. In addition, reduction in the dietary protein level by 5.48% had more different flora than that of 2.74% reduction in dietary CP level.

Personal Devices to Monitor Physical Activity and Nutritional Intake After Colorectal Cancer Surgery: Feasibility Study.

The use of self-monitoring devices is promising for improving perioperative physical activity and nutritional intake. This study aimed to assess the feasibility, usability, and acceptability of a physical activity tracker and digital food record in persons scheduled for colorectal cancer (CRC) surgery. This observational cohort study was conducted at a large training hospital between November 2019 and November 2020. The study population consisted of persons with CRC between 18- and 75 years of age who were able to use a smartphone or tablet and scheduled for elective surgery with curative intent. Excluded were persons not proficient in Dutch or following a protein-restricted diet. Participants used an activity tracker (Fitbit Charge 3) from 4 weeks before until 6 weeks after surgery. In the week before surgery (preoperative) and the fifth week after surgery (postoperative), participants also used a food record for 1 week. They shared their experience regarding usability (system usability scale, range 0-100) and acceptability (net promoter score, range -100 to +100). In total, 28 persons were included (n=16, 57% male, mean age 61, SD 8 years), and 27 shared their experiences. Scores regarding the activity tracker were as follows: preoperative median system usability score, 85 (IQR 73-90); net promoter score, +65; postoperative median system usability score, 78 (IQR 68-85); net promotor score, +67. The net promoter scores regarding the food record were +37 (preoperative) and-7 (postoperative). The perioperative use of a physical activity tracker is considered feasible, usable, and acceptable by persons with CRC in this study. Preoperatively, the use of a digital food record was acceptable, and postoperatively, the acceptability decreased.

Restricting a single amino acid cross-protects Drosophila melanogaster from nicotine poisoning through mTORC1 and GCN2 signalling.

Dietary interventions that restrict protein intake have repeatedly been shown to offer beneficial health outcomes to the consumer. Benefits such as increased stress tolerance can be observed when individual amino acids are restricted, thus mimicking dietary protein restriction. Here, we sought to further understand the relationship between dietary amino acids and stress tolerance using Drosophila melanogaster. Using a chemically defined medium for Drosophila, we found that transiently restricting adult flies of a single essential amino acid generally protects against a lethal dose of the naturally occurring insecticide, nicotine. This protection varied with the identity of the focal amino acid and depended on the duration and intensity of its restriction. To understand the molecular basis of these effects, we modified the signalling of two cellular sensors of amino acids, GCN2 and mTORC1, in combination with amino acid restriction. We found that GCN2 was necessary for diets to protect against nicotine, whereas the suppression of mTORC1 was sufficient to induce nicotine resistance. This finding implies that amino acid restriction acts via amino acid signalling to cross-protect against seemingly unrelated stressors. Altogether, our study offers new insights into the physiological responses to restriction of individual amino acids that confer stress tolerance.

Natural history of propionic acidemia in the Amish population

Propionic acidemia (PA) in the Amish is caused by a homozygous pathogenic variant (c.1606A>G; p.Asn536Asp) in the PCCB gene. Amish patients can have borderline or normal newborn screening (NBS) results and symptoms can present at any time from early childhood to mid-adulthood. Early diagnosis and initiation of treatment for PA in the non-Amish population improves patient outcomes. Here, we present data from a retrospective chart review of Amish patients diagnosed with PA from three different medical centers in order to document its natural history in the Amish and determine the influence of treatment on outcomes in this population. A total of 38 patients with average current age 19.9 years (range 4y-45y), 57.9% males, were enrolled in the study. Fourteen patients (36.8%) were diagnosed with a positive newborn screening (NBS) while 24 patients (63.2%) had negative or inconclusive NBS or had no record of NBS in their charts. These 24 patients were diagnosed by screening after a family member was diagnosed with PA (14; 58.3%), following a hospitalization for metabolic acidosis (5; 20.8%), hospitalization for seizures (3; 12.5%) or via cord blood (2; 8.3%). The majority of patients were prescribed a protein restricted diet (32; 84.2%), including metabolic formula (29; 76.3%). Most were treated with carnitine (35; 92.1%), biotin (2; 76.3%) and/or Coenzyme Q10 (16; 42.1%). However, treatment adherence varied widely among patients, with 7 (24.1%) of the patients prescribed metabolic formula reportedly nonadherent. Cardiomyopathy was the most prevalent finding (22; 63.2%), followed by developmental delay/intellectual disability (15; 39.5%), long QT (14; 36.8%), seizures (12; 31.6%), failure to thrive (4; 10.5%), and basal ganglia strokes (3; 7.9%). No difference in outcome was obvious for those diagnosed by NBS and treated early with dietary and supplement management, especially for cardiomyopathy. However, this is a limited retrospective observational study. A prospective study with strict documentation of treatment adherence and universal screening for cardiomyopathy and long QT should be conducted to better study the impact of early detection and treatment. Additional treatment options such as liver transplantation and future therapies such as mRNA or gene therapy should be explored in this population.

