Harnessing the Synergy of SGLT2 Inhibitors and Continuous Ketone Monitoring (CKM) in Managing Heart Failure among Patients with Type 1 Diabetes.

Heart failure (HF) management in type 1 diabetes (T1D) is particularly challenging due to its increased prevalence and the associated risks of hospitalization and mortality, driven by diabetic cardiomyopathy. Sodium-glucose cotransporter-2 inhibitors (SGLT2-is) offer a promising avenue for treating HF, specifically the preserved ejection fraction variant most common in T1D, but their utility is hampered by the risk of euglycemic diabetic ketoacidosis (DKA). This review investigates the potential of SGLT2-is in T1D HF management alongside emergent Continuous Ketone Monitoring (CKM) technology as a means to mitigate DKA risk through a comprehensive analysis of clinical trials, observational studies, and reviews. The evidence suggests that SGLT2-is significantly reduce HF hospitalization and enhance cardiovascular outcomes. However, their application in T1D patients remains limited due to DKA concerns. CKM technology emerges as a crucial tool in this context, offering real-time monitoring of ketone levels, which enables the safe incorporation of SGLT2-is into treatment regimes by allowing for early detection and intervention in the development of ketosis. The synergy between SGLT2-is and CKM has the potential to revolutionize HF treatment in T1D, promising improved patient safety, quality of life, and reduced HF-related morbidity and mortality. Future research should aim to employ clinical trials directly assessing this integrated approach, potentially guiding new management protocols for HF in T1D.

Idiopathic ketotic hypoglycemia in children: an update.

Idiopathic ketotic hypoglycemia (IKH) is defined as bouts of hypoglycemia with increased blood or urine ketones in certain children after prolonged fasting or during illness. IKH is divided into physiological IKH, which is most frequently observed in normal children with intercurrent acute illness, and pathological IKH, which occurs in children who lack counter-regulatory hormones, have a metabolic disease, or have Silver-Russell syndrome. The typical patient is a young child between the ages of 10 months and 6 years. Episodes nearly always occur in the morning after overnight fasting. Symptoms include those of neuroglycopenia, ketosis, or both. IKH may be diagnosed after ruling out various metabolic and hormonal conditions associated with ketotic hypoglycemia. Sufficient amounts of carbohydrates and protein, avoidance of prolonged fasting, and increased frequency of food ingestion are the main modes of treating IKH. It is crucial to understand the pathogenesis of IKH and to distinguish physiological IKH from pathological IKH. In this mini-review, we present a brief summary of IKH in terms of its definition, types, clinical presentation, diagnosis, and therapeutic approach in children.

Difference in ketone bodies levels between diurnal and nocturnal fasting in children: observational study

Introduction Children are susceptible to developing preoperative ketonemia, which can be affected by changes in the circadian rhythm and counter-regulatory hormones. It is unclear whether ketonemia depends on the timing of fasting. Objective To assess the effect of preoperative fasting time (diurnal vs. night) on the preoperative concentration of ketone bodies in children. Methods We conducted a prospective-observational clinical study between September 2020 and March 2021, including children under 48 months of age scheduled for elective surgery. Two groups were identified based on fasting time, as follows: diurnal fasting (group A, n = 40) and nocturnal fasting (group B, n = 52). Demographic data, duration of fasting, time of excess fasting, type of food intake, the concentration of ketone bodies and capillary blood glucose, level of anxiety, and dehydration were analyzed in both groups. Results Diurnal fasting was associated with higher incidence of ketonemia compared with nocturnal fasting (Group A: 62.5% (95% CI 48.1-82.0); group B: 38,5% (95% CI 26.5-52.5), P=0.02). Most of the patients exceeded the duration of fasting recommended by preoperative fasting guidelines (95.6%). The type of food eaten before surgery was significantly associated with the presence of ketonemia (P=0.01). Conclusions Preoperative ketonemia is relatively common in patients under 48 months of age, especially among those who undergo diurnal fasting compared to nocturnal fasting.

