Prior to the discovery of insulin, a very low-carbohydrate and probably ketogenic diet was used by some respected physicians to treat type 1 diabetes [1]. Many considerations may argue in favor of treating type 1 diabetes with a very low-carbohydrate diet (with the advantage of modest insulin dosing) today, compared with current standard of care. Among people with type 1 diabetes, current standard of care results in: a higher rate of obesity than the general population [2], an average of two symptomatic hypoglycemia episodes per week [3], nearly universal retinopathy within two decades of diagnosis [4], a much higher rate of cardiovascular mortality [5], and a higher incidence of cancer [6]. A higher rate of obesity is probably due to higher-than-required insulin to “cover” glucose [2]; hypoglycemia is caused by insulin “overshoot” [3]; and retinopathy, excess cardiovascular mortality, and probably cancer are due to chronic hyperglycemia [4–6]. Correspondingly, HbA1c, a measure of average blood glucose, was 8.3% on average in a recent study in 25,833 children and adults with type 1 diabetes, while the goal according to guidelines is 7.0% for adults and 7.5% for children, and the cutoff for diabetes is 6.5%. Thus, the large majority of people with type 1 diabetes have a blood sugar that is excessively high, and they do not meet official targets [7].

In response to the risks and difficulties in managing type 1 diabetes, very-low-carbohydrate diets (defined as <50 grams of carbohydrate per day) have seen a resurgence in recent years, spearheaded in part by the advocacy and sophisticated glycemic management strategies of Richard Bernstein, a physician and type 1 diabetes patient himself [8]; others within academia have also played an important role [9]. Very-low-carbohydrate diets have the potential to mitigate many or all of the risks discussed above. A recent systematic review, which included single-arm trials with up to 18 months of follow-up, have found several advantages to using a very-low-carbohydrate diet for type 1 diabetes, including improvements of HbA1c into the normal range (no other intervention has shown this effectiveness apart from islet cell transplants) and reduced insulin use [10]. Although no studies with multi-year follow-ups have been done, such improvements in glycemia in persons with type 1 diabetes suggest the potential for large benefits to cardiovascular risk and mortality, in line with the findings of DCCT/EDIC, which showed such benefits via glucose lowering by conventional strategies [11].

Moreover, if the hyperglycemia is the major risk driving increased cancer risk, a cancer risk reduction benefit is plausible. Additionally, the ketogenic diet may conceivably confer some protection from the symptoms of hypoglycemia, since ketones have been shown to provide the brain with an alternative source of energy substrate during periods of extreme hypoglycemia [12,13]. Likewise, limiting or eliminating hyperglycemia would likely prevent the development of retinopathy [4,11]. Finally, much animal work suggests that the beta-hydroxybutyrate produced by ketogenesis might be able to independently enhance the benefits of improved glycemia on retinopathy and other diabetic sequelae, via anti-inflammatory effects from the activation of GPR109A [14] and inhibition of NLRP3 [15]. However, although promising, many of these mechanisms remain speculative in humans and need to be tested in formal trials.

A recent, highly publicized study conducted using an online survey found exceptional management of hemoglobin A1c when subjects were placed on a very low carbohydrate diet, with an average HbA1c of 5.67%, 69% of respondents reporting five or fewer hypoglycemic events per month, an incidence of just 1% per year of ketoacidosis, and in general an extremely low incidence of severe diabetes-related adverse events at just 2% per year [16]. However, the patients surveyed represent a highly selected population that is probably more motivated and educated than average, and these findings need to be replicated in the general population in well-designed clinical trials. Importantly, an upcoming randomized clinical trial including children and adults and with a carefully controlled meal delivery design may help to illuminate the potential role of very low-carbohydrate diets in the treatment of type 1 diabetes in conventional medical practices (NCT03710928). Thus, the use of very-low-carbohydrate or ketogenic diets for type 1 diabetes shows promise and further investigation is underway.

References

1. Newburgh, L.H.; Marsh, P.L. The use of a high fat diet in the treatment of diabetes mellitus. Arch. Intern. Med. 1920, 26, 647.