ODP284 Hyperinsulinism-Hyperammonaemia syndrome: a dive into the rare presentation and diagnostic challenges encountered in adults

Abstract Background Hyperinsulinemic-hyperammonemia, a rare form of congenital hyperinsulinemia, can seldom present in adulthood if failed to be diagnosed during infancy, enabling it to be difficult to identify, and predisposing affected individuals to neurological complications. Case A 20-year-old female with intellectual disability, seizure disorder and ornithine transcarbamylase deficiency was admitted for recurrent episodes of asymptomatic hypoglycemia. Her medications included risperidone, fluoxetine, levetiracetam, lacosamide, ferrous sulphate and acetaminophen. Physical examination including vital signs was unremarkable. Relevant labs included a fasting glucose of 46mg/dl [70-99]. Further work up of hypoglycemia revealed an IGF-1 of 215ng/dl [85-350] and AM Cortisol of 6.5mcg/dl [5-25]. Given a low AM cortisol level under stress, an ACTH stimulation test was done with appropriate response of cortisol of 24 following cosyntropin administration, ruling out adrenal insufficiency. The patient continued to have h ypoglycemia noted on several glucometer checks every 4 hours where she remained asymptomatic. She was further evaluated with a mixed meal study where no hypoglycemia was noted. A 72 -hour fast was performed which was terminated based on a venous blood sample glucose reading of 50 mg/dl confirmed after hypoglycemia was noted on a glucometer check. The labs showed elevated C-peptide levels of 4ng/ml [0.4-2], insulin of 4mIU/L [&amp;lt;25] and proinsulin level of 2.3pmol/l [3-20]. Levels of insulin and proinsulin were noted to be inappropriately normal in the setting of hypoglycemia. Beta hydroxybutyrate was low at 0.1mmol/L [&amp;lt;0.5] and glucagon inappropriately normal at 36pg/ml [50-100]. Sulfonylurea, meglitinide and autoimmune antibody screen were negative. CT abdomen and pelvis was negative for pancreatic abnormality. In the absence of evidence for acquired causes of hyperinsulinemic hypoglycemia, congenital cases were investigated. Based on that, further labs were obtained including ammonia levels which was elevated at 177.2 u/dl [15-45]. Accordingly, GLUD-1 gene mutation was sent, given high suspicion for hyperinsulinemic hyperammonemia syndrome, which resulted positive and confirmed the diagnosis. She was started on a protein restricted diet and diazoxide which regulated her blood glucose levels effectively. Discussion Hyperinsulinism/hyperammonemia (HI/HA) syndrome is a form of congenital hyperinsulinism caused by activating mutations of the GLUD 1 gene which encodes Glutamate Dehydrogenase, a key enzyme in the beta cell pathway of amino acid-stimulated insulin secretion. The resultant syndrome is characterized by fasting and protein induced hypoglycemia, elevated serum ammonia levels without typical hyperammonemic symptoms. Management includes effective blood glucose control with an insulin inhibitor such as diazoxide and a protein restricted diet with consideration to predominantly include carbohydrates and fat. Conclusion Hyperinsulinemia hyperammonemia is a rare form of congenital hyperinsulinemia typically diagnosed during infancy and should be considered as a possible differential diagnosis in patients presenting with new onset hypoglycemia, as timely diagnosis and intervention can prevent forthcoming neurological complications. Presentation: No date and time listed

Risk of all-cause mortality in subjects with varying degrees of renal impairment with or without dietary protein restriction

Background and objectiveLow-protein diet (less than 0.8g/kg/day) has been practiced in the management of chronic kidney disease (estimated glomerular filtration rate [eGFR]<60ml/min/1.73m2 or urine albumin-to-creatinine ratios [UACR] ≥30mg/g) for decades. However, its effect on all-cause mortality is unclear. We investigated the association between a low-protein intake and all-cause mortality in subjects with varying degrees of renal impairment. Materials and methodsWe analyzed participants in the National Health and Nutrition Examination Survey (NHANES) from 2003 to 2010. They were divided into four groups according to their eGFR (≥60 or <60ml/min/1.73m2) and UACR (≥30 or <30mg/g). Daily protein intake of the NHANES participants could be assessed using information from the dietary interview questionnaires. The mortality data was retrieved by linking to the National Death Index till the end of 2011. The hazard ratios for all-cause mortality were evaluated by the weighted Cox proportional hazards regression models. ResultsA total of 8093 participants were analyzed. During a median follow-up of 4.7 years, participants with UACR≥30mg/g (with or without eGFR<60ml/min/1.73m2) had a higher risk of all-cause mortality compared with those having UACR<30mg/g and eGFR≥60ml/min/1.73m2 (reference group). The higher risk of mortality in participants with UACR≥30mg/g was consistently observed in those with or without a low-protein intake. ConclusionsA low-protein intake was not associated with a lower risk of all-cause mortality in subjects with varying degrees of renal impairment.