Introducción Los niños son susceptibles a desarrollar cetonemia preoperatoria que puede verse afectada por cambios en el ritmo circadiano y las hormonas contrarreguladoras. No está claro si la cetonemia depende de la hora del ayuno. Objetivo Evaluar el efecto del momento del ayuno preoperatorio (diurno vs. nocturno) sobre la concentración preoperatoria de los cuerpos cetónicos en niños. Métodos Llevamos a cabo un estudio clínico observacional entre septiembre de 2020 y marzo de 2021, en niños menores de 48 meses, programados para cirugía electiva. Se identificaron dos grupos basados en la hora del ayuno, como sigue: ayuno diurno (grupo A, n = 40) y ayuno nocturno (grupo B, n = 52). En ambos grupos se analizaron los datos demográficos, la duración del ayuno, el tiempo excesivo de ayuno, el tipo de ingesta de alimentos, la concentración de cuerpos cetónicos, la glicemia capilar, el nivel de ansiedad y la deshidratación. Resultados El ayuno diurno se asocio con una mayor incidencia de cenotemia en comparación con el ayuno nocturno (Grupo A: 62,5% (IC 95% 48,1-82,0); grupo B: 38,5% (95% CI 26.5-52.5), P=0.02). La mayoría de los pacientes excedieron el tiempo de ayuno recomendado según las guías de ayuno preoperatorio (95,6%). El tipo de alimentos ingeridos antes de la cirugía se asoció de manera importante con la presencia de cetonemia (P=0,01). Conclusiones La cetonemia preoperatoria es relativamente común en pacientes menores de 48 meses de edad, especialmente entre quienes se someten a ayuno diurno en comparación con ayuno nocturno.

Ketonemia variability through menstrual cycle in patients undergoing classic ketogenic diet.

Introduction: Ketogenic dietary therapies (KDT) are well-established, safe, non-pharmacologic treatments used for children and adults with drug-resistant epilepsy and other neurological disorders. Ketone bodies (KBs) levels are recognized as helpful to check compliance to the KDT and to attempt titration of the diet according to the individualized needs. KBs might undergo inter-individual and intra-individual variability and can be affected by several factors. Possible variations in glycemia and ketone bodies blood levels according to the menstrual cycle have not been systematically assessed yet, but this time window deserves special attention because of hormonal and metabolic related changes. Methods: This study aims at searching for subtle changes in KBs blood level during menstrual cycle in female patients undergoing a stable ketogenic diet, by analyzing 3-months daily measurement of ketone bodies blood levels and glucose blood levels throughout the menstrual cycle. Results: We report the preliminary results on six female patients affected by GLUT1DS or drug resistant epilepsy, undergoing a stable classic ketogenic diet. A significant increase in glucose blood levels during menstruation was found in the entire cohort. As far as the ketone bodies blood levels, an inversely proportional trend compared to glycemia was noted. Conclusion: Exploring whether ketonemia variations might occur according to the menstrual cycle is relevant to determine the feasibility of transient preventive diet adjustments to assure a continuative treatment efficacy and to enhance dietary behavior support. Clinical trial registration: clinicaltrials.gov, identifier NCT05234411.

Alterations and diagnostic performance of capillary ketonemia in pediatric acute appendicitis: a pilot study.

INTRODUCTION: The diagnostic performance of capillary ketonemia (CK) has been previously evaluated in context of pediatric acute gastroenteritis. To our knowledge, there is no literature on its performance in the setting of pediatric acute appendicitis (PAA). MATERIALS AND METHODS: In this study, 151 patients were prospectively included and divided into two groups: (1) patients with non-surgical abdominal pain in whom the diagnosis of PAA was excluded (n = 53) and (2) patients with a confirmed diagnosis of PAA (n = 98). In 80 patients (Group 1, n = 23 and group 2, n = 57) a CK was measured at the time of diagnosis. The PAA group was further classified into complicated (n = 18) and uncomplicated PAA (n = 39). Quantitative variables were compared between groups using the Mann-Whitney U test. Diagnostic performance of CK was evaluated with ROC curves. RESULTS: CK values were 0.3 [0.1-0.9] mmol/L in group 1 and 0.7 [0.4-1.4] mmol/L in group 2 (p = 0.01). Regarding the type of PAA, CK values were 0.6 [0.4-0.9] mmol/L in uncomplicated PAA and 1.2 [0.8-1.4] mmol/L in complicated PAA (p = 0.02). The AUC for the discrimination between groups 1 and 2 was 0.68 (95% IC 0.53-0.82) (p = 0.24) and the AUC for the discrimination between uncomplicated PAA and complicated PAA was 0.69 (95% IC 0.54-0.85) (p = 0.04). The best cut-off point (group 1 vs group 2) resulted in 0.4 mmol/L, with a sensitivity of 80.7% and a specificity of 52.2%. The best cut-off point (non-complicated vs complicated PAA) resulted in 1.1 mmol/L, with a sensitivity of 61.1% and a specificity of 76.9%. CONCLUSIONS: This study found significantly higher levels of CK in patients with PAA than in those with NSAP. Similarly, significantly higher levels were observed in patients with complicated than in those with uncomplicated PAA. Nevertheless, the diagnostic performance of CK was only moderate in the two settings analyzed. The potential usefulness of CK determination as a tool to guide the preoperative rehydration regimen of patients with PAA to prevent postoperative hyporexia and vomiting is a promising line of research and should be evaluated in future studies.

