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International Journal of Molecular... Feb 2024A variety of changes in mineral metabolism aiming to restore acid-base balance occur in acid loading and metabolic acidosis. Phosphate plays a key role in defense... (Review)
Review
A variety of changes in mineral metabolism aiming to restore acid-base balance occur in acid loading and metabolic acidosis. Phosphate plays a key role in defense against metabolic acidosis, both as an intracellular and extracellular buffer, as well as in the renal excretion of excess acid in the form of urinary titratable acid. The skeleton acts as an extracellular buffer in states of metabolic acidosis, as the bone matrix demineralizes, leading to bone apatite dissolution and the release of phosphate, calcium, carbonate, and citrate into the circulation. The renal handling of calcium, phosphate and citrate is also affected, with resultant hypercalciuria, hyperphosphaturia and hypocitraturia.
Topics: Humans; Calcium; Kidney; Acidosis; Citric Acid; Kidney Diseases; Citrates; Calcium, Dietary; Phosphates
PubMed: 38396761
DOI: 10.3390/ijms25042081 -
The Journal of Biological Chemistry Dec 2023Pyruvate dehydrogenase (PDH) is the rate-limiting enzyme for glucose oxidation that links glycolysis-derived pyruvate with the tricarboxylic acid (TCA) cycle. Although...
Pyruvate dehydrogenase (PDH) is the rate-limiting enzyme for glucose oxidation that links glycolysis-derived pyruvate with the tricarboxylic acid (TCA) cycle. Although skeletal muscle is a significant site for glucose oxidation and is closely linked with metabolic flexibility, the importance of muscle PDH during rest and exercise has yet to be fully elucidated. Here, we demonstrate that mice with muscle-specific deletion of PDH exhibit rapid weight loss and suffer from severe lactic acidosis, ultimately leading to early mortality under low-fat diet provision. Furthermore, loss of muscle PDH induces adaptive anaplerotic compensation by increasing pyruvate-alanine cycling and glutaminolysis. Interestingly, high-fat diet supplementation effectively abolishes early mortality and rescues the overt metabolic phenotype induced by muscle PDH deficiency. Despite increased reliance on fatty acid oxidation during high-fat diet provision, loss of muscle PDH worsens exercise performance and induces lactic acidosis. These observations illustrate the importance of muscle PDH in maintaining metabolic flexibility and preventing the development of metabolic disorders.
Topics: Animals; Mice; Acidosis, Lactic; Glucose; Muscle, Skeletal; Pyruvate Dehydrogenase Complex; Pyruvic Acid; Glutamine; Alanine; Gene Deletion; Diet; Mortality, Premature
PubMed: 37865313
DOI: 10.1016/j.jbc.2023.105375 -
Endocrine Journal Jul 2023Pseudohypoaldosteronism (PHA) type II (PHA2) is a genetic disorder that leads to volume overload and hyperkalemic metabolic acidosis. PHA2 and PHA type I (PHA1) have... (Review)
Review
Pseudohypoaldosteronism (PHA) type II (PHA2) is a genetic disorder that leads to volume overload and hyperkalemic metabolic acidosis. PHA2 and PHA type I (PHA1) have been considered to be genetic and pediatric counterparts to type IV renal tubular acidosis (RTA). Type IV RTA is frequently found in adults with chronic kidney disease and is characterized by hyperchloremic hyperkalemic acidosis with normal anion gap (AG). However, we recently observed that PHA1 was not always identical to type IV RTA. In this study, we focused on the acid-base balance in PHA2. Through a literature search published between 2008-2020, 46 molecularly diagnosed cases with PHA2 were identified (median age of 14 years). They comprised 11 sets of familial and 16 sporadic cases and the pathology was associated with mutations in WNK 4 (n = 1), KLHL3 (n = 17), and CUL3 (n = 9). The mean potassium (K) level was 6.2 ± 0.9 mEq/L (n = 46, range 4.0-8.6 mEq/L), whereas that of chloride (Cl) was 110 ± 3.5 mEq/L (n = 41, 100-119 mEq/L), with 28 of 41 cases identified as hyperchloremic. More than half of the cases (18/35) presented with metabolic acidosis. Although AG data was obtained only in 16 cases, all but one cases were within normal AG range. Both Cl and HCO3 levels showed significant correlations with K levels, which suggested that the degree of hyperchloremia and acidosis reflect the clinical severity, and is closely related to the fundamental pathophysiology of PHA2. In conclusion, our study confirmed that PHA2 is compatible with type IV RTA based on laboratory findings.
