Treatment of a Severe Form of Euglycemic Ketoacidosis in a Patient Treated with SGLT-2 Inhibitors with the Aid of Somatostatin.

Currently, the use of SGLT2 inhibitors is becoming more widespread, both for their role in controlling diabetes, and for their pleiotropic effects on glomerular hyperfiltration and heart failure. Along with their positive effects, these drugs can lead to various complications, the most severe being euglycemic ketoacidosis. The clinical case we have reported precisely describes this potentially serious complication which occurred in a 47-year-old patient who had been on SGLT2 inhibitor therapy for 5 years. In the resolution of this case we used, in addition to standard therapy, the continuous infusion of somatostatin, resulting in a rapid resolution of ketoacidosis and an improvement in the clinical condition.

Bacteremia due to Serratia rubidaea in intensive care unit: a case series.

INTRODUCTION: Bacteremia caused by Serratia rubidaea is seldom mentioned in comparison with other Enterobacteriaceae species. It primarily affects immunocompromised patients undergoing invasive procedures. Furthermore, the incidence, clinical features, and microbiological profile of this pathogen in the intensive care unit are rarely described. CASE PRESENTATION: We present four North African case studies of bacteremia in four young female patients admitted to the intensive care unit for ketoacidosis with a history of diabetes mellitus. All four patients developed catheter-related infections complicated by deep vein thrombosis. The catheter site was femoral in all cases, and the main clinical manifestation was poorly tolerated fever. The pathogen was isolated in multiple peripheral blood cultures (> 4) for each patient, showing a similar profile in all cases: resistance to third-generation cephalosporins and sensitivity to aminoglycosides, piperacillin, fluoroquinolones, and folate-pathway inhibitors. Targeted treatment consisted of a combination of ciprofloxacin 400 mg twice per day and trimethoprim/sulfamethoxazole 400/80 mg thrice per day for all four cases. However, in one case, this regimen was switched to amikacin due to adverse effects. The outcomes were favorable in the majority of cases. The patients described in this study were 21, 66, 22, and 27-year-old North African women. CONCLUSION: Most of the reported cases shared common risk factors and clinical aspects. Notably, a case of thrombosis complicating a catheter infection caused by Serratia rubidaea has not been previously reported in the literature. Furthermore, this bloodstream infection typically affects deeply immunocompromised patients. However, our four cases, admitted to the intensive care unit for ketoacidosis, only had a history of diabetes mellitus.

Dose-Dependent Beneficial Effect of Ketone Supplement-Evoked Ketosis on Anxiety Level in Female WAG/Rij Rats: Sometimes Less Is More.

While one-third of the population can be affected by anxiety disorders during their lifetime, our knowledge of the pathophysiology of these disorders is far from complete. Previously, it has been demonstrated in male animals that exogenous ketone supplement-evoked ketosis can decrease anxiety levels in preclinical rodent models, such as Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. Thus, in this study, we investigated whether intragastric gavage of the exogenous ketone supplement KEMCT (mix of 1,3-butanediol-acetoacetate diester/ketone ester/KE and medium-chain triglyceride/MCT oil in 1:1 ratio) for 7 days can alter the anxiety levels of female WAG/Rij rats using the light-dark box (LDB) test. We demonstrated that a lower dose of KEMCT (3 g/kg/day) increased blood R-ßHB (R-ß-hydroxybutyrate) levels and significantly decreased anxiety levels (e.g., increased the time spent in the light compartment) in female WAG/Rij rats on the seventh day of administration. Although the higher KEMCT dose (5 g/kg/day) increased blood R-ßHB levels more effectively, compared with the lower KEMCT dose, anxiety levels did not improve significantly. We conclude that ketone supplementation might be an effective strategy to induce anxiolytic effects not only in male but also in female WAG/Rij rats. However, these results suggest that the optimal level may be moderately, not highly, elevated blood R-ßHB levels when the goal is to alleviate symptoms of anxiety. More studies are needed to understand the exact mechanism of action of ketone supplementation on anxiety levels and to investigate their use in other animal models and humans for the treatment of anxiety disorders and other mental health conditions.

Adverse events and drug-drug interactions of sodium glucose co-transporter 2 inhibitors in patients treated for heart failure.

