Insulin Resistance Develops Due to an Imbalance in the Synthesis of Cyclic AMP and the Natural Cyclic AMP Antagonist Prostaglandylinositol Cyclic Phosphate (Cyclic PIP)

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

You make an interesting review on the possibility that Cyclic PIP could be one of the master regulators in the metabolism, and perhaps of the development of T2D. The point is interesting, and the problem is that the study of Cyclic PIP is not easy, most of the work was done by you or your co-workers. In my opinion, the value is to call attention to this aspect less known of the disease and to call for more effort to uncover it. The discussion is well done, and the supporting tables and figures are enough. On page 9, line 335, I think reference 30 is not the right one.

Author Response

Dear Referee 1,

For the critical reading of my manuscript with the title: insulin resistance develops due to an imbalance in the synthesis of cyclic AMP and the natural cyclic AMP antagonist prostaglandyl- inositol cyclic phosphate (cyclic PIP), I thank you very much. Especially I thank you for the encouraging comment.

I am very sorry that I did not recognize that I had two literature citations mixed up. I corrected this mishappening.

Kind regards, Heinrich Wasner

Reviewer 2 Report

Comments and Suggestions for Authors

The premise of this review is very interesting but it appears to be largely a "hypothesis" rather than a review.

The initial sections of the review that concentrate on the generation of cyclic PIP and interactions with cyclic AMP signaling are interesting and good review material. 

The later sections attempting to link cyclic PIP to insulin resistance are largely speculative and not supported by substantial literature.

In addition to this , I have two major concerns about this review in general. Firstly, the data presented in Table 2 is purely fabricated and not at all appropriate for a review article. I could see something similar in a hypothesis paper if this were well presented. Certainly no conclusions should be drawn from this invented data here.

Secondly, 10 references and 1 PhD thesis, out of 34, appear to stem from the authors own laboratory, which does not represent a comprehensive review of the literature.

Comments on the Quality of English Language

In general the quality of English is good, but I detected some errors which would suggest a re-proofing is necessary.

Author Response

Dear Referee 2,

I thank you very much for critically reading my manuscript on the development of insulin resistance as a result of an imbalance in the synthesis of cyclic AMP and cyclic PIP. According to your arguments corrections were made. I hope that they meet your expectations. Made changes in the text I have indicated in yellow.

I have deleted the Table 2 and the accompanying text. Instead, I have extended the aspect of diabetes related protein over-phosphorylation. Further on, I have given more information on the action of cyclic PIP, for instance, with respect to glucose uptake in adipocytes.
(I had made Table 2 because I thought that this Table could help to visualize the situa6on how a decreasing cyclic PIP but an increasing cyclic AMP synthesis derail the regulation of metabolism. The published facts for this Table are that cyclic AMP inhibits cyclic PIP synthesis just as cyclic PIP inhibits cyclic AMP synthesis, and additionally that stimulation of cyclic PIP synthesis decreases in case of developing diabetes. Of course, the administered changes of 1% were arbitrarily made.)

Published results, which made me write this manuscript are:
Inhibition of cyclic PIP synthesis causes insulin resistance: a) increased serum insulin levels, resulting from increased insulin release from pancreatic beta cells. (Cyclic PIP inhibits insulin release from pancreatic beta cells.); b) increased blood glucose levels, which correlate with a decreased glucose uptake in adipocytes aPer insulin stimulation. But cyclic PIP addition triggered an unchanged uptake of glucose into adipocytes. In liver and muscle of the treated rats, glycogen content is decreased by 87 and 66%. Decreased synthesis of cyclic PIP was determined in various diabetic animal models. Cyclic PIP inhibits adenylate cyclase and cyclic AMP inhibits cyclic PIP synthase.

Years ago, the reports on cyclic PIP were nearly overlooked, since the reports on peptide and then glycan mediators of insulin stood in the foreground. Additionally, not fortunate for the discovery of cyclic PIP was and still is that it is difficult to handle, because of its instability.

In my submission letter I had written, that the intention of this review is to write what cyclic PIP, as intracellular executor of insulin’s actions, can contribute to the topic development of insulin resistance. This is the reason why the literature citation contains many reports of cyclic PIP. Petersen and Shulman have recently written an excellent review on the published literature, and it is not my intention to repeat this. But, since the existence and action of cyclic PIP is not yet well recognized, my intention is to draw the attention of the scientific community to cyclic PIP and its way of action.

Certainly, my name is on nearly on all reports on cyclic PIP, but many experiments have been performed in other laboratories. All mass spectroscopy, related to the structure determination of cyclic PIP, was done by other scientists, I like to name Prof. Raimund Kaufmann (Institute of Laser-medicine, HHU Duesseldorf); the effects of cyclic PIP on the papillary muscle was performed by the physiologist Prof. Lemoine; the effect of cyclic PIP on autophagy and proteolysis was done by PD Dr. Junger; the effect of cyclic PIP on the slime mold Dictyostelium disc. was first determined by Prof. Guenther Gerisch (MPI of Biochemistry, Muenchen), who helped us then, to set up our own cell culture in order to do more experiments with this slime mold; experiments with the pancreatic beta cells were performed by Dr. Partke, from the same research facility but another research group. The characterization of cyclic PIP synthesis in monkey liver was performed in the lab. of Prof. B. Hansen by Dr. P. Shashkin, then in Baltimore. I helped to set up the assay system for cyclic PIP. I wished I could have helped also other scientists before I leave the scientific scene. Most likely people are kept away from this research topic because of the difficulties to work with this very unstable compound, and then because of the disturbances caused by confusing reports on the glycan mediators of insulin action. Most likely this will change when chemically synthesized cyclic PIP will be available. However, unfortunately this will still take some time.

With kind regards, Heinrich Wasner

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

My previous comments have been met satisfactorily.