Emerging Concepts: Type 2 Diabetes and the Ketogenic Diet

selection of healthy fat sources,
EMERGING CONCEPTS

Emerging concepts are innovative ideas or interventions that are surfacing and hold potential for eventual adoption into clinical practice. IFM has a strong history of successfully identifying and accelerating the acceptance of emerging concepts. We are pleased to bring you these features to keep you in-the-know on exciting innovations in functional medicine.

Many clinicians are using ketogenic diets therapeutically for patients with insulin resistance and type 2 diabetes. While research into the safety and efficacy of the ketogenic diet for this purpose and others is ongoing, the incidence of diabetes continues to increase, intensifying the need to find effective treatments. This article examines the current state of the research and provides considerations for those who may be considering using ketogenic diets with their patients with type 2 diabetes.

What is a Ketogenic Diet?

A ketogenic (keto) diet, sometimes called a very low-carbohydrate diet, is a carbohydrate-restricted food plan in which carb intake is kept to between five and ten percent of dietary calories, with the balance consisting of relatively high fat and moderate protein intake. The source of this fat and protein may vary widely, from plant-based to primarily animal-derived. Originally designed in 1921 to treat epilepsy, the keto diet was used widely in pediatric patients for many years until the advent of anti-seizure pharmaceuticals.1

More recently, the diet has been studied as a method of weight loss, for prevention and treatment of neurological disorders, and as a therapeutic intervention for conditions related to insulin resistance, including polycystic ovarian syndrome (PCOS) and type 2 diabetes.2,3 While the data on the diet’s efficacy in these conditions is somewhat heterogenous, there are some general takeaways that clinicians can draw from this work and that may warrant consideration as a treatment in the right circumstances.

Biochemical Benefits

The biochemical rationale for ketogenic diets as therapeutic treatments stems from the fact that very low carbohydrate intake and the resulting low levels of blood glucose leads the body to release less insulin and instead use fatty acids and their metabolites, known as ketone bodies, as the primary energy source.1 During ketogenesis, not only are insulin and glucose levels reduced, but other hormonal changes may occur that can have positive impacts on physiology.

As long as the body is deprived of carbohydrates, it remains in a state of nutritional ketosis, in which small amounts of keto acids are effectively buffered in the blood. This is in contrast to the changes in blood pH that occur with ketoacidosis, a condition in which large amounts of acid cause life-threatening alterations in blood chemistry.1 Other potential biochemical benefits of ketones include their ability to cross the blood-brain barrier and serve as a fuel source for neurons, which otherwise run only on glucose, and their ability to decrease free radical damage and enhance antioxidant capacity.1

Keto Diet, Obesity, and Diabetes

Research into the ketogenic diet and obesity began in the mid-1960s, and early results were mixed, although only a handful of studies were conducted, and they mostly used a fasting diet as the comparison group.4,5 More recent research has pretty consistently found that low-carbohydrate diets (both ketogenic and non) lead to greater weight loss than other food plans, including low-fat6–8 and standard low-calorie9 diets.

Ketogenic diets may also improve blood lipids, although the data here are mixed. In some studies, LDL cholesterol increased on a keto diet, though there was a wide range of variability among subjects (from no increase to a doubling of LDL levels).10 Other studies have found that keto diets may improve lipoprotein profiles,2,8,11 including several that have found significant decreases in triglycerides12 and increases in HDL cholesterol.13 Several more have found these benefits along with no change in LDL levels.14–16 Some studies have found that a ketogenic diet may allow patients to lower their use of diabetes medications17 or even functionally reverse their diabetes diagnosis.14,18

In obese and diabetic populations, almost every study of ketogenic diets has found improved glucose balance as measured by decreases in blood glucose levels and hemoglobin A1c,15,17,19 weight loss, retention of lean muscle mass, and improvements in at least some blood lipids.12–16 Ketogenic diets may also be more beneficial for metabolism: studies have found that basal metabolic rate (BMR), the amount of calories the body burns at rest, does not decrease on a keto diet20 but may drop by as much as 400 kcal/day on a low-fat diet when compared to a very low-carb diet.21

Another food plan that relies on ketosis is intermittent fasting, in which a patient will fast for one or more days a week (or every day by prolonging the overnight fast), with the rest of the diet consisting of ad libitum eating. The idea here is that the body will enter ketosis temporarily, perhaps conferring some of the same benefits as prolonged ketosis. Intermittent fasting has been shown to lead to a reduction in body fat mass and improvement in metabolic parameters among patients with obesity and type 2 diabetes,22–24 but the published evidence for its use in these conditions continues to lag behind the ketogenic diet.

