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Journal of Diabetes Science and... May 2024Ketone bodies are an energy substrate produced by the liver and used during states of low carbohydrate availability, such as fasting or prolonged exercise. High ketone... (Review)
Review
Ketone bodies are an energy substrate produced by the liver and used during states of low carbohydrate availability, such as fasting or prolonged exercise. High ketone concentrations can be present with insulin insufficiency and are a key finding in diabetic ketoacidosis (DKA). During states of insulin deficiency, lipolysis increases and a flood of circulating free fatty acids is converted in the liver into ketone bodies-mainly beta-hydroxybutyrate and acetoacetate. During DKA, beta-hydroxybutyrate is the predominant ketone in blood. As DKA resolves, beta-hydroxybutyrate is oxidized to acetoacetate, which is the predominant ketone in the urine. Because of this lag, a urine ketone test might be increasing even as DKA is resolving. Point-of-care tests are available for self-testing of blood ketones and urine ketones through measurement of beta-hydroxybutyrate and acetoacetate and are cleared by the US Food and Drug Administration (FDA). Acetone forms through spontaneous decarboxylation of acetoacetate and can be measured in exhaled breath, but currently no device is FDA-cleared for this purpose. Recently, technology has been announced for measuring beta-hydroxybutyrate in interstitial fluid. Measurement of ketones can be helpful to assess compliance with low carbohydrate diets; assessment of acidosis associated with alcohol use, in conjunction with SGLT2 inhibitors and immune checkpoint inhibitor therapy, both of which can increase the risk of DKA; and to identify DKA due to insulin deficiency. This article reviews the challenges and shortcomings of ketone testing in diabetes treatment and summarizes emerging trends in the measurement of ketones in the blood, urine, breath, and interstitial fluid.
Topics: Humans; Diabetic Ketoacidosis; Ketones; Ketone Bodies; Acetoacetates; 3-Hydroxybutyric Acid; Breath Tests; Point-of-Care Testing
PubMed: 36794812
DOI: 10.1177/19322968231152236 -
Trends in Endocrinology and Metabolism:... Apr 2024Hyperlactatemia and anemia commonly coexist and their crosstalk is a longstanding mystery with elusive mechanisms involved in physical activities, infections, cancers,... (Review)
Review
Hyperlactatemia and anemia commonly coexist and their crosstalk is a longstanding mystery with elusive mechanisms involved in physical activities, infections, cancers, and genetic disorders. For instance, hyperlactatemia leads to iron restriction by upregulating hepatic hepcidin expression. Increasing evidence also points to lactate as a crucial signaling molecule rather than merely a metabolic byproduct. Here, we discuss the mutual influence between anemia and hyperlactatemia. This opinion calls for a reconsideration of the multifaceted roles of lactate and lactylation in anemia and emphasizes the need to fill knowledge gaps, including the dose dependence of lactate's effects, its sources, and its subcellular localization.
Topics: Humans; Hyperlactatemia; Acidosis, Lactic; Lactic Acid; Anemia
PubMed: 38185594
DOI: 10.1016/j.tem.2023.12.006 -
Critical Care and Resuscitation :... Mar 2022To assess the incidence and impact of metabolic acidosis in Indigenous and non-Indigenous patients Retrospective study. Adult intensive care units (ICUs) from...
To assess the incidence and impact of metabolic acidosis in Indigenous and non-Indigenous patients Retrospective study. Adult intensive care units (ICUs) from Australia and New Zealand. Patients aged 16 years or older admitted to an Australian or New Zealand ICU in one of 195 contributing ICUs between January 2019 and December 2020 who had metabolic acidosis, defined as pH < 7.30, base excess (BE) < 4 mEq/L and PaCO ≤ 45 mmHg. The primary outcome was the prevalence of metabolic acidosis. Secondary outcomes included ICU length of stay, hospital length of stay, receipt of renal replacement therapy (RRT), major adverse kidney events at 30 days (MAKE30), and hospital mortality. Overall, 248 563 patients underwent analysis, with 11 537 (4.6%) in the Indigenous group and 237 026 (95.4%) in the non-Indigenous group. The prevalence of metabolic acidosis was higher in Indigenous patients (9.3% 6.1%; < 0.001). Indigenous patients with metabolic acidosis received RRT more often (28.2% 22.0%; < 0.001), but hospital mortality was similar between the groups (25.8% in Indigenous 25.8% in non-Indigenous; = 0.971). Critically ill Indigenous ICU patients are more likely to have a metabolic acidosis in the first 24 hours of their ICU admission, and more often received RRT during their ICU admission compared with non-Indigenous patients. However, hospital mortality was similar between the groups.