INTRODUCTION: Sodium glucose co-transporter 2-inhibitors (SGLT2-I), antihyperglycemic agents, are increasingly prescribed in chronic heart failure (CHF). Their risk for drug-drug interactions (DDI) seems low. Safety-data derive mainly from diabetes-patients. This review aims to summarize adverse-events (AE) and DDI of the SGLT2-I dapagliflozin, empagliflozin and sotagliflozin in patients with CHF. AREAS COVERED: Literature-search-terms in PubMed were 'adverse event/drug-drug interaction' and 'heart failure AND 'dapagliflozin' OR 'empagliflozin' OR 'sotagliflozin.'AEreported in randomized controlled trials (RCT) comprisegenitaland urinary-tract infections, hypotension, ketoacidosis, renal impairment, hypoglycemia, limb-amputations, Fournier's gangrene, bone-fractures, hepatopathy, pancreatitis, diarrhea, malignancy and venous thromboembolism. Their incidence is largely unknown, since they were not consistently evaluated in RCT of CHF. Further AE from meta-analyses, pharmacovigilance reports, case-series and case-reports include erythrocytosis, hypertriglyceridemia, myopathy, sarcopenia, skin problems, ventricular tachycardia, and urinary retention. The maximal observation period of RCT in CHF was 26 months.DDI were mainly studied in healthy volunteers for 3-8 days. In CHF or diabetes-patients, DDI were reported with interleukin-17-inhibitors, linezolid, lithium, tacrolimus, valproate, angiotensin-receptor-neprilysin-inhibitors and intravenous iron. EXPERT OPINION: Guidelines recommend treatment with SGLT2-I for CHF but no data on AE during long-term therapy and only little information on DDI are available, which stresses the need for further research. Evidence-based recommendations for ketoacidosis-prevention are desirable.

Lipolysis inhibition as a treatment of clinical ketosis in dairy cows: A randomized clinical trial.

Excessive and protracted lipolysis in adipose tissues of dairy cows is a major risk factor for clinical ketosis (CK). This metabolic disease is common in postpartum cows when lipolysis provides fatty acids as an energy substrate to offset negative energy balance. Lipolysis in cows can be induced by the canonical (hormonally induced) and inflammatory pathways. Current treatments for CK focus on improving glucose in blood (i.e., oral propylene glycol [PG], or i.v. dextrose). However, these therapies do not inhibit the canonical and inflammatory lipolytic pathways. Niacin (NIA) can reduce activation of the canonical pathway. Blocking inflammatory responses with cyclooxygenase inhibitors such as flunixin meglumine (FM) can inhibit inflammatory lipolytic activity. The objective of this study was to determine the effects of including NIA and FM in the standard PG treatment for postpartum CK on circulating concentrations of ketone bodies. A 4-group, parallel, individually randomized trial was conducted in multiparous Jersey cows (n = 80) from a commercial dairy in Michigan during a 7-mo period. Eligible cows had CK symptoms (lethargy, depressed appetite, and milk yield) and hyperketonemia (blood ß-hydroxybutyrate [BHB] ≥1.2 mmol/L). Cows with CK were randomly assigned to 1 of 3 groups where the first group received 310 g of oral PG once per day for 5 d; the second group received PG for 5 d + 24 g of oral NIA once per day for 3 d (PGNIA); and the third group received PG for 5 d + NIA for 3 d + 1.1 mg/kg i.v. FM once per day for 3 d (PGNIAFM). The control group consisted of cows that were clinically healthy (HC; untreated; BHB <1.2 mmol/L, n = 27) matching for parity and DIM with all 3 groups. Animals were sampled at enrollment (d 0), and d 3, 7, and 14 to evaluate ketone bodies and circulating metabolic and inflammatory biomarkers. Effects of treatment, sampling day, and their interactions were evaluated using mixed effects models. Logistic regression was used to calculate the odds ratio (OR) of returning to normoketonemia (BHB <1.2 mmol/L). Compared with HC, enrolled CK cows exhibited higher blood concentrations of dyslipidemia markers, including nonesterified fatty acids (NEFA) and BHB, and lower glucose and insulin levels. Cows with CK also had increased levels of biomarkers of pain (substance P), inflammation, including lipopolysaccharide-binding protein, haptoglobin, and serum amyloid A, and proinflammatory cytokines IL-4, MCP-1, MIP-1α, and TNFα. Importantly, 72.2% of CK cows presented endotoxemia and had higher circulating bacterial DNA compared with HC. By d 7, the percentage of cows with normoketonemia were higher in PGNIAFM = 87.5%, compared with PG = 58.33%, and PGNIA = 62.5%. At d 7 the OR for normoketonemia in PGNIAFM cows were 1.5 (95% CI, 1.03-2.17) and 1.4 (95% CI, 0.99-1.97) relative to PG and PGNIA, respectively. At d 3, 7, and 14, PGNIAFM cows presented the lowest values of BHB (PG = 1.36; PGNIA = 1.24; PGNIAFM = 0.89 ± 0.13 mmol/L), NEFA (PG = 0.58; PGNIA = 0.59; PGNIAFM = 0.45 ± 0.02 mmol/L), and acute phase proteins. Cows in PGNIAFM also presented the highest blood glucose increment across time points and insulin by d 7. These data provide evidence that bacteremia or endotoxemia, systemic inflammation, and pain may play a crucial role in CK pathogenesis. Additionally, targeting lipolysis and inflammation with NIA and FM during CK effectively reduces dyslipidemia biomarkers, improves glycemia, and improves overall clinical recovery.