Differential Diagnosis of Ketoacidosis in Hyperglycemic Alcoholic Diabetic Patient: Role of Insulin.

It is important to differentiate between diabetic ketoacidosis (DKA) and alcoholic ketoacidosis (AKA) in an alcoholic diabetic patient since it has significant management implications. Ketoacidosis in an alcoholic diabetic patient is a diagnostic challenge as both these clinical entities have metabolic acidosis with high anion gap. Most patients with DKA have hyperglycemia. The majority of AKA patients present with normal or low glucose levels; however, AKA may also present with high glucose levels, more so in diabetics. The situation becomes quite perplexing when an alcoholic diabetic patient presents with hyperglycemia since it can be attributed to DKA or AKA. How to cite this article: Garg SK, Garg P. Differential Diagnosis of Ketoacidosis in Hyperglycemic Alcoholic Diabetic Patient: Role of Insulin. Indian J Crit Care Med 2021; 25(10):1203-1204.

SGLT2 Inhibitor-Induced Low-Grade Ketonemia Ameliorates Retinal Hypoxia in Diabetic Retinopathy-A Novel Hypothesis.

Diabetic retinopathy (DR) is a well-recognized microvascular complication of diabetes. Growing evidence suggests that, in addition to retinal vascular damage, there is significant damage to retinal neural tissue in DR. Studies reveal neuronal damage before clinically evident vascular lesions and DR is now classified as a neurovascular complication. Hyperglycemia causes retinal damage through complex metabolic pathways leading to oxidative stress, inflammation, vascular damage, capillary ischemia, and retinal tissue hypoxia. Retinal hypoxia is further worsened by high oxygen consumption in the rods. Persistent hypoxia results in increases in vascular endothelial growth factor (VEGF) and other pro-angiogenic factors leading to proliferative DR/macular edema and progressive visual impairment. Optimal glucose control has favorable effects in DR. Other treatments for DR include laser photocoagulation, which improves retinal oxygenation by destroying the high oxygen consuming rods and their replacement by low oxygen consuming glial tissue. Hypoxia is a potent stimulator of VEGF, and intravitreal anti-VEGF antibodies are effective in regressing macular edema and in some studies, retinal neovascularization. In this review, we highlight the complex pathophysiology of DR with a focus on retinal oxygen/fuel consumption and hypoxic damage to retinal neurons. We discuss potential mechanisms through which sodium-glucose cotransporter 2 (SGLT2) inhibitors improve retinal hypoxia-through ketone bodies, which are energetically as efficient as glucose and yield more ATP per molecule of oxygen consumed than fat, with less oxidative stress. Retinal benefits would occur through improved fuel energetics, less hypoxia and through the anti-inflammatory/oxidative stress effects of ketone bodies. Well-designed studies are needed to explore this hypothesis.

Lactation Ketoacidosis: A Systematic Review of Case Reports.

Background and Objective: Lactation ketoacidosis is a rare cause of high anion gap metabolic acidosis affecting breastfeeding mothers. We aim to review and analyze all cases of lactation ketoacidosis reported. Materials and Methods: A systematic search of PubMed/MEDLINE and Cumulative Index to Nursing and Allied Health Literature (CINAHL), identifying relevant case reports published from 1 January 1970 to 31 December 2019. We extracted the following data: the first author, country, year of publication, age of the mother, age of the child, weight/body mass index (BMI) of the mother, precipitating factors, presenting symptoms, biochemical results, treatment, breastfeeding, and time from presentation to the resolution of ketoacidosis. Results: Sixteen case reports and 1 case series reporting 18 cases of lactation ketoacidosis were found. Presenting symptoms were nausea (72%, 13/18), vomiting (67%, 12/18), malaise (56%, 10/18), abdominal pain (44%, 8/18), dyspnea (33%, 6/18), headache (22%, 4/18), and palpitation (11%, 2/18). Dieting and physical exercise to lose weight were reported in 76% (14/18). The treatments included IV dextrose, sodium bicarbonate, insulin, rehydration, monitoring and replacement of electrolytes, and resumption of a balanced diet. The prognoses were good, with no mortalities. Conclusions: lactation ketoacidosis should be suspected in unwell breastfeeding women with high anion gap metabolic acidosis, after excluding other causes.