PubMed: 38046846
DOI: 10.51893/2022.1.OA2 -
Biomedicine & Pharmacotherapy =... Sep 2023β-hydroxybutyrate (β-HB), the most abundant ketone body, is produced primarily in the liver and acts as a substitute energy fuel to provide energy to extrahepatic... (Review)
Review
β-hydroxybutyrate (β-HB), the most abundant ketone body, is produced primarily in the liver and acts as a substitute energy fuel to provide energy to extrahepatic tissues in the event of hypoglycemia or glycogen depletion. We now have an improved understanding of β-HB as a signal molecule and epigenetic regulatory factor as a result of intensive research over the last ten years. Because β-HB regulates various physiological and pathological processes, it may have a potential role in the treatment of metabolic diseases. The liver is the most significant metabolic organ, and the part that β-HB plays in liver disorders is receiving increasing attention. In this review, we summarize the therapeutic effects of β-HB on liver diseases and its underlying mechanisms of action. Moreover, we explore the prospects of exogenous supplements and endogenous ketosis including fasting, caloric restriction (CR), ketogenic diet (KD), and exercise as adjuvant nutritional therapies to protect the liver from damage and provide insights and strategies for exploring the treatment of various liver diseases.
Topics: Humans; 3-Hydroxybutyric Acid; Ketone Bodies; Ketosis; Diet, Ketogenic; Liver Diseases
PubMed: 37487440
DOI: 10.1016/j.biopha.2023.115191 -
Endocrine Dec 2023Secondary diabetes mellitus (DM) in secretory pheochromocytomas and paragangliomas (PPGLs) is encountered in up to 50% of cases, with its presentation ranging from mild,... (Review)
Review
Secondary diabetes mellitus (DM) in secretory pheochromocytomas and paragangliomas (PPGLs) is encountered in up to 50% of cases, with its presentation ranging from mild, insulin resistant forms to profound insulin deficiency states, such as diabetic ketoacidosis and hyperglycemic hyperosmolar state. PPGLs represent hypermetabolic states, in which adrenaline and noradrenaline induce insulin resistance in target tissues characterized by aerobic glycolysis, excessive lipolysis, altered adipokine expression, subclinical inflammation, as well as enhanced gluconeogenesis and glucogenolysis. These effects are mediated both directly, upon adrenergic receptor stimulation, and indirectly, via increased glucagon secretion. Impaired insulin secretion is the principal pathogenetic mechanism of secondary DM in this setting; yet, this is relevant for tumors with adrenergic phenotype, arising from direct inhibitory actions in beta pancreatic cells and incretin effect impairment. In contrast, insulin secretion might be enhanced in tumors with noradrenergic phenotype. This dimorphic effect might correspond to two distinct glycemic phenotypes, with predominant insulin resistance and insulin deficiency respectively. Secondary DM improves substantially post-surgery, with up to 80% remission rate. The fact that surgical treatment of PPGLs restores insulin sensitivity and secretion at greater extent compared to alpha and beta blockade, implies the existence of further, non-adrenergic mechanisms, possibly involving other hormonal co-secretion by these tumors. DM management in PPGLs is scarcely studied. The efficacy and safety of newer anti-diabetic medications, such as glucagon-like peptide 1 receptor agonists and sodium glucose cotransporter 2 inhibitors (SGLT2is), as well as potential disease-modifying roles of metformin and SGLT2is warrant further investigation in future studies.
Topics: Humans; Insulin Resistance; Pheochromocytoma; Sodium-Glucose Transporter 2 Inhibitors; Insulin; Diabetic Ketoacidosis; Norepinephrine; Adrenal Gland Neoplasms; Diabetes Mellitus, Type 2
PubMed: 37731140
DOI: 10.1007/s12020-023-03492-7 -
Maedica Dec 2023ST waveform analysis (STAN) was introduced to improve the interpretation of cardiotocography (CTG) resulting in reduction of unnecessary interventions and metabolic...