Free Fatty Acids Induce Apoptosis of Mammary Epithelial Cells of Ketotic Dairy Cows via the Mito-ROS/NLRP3 Signaling Pathway.

Early lactation increases metabolic stress in ketotic dairy cows, leading to mitochondrial damage, apoptosis, and inflammatory response in mammary epithelial cells. The pyrin domain 3 (NLRP3) pathway involving the mitochondrial reactive oxygen species (Mito-ROS)-induced nucleotide-binding oligomerization domain-like receptor has been recognized as a key mechanism in this inflammatory response and cell apoptosis. This study aimed to elucidate the underlying regulatory mechanism of Mito-ROS-NLRP3 pathway-mediated mammary epithelial cell apoptosis in dairy cows with ketosis. Mitochondrial damage and cellular apoptotic program and NLRP3 inflammasome activation were observed in the mammary gland of ketotic cows. Similar damage was detected in MAC-T cells treated with exogenous fatty acids (FFAs). However, NLRP3 inhibitor MCC950 pretreatment or Mito-ROS scavenging by MitoTEMPO attenuated apoptosis in FFA-induced MAC-T cells by inhibiting the NLRP3 inflammasome pathway. These findings reveal that the Mito-ROS-NLRP3 pathway activation is a potent mechanism underlying mammary epithelial cell apoptosis in response to metabolic stress in ketotic dairy cows, which further contributes to reduced milk yield.

Ketosis-prone Diabetes and Hypogonadism: A New Clinical Association to be Aware of ?

BACKGROUND: Ketosis-prone diabetes (KPD) is an emerging entity, sharing features of both type 1 diabetes mellitus and type 2 diabetes mellitus. Patients with KPD usually present with diabetic ketoacidosis without the classic phenotype of autoimmune type 1 diabetes. In most cases, they are Afro-American adults, who require insulin therapy for the management of acute decompensation, then usually encountering insulin-free remission for prolonged periods of time with diet or with non-insulin agents. Meanwhile, hypogonadism is a known condition that could be associated with higher risk of developing both type 1 and type 2 diabetes and could be a risk factor for decompensated diabetes. The association of KPD and hypogonadism is reported for the first time in literature. CASE PRESENTATION: Here we report two peculiar cases of young African patients, affected by KPD and hypergonadotropic hypogonadism, respectively Klinefelter's syndrome and primary ovarian failure. Both patients were treated promptly for the ketoacidosis with intravenous fluids combined with continuous insulin infusion, and then switched to subcutaneous regimen. After the correct clinical evaluation, oral antidiabetic drugs were added. CONCLUSION: KPD remains an under-recognized and under-diagnosed type of diabetes. As hypogonadism is strongly linked to dysmetabolic disorders, the evaluation of sex hormones should be performed at the onset of diabetes. Further studies should investigate the hypothalamic-pituitary-gonadal axis and its role in the development of KDP and its manifestations and complications.

Parenteral medication considerations for the ketogenic diet.

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.

Ketones and the Heart: Metabolic Principles and Therapeutic Implications.