Topics: Adult; Humans; Child; Adolescent; Pseudohypoaldosteronism; Hypoaldosteronism; Acidosis; Mutation; Hyperkalemia
PubMed: 37081692
DOI: 10.1507/endocrj.EJ22-0607 -
American Journal of Physiology. Cell... Mar 2024Ketone bodies are short-chain fatty acids produced by the liver during periods of limited glucose availability, such as during fasting or low carbohydrate feeding....
Ketone bodies are short-chain fatty acids produced by the liver during periods of limited glucose availability, such as during fasting or low carbohydrate feeding. Recent studies have highlighted important nonmetabolic functions of the most abundant ketone body, β-hydroxybutyrate (BHB). Notably, many of these functions, including limiting specific sources of inflammation, histone deacetylase inhibition, NFκB inhibition, and GPCR stimulation, are particularly important to consider in immune cells. Likewise, dietary manipulations like caloric restriction or ketogenic diet feeding have been associated with lowered inflammation, improved health outcomes, and improved host defense against infection. However, the underlying mechanisms of the broad benefits of ketosis remain incompletely understood. In this Perspective, we contextualize the current state of the field of nonmetabolic functions of ketone bodies specifically in the immune system and speculate on the molecular explanations and broader physiological significance.
Topics: Humans; Ketone Bodies; Ketosis; 3-Hydroxybutyric Acid; Immune System; Inflammation
PubMed: 38189135
DOI: 10.1152/ajpcell.00478.2023 -
PloS One 2023Bone disease is highly prevalent in patients with chronic kidney disease (CKD), leading to an increased risk of bone fractures. This is due in part to metabolic...
Bone disease is highly prevalent in patients with chronic kidney disease (CKD), leading to an increased risk of bone fractures. This is due in part to metabolic acid-induced bone dissolution. Bisphosphonates (BPPs) are a potential treatment for inhibiting bone dissolution; however, there are limited studies observing the use of BPPs on acidotic patients. We aimed to determine efficacy of BPPs on maintaining bone health and pH regulation in acid-exposed mice. Using a diet-induced murine model of metabolic acidosis, we examined bone structure, composition, and mechanics as well as blood gases for three groups: control, acidosis, and acidosis + bisphosphonates (acidosis+BPP). Acidosis was induced for 14 days and alendronate was administered every 3 days for the acidosis+BPP group. The administration of BPP had little to no effect on bone structure, mechanics, and composition of the acidosis bones. However, administration of BPP did cause the mice to develop more severe acidosis than the acidosis only group. Overall, we discovered that BPPs may exacerbate acidosis symptoms by inhibiting the release of buffering ions from bone. Therefore, we propose that BPP administration should be carefully considered for those with CKD and that alkali supplementation could help minimize acidifying effects.
Topics: Animals; Mice; Alendronate; Ammonium Chloride; Diphosphonates; Acidosis; Osteolysis; Renal Insufficiency, Chronic
PubMed: 37713420
DOI: 10.1371/journal.pone.0291649 -
American Journal of Health-system... Sep 2023This initiative conducted a needs assessment regarding the extent of potential risk for accidental carbohydrate exposure in patients on the ketogenic diet in acute care... (Review)
Review
PURPOSE
This initiative conducted a needs assessment regarding the extent of potential risk for accidental carbohydrate exposure in patients on the ketogenic diet in acute care settings at 2 academic medical centers.
SUMMARY
Medications used in the emergency department, intensive care unit, or operating room can contain carbohydrates or be diluted in carbohydrate-containing fluids. Use of these medications can shift patients on the ketogenic diet out of ketosis, causing breakthrough seizures. Despite standard clinical practices, there are no consensus guidelines to date for the logistical management of these patients during hospital admissions. This lack of standardized management increases the risk for parenteral medication errors during transitions within the healthcare system. A review of the literature demonstrates increased medication safety errors compounded by this lack of systemwide endeavors. Initiatives enhancing provider education and quality improvement safety measures have been reported; however, the extent of the potential risk with regard to medication formulation has not been assessed. Fifty medications were evaluated for their potential risk for carbohydrate exposure in a real-world quality improvement needs assessment conducted at 2 academic medical centers.
CONCLUSION
Because of increased exposure to carbohydrate-containing medications and medication safety errors, the authors recommend developing institutional protocols, an order set in the electronic medical record, and a multidisciplinary approach for patients on the ketogenic diet. Further research is warranted to assess the impact of these quality improvement measures on safety and clinical outcomes and to justify the development and implementation of consensus guidelines in centers of excellence that serve these patients.