[Starvation ketoacidosis during prolonged fasting of 26 days]. / Hypercétose dans un contexte de jeûne prolongé de 26 jours.

Ketosis is a metabolic situation involving an increase in blood and urine concentrations of ketones that, when prolonged, leads to acidosis. Moderate ketosis usually appears after a fast of a few hours, but its prolongation exposes to hyperketosis. Observation: A 25-year-old woman presented to the emergency department for cohercitive vomiting. She was fasting for a long time in a spiritual setting and had a restricted diet limited to water and vitamin supplements. Clinical and biological assessment was in favour of fasting ketoacidosis. Evolution was favorable with intravenous hydration, poly-ionic and micronutrient supplementation and a gradual resumption of oral feeding. Conclusion: We report the case of a patient with fasting ketoacidosis. Besides consequences of this ketoacidosis, the challenge was also in resuming oral feeding in order to avoid a potentially fatal inappropriate renutrition syndrome.

Alcohol-induced ketonemia is associated with lowering of blood glucose, downregulation of gluconeogenic genes, and depletion of hepatic glycogen in type 2 diabetic db/db mice.

Alcoholic ketoacidosis and diabetic ketoacidosis are life-threatening complications that share the characteristic features of high anion gap metabolic acidosis. Ketoacidosis is attributed in part to the massive release of ketone bodies (e.g., ß-hydroxybutyrate; ßOHB) from the liver into the systemic circulation. To date, the impact of ethanol consumption on systemic ketone concentration, glycemic control, and hepatic gluconeogenesis and glycogenesis remains largely unknown, especially in the context of type 2 diabetes. In the present study, ethanol intake (36% ethanol- and 36% fat-derived calories) by type 2 diabetic db/db mice for 9 days resulted in significant decreases in weight gain (∼19.5% ↓) and caloric intake (∼30% ↓). This was accompanied by a transition from macrovesicular-to-microvesicular hepatic steatosis with a modest increase in hepatic TG (∼37% ↑). Importantly, ethanol increased systemic ßOHB concentration (∼8-fold ↑) with significant decreases in blood glucose (∼4-fold ↓) and plasma insulin and HOMA-IR index (∼3-fold ↓). In addition, ethanol enhanced hepatic ßOHB content (∼5-fold ↑) and hmgcs2 mRNA expression (∼3.7-fold ↑), downregulated key gluconeogenic mRNAs (e.g., Pcx, Pck1, and G6pc), and depleted hepatic glycogen (∼4-fold ↓). Furthermore, ethanol intake led to significant decreases in the mRNA/protein expression and allosteric activation of glycogen synthase (GS) in liver tissues regardless of changes in the phosphorylation of GS, GSK-3ß, or Akt. Together, our findings suggest that ethanol-induced ketonemia may occur in concomitance with significant lowering of blood glucose concentration, which may be attributed to suppression of gluconeogenesis in the setting of glycogen depletion in type 2 diabetes.

Evaluation of the Precision Xtra meter for monitoring blood ß-hydroxybutyrate concentrations in late-gestation ewes.

Blood samples were collected from late-gestation ewes to determine the agreement of a point-of-care (POC) Precision Xtra meter and a standard laboratory test for ß-hydroxybutyrate (BHBA). Fresh whole blood samples were immediately tested with the POC instrument, and serum samples were analyzed with a standard commercial biochemical analyzer. Ewes were classified as having ketonemia if their BHBA concentrations were ≥800 µmol/L. Scatter plots, paired t-tests, Bland-Altman limits of agreement, and Gwet AC1 tests were used to compare results. The 2 tests had very good agreement. The values between instruments were not statistically different based on paired t-tests ( p = 0.312). The intercept and slope of a linear mixed model, containing the standard test results as an outcome and the POC meter results as a predictor, were 0.02 (95% CI: 0.00, 0.04) and 0.98 (95% CI: 0.96, 1.01), respectively. When the samples were classified into ketonemic classes (non-ketonemic and ketonemic) based on BHBA concentrations obtained from each test, the Gwet AC1 statistic was 0.94 (95% CI: 0.91, 0.97; p < 0.001). The ketosis classification agreed in 95% of samples. Based on the Bland-Altman plot and limits of agreement, the optimal cutoff to diagnose ketonemia with the POC meter was 1,000 µmol/L, which is 200 µmol/L higher than the laboratory BHBA medical decision limit. The Precision Xtra meter provided excellent correlation and substantial agreement with the standard laboratory technique for measuring blood BHBA in late-gestation ewes.