The ketone bodies beta-hydroxybutyrate and acetoacetate are hepatically produced metabolites catabolized in extrahepatic organs. Ketone bodies are a critical cardiac fuel and have diverse roles in the regulation of cellular processes such as metabolism, inflammation, and cellular crosstalk in multiple organs that mediate disease. This review focuses on the role of cardiac ketone metabolism in health and disease with an emphasis on the therapeutic potential of ketosis as a treatment for heart failure (HF). Cardiac metabolic reprogramming, characterized by diminished mitochondrial oxidative metabolism, contributes to cardiac dysfunction and pathologic remodeling during the development of HF. Growing evidence supports an adaptive role for ketone metabolism in HF to promote normal cardiac function and attenuate disease progression. Enhanced cardiac ketone utilization during HF is mediated by increased availability due to systemic ketosis and a cardiac autonomous upregulation of ketolytic enzymes. Therapeutic strategies designed to restore high-capacity fuel metabolism in the heart show promise to address fuel metabolic deficits that underpin the progression of HF. However, the mechanisms involved in the beneficial effects of ketone bodies in HF have yet to be defined and represent important future lines of inquiry. In addition to use as an energy substrate for cardiac mitochondrial oxidation, ketone bodies modulate myocardial utilization of glucose and fatty acids, two vital energy substrates that regulate cardiac function and hypertrophy. The salutary effects of ketone bodies during HF may also include extra-cardiac roles in modulating immune responses, reducing fibrosis, and promoting angiogenesis and vasodilation. Additional pleotropic signaling properties of beta-hydroxybutyrate and AcAc are discussed including epigenetic regulation and protection against oxidative stress. Evidence for the benefit and feasibility of therapeutic ketosis is examined in preclinical and clinical studies. Finally, ongoing clinical trials are reviewed for perspective on translation of ketone therapeutics for the treatment of HF.

Diabetic ketoacidosis with SGLT2 inhibitor use - a patient series. / Diabetisk ketoacidose ved bruk av SGLT2-hemmer ­ en pasientserie.

BACKGROUND: Inhibitors of sodium glucose cotransporter 2 (SGLT2 inhibitors) are increasingly being used to treat type 2 diabetes. Results from previous studies suggest a rising incidence of diabetic ketoacidosis with the use of this medication. MATERIAL AND METHOD: We performed a diagnosis search in the electronic patient records at Haukeland University Hospital for the period 1 January 2013-31 May 2021 with the aim of identifying patients with diabetic ketoacidosis who used SGLT2 inhibitors. A total of 806 patient records were reviewed. RESULTS: Twenty-one patients were identified. Thirteen had severe ketoacidosis, and ten had normal blood glucose levels. Probable triggering causes were found in 10 of the 21, with recent surgery being the most common (n = 6). Three of the patients were not tested for ketones, and 9 were not tested for antibodies to rule out type 1 diabetes. INTERPRETATION: The study showed that severe ketoacidosis occurs in patients with type 2 diabetes using SGLT2 inhibitors. It is important to be aware of this risk and the fact that ketoacidosis can occur without hyperglycaemia. Arterial blood gas and ketone tests must be performed to make the diagnosis.

Risk factors of dapagliflozin-associated diabetic ketosis/ketoacidosis in patients with type 2 diabetes mellitus: A matched case-control study.

OBJECTIVE: To investigate the risk factors of dapagliflozin-associated diabetic ketosis/ketoacidosis (DK/DKA) in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: A case-control study was conducted in a general hospital in China from 2018 to 2021. T2DM patients who developed DK/DKA after dapagliflozin treatment were identified. Each patient in the DA/DKA group was matched with a patient in the non-DK/DKA group in terms of the baseline characteristics. Receiver operating characteristic (ROC) curve analysis and logistic regressions were performed. RESULTS: Out of 1,684 hospitalized patients taking dapagliflozin, 170 were diagnosed with dapagliflozin-associated DK/DKA. A total of 137 cases were matched with 137 controls. The mean time-to-onset (TTO) of DK/DKA was 28.59 days. Logistic regression showed that current drinking (OR = 7.656, p < 0.001), T2DM duration ≥ 7.625 years (OR = 2.399, p = 0.017), acute ST-elevations myocardial infarction (STEMI) (OR = 12.770, p = 0.028), acute infection (OR = 2.862, p = 0.043), insulin dose reduction/cessation before dapagliflozin exposure (OR = 6.751, p < 0.001), and a major plus or major operation (OR = 2.652, p = 0.022) were risk factors for dapagliflozin-associated DK/DKA. Furthermore, T2DM duration ≥ 7.625 years (p = 0.046) and acute STEMI (p < 0.001) were independently associated with more severe DK/DKA. CONCLUSION: Current drinking, long T2DM duration, STEMI, acute infection, insulin deficiency, and major operation are the risk factors associated with DK/DKA in T2DM patients. Furthermore, long T2DM duration and STEMI were associated with more severe DK/DKA situations.

