Type 1 diabetes and low carbohydrate diets-Defining the degree of nutritional ketosis.

AIMS: Adopting a low- or very low-carbohydrate (LCD or VLCD) diet in type 1 diabetes mellitus (T1D) is a controversial intervention. The main fear is that these diets may increase the risk of diabetic ketoacidosis. However, there is little data about the ketoacidosis risk and the level of physiological nutritional ketosis in individuals following these diets. We aimed to define the level of ketosis in those with T1D following carbohydrate restricted diets in a real-world observational study. METHODS: Patients with T1D who had self-selected dietary carbohydrate restriction were enrolled from local clinics and were compared to those following an unrestricted regular carbohydrate control diet (RCCD). Participants completed a 3-day diary, documenting food intake, ketones, and blood/interstitial glucose concentrations. RESULTS: Participants were divided into three groups according to mean carbohydrate intake: VLCD (<50 g carbohydrates/day) n = 6, LCD (50-130 g carbohydrates/day) n = 6, and RCCD (>130 g carbohydrates/day) n = 3. Mean beta-hydroxybutyrate (BOHB) concentrations were 1.2 mmol/l (SD 0.14), 0.3 mmol/l (SD 0.12) and 0.1mmol/l (SD 0.05) in the VLCD, LCD and RCCD groups, respectively (p = 0.02). Post hoc Dunn test demonstrated this reached statistical significance between the VLCD and RCCD groups (p = 0.02). CONCLUSION: Carbohydrate restricted diets, in particular VLCDs, are associated with a higher BOHB level. However, the degree of ketosis seen is much lower than we expected, and significantly lower than the level typically associated with diabetic ketoacidosis. This may suggest the risk of ketoacidosis is lower than feared, although safety will need to be evaluated further in large scale randomised trials.

Does the ketogenic ratio matter when using ketogenic diet therapy in pediatric epilepsy?

The ketogenic diet (KD) is a widely used therapeutic option for individuals with medically refractory epilepsy. As the diet's name implies, ketosis is a historically important component of the diet, but it is not well understood how important ketosis is for seizure control. The ketogenic ratio is defined as the ratio of fat to carbohydrate plus protein by weight in the diet (grams). Traditionally, the classic KD contains a 4:1 ratio, and a very high proportion of fat in the diet. The classic KD, with its high proportion of fat and limited carbohydrate intake can be restrictive for patients with epilepsy. Recently, there is experience with use of lower ketogenic ratios and less-restrictive diets such as the modified Atkins diet and the low glycemic index treatment. In this narrative review, we examine the role of ketosis and ketogenic ratios in determining the efficacy of the KD in children with epilepsy.

Younger patients and low c-peptide immunoreactivity index but not nutritional states affect fasting blood ketone levels in Japanese with type 1 diabetes after sodium-glucose cotransporter 2 inhibitor administration.

AIM: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are available for individuals with type 1 diabetes, but appropriate use is recommended to prevent ketosis or ketoacidosis. This study aimed to evaluate the risk of ketosis in people with type 1 diabetes, focusing on the relationship between nutritional assessment, glycaemic status, c-peptide immunoreactivity (CPR) index and body composition. MATERIALS AND METHODS: In total, 46 Japanese patients with type 1 diabetes were included, and dietary assessment from food photographs and ketone levels were evaluated before and after taking SGLT2is. The effect of diet on morning ketone levels was also investigated. RESULTS: All patients had an increase in mean ketone concentrations after taking SGLT2is (before 0.12 ± 0.06 mmol/L, after 0.23 ± 0.16 mmol/L). A significant negative correlation was found between average morning ketone levels and age (r = -0.514, p < .001) and the CPR index (r = -0.523, p = .038) after taking SGLT2is. Using a mixed-effects model based on the results before starting the inhibitors, it was noted that both patient-to-patient and age, or patient-to-patient and capacity of insulin secretion, influenced the ketone levels. Multiple regression analysis showed that factors associated with the risk of increasing ketone levels after taking SGLT2is were younger age (ß = -0.504, p = .003) and a low ratio of basal to bolus insulin (ß = -0.420, p = .005). CONCLUSIONS: When administering SGLT2is to patients with a low CPR index or younger patients with type 1 diabetes, adequate instructions to prevent ketosis should be given.

Utilization of the ketogenic diet for adults with status epilepticus.