Concerns About Keto

So why are conventional guidelines not touting the use of ketogenic diets, both for obese and diabetic patients? There are still enough potential concerns about the diet and the body of research supporting its use in these populations, so much so that JAMA Internal Medicine recently published a Viewpoint decrying its use.25

While ketogenic diets have generally been found to be safe in the short term, one concern mentioned in this publication was all-cause mortality.25 In particular, two recent meta-analyses found that low carbohydrate diets were associated with a small increase in all-cause mortality.26,27 However, in one of these, the effect disappeared for those whose primary macronutrient source was plant-based rather than animal-based.27 On the other hand, a more recent prospective study, the Prospective Urban Rural Epidemiology (PURE) study, found the opposite: increased mortality with higher carbohydrate intake and lower mortality associated with higher fat intake, although this study was conducted across several countries, including many in which the main source of carbohydrates was refined; replacing these foods with almost anything is likely to be beneficial.28

Another potential issue with the keto diet is the mostly innocuous “keto flu” that may occur during the early days of the diet, in which patients may feel fatigued, feel weak, or experience GI disturbances.25 There is also a long list of relatively rare potential poor outcomes that mostly boil down to this: as with any dietary plan, there is an opportunity cost. By choosing to eat some things and avoid others, patients are missing out on any potential nutritive value of the foods that are not consumed. Not eating fruits, legumes, and high-fiber whole grains may be eliminating sources of many beneficial nutrients, and if patients and their clinicians are not mindful of the need to replace these nutrients, these rare side effects become more likely.25

One last concern is duration. Generally, ketogenic diets are not followed indefinitely, and no studies have been done on the safety of long-term, uninterrupted ketogenic diets. Patients usually follow a ketogenic diet for a minimum of two to three weeks and up to six to twelve months.1

Factors to Consider

While ketogenic diets have strict limits on the amount of carbohydrates consumed, there is considerable variation in the macronutrient distribution that forms the balance of the diet. Some incarnations focus on very high fat intake (with low protein), while others use more moderate levels of both fat and protein. While little research has directly compared high-fat keto versus moderate-fat keto, there is a theoretical basis for using a higher-fat version: limiting protein intake to less than one gram per pound of body weight prevents new glucose formation via gluconeogenesis;1 the amino acids from protein can be turned into glucose, but fat cannot.

On balance, there is pretty good evidence that keto diets in obese and diabetic populations lead to weight loss, improved glucose balance, reduced insulin resistance, and retention of lean muscle mass, as well as improvements in at least some blood lipids and probably also basal metabolic rate.

Considerations include:

  • The potential for increased all-cause mortality. This is somewhat murky but also may be tempered by a primarily plant-based keto dietary pattern.
  • A rise in LDL cholesterol. While not found in every study, one interesting point here is the variability among patients. Since everyone reacts to diets differently, it is worth considering a blood lipid panel for patients who have been on a keto diet for a few weeks to see how their LDL levels are responding and perhaps discontinuing the diet for those who show large increases.
  • Dietary insufficiencies without the nutrients found in whole grains, legumes, and fruits. Consider simple supplementation of these nutrients or food plans that specifically address these deficiencies.
  • Issues with renal function. Close monitoring of renal function may be indicated in certain patients on a ketogenic diet. There is also a potential risk of diabetic ketoacidosis (DKA) with concomitant SGLT2 inhibitor use. SGLT2 drugs come with a risk of DKA, and theoretically, very low-carbohydrate diets could increase this potential in type 2 diabetics taking these drugs. Although there is no good data on the issue, the recommendation is for caution with the use of ketogenic diets with concomitant use of SGLT2 inhibitors.29
  • Ketosis monitoring. In order to determine if a patient is in nutritional ketosis, consider some type of monitoring. While blood testing is historically the most accurate way to measure ketosis, non-invasive methods are also available, including breath testing, which some research suggests is as good as blood testing,30,31 and urine testing, which may be useful but has some significant drawbacks.32

Functional Medicine Considerations

Functional medicine recognizes the unique genetic and environmental history of each patient; thus, no diet (nor any other treatment) will be right for all patients with a condition. Leaving aside potential adverse reactions for a moment, some patients may find a ketogenic diet hard to follow and so may have better success on a different dietary plan.

Regarding potential side effects related to nutrient imbalances or insufficiencies on the ketogenic diet, functional medicine clinicians of all types are well-suited to help prevent these issues. Explicit instructions on what to eat (not just what not to eat) and supplementation are key steps in the functional medicine therapeutic process. So is tailoring the treatment to fit the patient and assessing whether or not it is working properly. In carefully selected diabetic patients, and in conjunction with other established interventions with acceptable safety profiles, a personalized ketogenic diet may be an effective adjunctive intervention.