Exogenous ketone supplementation: an emerging tool for physiologists with potential as a metabolic therapy.

NEW FINDINGS: What is the topic of this review? The integrative physiological response to exogenous ketone supplementation. What advances does it highlight? The physiological effects and therapeutic potential of exogenous ketones on metabolic health, cardiovascular function, cognitive processing, and modulation of inflammatory pathways and immune function. Also highlighted are current challenges and future directions of the field. ABSTRACT: Exogenous oral ketone supplements, primarily in form of ketone salts or esters, have emerged as a useful research tool for manipulating metabolism with potential therapeutic application targeting various aspects of several common chronic diseases. Recent literature has investigated the effects of exogenously induced ketosis on metabolic health, cardiovascular function, cognitive processing, and modulation of inflammatory pathways and immune function. This narrative review provides an overview of the integrative physiological effects of exogenous ketone supplementation and highlights current challenges and future research directions. Much of the existing research on therapeutic applications - particularly mechanistic studies - has involved pre-clinical rodent and/or cellular models, requiring further validation in human clinical studies. Existing human studies report that exogenous ketones can lower blood glucose and improve some aspects of cognitive function, highlighting the potential therapeutic application of exogenous ketones for type 2 diabetes and neurological diseases. There is also support for the ability of exogenous ketosis to improve cardiac metabolism in rodent models of heart failure with supporting human studies emerging; long-terms effects of exogenous ketone supplementation on the human cardiovascular system and lipid profiles are needed. An important avenue for future work is provided by research accelerating technologies that enable continuous ketone monitoring and/or the development of more palatable ketone mixtures that optimize plasma ketone kinetics to enable sustained ketosis. Lastly, research exploring the physiological interactions between exogenous ketones and varying metabolic states (e.g., exercise, fasting, metabolic disease) should yield important insights that can be used to maximize the health benefits of exogenous ketosis.

Effect of empagliflozin in patients with type 2 diabetes during Ramadan on volume status, ketonaemia, and hypoglycaemia.

BACKGROUND AND AIMS: Patients with type 2 diabetes (T2D) carry higher risk of glycaemic variability during Ramadan. Glucose-lowering medications such as SGLT2 inhibitors are also associated with genitourinary infection, acute kidney injury, and euglycaemic diabetic ketoacidosis. Limited data is available on the effects of SGLT2 inhibitors on T2D patients during Ramadan. We investigated effects of empagliflozin use in fasting T2D patients. METHODS: This was a prospective cohort study in a single diabetes centre in Malaysia. Empagliflozin group were on study drug for at least three months. For control group, subjects not receiving SGLT2 inhibitors were recruited. Follow-up were performed before and during Ramadan fasting. Anthropometric measurements, blood pressure, renal profile, and blood ketone were recorded during visits. Hypoglycaemia symptoms were assessed via hypoglycaemia symptom rating questionnaire (HypoSRQ). RESULTS: We recruited a total of 98 subjects. Baseline anthropometry, blood pressure, and renal parameters were similar in two groups. No significant changes in blood pressure, weight, urea, creatinine, eGFR, or haemoglobin levels during Ramadan was found in either group. Likewise, no difference was detected in blood ketone levels (empagliflozin vs control, 0.17 ± 0.247 mmol/L vs 0.13 ± 0.082 mmol/L, p = 0.304) or hypoglycaemia indices (empagliflozin vs control, 19.1% vs 16%, p = 0.684). CONCLUSIONS: Ramadan fasting resulted in weight loss and reduction in eGFR levels in patients with T2D. Empagliflozin use during Ramadan is safe and not associated with increased risk of dehydration, ketosis, or hypoglycaemia. Therefore, empagliflozin is a viable glucose-lowering drug for patients with T2D planning for Ramadan fasting.

A randomized controlled trial examining the effects of treatment with propylene glycol and injectable cyanocobalamin on naturally occurring disease, milk production, and reproductive outcomes of dairy cows diagnosed with concurrent hyperketonemia and hypoglycemia.