BACKGROUND: The ketogenic diet (KD) is a high-fat, low-carbohydrate diet with therapeutic potential in refractory seizures, both in outpatient and inpatient settings. Successful implementation of KD involves a multifaceted, interdisciplinary approach to address anticipated challenges. We sought to characterize the utilization of KD among healthcare providers caring for adults with status epilepticus (SE). METHODS: We distributed a web-based survey through professional societies, including the American Academy of Neurology (AAN), Neurocritical Care Society (NCS), American Epilepsy Society (AES), Neuro Anesthesia and Critical Care Society (NACCS), and the Academy of Nutrition and Dietetics (AND), and via research contacts. We asked respondents about practice experience and experience using KD as a treatment for SE. Descriptive statistics and Chi-square tests were used to analyze the results. RESULTS: Of 156 respondents, 80% of physicians and 18% of non-physicians reported experience with KD for SE. Anticipated difficulty in achieving ketosis (36.3%), lack of expertise (24.2%), and lack of resources (20.9%) were identified as the most important barriers limiting the utilization of KD. The absence of dietitians (37.1%) or pharmacists (25.7%) support was the most important missing resource. Reasons for stopping KD included perceived ineffectiveness (29.1%), difficulty achieving ketosis (24.6%), and side effects (17.3%). Academic centers had more experience with the use of KD and greater EEG monitoring availability and fewer barriers to its implementation. The need for randomized clinical trials supporting efficacy (36.5%) and better practice guidelines for implementation and maintenance of KD (29.6%) were cited most frequently as factors to increase utilization of KD. CONCLUSION: This study identifies important barriers to the utilization of KD as a treatment for SE despite evidence supporting its efficacy in the appropriate clinical context, namely lack of resources and interdisciplinary support, and lack of established practice guidelines. Our results highlight the need for future research to improve understanding of the efficacy and safety of KD along with better interdisciplinary collaborations to increase its utilization.

Potential Clinical Applications for Continuous Ketone Monitoring in the Hospitalized Patient with Diabetes.

PURPOSE OF REVIEW: In this review, the authors discuss potential clinical applications for continuous ketone monitoring (CKM) in a broad continuum of clinical settings from pre-hospital care and the emergency department to acute inpatient management and post-discharge follow-up. RECENT FINDINGS: Though in its early stages, the concept of a novel continuous ketone sensing technology exerts great potential for use in the detection and hospital management of DKA, namely to overcome diagnostic barriers associated with ketoacidosis in patients with diabetes and obtain real-time BOHB levels, which may be useful in understanding both patients' response to treatment and DKA trajectory. Peri- and intra-operative use of CKM technology can potentially be applied in a number of urgent and elective surgical procedures frequently underwent by patients with diabetes and in the observation of patients during peri-operative fasting. In transitional care management, CKM technology could potentially facilitate patients' safe transition through levels of care, following hospital discharge from a DKA episode. This evaluation of the literature presents the potential advantages of adopting CKM and integrating this technology into the care algorithm of patients at risk for ketoacidosis.

Ketonuria and Seizure Control in the Medium Chain Triglyceride and Classic Ketogenic Diets.

We hypothesized that children receiving medium-chain triglyceride ketogenic diet (MCTKD) experience similar seizure reduction despite lower ketosis compared with classic ketogenic diet (CKD). Children initiating CKD or MCTKD were enrolled in a prospective observational study. Forty-five children completed 6 months of KD (n = 17 MCTKD, n = 28 CKD). The proportion achieving ≥50% seizure reduction was 71% CKD group and 59% MCTKD group; ≥90% reduction was 32% and 36% in CKD and MCTKD groups, respectively. CKD had higher urine ketones (≥8 mmol/L: 79% vs. 36%, p = 0.005). Children receiving MCTKD experience similar seizure control to CKD despite lower urine ketone measures.

First Report Of 50-Day Continuous Fasting in Symptomatic Multivessel Coronary Artery Disease and Heart Failure: Cardioprotection Through Natural Ketosis.

A 64-year-old man with angina and dyspnea due to severe two vessel coronary artery disease (CAD) was recommended for revascularization. The patient had recently learned Siddha fasting and self-inquiry meditative methods at Heartful Living, our eight-week physicianled cardiac wellness group clinic. He declined coronary artery bypass surgery and instead self-initiated a 50-day water-only fast and then switched to a vegan diet. During the fast, the patient experienced severe dehydration and electrolyte abnormalities, requiring IV fluids and electrolyte replacement. However, his hemodynamics remained stable and he had no angina, likely due to natural ketosis mediated cardioprotection. This is the first report of such a prolonged fast targeting cardiac resilience and clinical benefits in severe CAD.

Significant reduction of ketoacidosis at diabetes onset in children and adolescents with type 1 diabetes-The Stuttgart Diabetes Awareness Campaign, Germany.