Three-Country Snapshot of Ornithine Transcarbamylase Deficiency.

X-linked ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle defect. The disease severity ranges from asymptomatic carrier state to severe neonatal presentation with hyperammonaemic encephalopathy. We audited the diagnosis and management of OTCD, using an online 12-question-survey that was sent to 75 metabolic centres in Turkey, France and the UK. Thirty-nine centres responded and 495 patients were reported in total. A total of 208 French patients were reported, including 71 (34%) males, 86 (41%) symptomatic and 51 (25%) asymptomatic females. Eighty-five Turkish patients included 32 (38%) males, 39 (46%) symptomatic and 14 (16%) asymptomatic females. Out of the 202 UK patients, 66 (33%) were male, 83 (41%) asymptomatic and 53 (26%) symptomatic females. A total of 19%, 12% and 7% of the patients presented with a neonatal-onset phenotype in France, Turkey and the UK, respectively. Vomiting, altered mental status and encephalopathy were the most common initial symptoms in all three countries. While 69% in France and 79% in Turkey were receiving protein restriction, 42% were on a protein-restricted diet in the UK. A total of 76%, 47% and 33% of patients were treated with ammonia scavengers in Turkey, France and the UK, respectively. The findings of our audit emphasize the differences and similarities in manifestations and management practices in three countries.

Excretion of excess nitrogen and increased survival by loss of SLC6A19 in a mouse model of ornithine transcarbamylase deficiency.

Protein catabolism ultimately yields toxic ammonia, which must be converted to urea by the liver for renal excretion. In extrahepatic tissues, ammonia is temporarily converted primarily to glutamine for subsequent hepatic extraction. Urea cycle disorders (UCDs) are inborn errors of metabolism causing impaired ureagenesis, leading to neurotoxic accumulation of ammonia and brain glutamine. Treatment includes dietary protein restriction and oral "ammonia scavengers." These scavengers chemically combine with glutamine and glycine to yield excretable products, creating an alternate pathway of waste nitrogen disposal. The amino acid transporter SLC6A19 is responsible for >95% of absorption and reabsorption of free neutral amino acids in the small intestine and kidney, respectively. Genetic SLC6A19 deficiency causes massive neutral aminoaciduria but is typically benign. We hypothesized that inhibiting SLC6A19 would open a novel and effective alternate pathway of waste nitrogen disposal. To test this, we crossed SLC6A19 knockout (KO) mice with spfash mice, a model of ornithine transcarbamylase (OTC) deficiency. Loss of SLC6A19 in spfash mice normalized plasma ammonia and brain glutamine and increased median survival in response to a high protein diet from 7 to 97 days. While induced excretion of amino acid nitrogen is likely the primary therapeutic mechanism, reduced intestinal absorption of dietary free amino acids, and decreased muscle protein turnover due to loss of SLC6A19 may also play a role. In summary, the results suggest that SLC6A19 inhibition represents a promising approach to treating UCDs and related aminoacidopathies.

The Role of Diet and Dietary Patterns in Parkinson's Disease.

Parkinson's Disease (PD) is a neurodegenerative disorder associated with diminished nutrition status and decreased quality of life. While the prevalence of PD is expected to increase, no preventative or curative therapy for PD exists at this time. Although nutrition and diet represent modifiable risk factors for reducing chronic disease risk, research on the impact of single nutrients on PD has yielded mixed results. As a result, this single-nutrient approach may be the driving force behind the inconsistency, and a holistic dietary approach may overcome this inconsistency by accounting for the interactions between nutrients. The following review aims to examine the impact of a generally healthy dietary pattern, the protein-restricted diet (PRD), the ketogenic diet (KD), the Mediterranean diet (MD), and the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet on PD risk, progression, and severity. While most of the included studies support the role of diet and dietary patterns in reducing the risk of PD or alleviating PD severity, the inconsistent results and need for further evidence necessitate more research being conducted before making dietary recommendations. Research on the potential beneficial effects of dietary patterns on PD should also investigate potential risks.

