The advice for patients with type 2 diabetes to follow a Paleolithic diet resulted in lower HbA1c, TG, DBP, weight and waist circumference, and higher HDL, as compared to a Diabetes diet according to current guidelines. In addition, fasting glucose and SBP tended to decrease more after the Paleolithic diet. Changes in glucose tolerance were not significantly different between diets. The two diets differed mainly in that the Paleolithic diet was lower in cereals and dairy products, and higher in fruits, vegetables, meat and eggs. Further, the Paleolithic diet was lower in total energy, energy density, carbohydrate, dietary GL, saturated fatty acids and calcium, and higher in unsaturated fatty acids, dietary cholesterol and several vitamins. Dietary GI was lower in the Paleolithic diet (GI = 50) than in the Diabetic diet (GI = 55).
Possible mechanisms and explanations
No advice was given to restrict food intake. Therefore, the lower reported energy intake during the Paleolithic diet despite no difference in weight of reported food intake agrees with the notion that such a diet is satiating and facilitates a reduced caloric intake [4, 27]. Accordingly, energy density was lower in the Paleolithic diet and also correlated with alterations of both weight and waist circumference. The higher amount of fruit and vegetables during the Paleolithic period may have promoted weight loss due to its high content of water, which is thought to be satiating . Interestingly, the Paleolithic diet appeared to be satiating despite a lower content of fiber in this study. The slightly higher relative protein intake, as percentage of total calorie intake, may also have added to a satiating effect [29, 30]. Alternative explanations on satiation, such as dietary effects on leptin resistance, could also be considered .
A reduced energy intake would evidently be a major explanation for the beneficial effects of the Paleolithic diet on weight and waist circumference. Meta-analyses and large trials with various lifestyle interventions indicate that reduced caloric intake is more important for long-term weight loss than other known dietary factors, including macronutrient composition [32–40]. In studies shorter than 6 months, such as this one, differences in GI and/or GL may also have played a role for weight change. A Cochrane review found that overweight or obese people lost slightly more weight during 5–12 weeks of low GI diets , and short-term carbohydrate restriction possibly results in greater weight loss than low-fat diets . However, dietary GI and dietary GL did not correlate with alterations of weight, waist circumference or metabolic variables in our study. It should also be noted that, in the present study, reported mean absolute carbohydrate intake in the Paleolithic diet (g per day) was only slightly below the 130 g per day recommended by the American Diabetes Association, and clearly above 50 g per day, which has been proposed as the level below which a diet should be termed a low carbohydrate diet .
Paleolithic diet improved the glycemic control in the subjects, as evident by the reduction of HbA1c levels by -0.4 percentage points lower as compared to the diabetes diet. Since both glucose and insulin levels declined during Paleolithic diet, a main mechanism behind the improved glycemic control is probably improved insulin sensitivity, which may have allowed the released insulin to work more efficiently. The difference in reduction in HbA1c of 0.4% units between the Paleolithic and Diabetes diet is close to the average 0.5% units in a recent Cochrane review of diets with a low glycemic index or glycemic load . However, the differences in GI between diets in that meta-analysis were considerably larger than in our trial. Glucose tolerance, which also determines the glucose response and thereby HbA1c, did not improve more during the Paleolithic diet. This result agrees with findings from Frassetto et al , but differs from our previous parallel-group trial which compared a Paleolithic diet with a Mediterranean-like diet in subjects with diabetes or impaired glucose tolerance . Glucose tolerance has not been shown to improve after reduced carbohydrate intake in earlier dietary studies [43–46].
The much higher fruit intake of the Paleolithic diet probably resulted in a slightly higher intake of fructose which may have aided in the reduction of HbA1c. Fructose in exchange for starch, sucrose or glucose decreases postprandial glycemia , while the effect on glucose tolerance and insulin sensitivity is more uncertain . The effect of fruit on TG and other risk factors is expected to have been neutral in this study [48, 49]. Total intake of monosaccharides was 46 g per day, including approximately equal amounts of glucose and fructose, which was well below the suggested safety limit of 50 g fructose per day . Our study lends further support to the notion that fruit intake should not be restricted in patients with type 2 diabetes.
The lower DBP after the Paleolithic diet compared to the Diabetes diet did not correlate with sodium intake, which did not differ significantly and was rather low in both diets (2.5 g and 3.0 g per day respectively for the Paleolithic and Diabetes diet).
The reduction of TG after the Paleolithic diet was possibly due to greater loss of abdominal fat  or lower GL compared to the Diabetes diet , although no correlation of TG with waist loss or GL was seen in exploratory analyses. A small additional effect on TG may be attributable to a trend for higher content of long-chain omega-3 fatty acids in the Paleolithic diet, while the higher dietary cholesterol content of the Paleolithic diet is probably of minor significance .