The objective of this study was to assess the effects of treatment with propylene glycol (PG) and cyanocobalamin (B12) on health, milk production, and reproductive outcomes of cows diagnosed with hyperketonemia (HK), hypoglycemia (HG), or concurrent HKHG. Glucose and ß-hydroxybutyric acid (BHBA) concentrations were assessed in whole blood using a handheld device in lactating dairy cows (n = 2,418) between 3 and 9 d postpartum. Cows categorized as HK (n = 232, BHBA ≥1.2 mmol/L), HG (n = 161, glucose ≤2.2 mmol/L), and concurrent HKHG (n = 204, BHBA ≥1.2 mmol/L, and glucose ≤2.2 mmol/L) were randomized to receive treatment or to remain untreated (control). Treatment consisted of a single dose of B12 (10 mg, intramuscularly) and 300 mL of PG orally for 5 d, starting on the day of cow-side testing. Milk production, health, and reproductive outcomes were analyzed according to groups. Statistical analysis was carried out using SAS version 9.4 (SAS/STAT, SAS Institute Inc.). Treatment in HG cows decreased clinical ketosis, increased milk production in the fifth week of lactation for multiparous cows, and tended to increase 305-d mature-equivalent milk yield (305ME) for primiparous cows compared with untreated cows with the same metabolic profile. For cows with HKHG, treatment increased 305ME in multiparous cows and tended to increase 305ME in primiparous cows. No differences were found for treatment among any of the metabolic groups regarding reproductive outcomes, nor were any treatment effects found among HK cows. Glycemic status may help identify metabolically challenged early postpartum dairy cows, which may have differential response to PG and B12 treatment.

Changes in the rumen microbiota community in ketosis cows during propylene glycol treatment.

Ketosis, a common metabolic disorder in dairy cattle, occurs during early lactation and leads to higher concentrations of non-esterified fatty acids (NEFAs) and ß-hydroxybutyrate (BHBA), and is generally believed to be caused by excessive negative energy balance (NEB). Propylene glycol (PG), a gluconeogenic precursor, has been proved to promote gluconeogenesis and alleviate NEB. Oral administration of PG is widely considered one of the most effective therapeutic options for treating ketosis. Thus, in this study, we assessed the effects of PG on rumen microbiota via 16S rDNA analysis. The results show that one dose (500 mL) of PG treatment could rapidly reduce the blood BHBA level in ketosis cows by increasing the level and proportion of propionate in the rumen. Meanwhile, PG also had certain effects on the rumen bacterial community. Compared with before treatment, the relative abundances of Prevotella, Succinivibrionaceae_UCG-001 and Prevotellaceae_UCG-001 increased significantly, while those of Christensenellaceae_R-7_group, Butyrivibrio and Saccharofermentans significantly decreased. LEfSe analysis revealed that after PG treatment, only Rikenellaceae_RC9_gut_group was enriched in the rumen fluid at the genus level. In conclusion, the present study indicates that ketosis is accompanied by alterations in the rumen microbiota community. PG treatment changes the composition of rumen microbiota to a healthier state and contributes to rapid recovery from ketosis. These results support the usage of PG for treating such metabolic diseases that challenge high-yield cows due to their minimized cost and maximized safety without any adverse events.

[Controlling carbohydrate content in antiepileptic medications for children on a ketogenic diet]. / Control de carbohidratos en los medicamentos antiepilépticos para niños con dieta cetogénica.

Introduction: Introduction: patients who follow a ketogenic diet for the control of epileptic seizures must carry out a strict control of carbohydrates from the foods they eat and the medicines they are prescribed. In the initiation of a ketogenic diet and when a doctor prescribes a new medication, it is necessary to select the most appropriate pharmaceutical form so that the supply of excipients in the form of carbohydrates from the drugs is minimized. Objectives: the goal of the present paper was to compile a list of carbohydrate and caloric contents in antiepileptic drugs commonly used in pediatric neurology. Methods: in each medication included in the list, the content of excipients considered carbohydrates and derivatives that could influence the patient's ketosis was reviewed. The caloric content from carbohydrates and polyols in each medication was calculated. Results: the table provides the total carbohydrate and caloric content for antiepileptic medications in pediatric patients consuming the ketogenic diet. Conclusions: this table is intended to be a useful tool to help clinicians select a pharmaceutical form that is less likely to affect the ketogenic diet. Additionally, knowing the carbohydrate content of a new medication will allow adjustment of the diet to maintain ketosis.