Protein preference and elevated plasma FGF21 induced by dietary protein restriction is similar in both male and female mice

Animals that are moderately protein restricted respond to this dietary stress by increasing consumption of protein-containing foods. This is true in many species, including rodents. Rodent models of protein restriction have typically relied on only male subjects, and there are plausible reasons why female rodents may respond differently to dietary protein restriction. To address this gap in knowledge, the current experiments examined protein preference after two weeks on a 5% protein diet or 20% protein control diet, in male and female mice. We found that female protein-restricted mice, like male protein-restricted mice, increase consumption of 4% casein (protein) relative to 4% maltodextrin (carbohydrate) when presented with both simultaneously. Interestingly, this increased consumption was due to more bursts in females and more licks per burst in males, indicating possible differences in mechanism by which increased intake is achieved. Stage of the estrous cycle did not affect female responses. Moreover, we measured plasma fibroblast growth factor 21 (FGF21) – a hormone induced by protein restriction and necessary for protein preference – in male and female mice. Here, we found no statistical differences between protein-restricted males, females in diestrus, or females in proestrus. In non-restricted mice FGF21 levels were low, but significantly higher in females in proestrus than females in diestrus or males. Overall, these experiments highlight the importance of including female subjects in studies of food choice and macronutrient restriction.

The role and control of arginine levels in arginase 1 deficiency.

Arginase 1 Deficiency (ARG1-D) is a rare urea cycle disorder that results in persistent hyperargininemia and a distinct, progressive neurologic phenotype involving developmental delay, intellectual disability, and spasticity, predominantly affecting the lower limbs and leading to mobility impairment. Unlike the typical presentation of other urea cycle disorders, individuals with ARG1-D usually appear healthy at birth and hyperammonemia is comparatively less severe and less common. Clinical manifestations typically begin to develop in early childhood in association with high plasma arginine levels, with hyperargininemia (and not hyperammonemia) considered to be the primary driver of disease sequelae. Nearly five decades of clinical experience with ARG1-D and empirical studies in genetically manipulated models have generated a large body of evidence that, when considered in aggregate, implicates arginine directly in disease pathophysiology. Severe dietary protein restriction to minimize arginine intake and diversion of ammonia from the urea cycle are the mainstay of care. Although this approach does reduce plasma arginine and improve patients' cognitive and motor/mobility manifestations, it is inadequate to achieve and maintain sufficiently low arginine levels and prevent progression in the long term. This review presents a comprehensive discussion of the clinical and scientific literature, the effects and limitations of the current standard of care, and the authors' perspectives regarding the past, current, and future management of ARG1-D.

Plant-Based Diets Improve Maternal-Fetal Outcomes in CKD Pregnancies.

Reducing protein intake in patients with chronic kidney disease (CKD) limits glomerular stress induced by hyperfiltration and can prevent the progression of kidney disease; data in pregnancy are limited. The aim of this study is to analyze the results obtained in CKD patients who followed a plant-based moderately protein-restricted diet during pregnancy in comparison with a propensity-score-matched cohort of CKD pregnancies on unrestricted diets. A total of 52 CKD pregnancies followed up with a protein-restricted plant-based diet (Torino, Italy) were matched with a propensity score based on kidney function and proteinuria with CKD pregnancies with unrestricted protein intake (Cagliari Italy). Outcomes included preterm (<37 weeks) and very preterm (<34 weeks) delivery and giving birth to a small-for-gestational-age baby. The median age in our cohort was 34 years, 63.46% of women were primiparous, and the median body mass index (BMI) was 23.15 kg/m2 with 13.46% of obese subjects. No statistical differences were found between women on a plant-based diet and women who were not in terms of age, parity, BMI, obesity, CKD stage, timing of referral, or cause of CKD. No differences were found between the two groups regarding the week of delivery. However, the combined negative outcome (birth before 37 completed gestational weeks or birth-weight centile <10) occurred less frequently in women following the diet than in women in the control group (61.54% versus 80.77%; p = 0.03). The lower risk was confirmed in a multivariable analysis adjusted for renal function and proteinuria (OR: 0.260 [Q1:0.093–Q3:0.724]; p = 0.010), in which the increase in proteinuria from the first to the last check-up before delivery was lower in patients on plant-based diets (median from 0.80 to 1.87 g/24 h; p: ns) than in controls (0.63 to 2.39 g/24 h p < 0.0001). Plant-based, moderately protein-restricted diets in pregnancy in patients with CKD are associated with a lower risk of preterm delivery and small-for-gestational-age babies; the effect may be mediated by better stabilization of proteinuria.