Caffeine intake increases plasma ketones: an acute metabolic study in humans.

Brain glucose uptake declines during aging and is significantly impaired in Alzheimer's disease. Ketones are the main alternative brain fuel to glucose so they represent a potential approach to compensate for the brain glucose reduction. Caffeine is of interest as a potential ketogenic agent owing to its actions on lipolysis and lipid oxidation but whether it is ketogenic in humans is unknown. This study aimed to evaluate the acute ketogenic effect of 2 doses of caffeine (2.5; 5.0 mg/kg) in 10 healthy adults. Caffeine given at breakfast significantly stimulated ketone production in a dose-dependent manner (+88%; +116%) and also raised plasma free fatty acids. Whether caffeine has long-term ketogenic effects or could enhance the ketogenic effect of medium chain triglycerides remains to be determined.

Retrospective comparison of early- versus late-insulin therapy regarding effect on time to resolution of diabetic ketosis and ketoacidosis in dogs and cats: 60 cases (2003-2013).

OBJECTIVE: To determine whether early insulin administration (≤6 h after admission) results in more rapid resolution of diabetic ketosis (DK) and ketoacidosis (DKA), shorter duration of hospitalization, and higher incidence of complications, and whether more severe ketonuria is associated with longer time to resolution of DK/DKA. DESIGN: Retrospective study (January 1, 2003-March 1, 2013). SETTING: University teaching hospital. ANIMALS: Sixty dogs and cats with DK or DKA receiving short-acting insulin therapy. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Medical records were reviewed and data recorded including signalment; previous history of diabetes; intake temperature, blood pressure, blood glucose, pH, base excess, and degree of ketonuria; time to short-acting insulin therapy and resolution of DK/DKA; length of hospitalization; and complications. Insulin was initiated ≤6 hours in the early group and >6 hours in the late group after hospital admission. Early group patients had more rapid resolution of DK/DKA after starting short-acting insulin therapy (36.4 ± 22.6 vs. 55.4 ± 26.6 h, P = 0.014). There was no difference in duration of hospitalization or complications. More severe ketonuria resulted in longer time to resolution of DK/DKA after initiation of short-acting insulin (severe: 50.9 ± 24.2; moderate: 29.6 ± 19; mild: 23.4 ± 21.9 h, P = 0.005, all individual pairwise comparisons P < 0.05). CONCLUSIONS: Early insulin administration is associated with more rapid resolution of DK/DKA without an associated increase in complication rates. DK/DKA took longer to resolve with more severe ketonuria. Prospective studies are warranted to identify specific time targets for insulin administration in DK/DKA patients.

Sodium-glucose co-transporter-2 inhibitors and euglycemic ketoacidosis: Wisdom of hindsight.

Sodium-glucose co-transporter-2 inhibitors (SGLT-2i) are newly approved class of oral anti-diabetic drugs, in the treatment of type 2 diabetes, which reduces blood glucose through glucouresis via the kidney, independent, and irrespective of available pancreatic beta-cells. Studies conducted across their clinical development program found, a modest reduction in glycated hemoglobin ranging from -0.5 to -0.8%, without any significant hypoglycemia. Moreover, head-to-head studies versus active comparators yielded comparable efficacy. Interestingly, weight and blood pressure reduction were additionally observed, which was not only consistent but significantly superior to active comparators, including metformin, sulfonylureas, and dipeptydylpeptide-4 inhibitors. Indeed, these additional properties makes this class a promising oral anti-diabetic drug. Surprisingly, a potentially fatal unwanted side effect of diabetic ketoacidosis has been noted with its widespread use, albeit rarely. Nevertheless, this has created a passé among the clinicians. This review is an attempt to pool those ketosis data emerging with SGLT-2i, and put a perspective on its implicated mechanism.