BACKGROUND: To prevent the potentially life-threatening complication, diabetic ketoacidosis (DKA) at type 1 diabetes onset in children and adolescents, awareness campaigns can lead to a significant reduction of DKA. As in Germany, the incidence of DKA at diabetes onset had remained at a constant rate over the last 15 years and increasing numbers of very young children present with higher risk for DKA we decided to set up the Stuttgart Ketoacidosis Awareness Campaign. METHODS: Over 3 years (2015-2017) the campaign was conducted using information flyers and posters illustrating the typical symptoms of diabetes at school entry health examinations at the Public Health Department, in day-care facilities, in all pediatric practices and by regular public activities. The period between 2011 and 2013 was selected as a reference period. RESULTS: Approximately 17 000 children, median age 4.5 years, and their families were informed about the campaign during the preschool health examination. A total of 118 children and adolescents were treated with newly diagnosed type 1 diabetes compared with 127 during the reference period. During the campaign the incidence of DKA decreased significantly from 28% to 16%. CONCLUSIONS: Awareness campaigns like the Stuttgart Ketoacidosis Awareness Campaign about the typical clinical symptoms of type 1 diabetes can significantly reduce the risk for DKA at diabetes onset. Important factors for the success of our campaign were the close cooperation between the children's hospital and the public health department, the targeted approach of families, teachers, and pediatricians and the duration of the campaign over 3 years.

Sodium-glucose co-transporter type-2 inhibitors: pharmacology and peri-operative considerations.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are an emerging class of oral hypoglycaemic agents with therapeutic benefits beyond better glycaemic control. A major concern of the sodium-glucose co-transporter 2 inhibitors is their propensity to cause euglycaemic ketoacidosis in the peri-operative period and the potential for this critical diagnosis to be delayed or missed entirely. This review attempts to collate the case reports of sodium-glucose co-transporter 2 inhibitor ketoacidosis associated with surgery to highlight and put a perspective on this peri-operative issue. Preventive strategies and the management of the ketoacidosis are discussed.

An acidosis-sparing ketogenic (ASK) diet to improve efficacy and reduce adverse effects in the treatment of refractory epilepsy.

Diets that increase production of ketone bodies to provide alternative fuel for the brain are evolving from the classic ketogenic diet for epilepsy devised nearly a century ago. The classic ketogenic diet and its more recent variants all appear to have similar efficacy with approximately 50% of users showing a greater than 50% seizure reduction. They all require significant medical and dietetic support, and there are tolerability issues. A review suggests that low-grade chronic metabolic acidosis associated with ketosis is likely to be an important contributor to the short term and long term adverse effects of ketogenic diets. Recent studies, particularly with the characterization of the acid sensing ion channels, suggest that chronic metabolic acidosis may increase the propensity for seizures. It is also known that low-grade chronic metabolic acidosis has a broad range of negative health effects and an increased risk of early mortality in the general population. The modified ketogenic dietary treatment we propose is formulated to limit acidosis by measures that include monitoring protein intake and maximizing consumption of alkaline mineral-rich, low carbohydrate green vegetables. We hypothesize that this acidosis-sparing ketogenic diet is expected to be associated with less adverse effects and improved efficacy. A case history of life-long intractable epilepsy shows this diet to be a successful long-term strategy but, clearly, clinical studies are needed.

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.

Experience with the ketogenic diet in premature neonates.

The ketogenic diet is a time-tested, potent, nonpharmacological treatment of epilepsy. However, the use of the ketogenic diet in premature neonates with epilepsy has not been previously reported. We share our experience with the use of ketogenic diet therapy in two premature neonates. Two identical twin premature neonates with SCN2A-related developmental and epileptic encephalopathy, whose seizures were refractory to multiple anti-seizure medications, were started on the classic ketogenic diet at the conceptual age of 35 weeks. Ketosis was achieved and maintained (range 2-5 mmol/L of serum beta-hydroxybutyrate level). Seizure frequency was significantly reduced (>90% reduction in both patients), and some anti-seizure medications were able to be discontinued. Initial transient weight loss and one episode of asymptomatic hypoglycemia were observed and corrected. The ketogenic diet was found to be a safe, well-tolerated, and effective treatment for seizures in two premature neonates. The side effects are tolerable and correctable. The ketogenic diet, therefore, is a treatment option for refractory seizures in this age group, when administered under expert guidance.

Continuous Ketone Monitoring Consensus Report 2021.

