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Low carbohydrate and ketogenic diets in type 2 diabetes

Clifton, Peter; Carter, Sharayah; Headland, Michelle; Keogh, Jennifer

doi: 10.1097/MOL.0000000000000241
BIMONTHLY UPDATE: Edited by Alan Rees
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Alliance for Research in Exercise, Nutrition and Activity (ARENA), School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia

Correspondence to Peter Clifton, University of South Australia, Level 5 room P5–16, Playford Building, GPO Box 2471, Adelaide, SA 5001, Australia. Tel: +61403197998; e-mail: Peter.clifton@unisa.edu.au

There have been many reviews on this question with generally favourable outcomes in terms of all-day glucose levels and glycosylated hemoglobin A1 concentration (HbA1c) but the most recent meta-analysis [1] was negative although only four of a possible 12 studies in type 2 diabetes longer in duration than 12 weeks were included.

The 6-month data from a 2-year low-carbohydrate weight-loss study in type 2 diabetes has shown favourable effects on HbA1c and medication use [2]. In this study, the low carbohydrate diet was restricted to 14% of energy as carbohydrate (a target of <50 g/day was set) and compared with a high carbohydrate diet of 53% carbohydrate with an emphasis on low glycemic index foods. Importantly, saturated fat was restricted to less than 10% in both diets so the difference in calories was made up with both protein and unsaturated fat. The diets were isocaloric; 115 participants commenced the study and 93 completed 6 months. The weight loss was excellent at 11.5–12 kg. Although overall HbA1c changes were not different, medication reductions were twice as great in the low carbohydrate group and reductions in glycemic variability were also twice as great. On post-hoc analysis, those individuals with a baseline HbA1c of more than 7.8% (nine low carbohydrate and 14 high carbohydrate individuals) had a lower HbA1c of about 0.6% on the low carbohydrate diet (P < 0.05). A further report from the same study at 12 months showed a fall in HbA1c of 1% in both the groups with no differences between the two diets although medication reductions occurred more frequently in the low carbohydrate group [3▪▪].

Similar benefits of a low-carbohydrate weight-loss diet in type 2 diabetes were seen in a smaller cohort in which weight loss was the same in both the low carbohydrate and high carbohydrate group but HbA1c was lower by 0.8% in the low carbohydrate diet. A more than 50% reduction in medication occurred in 70% of the low carbohydrate group versus 30% of the high carbohydrate group [4]. Gower and Goss [5] found that in 30 women with polycystic ovary syndrome (a risk factor for type 2 diabetes), the low carbohydrate diet lowered fasting insulin and glucose and improved insulin sensitivity and the β-cell response to a test meal. In the low carbohydrate diet, women lost intra-abdominal fat whereas on the high carbohydrate diet lean mass was lost but the two groups were not contrasted statistically. A carbohydrate-free diet in a noncalorie-restricted diet lowers 24-h glucose and insulin levels in people with type 2 diabetes by 39 and 48%, respectively, whereas complete fasting lowers them by 49 and 69%, respectively. Thus, the carbohydrate restriction accounts for 71% of the effect of fasting in type 2 diabetes [6▪]. A position statement on the benefits of low carbohydrate diets for type 2 diabetes has been recently published [7▪] while the mechanisms of the effect of a ketogenic diet on appetite and food intake have been reviewed by Paoli et al. [8▪]. A diet with less than 100 g of carbohydrate per day induces ketones which are acetyl-CoA derivatives formed when there is insufficient oxaloacetate available in the TCA cycle for acetyl-COA to enter. Ketones can be used for energy by muscle and after a delay the brain can use them as well.

Fibroblast growth factor 21 (FGF21) is a novel liver protein that increases in obesity but ameliorates obesity-associated hyperglycaemia and hyperlipidaemia primarily via effects on adipose tissue and the pancreas. It also increases in response to dietary restriction. In mice, ketogenic diets that increase FGF21 do not enhance longevity despite lower weight and fat mass and lower glucose and insulin as the ketogenic mice had hepatic steatosis and inflammation [9▪▪]. The ketogenic diet appeared to impair FGF21 signalling, downregulating lipoprotein lipase and CD36 but reducing inflammation in white adipose tissue [10▪▪]. In both mice and humans, the stress of protein deficiency rather than restricted carbohydrate appears to be the main driver of increased FGF21 production [11].

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Acknowledgements

None.

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Financial support and sponsorship

None.