Introducción: Introducción: los pacientes que siguen una dieta cetogénica para el control de las crisis epilépticas deben llevar a cabo un estricto control de los hidratos de carbono procedentes tanto de los alimentos que consumen como de los medicamentos que tienen pautados. Tanto en la instauración de la dieta cetogénica como cuando el médico prescribe un medicamento nuevo es necesario el ajuste de la medicación a las formas farmacéuticas más adecuadas, de forma que se minimice el aporte de excipientes en forma de hidratos de carbono de los medicamentos. Objetivos: el objetivo que planteamos en el presente trabajo fue elaborar un listado de medicamentos antiepilépticos de utilización habitual en neurología pediátrica que incluyera información sobre su contenido calórico en forma de hidratos de carbono para la administración a pacientes con dieta cetogénica. Métodos: en cada medicamento incluido en el listado se revisó el contenido en excipientes considerados hidratos de carbono y derivados que pudieran influir en la cetosis del paciente. Se calculó el contenido calórico procedente de los hidratos de carbono y polioles de cada medicamento. Resultados: elaboración de una tabla para consulta del contenido calórico de distintos medicamentos antiepilépticos utilizados en neurología pediátrica para pacientes con dieta cetogénica. Conclusiones: la tabla publicada pretende ser una herramienta útil que permita la consulta del contenido calórico de distintos medicamentos antiepilépticos y la selección del medicamento idóneo que menos afecte a la dieta cetogénica. Con el contenido calórico en carbohidratos de las medicaciones pautadas se podrán realizar los ajustes necesarios en la dieta para mantener la cetosis necesaria.

[About the safety profile of SGLT2 inhibitors]. / À propos de la sécurité d'emploi des inhibiteurs des SGLT2 (gliflozines).

Since their launch, sodium-glucose cotransporter type 2 inhibitors (SGLT2is) were suspected to be associated with various adverse events. They contributed to delay, as in France, or to restrict the use of this new pharmacological class in clinical practice, despite remarkable results reported in large cardiovascular or renal clinical trials. This article is devoted to three major adverse events that were imputed to SGLT2is : lower-limb extremity amputations, euglycaemic ketoacidosis and acute kidney injuries. In contrast to pharmacovigilance reports that raised suspicion, analysis of all data from the literature, either placebo-controlled trials or retrospective observational cohort studies, led to rather reassuring conclusions. The incidence of amputations does not appear to be increased while cases of acute kidney injury are reduced instead of increased as suspected earlier. Ketoacidosis events are almost doubled with SGLT2is versus comparators, yet their incidence remains extremely low among patients with type 2 diabetes. Of note, this potentially severe complication contributes to the denial of marketing authorization and reimbursement of SGLT2is in the population with type 1 diabetes.

Depuis leur mise sur le marché, les inhibiteurs des cotransporteurs sodium-glucose de type 2 (iSGLT2) ont été incriminés dans diverses manifestations indésirables. Celles-ci ont contribué à retarder, comme en France, ou à limiter la prescription de cette nouvelle classe pharmacologique en pratique clinique, malgré les résultats remarquables rapportés dans de grands essais à visée cardiovasculaire ou rénale. Cet article fait le point sur trois effets secondaires délétères importants imputés aux iSGLT2 : les amputations des extrémités des membres inférieurs, les acidocétoses dites euglycémiques et les insuffisances rénales aiguës. Malgré des données de pharmacovigilance qui avaient soulevé la suspicion, l'analyse de l'ensemble des données de la littérature, que ce soit les essais prospectifs contrôlés versus placebo ou les études observationnelles rétrospectives de cohorte versus des comparateurs actifs, aboutit à des conclusions assez rassurantes. Les amputations ne semblent pas être augmentées tandis que les cas d'insuffisance rénale aiguë sont plutôt en diminution au lieu de présenter une incidence accrue. Les cas d'acidocétose sont environ doublés sous iSGLT2 par rapport aux comparateurs, mais leur incidence reste extrêmement basse chez les patients diabétiques de type 2. Rappelons, néanmoins, que c'est cette complication potentiellement grave qui a entraîné le refus d'autorisation de mise sur le marché et du remboursement des iSGLT2 dans la population diabétique de type 1.

Relationship of concomitant anti-diabetic drug administration with sodium-glucose co-transporter 2 inhibitor-related ketosis.