Hear from functional medicine experts at IFM’s upcoming Cardiometabolic Advanced Practice Module (APM) to learn more about effective clinical applications and therapeutic approaches for patients with cardiometabolic conditions.

Learn More About Cardiometabolic Function

Related Articles

The Right Food Plan for Cardiometabolic Patients

Time-Restricted Feeding, Circadian Rhythms, and CVD

Fasting and Mitochondrial Health

References

  1. Masood W, Annamaraju P, Uppaluri KR. Ketogenic diet. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK499830/. Published August 2021. Accessed November 15, 2021.
  2. Stocker RK, Reber Aubry E, Bally L, Nuoffer J-M, Stanga Z. Ketogenic diet and its evidence-based therapeutic implementation in endocrine diseases. Praxis (Bern 1994). 2019;108(8):541-553. doi:10.1024/1661-8157/a003246.
  3. Paoli A, Mancin L, Giacona MC, Bianco A, Caprio M. Effects of a ketogenic diet in overweight women with polycystic ovary syndrome. J Transl Med. 2020;18(1):104. doi:10.1186/s12967-020-02277-0.
  4. Weight reduction: fasting versus a ketogenic diet. Nutr Rev. 1966;24(5):133-134. doi:10.1111/j.1753-4887.1966.tb08390.x.
  5. Benoit FL, Martin RL, Watten RH. Changes in body composition during weight reduction in obesity. Balance studies comparing effects of fasting and a ketogenic diet. Ann Intern Med. 1965;63(4):604-612. doi:10.7326/0003-4819-63-4-604.
  6. Tobias DK, Chen M, Manson JE, Ludwig DS, Willett W, Hu FB. Effect of low-fat diet interventions versus other diet interventions on long-term weight change in adults: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2015;3(12):968-979. doi:10.1016/S2213-8587(15)00367-8.
  7. Bueno NB, de Melo ISV, de Oliveira SL, da Rocha Ataide T. Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials. Br J Nutr. 2013;110(7):1178-1187. doi:10.1017/S0007114513000548.
  8. Choi YJ, Jeon S-M, Shin S. Impact of a ketogenic diet on metabolic parameters in patients with obesity or overweight and with or without type 2 diabetes: a meta-analysis of randomized controlled trials. Nutrients. 2020;12(7):2005. doi:10.3390/nu12072005.
  9. Moriconi E, Camajani E, Fabbri A, Lenzi A, Caprio M. Very-low-calorie ketogenic diet as a safe and valuable tool for long-term glycemic management in patients with obesity and type 2 diabetes. Nutrients. 2021;13(3):758. doi:10.3390/nu13030758.
  10.  Retterstøl K, Svendsen M, Narverud I, Holven KB. Effect of low carbohydrate high fat diet on LDL cholesterol and gene expression in normal-weight, young adults: a randomized controlled study. Atherosclerosis. 2018;279:52-61. doi:10.1016/j.atherosclerosis.2018.10.013.
  11.  Yuan X, Wang J, Yang S, et al. Effect of the ketogenic diet on glycemic control, insulin resistance, and lipid metabolism in patients with T2DM: a systematic review and meta-analysis. Nutr Diabetes. 2020;10(1):38. doi:10.1038/s41387-020-00142-z.
  12.  Saslow LR, Mason AE, Kim S, et al. An online intervention comparing a very low-carbohydrate ketogenic diet and lifestyle recommendations versus a plate method diet in overweight individuals with type 2 diabetes: a randomized controlled trial. J Med Internet Res. 2017;19(2):E36. doi:10.2196/jmir.5806.
  13.  Zinn C, McPhee J, Harris N, Williden M, Prendergast K, Schofield G. A 12-week low-carbohydrate, high-fat diet improves metabolic health outcomes over a control diet in a randomised controlled trial with overweight defence force personnel. Appl Physiol Nutr Metab. 2017;42(11):1158-1164. doi:10.1139/apnm-2017-0260.
  14.  Walton CM, Perry K, Hart RH, Berry SL, Bikman BT. Improvement in glycemic and lipid profiles in type 2 diabetics with a 90-day ketogenic diet. J Diabetes Res. 2019;2019:8681959. doi:10.1155/2019/8681959.