2. Mottalib, A.; Kasetty, M.; Mar, J.Y.; Elseaidy, T.; Ashrafzadeh, S.; Hamdy, O. Weight Management in Patients with Type 1 Diabetes and Obesity. Curr. Diab. Rep. 2017, 17.

3. McCrimmon, R.J.; Sherwin, R.S. Hypoglycemia in Type 1 Diabetes. Diabetes 2010, 59, 2333–2339.

4. Fong, D.S.; Aiello, L.; Gardner, T.W.; King, G.L.; Blankenship, G.; Cavallerano, J.D.; Ferris, F.L.; Klein, R. Retinopathy in Diabetes. Diabetes Care 2004, 27, S84–S87.

5. Lind, M.; Svensson, A.-M.; Kosiborod, M.; Gudbjörnsdottir, S.; Pivodic, A.; Wedel, H.; Dahlqvist, S.; Clements, M.; Rosengren, A. Glycemic Control and Excess Mortality in Type 1 Diabetes. N. Engl. J. Med. 2014, 371, 1972–1982.

6. Carstensen, B.; Read, S.H.; Friis, S.; Sund, R.; Keskimäki, I.; Svensson, A.M.; Ljung, R.; Wild, S.H.; Kerssens, J.J.; Harding, J.L.; et al. Cancer incidence in persons with type 1 diabetes: a five-country study of 9,000 cancers in type 1 diabetic individuals. Diabetologia 2016, 59, 980–988.

7. Beck, R.W.; Tamborlane, W. V.; Bergenstal, R.M.; Miller, K.M.; DuBose, S.N.; Hall, C.A. The T1D exchange clinic registry. J. Clin. Endocrinol. Metab. 2012, 97, 4383–4389.

8. Bernstein, R.K. Dr. Bernstein’s diabetes solution : the complete guide to achieving normal blood sugars; Little, Brown and Co, 2011; ISBN 0316182699.

9. Feinman, R.D.; Pogozelski, W.K.; Astrup, A.; Bernstein, R.K.; Fine, E.J.; Westman, E.C.; Accurso, A.; Frassetto, L.; Gower, B.A.; McFarlane, S.I.; et al. Dietary carbohydrate restriction as the first approach in diabetes management: Critical review and evidence base. Nutrition 2015, 31, 1–13.

10. Turton, J.L.; Raab, R.; Rooney, K.B. Low-carbohydrate diets for type 1 diabetes mellitus: A systematic review. PLoS One 2018, 13, e0194987.

11. Nathan, D.M. The diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: Overview. Diabetes Care 2014, 37, 9–16.

12. Passonneau, J. V. Cerebral metabolism and neural function; Williams & Wilkins, 1980; ISBN 9780683067880.

13. Drenick, E.J.; Alvarez, L.C.; Tamasi, G.C.; Brickman, A.S. Resistance to Symptomatic Insulin Reactions after Fasting. J. Clin. Invest. 1972, 51, 2757–2762.

14. Gambhir, D.; Ananth, S.; Veeranan-Karmegam, R.; Elangovan, S.; Hester, S.; Jennings, E.; Offermanns, S.; Nussbaum, J.J.; Smith, S.B.; Thangaraju, M.; et al. GPR109A as an anti-inflammatory receptor in retinal pigment epithelial cells and its relevance to diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 2012, 53, 2208–2217.

15. Youm, Y.-H.; Nguyen, K.Y.; Grant, R.W.; Goldberg, E.L.; Bodogai, M.; Kim, D.; D’Agostino, D.; Planavsky, N.; Lupfer, C.; Kanneganti, T.D.; et al. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat. Med. 2015, 21, 263–9.

16. Lennerz, B.S.; Barton, A.; Bernstein, R.K.; Dikeman, R.D.; Diulus, C.; Hallberg, S.; Rhodes, E.T.; Ebbeling, C.B.; Westman, E.C.; Yancy, W.S.; et al. Management of Type 1 Diabetes With a Very Low-Carbohydrate Diet. Pediatrics 2018, 141, e20173349.







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