OBJECTIVE: The use of sodium-glucose co-transporter 2 inhibitors (SGLT2is) may be associated with ketoacidosis. Therefore, the associated risk factors should be identified. In particular, information regarding the effects of the co-administration of anti-diabetic drugs is lacking. METHODS: We performed a retrospective study of 68 consecutive patients with diabetes who were taking an SGLT2i and attending a single medical center. After a period of treatment (median 78 days), their circulating ketone concentrations were measured. The concomitant use of other anti-diabetic drugs was analyzed to identify independent risk factors associated with ketosis. RESULTS: Twenty-five participants were taking empagliflozin, 23 were taking dapagliflozin, and 20 were taking canagliflozin. During the treatment period, no ketoacidotic events were recorded and their mean circulating ketone concentrations at the end of the study period were similar (0.3 mmol/L in the empagliflozin group, 0.26 mmol/L in the dapagliflozin group, and 0.25 mmol/L in the canagliflozin group). After adjustment for the use of anti-diabetic drugs, pioglitazone was found to be independently associated with a risk of high circulating ketone concentration (B value: 0.361, 95% confidence interval: 0.181-0.541). CONCLUSION: SGLT2i-associated ketoacidosis was found to be infrequent, but the concomitant use of pioglitazone was associated with a higher risk of ketosis.

Reducing milking frequency from twice to once daily as an adjunct treatment for ketosis in lactating dairy cows-A randomized controlled trial.

This randomized controlled trial investigated the effects of temporarily reducing milking frequency (MF) on the resolution of ketosis and milk production in dairy cows in early lactation. To detect ketosis [blood ß-hydroxybutyrate (BHB) ≥1.2 mmol/L], Holstein cows were screened daily from 3 to 16 d in milk using a cow-side meter. Cows diagnosed with ketosis (n = 104) were randomly assigned to twice-daily milking (TDM) or reduced to once-daily milking (ODM) for 2 wk, then returned to twice-daily milking. Both treatment groups received a 5-d treatment of an oral propylene glycol drench (PG; 300 g) beginning on the afternoon of the diagnosis; cows received additional 5-d PG treatments if they had a ketotic test result (blood BHB ≥1.2 mmol/L) at least 4 d after finishing the first PG treatment. Blood BHB tests were conducted for the first 3 d after ketosis diagnosis, and then once every 3 d for 21 d of trial (DOT). Milk and milk component data were collected weekly for 15 wk following trial enrollment. The ODM group showed rapidly and markedly decreased blood BHB concentrations (primiparous cows: 1 DOT, 0.92 ODM vs. 1.22 TDM, 15 DOT, 0.55 vs. 0.81 mmol/L; multiparous cows: 1 DOT, 1.01 vs. 1.40, 15 DOT, 0.78 vs. 1.65 mmol/L). In addition, a logistic regression model indicated that ODM cows were less likely to have blood BHB concentrations ≥1.2 mmol/L [primiparous cows: 3 DOT: ODM 1% (95% confidence interval: 0-10%) vs. TDM 43% (30-58%), 15 DOT ODM 0% (0-0.2%) vs. TDM 22% (13-36%); multiparous cows: 3 DOT: ODM 33% (24-44%) vs. TDM 59% (48-69%), 15 DOT ODM 20.9% (13-31%) vs. TDM 64% (53-74%)]. The proportion of ODM cows that required additional treatments of PG were substantially lower than the TDM group (ODM: 39%; TDM: 64%) than the TDM cows during the initial 21-d period. However, during the 2-wk treatment period, cows in the ODM group produced 26% less milk and 25% less energy-corrected milk than the TDM cows. During wk 3 to 15, when all cows were milked twice daily, ODM cows produced less milk (-14%) and energy-corrected milk (-12%) compared with the TDM group. Milk protein percentage was greater, and milk fat percentage and linear score tended to be greater in the ODM group over 15 wk. In conclusion, a 2-wk reduction of MF in ketotic cows from twice to once daily with treatment with PG resolved ketosis and decreased blood BHB concentrations more effectively than treating TDM cows with PG alone. However, the 2-wk MF reduction had immediate and long-term (up to 13 wk after cessation of MF reduction) negative effects on milk production.

Ketogenic diet-induced prurigo pigmentosa: a rising association.

Prurigo pigmentosa (PP) is an uncommon inflammatory dermatosis first described in 1971. It is characterized by recurrent crops of pruritic erythematous papulovesicles that resolve with a macular reticulated hyperpigmentation. The exact etiology is yet to be determined, however with the expanded application of the ketogenic diet (KD) in recent years, conditions accompanied with ketosis are more commonly being described in association with PP. Antibiotics as well as resolution of ketosis can effectively treat the dermatitis. Given the publicity and growing popularity of the ketogenic diet and numerous references to the "Keto-Rash" on social media, we reviewed the KD-induced PP cases to raise awareness of this increasingly recognized entity and provide an update to clinicians, particularly dermatologists, regarding this possible side effect of KD.