Ketogenic Diet and Diabetes
According to recommendations made by international diabetes guidelines, the therapy of type 2 diabetes mellitus entails both pharmaceutical and lifestyle changes [1, 2, 3] Nutritional recommendations frequently emphasize cutting back on excess carbohydrates and restricting fat intake to 20–35% of total calories, with a particular emphasis on reducing saturated fats. Conversely, some diets advocate substantially reducing your intake of carbohydrates while increasing your intake of fats, which become your primary source of calories. These regimens are known as ketogenic diets. Here we review the Ketogenic diet and Diabetes Type II, with respect to glucose control, medication, and weight loss.
The Ketogenic diet is named as such as the high carbohydrate restriction (50 g/day), and the abundance of free fatty acids causes ketosis. These include acetoacetate (AcAc), 3-hydroxybutyrate (BHOB), which is a fuel, and acetone, which is created when AcAc spontaneously decarboxylates . With an increase in liver fatty acid oxidation and ketone body synthesis, this combination causes a fundamental shift in energy metabolism . Some very low-carbohydrate Ketogenic diets are even more restrictive, with a carbohydrate intake of less than 30 g/day [7, 8].
Ketogenic diets may benefit various cardiovascular risk variables in people with type 2 diabetes [9, 10, 11, 12, 13]. Notably, the use of ketone bodies has demonstrated protective effects on the heart and blood vessels in non-diabetics , findings that need to be verified in people with diabetes mellitus. Due to the high fat intake, there have been worries about long-term adverse effects, notably lipid metabolism and fatty liver disease; however, current investigations have not supported these views [15, 16]. This article discusses the ketogenic diet’s impact on body weight, medication use, and glycemic variability in people with Diabetes, as well as its effectiveness and tolerability/ practicality for treating the disease.
Effects of the Ketogenic Diet on Glucose Control in Diabetes
Glycated hemoglobin (HbA1c) was positively impacted, with reductions in short-term studies ranging from 0.6% after three weeks  to 0.9% after four months  to even 1.3% after 32 weeks . In other studies, 55% of the intervention group had an HbA1c of 6.5% compared to 0% in the control group (p=0.02) .
Another trial that followed participants for 90 days also observed a decrease in HbA1c from 8.9 to 5.6% (p0.0001) . Compared to a hypocaloric diet, the Ketogenic diet had a two-fold higher likelihood of lowering HbA1c below 7% . A significant drop in the HbA1c level from 7.8 to 6.3% was reported after 24 weeks in another trial where glucose-lowering medications were stopped before the Ketogenic diet . Long-term follow-ups showed that the HbA1c-lowering impact could still be seen, with significant reductions from 7.6 to 6.3% after one year , even though most improvements occurred in the first 70 days and from 7.5 to 5.9% after 15 months .
Even after 15 months, the same investigators reported remission in 10 of 24 Diabetes subjects (HbA1c 5.7% and no medication) .
When Saslow et al. compared a moderate-carb, calorie-restricted, low-fat diet (MCRC) with a very low-carb ketogenic diet (VLCKD) for a year, they discovered that the VLCKD group had an even more significant decrease in HbA1c levels than the MCRC group (VLCKD diet 6.6 to 6.1%; MCRC 6.9 to 6.7%) .
In several studies, the HbA1c level decreased significantly, although there were no differences from the control group. In research by Goldstein et al., the Atkins Ketogenic diet was compared to a traditional hypocaloric diet. At six weeks, three months, six months, and one year, the HbA1c levels in both groups decreased similarly, with no statistically significant changes between the groups . Tay et al. found a comparable 1% HbA1c decrease in both groups after 52 weeks when they compared an isocaloric, very-low-carbohydrate, high-fat diet to a high-carbohydrate, low-fat diet .
Last but not least, a study contrasting a standard isocaloric higher carbohydrate low-fat diet (HighCHO) with a very-low-carbohydrate diet (LowCHO) found a similar decrease in HbA1c after 12 months (LowCHO 7.2 to 6.3%, HighCHO 7.4 to 6.3%) (p0.001) .
With a Ketogenic diet, the glycemic variability appears to be reduced. Tay et al. found that in the low-carb group, individuals were more often in the euglycemic range (p=0.07) and were less often in the hyperglycemic range, which improved blood glucose stability . However, both groups experienced a comparable amount of time in the hypoglycemia range . In both short- and long-term investigations, the Ketogenic diets are also linked to appreciable reductions in fasting plasma glucose and mean glucose levels [21, 22, 25, 28,29, 30].