This article is the work product of the Continuous Ketone Monitoring Consensus Panel, which was organized by Diabetes Technology Society and met virtually on April 20, 2021. The panel consisted of 20 US-based experts in the use of diabetes technology, representing adult endocrinology, pediatric endocrinology, advanced practice nursing, diabetes care and education, clinical chemistry, and bioengineering. The panelists were from universities, hospitals, freestanding research institutes, government, and private practice. Panelists reviewed the medical literature pertaining to ten topics: (1) physiology of ketone production, (2) measurement of ketones, (3) performance of the first continuous ketone monitor (CKM) reported to be used in human trials, (4) demographics and epidemiology of diabetic ketoacidosis (DKA), (5) atypical hyperketonemia, (6) prevention of DKA, (7) non-DKA states of fasting ketonemia and ketonuria, (8) potential integration of CKMs with pumps and automated insulin delivery systems to prevent DKA, (9) clinical trials of CKMs, and (10) the future of CKMs. The panelists summarized the medical literature for each of the ten topics in this report. They also developed 30 conclusions (amounting to three conclusions for each topic) about CKMs and voted unanimously to adopt the 30 conclusions. This report is intended to support the development of safe and effective continuous ketone monitoring and to apply this technology in ways that will benefit people with diabetes.

Association between ketosis and metabolic adaptation at the level of resting metabolic rate.

BACKGROUND: The ketone body ß-hydroxybutyrate (ßHB) has been shown to act as a signaling molecule that regulates metabolism and energy homeostasis during starvation in animal models. A potential association between ßHB and metabolic adaptation (a reduction in energy expenditure below predicted levels) in humans has never been explored. OBJECTIVE: To determine if metabolic adaptation at the level of resting metabolic rate (RMR) was associated with the magnitude of ketosis induced by a very-low energy diet (VLED). A secondary aim was to investigate if the association was modulated by sex. METHODS: Sixty-four individuals with obesity (BMI: 34.5 ± 3.4 kg/m2; age: 45.7 ± 8.0 years; 31 males) enrolled in a 1000 kcal/day diet for 8 weeks. Body weight/composition, RMR and ßHB (as a measure of ketosis) were determined at baseline and week 9 (W9). Metabolic adaptation was defined as a significantly lower measured versus predicted RMR (from own regression model). RESULTS: Participants lost on average 14.0 ± 3.9 kg and were ketotic (ßHB: 0.76 ± 0.51 mM) at W9. A significant metabolic adaptation was seen (-84 ± 106 kcal/day, P < 0.001), with no significant differences between sexes. [ßHB] was positively correlated with the magnitude of metabolic adaptation in females (r = 0.432, P = 0.012, n = 33), but not in males (r = 0.089, P = 0.634, n = 31). CONCLUSION: In females with obesity, but not males, the larger the [ßHB] under VLED, the greater the metabolic adaptation at the level of RMR. More studies are needed to confirm these findings and to explore the mechanisms behind the sex difference in the association between ketosis and metabolic adaptation. TRIAL REGISTRATION NAME: Clinicaltrials.gov. STUDY REGISTRATION ID: NCT02944253. URL: https://clinicaltrials.gov/ct2/show/NCT02944253.

Reducing Prescribing Errors in Hospitalized Children on the Ketogenic Diet.

BACKGROUND: Children on the ketogenic diet must limit carbohydrate intake to maintain ketosis and reduce seizure burden. Patients on ketogenic diet are vulnerable to harm in the hospital setting where carbohydrate-containing medications are commonly prescribed. We developed clinical decision support to reduce inappropriate prescription of carbohydrate-containing medications in hospitalized children on ketogenic diet. METHODS: A clinical decision support alert was developed through formative and summative usability testing. The alert warned prescribers when they entered an order for a carbohydrate-containing medication in patients on ketogenic diet. The alert was implemented using a quasi-experimental design with sequential crossover from control to intervention at two tertiary care pediatric hospitals within a single health system. The primary outcome was carbohydrate-containing medication orders per patient-day. RESULTS: During the study period, there were 280 ketogenic diet patient admissions totaling 1219 patient-days. The carbohydrate-containing medication order rate declined from 0.69 to 0.35 orders per patient-day (absolute rate reduction 0.34, 95% confidence interval 0.25-0.43), corresponding to 256 inappropriate orders prevented. The alert fired 398 times and was accepted (i.e., the order was removed) 227 times for an overall acceptance rate of 57%. CONCLUSIONS: Implementation of a clinical decision support alert at order-entry resulted in a sustained reduction in carbohydrate-containing medication orders for hospitalized patients on ketogenic diet without an increase in alert burden. Clinical decision support developed with user-centered design principles can improve patient safety for children on ketogenic diet by influencing prescriber behavior.

