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Better Resting Leptin Levels in Diabetics on a Paleo Diet

By Maelán Fontes, M.S.
July 12, 2016
Better Resting Leptin Levels in Diabetics on a Paleo Diet image

Maelan Fontes, co-author of a recent study looking at the effects of the Paleo Diet on diabetics shares with their findings. Their study was titled Palaeolithic diet decreases fasting plasma leptin concentrations more than a diabetes diet in patients with type 2 diabetes: a randomized cross-over trial.

Type 2 diabetes has dramatically increased (doubled) since 1980, affecting 56 million people in Europe in 2013, and it is estimated that these numbers will increase to 64.2 million by 2030. Type 2 diabetes comprises 85-90% of all diabetes cases 1. It is one of the important causes of mortality, disability and economic cost in the world, due to the increased risk of micro (nephropathy, neuropathy, retinopathy) 2 and macrovascular (coronary heart disease, peripheral vascular disease and stroke) 3 complications. In 2013 more than 618,000 people in Europe died from diabetes complications. This economic burden was estimated to be around $131 million in 2011 1.

Type 2 diabetes has been defined as a combination of insulin resistance 4 and pancreatic beta cell failure 5. However, recent investigations indicate that these are consequences rather than the primary causes of the disease 6,7.

When people eat in excess (usually a combination of fats and refined carbohydrates common in processed foods) the extra calories are stored as triglycerides in the adipose tissue 8. However, people susceptible to the metabolic syndrome and/or type 2 diabetes tend to accumulate those calories in vital organs such as the liver, pancreas, heart or muscle, leading to what is known as “lipotoxicity” 8 because those organs are not designed to store high amounts of triglycerides. In order to avoid lipotoxicity the organs develop insulin resistance, limiting the amount of glucose that can overflow into the cells and be converted to fatty acids 9.

The final consequence of lipotoxicity is a progressive failure of the pancreatic beta cells, leading to decreased insulin secretion after a carbohydrate-containing meal. Insulin resistance may in fact be a protective mechanism to counteract lipotoxicity.

Interestingly, leptin, the key hormone that regulates appetite, is also fundamental to type 2 diabetes 7. Leptin facilitates beta-oxidation of toxic lipids in the liver, pancreas, heart or muscle, thus alleviating lipotoxicity 7,10. In fact, a 2002 study from the Journal of Clinical Investigation showed that administering leptin to humans deficient in leptin improved insulin sensitivity 11.

Another important hallmark of most patients with diabetes is high levels of a hormone called glucagon both in the fasting and postprandial state. Glucagon is responsible for increasing glucose production within the body by two processes called gluconeogenesis and glycogenolysis 6. High glucagon levels can be dangerous after a meal in a patient with type 2 diabetes because he is faced with a double hit of glucose coming from the food and being produced by the liver 12.

Interestingly, one of the principal functions of insulin is to decrease the secretion of glucagon from the alfa cells in the pancreas. In fact, glucagon play such a master role in diabetes, that a new glucagonocentric paradigm has been come the accepted norm 6.

Lipotoxicity causes insulin resistance which then reduces the capacity of insulin to decrease glucagon secretion in the fasting and post-prandial state. Leptin is not only able to alleviate lipotoxicity (and improve insulin sensitivity) but also can control glucagon secretion. At least in animal models 7.

And just like with insulin, for leptin to carry out its functions leptin receptors need to remain sensitive. Patients with the metabolic syndrome, type 2 diabetes and obesity are usually leptin resistant.

In other words, while most of us associate insulin-sensitivity with diabetes, leptin-sensitivity is just as important if not more crucial to prevent both lipotoxicity and hyperglucagonaemia. Two processes central to diabetes.

The study by our group published a few weeks ago was a dietary intervention testing the effects of a Palaeolithic versus a diabetes diet in patients with type 2 diabetes 13. We performed a post hoc analysis where we conducted the study and then analysed all data collected after the test for any potential trends.

The study included 13 participants that followed each diet for two consecutive periods of three months in what is called a crossover design. In a previous publication we reported significant improvements in glycated haemoglobin (HbA1c) – a key marker of diabetes, blood lipids, blood pressure, weight and waist circumference 14 along with increased satiety 15.

In this publication our aim was to investigate if the beneficial effects from a Palaeolithic diet could be tentatively explained by associated changes in leptin, glucagon and other hormones.

There was a significant decrease in fasting leptin levels after the Palaeolithic diet compared to the diabetes diet. Glucagon was also lower after the Palaeolithic diet but this difference was not statistically significant.