Effects of the Ketogenic Diet on the use of Glucose-Lowering Drugs in Diabetes
Numerous studies have noted a decrease in the need for glucose-lowering medicines after the Ketogenic diet. 60% of patients in a study by Saslow et al. stopped taking sulfonylureas, DPP-4 inhibitors, and/or metformin following a Ketogenic diet, but none of the subjects in the control group were able to do so . Relative to the control group, Tay et al. found that glucose-lowering medications decreased more after the Ketogenic diet (p=0.02) .
Participants in the Ketogenic diet group had significantly fewer prescriptions for all diabetic drugs at the 1-year follow-up than those in the control group . In particular, the overall prescriptions (excluding metformin) decreased in the intervention group from 57 to 30%; 94% of users reduced or stopped their insulin therapy; 100% of users stopped using sulfonylureas; and metformin usage declined marginally (from 71 to 65%, p=0.04). There were no dose variations between the research groups in a trial that only included metformin users . Authors hypothesized that this is likely explained by metformin’s safety, which prevents quick dose modifications .
Finally, after 15 months, Webster et al. found a decrease in the use of glucose-lowering drugs, including the discontinuation of insulin in 8 of 11 patients . Many studies required participants to stop taking all drugs or reduce their dosages before the Ketogenic diet, which makes it challenging to interpret the findings [21, 30]. In numerous studies, decreased medication use was seen in both arms (Ketogenic diet and control diet), indicating that even moderate weight loss can improve glycemic control [29, 31].
Effects on Weight Weight changes appear to be influenced by the length of interventional trials. After three weeks in short-term studies, both the weight-lowering strategy used in the control group and the Ketogenic diet, significant changes in weight reduction and body fat were documented [21, 23]. With a strict low-calorie Ketogenic diet throughout an 8-week intervention, Romano et al. observed a marked reduction in abdominal fat mass with intact lean mass (15.77% at the conclusion) .
Participants in studies comparing hypocaloric diets lost weight significantly more with the VLCKD than the control arm after four months (BMI 33.3 to 27.9 kg/m2 vs. standard low-calorie diet BMI 32.9 to 31.0 kg/m2) (p0.001)  and after six months (VLCKD BMI-12% vs. LCD BMI-6%; p0.0001 [ 30]). When comparing the Ketogenic diet with the calorie-restricted diet , or LowCHO with isocaloric HighCHO , or when comparing changes in fat mass and waist circumference after 12 months , several investigators did not report any statistical differences between the groups after 12 months of follow-up. In a study by Goldstein et al., only patients with strong dietary compliance—as shown by the presence of urine ketones—reported better weight reduction with a Ketogenic diet after six months compared to a regular calorie-restricted diet (3.7 kg, p=0.026); however, this benefit did not continue at 12 months .
Weight loss of 16 kg (p0.001) was reported in a descriptive study by Webster et al. to have continued after 15 months of a Ketogenic diet . After 12 months of follow-up, Saslow et al. concluded that participants on the VLCKD decreased their BMI more than patients in a group on a moderate-carb, calorie-restricted, low-fat diet (respectively 8.35% and 3.8%) . Patients received online assistance in a different trial conducted by the same team. In that study, 90% of participants on the Ketogenic diet lost 5% of their body weight, compared to only 29% in the control group (p=0.01) .
Effect on Lipids, Kidney, and Liver function
The effects of a Ketogenic diet on the lipid profile vary. Some authors observed improvements in LDL-cholesterol [23, 24 , 30] and triglycerides [20, 23,, 24, 26, 28, 29, 30, 31], while others reported no appreciable change and found an increase in triglycerides .
After four months  or 12 months of the Ketogenic diet , no observable changes in renal parameters, including the urinary albumin-to-creatinine ratio, estimated glomerular filtration rate, creatinine, and blood urea, were recorded. In the first 70 days of follow-up, the research found that glomerular function had improved .
After four months of follow-up, liver function tests, specifically alanine aminotransferase (ALT) and aspartate aminotransferase (AST) showed no differences . AST and ALT levels were observed to have significantly decreased after eight weeks  and 70 days .
