Review Reports

Round 1

Reviewer 1 Report

Both the quality and interest to readers can be improved by narrowing topic focus of this wandering communication. 

The efficacy and safety of ketogenic diets is of great interest in the treatment of metabolic syndrome, type 2 diabetes and NAFL. With that in mind the following suggestions to improve impact include:

1. Delete section 1.2 (lines 81-157) this section is editorial, is not supported by subsequently presented data and is extraneous to the focus of the review. What is said in lines 73-80.
2. Tables 2-4 can be combined and reduced to two. One that describes the study characteristics (first 5 columns are identical in the current 3 tables and suffice for this purpose ). A second table that describes the observed outcomes on the variables related to BW, lipids and glucose variables is readily made by combining the last 4 columns of each of the current 3 tables and including column to relate to studies described in the first table. The three tables are initially confusing and seem to be duplicates particularly as the template seems to have given the authors problems as table titles and bottom line text was cut off on several pages. 
3. Section 4.3 (lines 473 - 536) comes out of the blue. It is a very interesting and likely correct in many ways but the article provides no foundation for jumping into speculation on molecular mechanisms. Albeit would be appropriate to suggest in conclusions that determining the effect of KD interventions on molecular mechanisms know to relate to MetS, T2D and NAFL are needed.  In the mean time, relevant details related to efficacy and safety are discussed superficially and seem to be after thoughts. For example, diets with 20-30g CHO/day v. 50gCHO/day are suggested to differ in efficacy - do these differences relate the variable outcomes reported in the studies reviewed? Please link and integrate to support conclusions. Were  measures of efficacy reported in the studies reviewed? If so what are the measures used and do the authors find them adequate? Compliance was stated as another variable - what are the indicators of compliance and were they reported for all studies or are the authors speculating based on their personal perception of how easy it is to stay on a particular diet?  
4. Using a ketogenic diet to treat epilepsy is a different topic, or are the subjects in those studies also obese or otherwise glucose intolerant? Is there a known relationship between efficacy against epilepsy and that of efficacy against glucose disorders or are the authors using epilepsy suppression as an index of compliance?  The only commentary on adverse events seems to come from studies with epileptics - why is that? Are there a very long term adverse events in all populations or only epileptics? The authors seem to conclude that 6 months use is ok - is this for the 20-30 g/d diet or 50 g/d diet both?  How much improvement is possible with these two diets, how should a clinician follow to make sure subjects are compliant. 

Specific comments:

Line 167-168 this is a dogmatic and unreferenced. Many would argue that smoking keeps them slim - especially in Europe. This should be stricken. Examples of grammar/phraseology issues: tenses and adverbial transformations need to be cleaned up - get another editor to help. Check for appropriate capitalization, seems to be used to add emphasis. Abbreviation use is inconsistent.

Line 422 not sure BHB was defined as the individual ketone molecules were earlier, please check.

Line 450 replace "its adhesion" with "diet compliance."

Line 453 - 454 suggest change along the lines of "The restrictive nature of KD creates challenges to diet compliance related to psychosocial variables."

Line 458 - strike the isolated "but"

Line 460 - need a reference for the statement about kidney stones, acidosis, vitamin & mineral deficiencies. In fact, the authors should develop this aspect of the review more fully. How long is long term? What vitamins and minerals?

Line 471-472 - does not link to prior portion of sentence in a logical way.

Line 538 - safe diet, not safety diet.

Line 539 - use abbreviations consistently once introduced; MetS was used previously so use here.

Line 541 - use KD instead of writing in full (see prior comment)

Line 542 - Further not Furthers

Final sentence - agree with the conclusion but would be better supported if authors more fully developed links between variability in diet composition in the studies reviewed to the variability in efficacy and safety of those interventions.

Author Response

Please see the attachment

 

Reviewer 2 Report

This review points out to some specific effects of a ketogenic diet without calorie restriction.

Major criticism

The long intro with physiopathological mechanism is too long especially for the "inflammation" narrative that has no clear relation with a “metabolic” type of diet without calorie restriction.

On the contrary, the authors appear to be completely obvious to a growing knowledge about the role of natriuretic peptide in energy metabolism, insulin resistance, weigh loss and blood pressure regulation. The role of these peptides is known from the early nineties when their receptors where found highly expressed in adipose tissue and starvation down regulated the expression of the clearance receptor facilitating their lipolytic activity strong as that of catecholamines. The metabolic activities of these peptides are more related than many inflammatory pathways that are steadily “fashionable” in research but lack of the sounding ground of metabolic hormones such as the natriuretic hormones from the heart that should be integrated both in the introduction and in the discussion. The keep these part shorter reduce lightly portion of the inflammation story.

Minor criticism

The tables must be improved moving to the left the parameter of interest and the reference on the column on the right. Improve the overall readability as well.

Author Response

Please see the attachment

Author Response File: Author Response.pdf