ST waveform analysis (STAN) was introduced to improve the interpretation of cardiotocography (CTG) resulting in reduction of unnecessary interventions and metabolic acidosis. A systematic review was conducted with the aim to evaluate the effect of STAN method compared with isolated CTG on perinatal and neonatal outcomes. A search of electronic databases (PubMed, Cochrane, Scopus) was conducted to identify randomized controlled trials (RCTs) in English language. Outcomes considered operative deliveries, fetal blood sampling (FBS), metabolic acidosis, perinatal and neonatal death, neonatal seizures, neonatal encephalopathy, transfer to the neonatal intensive care unit (NICU) and Apgar score. Seven RCTs were included in the present review. The first two RCTs showed that the combination of STAN and CTG was a better option than using CTG alone, because there was a documented reduction in the rate of operative deliveries due to fetal distress and metabolic acidosis. The following studies showed no statistically significant changes with the combination of methods, except from a reduction in FBS. The findings from the RCTs were inconclusive. Most studies did not demonstrate a superiority of the combination regarding operative deliveries and neonatal outcomes but there were many methodological differences between the trials.
PubMed: 38348066
DOI: 10.26574/maedica.2023.18.4.684 -
Clinical Medicine (London, England) Nov 2023Lactic acidosis is commonly associated with tissue hypoperfusion and gives rise to concern regarding hypoxia or underlying hypotension. In the cancer patient, especially...
Lactic acidosis is commonly associated with tissue hypoperfusion and gives rise to concern regarding hypoxia or underlying hypotension. In the cancer patient, especially one undergoing chemotherapy, there is always concern for sepsis; however, in the otherwise clincially stable patient with cancer, type B lactic acidosis can also be related to their underlying malignancy. It is considered a haematological emergency given its high mortality rate. However, despite the urgency to treat type B lactic acidosis in these circumstances, treatment options beyond treatment of the malignancy are limited, and its presence portends a poor prognosis. This case highlights our current understanding of type B lactic acidosis and an approach to lactic acidosis evaluation in the cancer patient.
Topics: Humans; Acidosis, Lactic; Neoplasms; Sepsis
PubMed: 38065594
DOI: 10.7861/clinmed.2023-0391 -
Communications Biology Jul 2023Fructose-1,6-bisphosphatase (FBPase) deficiency, caused by an FBP1 mutation, is an autosomal recessive disorder characterized by hypoglycemic lactic acidosis. Due to the...
Fructose-1,6-bisphosphatase (FBPase) deficiency, caused by an FBP1 mutation, is an autosomal recessive disorder characterized by hypoglycemic lactic acidosis. Due to the rarity of FBPase deficiency, the mechanism by which the mutations cause enzyme activity loss still remains unclear. Here we identify compound heterozygous missense mutations of FBP1, c.491G>A (p.G164D) and c.581T>C (p.F194S), in an adult patient with hypoglycemic lactic acidosis. The G164D and F194S FBP1 mutants exhibit decreased FBP1 protein expression and a loss of FBPase enzyme activity. The biochemical phenotypes of all previously reported FBP1 missense mutations in addition to G164D and F194S are classified into three functional categories. Type 1 mutations are located at pivotal residues in enzyme activity motifs and have no effects on protein expression. Type 2 mutations structurally cluster around the substrate binding pocket and are associated with decreased protein expression due to protein misfolding. Type 3 mutations are likely nonpathogenic. These findings demonstrate a key role of protein misfolding in mediating the pathogenesis of FBPase deficiency, particularly for Type 2 mutations. This study provides important insights that certain patients with Type 2 mutations may respond to chaperone molecules.
Topics: Humans; Fructose-1,6-Diphosphatase Deficiency; Fructose-Bisphosphatase; Fructose; Acidosis, Lactic; Phenotype; Genotype; Hypoglycemic Agents
PubMed: 37507476
DOI: 10.1038/s42003-023-05160-y