Compliance and Practicality of the Ketogenic diet for Diabetes
Ketogenic diets are notoriously challenging to maintain over time due to their restrictive pattern. However, positive psychological support and reinforcing mindful eating tend to increase adherence. After a year, the mean retention rate in Saslow et al. trial was 85.3%, but as soon as the assistance decreased, the dropout rate increased . According to the data, 8% of individuals dropped out after receiving personal support, compared to 46% when receiving only online support (p=0.07) .
The development of behavioral adherence techniques with coaching, such as mindful eating, social support, and positive affect control, is crucial for the intervention’s success. Factors like unhappiness with unmet goals like better glycemic control and/or weight loss may harm adherence. Notably, a stronger psychological foundation distinctly supports dietary commitment , and it is necessary to receive at least some human attention (online or in-person meetings) .
Biological ketosis was not seen over the 12-month observation period, which was used by Goldstein et al. to indicate a progressive decline in the adherence rate to fulfill the carbohydrate restriction target . The lack of adherence, especially over an extended period, may be explained by the monotony of the diet and the common and, at times, unnecessary suggestions to avoid specific foods, including grains, legumes, fresh fruits, and vegetables. This is especially true in the Mediterranean region, where eating a diet high in grains, fruit, and vegetables is commonplace.
Additionally, the weight loss appears to have stopped after the first six months. According to Goldstein et al., obese diabetic patients in a Mediterranean environment had limited long-term compliance and effectiveness with the Ketogenic diet . Other authors have noted that support from peers and providers may be required to successfully adhere to the Ketogenic diet and maintain nutritional ketosis . With the proper assistance, most individuals could enter and sustain nutritional ketosis for up to a year, showing long-lasting effectiveness .
The main drivers of Ketogenic diet adoption, according to Wong et al., were better blood glucose control or a reduction in the need for diabetic medication, followed by weight loss and diabetes reversal . The most significant obstacles to sustaining good adherence were a need for more assistance from healthcare professionals and a lack of information supported by evidence .
The emergence of quick results and additional health advantages (improvements in cognitive capacities, decreases in levels of chronic pain, increases in energy levels, and improvements in sleep quality) support the incentive to adhere to the Ketogenic diet . Further, participants were less driven to think about food due to reduced hunger .
However, another critical difficulty is maintaining adherence to the Ketogenic diet when going to restaurants or meeting with friends and family. Based on their own experiences, Ketogenic diet users felt that the benefits outweighed the challenges associated with following the diet . Nevertheless, participants said that adhering to a Ketogenic diet was simpler, tastier, and more enjoyable overall than other diets they had previously tried , and many participants discovered that the adverse effects were less severe and long-lasting than anticipated .
In a real-world scenario, Webster et al. assessed the experiences of people with Diabetes and a Ketogenic diet . The ketogenic diet did not alter throughout the investigation. Participants reported alterations in their eating habits, including decreased appetites for sugary foods and snacks. Without experiencing hunger, many individuals dropped weight. It was considered advantageous as there was no requirement for estimating portions or keeping track of calories. Reducing medication use or being able to forego insulin therapy appeared motivating and empowering. The difficulties associated with socializing were the primary source of the reported challenges.
Along with increased energy, several patients also noticed increased physical activity. Because of this, the central mechanism(s) behind the beneficial health effects are confounded and, thus, yet unknown and may involve multiple factors .
During the 52-week follow-up period, the study by Goday et al. did not document any significant adverse effects . The asthenia, headaches, nausea, and vomiting were all mild side effects. 80% of VLCKD diet participants reported them, compared to 41% of the control group (low-calorie diet). (p<0.001). With time, these adverse effects subsided in the VLCKD diet group. After the trial, the VLCKD group reported constipation and orthostatic hypotension the most frequently (p 0.005). Similar dietary patterns were observed in both research groups . In obese patients, the low-calorie Ketogenic diet appears safe .
Considerations for Diabetic Patients
A ketogenic diet appears to have overall beneficial effects in Diabetes patients and remains in long-term trials. However, it is essential to characterize the key factors contributing to better clinical outcomes.
Despite the significant drops in HbA1 that have been observed in several studies, the study designs do not offer conclusive proof that the Ketogenic diet has a causal effect or that it will have long-term benefits for all diabetic patients. Furthermore, the impact of adding carbohydrates into the diet has yet to be researched.
Notably, all interventional groups received diet counseling that included lifestyle advice. Further, all groups lost weight, which may explain the impact on HbA1c levels regardless of the kind of diet. Consequently, it is challenging to distinguish between the influence of other lifestyle modifications and support and the effect of the nutritional intervention. Future research into the advantages of the Ketogenic diet must therefore include strong control groups to prevent biases caused by factors like exercise, calorie restriction, and intense coaching.