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Conflicts of interest

P.C. is a Principal Research Scientist funded by the National Health and Medical Research Council. J.K. is a National Heart Foundation Research Fellow. There are no conflicts of interests.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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REFERENCES

1. Naude CE, Schoonees A, Senekal M, et al. Low carbohydrate versus isoenergetic balanced diets for reducing weight and cardiovascular risk: a systematic review and meta-analysis. PLoS One 2014; 9:e100652.
2. Tay J, Luscombe-Marsh ND, Thompson CH, et al. Brinkworth GDA very low-carbohydrate, low-saturated fat diet for type 2 diabetes management: a randomized trial. Diabetes Care 2014; 37:2909–2918.
3▪▪. 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; pii: ajcn112581. [Epub ahead of print].

This was a large, very tightly controlled, very low carbohydrate diet with carbohydrate replaced with unsaturated fat and clearly shows the benefit of a low carbohydrate diet.

4. Mayer SB, Jeffreys AS, Olsen MK, et al. Two diets with different haemoglobin A1c and antiglycaemic medication effects despite similar weight loss in type 2 diabetes. Diabetes Obes Metab 2014; 16:90–93.
5. Gower BA, Goss AM. A lower-carbohydrate, higher-fat diet reduces abdominal and intermuscular fat and increases insulin sensitivity in adults at risk of type 2 diabetes. J Nutr 2015; 145:177S–183S.
6▪. Nuttall FQ, Almokayyad RM, Gannon MC. Comparison of a carbohydrate-free diet vs. fasting on plasma glucose, insulin and glucagon in type 2 diabetes. Metabolism 2015; 64:253–262.

This article carefully discriminates between energy reduction versus carbohydrate reduction in the effect of fasting on glucose levels.

7▪. Feinman RD, Pogozelski WK, Astrup A, et al. Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base. Nutrition 2015; 31:1–13.

A good review from a group of low carbohydrate advocates.

8▪. Paoli A, Bosco G, Camporesi EM, Mangar D. Ketosis, ketogenic diet and food intake control: a complex relationship. Front Psychol 2015; 6:27.

An interesting article exploring the effects of ketosis on appetite control.

9▪▪. Douris N, Melman T, Pecherer JM, et al. Adaptive changes in amino acid metabolism permit normal longevity in mice consuming a low-carbohydrate ketogenic diet. Biochim Biophys Acta 2015; 1852 (10 Pt A):2056–2065.

An exploration of the long-term effects of a low carbohydrate diet explaining why weight loss with this diet does not confer benefits.

10▪▪. Asrih M, Altirriba J, Rohner-Jeanrenaud F, Jornayvaz FR. Ketogenic diet impairs FGF21 signaling and promotes differential inflammatory responses in the liver and white adipose tissue. PLoS One 2015; 10:e0126364.

Exploration of the effect of ketosis on FGF21.

11. Laeger T, Henagan TM, Albarado DC, et al. FGF21 is an endocrine signal of protein restriction. J Clin Invest 2014; 124:3913–3922.
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FURTHER RECOMMENDED READING

▪▪. Imamura F, O’Connor L, Ye Z, et al. Consumption of sugar sweetened beverages, artificially sweetened beverages, and fruit juice and incidence of type 2 diabetes: systematic review, meta-analysis, and estimation of population attributable fraction. BMJ 2015; 351:h3576doi: 10.1136/bmj.h3576.

    This paper provides the most up to date estimate of how important these drinks are in the development of type 2 diabetes.

    ▪▪. Liu JJ, Foo JP, Liu S, Lim SC. The role of fibroblast growth factor 21 in diabetes and its complications: A review from clinical perspective. Diabetes Res ClinPract 2015; 108:382–389.

      A very comprehensive review on the role of FGF21 in diabetes.

      ▪. Kim SH, Kim KH, Kim HK, et al. Fibroblast growth factor 21 participates in adaptation to endoplasmic reticulum stress and attenuates obesity-induced hepatic metabolic stress. Diabetologia 2015; 58:809–818.

      This paper is important as it shows the increased FGF21 seen in obesity and fatty liver is a protective response and reduces hepatic lipid accumulation.

      ▪. Reinehr T, Karges B, Meissner T, et al. Fibroblast growth factor 21 and fetuin-A in obese adolescents with and without type 2 diabetes. J Clin Endocrinol Metab 2015; jc20152192.
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