Type 1 diabetes and epilepsy: efficacy and safety of the ketogenic diet.

Diabetes type 1 seems to be more prevalent in epilepsy, and low-carbohydrate diets improve glycemic control in diabetes type 2, but data on the use of the classic ketogenic diet (KD) in epilepsy and diabetes are scarce. We present 15 months of follow-up of a 3 years and 6 months old girl with diabetes type 1 (on the KD), right-sided hemiparesis, and focal epilepsy due to a malformation of cortical development. Although epileptiform activity on electroencephalography (EEG) persisted (especially during sleep), clinically overt seizures have not been reported since the KD. An improved activity level and significant developmental achievements were noticed. Glycosylated hemoglobin (HbA1c) levels improved, and glycemic control was excellent, without severe side effects. Our experience indicates that diabetes does not preclude the use of the KD.

Mixed movement disorder as the presenting manifestation of non-ketotic hyperglycemia.

Focal neurological symptoms may provide the first clue to the presence of nonketotic hyperglycemia (NKH). We report a patient with hemichorea-hemiballism (HC-HB) as the first manifestation of NKH. CT Brain revealed hyperdensity in bilateral globus pallidus (GP) and putamen predominantly on right side. Blood sugar was 580 mg/dl and s. osmolality was 316 mosm/l. This condition resolved after correction of hyperglycemia. The possible mechanism by which NKH causes this condition is discussed.

An overlooked danger of ketogenic diets: Making the case that ketone bodies induce vascular damage by the same mechanisms as glucose.

Intense debate surrounds the use of low-carbohydrate, ketogenic diets for the promotion of weight loss and avoidance of cardiovascular disease. The rationale behind these diets is that they promote fat oxidation and minimize the addition of glucose to proteins in the formation of adducts that trigger inflammation. Although nutritional ketosis is widely assumed to be a safe metabolic condition, proper consideration has not been given to the fact that ketones are reactive toward proteins through the same mechanisms as glucose. Here, the case is made that ketone bodies are more potent than glucose in bringing about the protein modifications to which the harmful effects of glucose have been attributed. It is suggested, therefore, that attempts to minimize such protein modifications through nutritional ketosis are futile and may lead to adverse health outcomes.

Status epilepticus with visual seizures in ketotic hyperglycemia.

Metabolic disturbances are often associated with epileptic seizures, but the pathogenesis of this relationship is poorly understood. We describe the case of a 48-year-old man who presented with complex partial status epilepticus with visual seizures in the context of ketotic hyperglycemia. The EEG revealed a temporal epileptogenic focus and alterations were apparent on MRI in the acute phase and 4 months later. Very few cases of seizures in ketotic patients have been reported because ketone bodies have a protective effect against epilepsy. Seizures in hyperglycemia tend to be partial, and the only reports of visual seizures were due to occipital foci. Neuroradiological alterations have been reported in epileptic seizures, although usually in generalized seizures. The clinical, electrical, and imaging characteristics of this case are interesting and suggest that partial seizures can also cause long-term neuronal damage.

Role of Ketogenic Diets in Neurodegenerative Diseases (Alzheimer's Disease and Parkinson's Disease).

The goal of this review was to assess the effectiveness of ketogenic diets on the therapy of neurodegenerative diseases. The ketogenic diet is a low-carbohydrate and fat-rich diet. Its implementation has a fasting-like effect, which brings the body into a state of ketosis. The ketogenic diet has, for almost 100 years, been used in the therapy of drug-resistant epilepsy, but current studies indicate possible neuroprotective effects. Thus far, only a few studies have evaluated the role of the ketogenic diet in the prevention of Parkinson's disease (PD) and Alzheimer's disease (AD). Single studies with human participants have demonstrated a reduction of disease symptoms after application. The application of the ketogenic diet to elderly people, however, raises certain concerns. Persons with neurodegenerative diseases are at risk of malnutrition, while food intake reduction is associated with disease symptoms. In turn, the ketogenic diet leads to a reduced appetite; it is not attractive from an organoleptic point of view, and may be accompanied by side effects of the gastrointestinal system. All this may lead to further lowering of consumed food portions by elderly persons with neurodegenerative diseases and, in consequence, to further reduction in the supply of nutrients provided by the diet. Neither data on the long-term application of the ketogenic diet in patients with neurodegenerative disease or data on its effects on disease symptoms are available. Further research is needed to evaluate the suitability of the ketogenic diet in the therapy of AD- or PD-affected persons.