Comparison with findings from other studies
All improvements in markers of the metabolic syndrome on the Paleolithic diet are in line with findings from epidemiological studies in non-Western populations [14–16]. Improvements in HbA1c , weight [4, 12, 52], BMI , waist circumference [4, 52], DBP , and TG , compared to baseline, on a Paleolithic diet have been observed before in intervention studies, while improvements in HDL have not. Similar differences in weight and DBP on a Paleolithic diet, compared to a cereal based diet, have been observed before in an intervention study on domestic pigs . A lower reported energy intake and energy density of food despite food intake ad libitum agrees with our earlier findings that a Paleolithic diet facilitates a reduction of caloric intake [4, 11, 27].
Also, lower intake of cereals, dairy products, carbohydrates, dietary GL and saturated fat, and higher intake of fruit and potassium have been observed before [4, 10]. Lower intake of potatoes, bakery, fiber, phosphorous and calcium, and higher intake in vegetables, meat, eggs, monosaccharides, dietary cholesterol, vitamin B6, vitamin C, niacin and selenium have not been observed before in intervention studies with a Paleolithic diet. Dietary GI for a Paleolithic diet has not been determined before.
Limitations of the present study
A limitation of this study, as with most other dietary trials, is the lack of blinding after randomization. To minimize this problem, all study participants were informed of the intention to compare two healthy diets in the treatment of type 2 diabetes and that it was unknown if any of them would be superior to the other. Also, written information with dietary advice and food recipes were similarly formulated for both diets. Furthermore, for increased conformity, the dietary advice and data collection procedure were discussed by all those administering the interventions at several meetings prior to start of study.
Another limitation of this study is its small size which did not reach the number of participants needed as calculated in the pre-study power calculation. The decision to end the study was taken when recruitment for the study had not yielded new participants for more than six months. The population of patients with type 2 diabetes is much larger and therapy continues for substantially longer than in this study. Moreover, many patients with type 2 diabetes have illnesses and treatments that excluded them from the current study. Consequently, the results of this study do not address the occurrence of rare adverse events, nor can they be extrapolated to all patients seen in general clinical practice.
The carry-over effects on HbA1c were not due to carry-over or period effects in reported food intake. Instead, they could be true carry-over effects of the first diet. This is particularly likely for HbA1c, since HbA1c represents a weighted average of the blood glucose concentration over the previous two to three months (. If results from the second period were discarded (owing to carryover ), the reduction of HbA1c from the Paleolithic diet compared to the Diabetes diet was still significant (p = 0.01) and even larger (-1.3% units) than when results from the second period were included. However, this approach could lead to biased answers to our hypothesis and results from both periods are therefore used in this study .
The lack of carry-over or period effects in reported food intake indicates fairly good adherence to intervention diets. Reported food intake in this study seemed reasonable both in distribution and quantity, as subjectively assessed by a nutrition engineer skilled in analyzing reported food intake (YG). Furthermore, the reported lower energy intake of 1.3 MJ per day on a Paleolithic diet equals about 3.2 kg fat during three months, which almost exactly accounts for the observed 3.3 kg difference in weight loss between diets. This indicates both good reporting by the participants and good adherence to reported food intake during the study.
Clinical and research implications
The favourable results in this study are in line with previous findings and increase the generalizability of the Paleolithic diet by testing it in both men and women in a primary care setting. A limitation of the study is the small size of the study population. This prevents the conclusions from resulting in nutritional recommendations for patients with type 2 diabetes. A long-term study in a larger population is therefore required. In parallel, further research into possible mechanisms for the beneficial effects of a Paleolithic diet should be done.
Total protein intake in g per day did not differ between the diets, but, as a result of the difference in total energy intake, the energy percentage (E%) from dietary protein on the Paleolithic diet (24 E%) slightly exceeded US and European recommendations for people with diabetes (<20 E%) [17, 55]. The debatable disadvantage for long-term kidney function [56, 57] should be weighed against the benefits of attenuated postprandial glycemia when protein replaces starch or glucose .
Calcium intake did not meet recommendations for any of the diets, and it was particularly low in the Paleolithic diet. Recent calcium balance studies indicate that human calcium requirements are lower than previously thought , and meta-analyses of randomized controlled trials suggest that the effect of calcium supplementation for bone strength is limited [60, 61]. It has been suggested that absorption and excretion of calcium are more important than calcium intake for whole-body calcium balance . In this context, the lower content of calcium-binding phytate and the lower dietary acid load from a Paleolithic diet may hypothetically compensate for the low amount of calcium . Supporting this view are the findings of Frassetto et al, where calcium intake remained unchanged and urine calcium decreased after a Paleolithic diet compared to baseline .
As has been discussed, there may be a challenge to implement and adopt the Paleolithic diet on a worldwide scale in subjects with type 2 diabetes. However, this aspect is beyond the objective of this paper and requires more research.