  15.  Tay J, Luscombe-Marsh ND, Thompson CH, et al. Comparison of low- and high-carbohydrate diets for type 2 diabetes management: a randomized trial. Am J Clin Nutr. 2015;102(4):780-790. doi:10.3945/ajcn.115.112581.
  16.  Yancy WS, Olsen MK, Guyton JR, Bakst RP, Westman EC. A low-carbohydrate, ketogenic diet versus a low-fat diet to treat obesity and hyperlipidemia: a randomized, controlled trial. Ann Intern Med. 2004;140(10):769-777. doi:10.7326/0003-4819-140-10-200405180-00006.
  17.  Tinguely D, Gross J, Kosinski C. Efficacy of ketogenic diets on type 2 diabetes: a systematic review. Curr Diab Rep. 2021;21(9):32. doi:10.1007/s11892-021-01399-z.
  18.  Cox N, Gibas S, Salisbury M, Gomer J, Gibas K. Ketogenic diets potentially reverse type II diabetes and ameliorate clinical depression: a case study. Diabetes Metab Syndr. 2019;13(2):1475-1479. doi:10.1016/j.dsx.2019.01.055.
  19.  Hussain TA, Mathew TC, Dashti AA, Asfar S, Al-Zaid N, Dashti HM. Effect of low-calorie versus low-carbohydrate ketogenic diet in type 2 diabetes. Nutrition. 2012;28(10):1016-1021. doi:10.1016/j.nut.2012.01.016.
  20.  Gomez-Arbelaez D, Crujeiras AB, Castro AI, et al. Resting metabolic rate of obese patients under very low calorie ketogenic diet. Nutr Metab (Lond). 2018;15:18. doi:10.1186/s12986-018-0249-z.
  21.  Ebbeling CB, Feldman HA, Klein GL, et al. Effects of a low carbohydrate diet on energy expenditure during weight loss maintenance: randomized trial. BMJ. 2018;363:K4583. doi:10.1136/bmj.k4583.
  22.  Morales-Suarez-Varela M, Collado Sánchez E, Peraita-Costa I, Llopis-Morales A, Soriano JM. Intermittent fasting and the possible benefits in obesity, diabetes, and multiple sclerosis: a systematic review of randomized clinical trials. Nutrients. 2021;13(9):3179. doi:10.3390/nu13093179.
  23.  Borgundvaag E, Mak J, Kramer CK. Metabolic impact of intermittent fasting in patients with type 2 diabetes mellitus: a systematic review and meta-analysis of interventional studies. J Clin Endocrinol Metab. 2021;106(3):902-911. doi:10.1210/clinem/dgaa926.
  24.  Vitale R, Kim Y. The effects of intermittent fasting on glycemic control and body composition in adults with obesity and type 2 diabetes: a systematic review. Metab Syndr Relat Disord. 2020;18(10):450-461. doi:10.1089/met.2020.0048.
  25.  Joshi S, Ostfeld RJ, McMacken M. The ketogenic diet for obesity and diabetes—enthusiasm outpaces evidence. JAMA Intern Med. 2019;179(9):1163-1164. doi:10.1001/jamainternmed.2019.2633.
  26.  Noto H, Goto A, Tsujimoto T, Noda M. Low-carbohydrate diets and all-cause mortality: a systematic review and meta-analysis of observational studies. PLoS One. 2013;8(1):E55030. doi:10.1371/journal.pone.0055030.
  27.  Seidelmann SB, Claggett B, Cheng S, et al. Dietary carbohydrate intake and mortality: a prospective cohort study and meta-analysis. Lancet Public Health. 2018;3(9):E419-E428. doi:10.1016/S2468-2667(18)30135-X.
  28.  Dehghan M, Mente A, Zhang X, et al. Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study. Lancet. 2017;390(10107):2050-2062. doi:10.1016/S0140-6736(17)32252-3.
  29.  Goldenberg RM, Berard LD, Cheng AYY, et al. SGLT2 Inhibitor–associated diabetic ketoacidosis: clinical review and recommendations for prevention and diagnosis. Clin Ther. 2016;38(12):2654-2664. doi:10.1016/j.clinthera.2016.11.002.
  30.  Güntner AT, Kompalla JF, Landis H, et al. Guiding ketogenic diet with breath acetone sensors. Sensors (Basel). 2018;18(11):E3655. doi:10.3390/s18113655.
  31.  Musa-Veloso K, Likhodii SS, Cunnane SC. Breath acetone is a reliable indicator of ketosis in adults consuming ketogenic meals. Am J Clin Nutr. 2002;76(1):65-70. doi:10.1093/ajcn/76.1.65.
  32.  Dhatariya K. Blood ketones: measurement, interpretation, limitations, and utility in the management of diabetic ketoacidosis. Rev Diabet Stud. 2016;13(4):217-225. doi:10.1900/RDS.2016.13.217.