Topics: Humans; Diet, Ketogenic; Seizures; Carbohydrates; Medication Errors; Ketosis
PubMed: 37257050
DOI: 10.1093/ajhp/zxad121 -
Mitochondrion Sep 2023Human induced pluripotent stem cells (hiPSCs) for MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes) may allow deeper... (Review)
Review
Human induced pluripotent stem cells (hiPSCs) for MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes) may allow deeper understanding of how tissue-specific mitochondrial dysfunction result in multi-systemic disease. Here, we summarize how the m.3243G mtDNA mutation affects mitochondrial function in different tissues using iPSC and iPSC-differentiated cell type disease models and what significant findings have been replicated in the independent studies. Through this brief review and with a focus on mitochondrial dysfunction in iPSC-differentiated cell types, namely fibroblast, neuron, and retinal pigment epithelium cells, we aim to bring awareness of hiPSC as a robust mitochondrial disease model even if many unanswered questions remain.
Topics: Humans; MELAS Syndrome; Induced Pluripotent Stem Cells; Acidosis, Lactic; Cell Differentiation; Mitochondria
PubMed: 37633406
DOI: 10.1016/j.mito.2023.08.003 -
The Canadian Veterinary Journal = La... Nov 2023Metabolic acidosis (MA) is the most common acid-base disorder reported in horses with colitis but its association with survival is yet to be determined.
BACKGROUND
Metabolic acidosis (MA) is the most common acid-base disorder reported in horses with colitis but its association with survival is yet to be determined.
OBJECTIVE
Investigate the types of MA in horses with colitis to determine effects of various anions on fatality rates.
ANIMALS AND PROCEDURES
We studied 158 horses with colitis. Horses were classified into 4 groups depending on the anion contributing to MA: i) no MA, ii) lactic acidosis (LA), iii) unmeasured strong ion (USI) acidosis, and iv) hyperchloremic acidosis (HA).
RESULTS
Sixty percent (95/158) of horses had no MA, 22% (34/158) had LA, 12% (19/158) had HA, and 6% (10/158) had USI acidosis. The fatality rate of horses without MA was 20% (20/95), whereas the rates for those with LA, USI, and HA were 53% (18/34), 30% (3/10), and 16% (3/19), respectively. Horses with LA were more likely to die or be euthanized than horses without MA (OR: 4.2, 95% CI: 1.83 to 9.72, < 0.001) and HA (OR: 5.9, 95% CI: 1.47 to 24.4, < 0.01).
CONCLUSION AND CLINICAL RELEVANCE
Lactic acidosis was the most common type of MA in horses with colitis, and it was associated with non-survival.
Topics: Animals; Horses; Acidosis, Lactic; Acidosis; Colitis; Horse Diseases
PubMed: 37915775
DOI: No ID Found -
Pflugers Archiv : European Journal of... Apr 2024Maintaining an appropriate acid-base equilibrium is crucial for human health. A primary influencer of this equilibrium is diet, as foods are metabolized into... (Review)
Review
Maintaining an appropriate acid-base equilibrium is crucial for human health. A primary influencer of this equilibrium is diet, as foods are metabolized into non-volatile acids or bases. Dietary acid load (DAL) is a measure of the acid load derived from diet, taking into account both the potential renal acid load (PRAL) from food components like protein, potassium, phosphorus, calcium, and magnesium, and the organic acids from foods, which are metabolized to bicarbonate and thus have an alkalinizing effect. Current Western diets are characterized by a high DAL, due to large amounts of animal protein and processed foods. A chronic low-grade metabolic acidosis can occur following a Western diet and is associated with increased morbidity and mortality. Nutritional advice focusing on DAL, rather than macronutrients, is gaining rapid attention as it provides a more holistic approach to managing health. However, current evidence for the role of DAL is mainly associative, and underlying mechanisms are poorly understood. This review focusses on the role of DAL in multiple conditions such as obesity, cardiovascular health, impaired kidney function, and cancer.
Topics: Animals; Humans; Diet; Acid-Base Equilibrium; Kidney; Acidosis; Obesity
PubMed: 38282081
DOI: 10.1007/s00424-024-02910-7 -
Medicina 2024Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that are increasingly used in cancer treatments. As experience in the use of immunotherapy increases, more... (Review)
Review
Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that are increasingly used in cancer treatments. As experience in the use of immunotherapy increases, more is known about its safety profile and immune-mediated adverse effects. Among them is diabetic ketoacidosis (DKA), a rare but serious fatal complication of treatment. In this paper we describe the cases of three patients who presented with episodes of DKA during treatment with ICIs, two of which manifested with fulminant forms, leading to an acute course with initially normal glycosylated hemoglobin values. In addition, we conducted a review of the literature on DKA associated with ICIs in order to highlight the importance of noticing these potentially fatal complications and promptly establishing appropriate therapy.
Topics: Humans; Diabetic Ketoacidosis; Antibodies, Monoclonal; Immunotherapy; Drug-Related Side Effects and Adverse Reactions; Diabetes Mellitus
PubMed: 38271940
DOI: No ID Found