Pro-inflammatory states are present in patients with Diabetes and/or obesity [32, 33, 34], and a Ketogenic diet may have therapeutic effects on inflammation and positively modulate cardiovascular risk variables. Inhibiting the NLRP3 inflammasome in lipopolysaccharide (LPS)-stimulated human monocytes, for instance, BHOB, one of the serum ketones detected in abundance on the Ketogenic diet, promotes a reduction in inflammation [35, 36, 37]. This results in a decreased production of the inflammatory cytokines IL-1beta and IL-18. Clinical data showing a decrease in inflammatory markers with the Ketogenic diet  supported this observation.
The Ketogenic Diet studies have some limitations, as most did not assess the presence of ketosis (by testing plasma or capillary BHOB). To evaluate the success of the Ketogenic diet, this would have been a crucial outcome to consider.
While positive outcomes were reported in long-term investigations, they did not significantly differ from controls. The calorie restriction in all dietary regimens may help to explain this. Determining if there is an ideal target demographic for the Ketogenic diet is also important. Variables to take into account include the age of diabetes onset (recent or long-lasting) and the type of glucose-lowering medications.
Ketogenic diet adherence requires a significant amount of personal investment. In fact, the patient must follow precise guidelines in order to enter a ketogenic state, which might be challenging depending on dietary preferences. Moreover, some low-income households may not be able to afford a Ketogenic diet. Long-term adherence can be taxing, especially during social interactions. Healthcare professionals must be aware of the possibility that following a Ketogenic diet in specific individuals with Diabetes may be a symptom of an underlying eating disorder, which is more common in this population. Last but not least, a Ketogenic diet is not advised for women who may be pregnant or nursing.
Nephrolithiasis, a worsening of dyslipidemia, and hypoglycemia episodes if the glucose-lowering medication is not adjusted represent known hazards related to the Ketogenic diet. Because the Ketogenic diet can significantly drop blood glucose levels, diabetic people should always be closely monitored by a doctor. There have been several published suggestions for modifying diabetes medications . Biguanides, DPP-4 inhibitors, and GLP-1 agonists should be viewed as optional, and SGLT2 inhibitors should be avoided during a Ketogenic diet because they are linked to an increased risk of ketoacidosis in some Diabetes patients with relative insulin deficiency. Insulin, sulfonylureas, and glinides should all be gradually reduced by about 50%.
Future research should examine the impact of an intermittent Ketogenic diet, albeit if the intervention is too brief, a ketotic state might not be possible. It is possible that triggering brief periods of ketosis is advantageous. If so, it is essential to determine how long the ketotic state lasts and how long it lasts between episodes.
Additionally, it would be necessary to prevent consuming too many calories and/or carbohydrates in between these Ketogenic diet intervals. Which patients will benefit from a Ketogenic diet the most, particularly at the cardiovascular level, is a crucial research axis. Furthermore, it is crucial to investigate how the Ketogenic diet affects glycemic variability. Given that glycemic fluctuation is a recognized independent cardiovascular risk factor [40–43], this is of concern. It is possible that the glycemic fluctuation is less pronounced compared to a diet high in carbohydrates based on the nutritional composition of the Ketogenic diet. If verified, this could lend support for a possible cardio-vascular advantage of the Ketogenic diet.
Interventional diet studies cannot be single- or double-blinded. Thus, limitations in extrapolating causal relationships are expected. Nevertheless, the ketogenic diet appears to be a promising dietary intervention for enhancing glycemic control in Diabetes patients.
The advantages of a ketogenic state, however, need to be supported by careful investigations. Dietitians and doctors should provide assistance for their patients on the Ketogenic diet to prevent side effects and modify the dosages of glucose-lowering medications. Additionally, strong support maximizes long-term adherence and tolerability of the Ketogenic Diet, which is supported by the results of several Ketogenic Diet Randomized Controlled Trials (RCTs).
Key Takeaways from this Article:
•The ketogenic diet is a high-fat, low-carbohydrate diet that has been shown to improve glycemic control in people with diabetes.
• The ketogenic diet may also help to reduce the need for medication and promote weight loss.
• However, the ketogenic diet can be difficult to maintain over time and may not be practical for everyone with diabetes.