These data suggest that the Palaeolithic diet improved leptin sensitivity which may explain why leptin levels were lower. Hypothetically, if leptin sensitivity improved, insulin sensitivity would also improve in the alfa cells leading to better glucagon control. Our working hypothesis was that bioactive compounds in grains (gluten derived peptides) may reduce leptin sensitivity inducing lipotoxicity which can result in insulin resistance and hyperglucagonaemia, as previously explained.

However, there was a significant weight loss with the Palaeolithic diet compared to the diabetes diet which precludes a definitive conclusion. Furthermore, the post hoc nature of this study (the study was not originally designed to analyze those hormones) is a limitation, which means that these results need to be confirmed in future trials.

The Palaeolithic intervention was characterized by a significantly lower intake of grains and dairy products, and a higher intake of fruits and vegetables. The resulting lowered fasting leptin can have important effects on glucose control in patients with type 2 diabetes. However, more adequately powered studies should be run to test this hypothesis.

I would like to thank my coauthors Staffan Lindeberg, Tommy Jönsson, Yvonne Granfeldt, Filip Knop, Óscar Picazo, Pedro Carrera-Bastos, Madhvi Chanrai, Jan Sundquist, Kristina Sundquist and Ashfaque Memon for their amazing support and contribution to publish these data.

Maelán Fontes Villalba, MS, PhD student and Staffan Lindeberg, MD, PhD.
Center for Primary Health Care Research
Clinical Research Center, Faculty of Medicine, Lund University
Malmö, Sweden


[1.] International Diabetes Federation. IDF Diabetes Atlas, 5th edn. Brussels, Belgium: International Diabetes Federation, 2011. [Internet]. 2012 ed. International Diabetes Federation; [cited 2013 Oct 18]. Available from: //

[2.] Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. The lancet. 2000 Jan 22;355(9200):253–9.

[3.] Pyŏrälä K, Pedersen TR, Kjekshus J, Faergeman O, Olsson AG, Thorgeirsson G. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care. 1997 Apr;20(4):614–20.

[4.] Rothman DL, Magnusson I, Cline G, Gerard D, Kahn CR, Shulman RG, et al. Decreased muscle glucose transport/phosphorylation is an early defect in the pathogenesis of non-insulin-dependent diabetes mellitus. Proc Natl Acad Sci USA. 1995 Feb 14;92(4):983–7.

[5.] Porte D, Kahn SE. beta-cell dysfunction and failure in type 2 diabetes: potential mechanisms. Diabetes. 2001 Feb;50 Suppl 1:S160–3.

[6.] Unger RH, Cherrington AD. Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. J Clin Invest. 2012 Jan 3;122(1):4–12.

[7.] Unger RH, Roth MG. A new biology of diabetes revealed by leptin. Cell Metab. 2015 Jan 6;21(1):15–20.

[8.] Unger RH, Scherer PE. Gluttony, sloth and the metabolic syndrome: a roadmap to lipotoxicity. Trends Endocrinol Metab. 2010 Jun;21(6):345–52.

[9.] Unger RH. Lipid overload and overflow: metabolic trauma and the metabolic syndrome. Trends Endocrinol Metab. 2003 Nov;14(9):398–403.

[10.] Unger RH. Hyperleptinemia: protecting the heart from lipid overload. Hypertension. 2005 Jun;45(6):1031–4.

[11.] Petersen KF, Oral EA, Dufour S, Befroy D, Ariyan C, Yu C, et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest. 2002 May 15;109(10):1345–50.

[12.] Unger RH, Orci L. Paracrinology of islets and the paracrinopathy of diabetes. Proc Natl Acad Sci USA. 2010 Sep 14;107(37):16009–12.

[13.] Fontes Villalba M, Lindeberg S, Granfeldt Y, Knop FK, Memon AA, Carrera-Bastos P, et al. Palaeolithic diet decreases fasting plasma leptin concentrations more than a diabetes diet in patients with type 2 diabetes: a randomised cross-over trial. Cardiovasc Diabetol. 2016;15(1):80.

[14.] Jönsson T, Granfeldt Y, Ahrén B, Branell U-C, Pålsson G, Hansson A, et al. Beneficial effects of a Paleolithic diet on cardiovascular risk factors in type 2 diabetes: a randomized cross-over pilot study. Cardiovasc Diabetol. 2009;8(1):35.

[15.] Jönsson T, Granfeldt Y, Lindeberg S, Hallberg A-C. Subjective satiety and other experiences of a Paleolithic diet compared to a diabetes diet in patients with type 2 diabetes. Nutr J. 2013;12(1):105.

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