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The effect of Proinsulin C-peptide on HRV and the LF/HF rate

Published: 25. April 2021.

Authors:     Dr. Zita Csomai physician, naturopath
Gábor Varga

Participants of the research team:

Tímea Gyertyán-Ági      special teacher, specialist in motor therapy
Nikolett Horváth            special educator, rehabilitational speech therapist
Erika Szücsné Göblyös qualified special educator, speech therapist, specialist in motor therapy
Anita Varga                    nurse, assistant, district nurse

Preface

Heart Rate Variability (HRV) is an indicator of the balanced functioning of the brain.

When we take a breath and inhale, our heartbeat accelerates, when we exhale, it slows down. Heart Rate Variability (HRV) measures the dynamic change of this process. The more evenly our heart beats, the greater the problem may be with the complex function of regulating heartbeat in our central nervous system. But also too high HRV value may refer to health problems, arrhythmia. Researchers relate the general health status mainly to the HRV value measuring the functioning of the vagus nerve. Diseases like diabetes, cancer, arteriosclerosis, schizophrenia, autismus, Altzheimer’s and Parkinsos’s disease, etc. are often related to lower HRV values. Since it is mostly the healthy functioning of the prefrontal cortex that is in charge of the HRV values, the integrity of brain functions determine and influence the incidence of the different chronic diseases.[i] The particular values of HRV are in connection with the extent of inflammatory processes in the body, the lower these values are, the higher certain inflammatory markers may be.[ii] The so-called cholinergic anti-inflammatory pathway is in charge of the anti-inflammatory effect of the vagus nerve. The impairment of the vagus nerve system and the increased inflammation due to that also predicts the eventual early death.[iii]

Researchers correlate the impairment of the cholinergic anti-inflammatory pathway with the emergence of respiratory failure due to COVID-19 infection especially in cases with the comorbidity of e.g. Altzheimers’s disease or unhealthy lifestyle.[iv] Researchers even defined a limit in the value of RMSSD, the HRV transmitted by the vagus nerve, below that the chance of developing chronic diseases, such as cardiovascular problems is significantly increased.[v]

In this regard it is a cause for concern that children suffering from type 1 diabetes mellitus, where the total or partial lack of insulin  and of the other associated peptide, proinsulin C-peptide is typically observed, HRV is significantly reduced.[vi]

Researchers state that this may be primarily due to the glycemic control, but the glycemic control is the best in those patients with type  1 diabetes, whose residual C-peptide production is relatively high.[vii] [viii] [ix]

It is worth mentioning that adding supplementary C-peptide significantly raises the low HRV value in  patients with type 1 diabetes mellitus.[x]

Regarding the patients in concern raised HRV may certainly be the result of the effect of proinsulin C-peptide on the central nervous system, despite the fact that the transfer of C-peptide through the blood-brain barrier is 5 times lower than the transfer of insulin.[xi]

In animal experiments the effect of c-peptide regarding the activation of the vagus nerve, administered directly into the brain, avoiding the blood-brain barrier, was the same in much less quantities than in systemic dosages.[xii]

In the future the idea of therapeutic application of proinsulin C-peptide may arise in people with chronic diseases due to its effect on raising and optimizating HRV and eventually regenerating brain functions, especially because it can easily and effectively get into the central nervous system through intranasal administration, avoiding the blood-brain barrier.[xiii]

Introduction

More than 2 years ago cosmetics containing proinsulin C-peptide became available in trade flows for the first time in the world. For a number of people this made it possible to use it off label, as a nasal spray, similarly to intranasal insulin. The experiences gained during these two years are astonishing and surprising. In our case study primarily the effect of C-peptide on HRV is analyzed, which is an indicator of the parasympathetic system of the body.

HRV, RMSSD, LF/LH rate were measured by Elite HRV equipment.

HRV value

HRV value is the responsiveness of the heart, it means the emotional, hormonal and neurological balance of the whole person, as well as the reactivity in life situations. The higher heart rate variability, that is HRV, is a complex measure of health. It describes how the heart can constantly change the period between two heart beats while reacting to the changing loads of the internal and external environment. The adaptive ability of the heart is based on the optimal interplay of the sympathetic and parasympathetic nervous system.  Adequate heart rate variability can be achieved in the body if the two systems are in balance. If the sympathetic system starts predominating, HRV is going to decrease. This in turn will increase the risk of developing cardiovascular diseases.

The HRV and RMSSD values change with age. Both too high and too low HRV may refer to health problems. It can also be said about HRV, that it reflects  the health state of the brain as well.

When analyzing the results we used the chart of the Elite HRV equipment, the ideal range concerning age was defined according to those values.

Figure 1 – Mean HRV depending on age

Mean HRV depending on age

AgeSexRMSSDElite HRV
18-25Male86.568.7
Female68.765.1
25-35Male66.064.5
Female55.761.8
35-45Male50.460.3
Female45.658.7
45-55Male39.656.7
Female41.757.4
55-65Male32.153.3
Female32.553.5
65-75Male30.652.7
Female24.849.4
75+Male33.153.9
Female25.549.9


LF/HF rate

The LF range is primarily determined by the sympathetic system. The LF value reflects the sympathetic and parasympathetic values in a rate of 3:1 (three-quarters sympathetic, one-quarter parasympathetic). The raised sympathetic activity may be caused by lack of sleep, stress or sickness.

The HF range is affected by the parasympathetic activity.

The LF/HF rate refers to the vegetative balance. The optimal value is 1.5-2 (ms²). If the value is lower than this, there is a parasympathetic, if higher, than a sympathetic prevalence.

Description of the proinsulin C peptide spray

The participants of our study were using the Vargapeptide skin-spray off label, as an intranasal spray, on their own responsibility. The spray is produced and distributed by the Max-Immun Ltd.  

This was applied in the same way as the intranasal insulin was and is administered in the population of children with Phelan-McDermid syndrome.

A 20 ml bottle contains a solutiotion of 18 ml C-peptide.One puff off the spray contains 0,108 mg proinsulin C-peptide. In Varga Peptide 0,5 this amount is half of it, 0,05 g, in Varga Peptide 2 the amount is 0,216 mg.The spray contains 0,8 % NaCl. The other ingredients fulfill the requirements of pharmaceutical grade purity.  The purity of  proinsulin C-peptide is 98-99%.

Description of the investigation

Selection

The participants of the study were selected in May 2020.

The first assessment consisted of an initial measurement and a survey using a questionnaire

The schedule of the measurements:

  1. initial measurement
  2. after one week
  3. after one month
  4. after 3 months
  5. after 6 months


Statistical data

There were 85 participants in our investigation. Out of these persons 2 patients quitted after 3 months, 1 patient could not continue due to the COVID pandemic and 1 patient with chronic diseases died (chronic renal disease, hypertonia), therefore the measurement after 3 month was already impossible to be executed.

The age range of patients was 3-78 years, the average age was 46.85 years. 

The distribution of sexes was 30 males, 55 females.

Figure 2 – Distribution of sexes


Diseases

The participants of the investigation were not selected according to certain diseases, therefore a wide range of  diseases can be found, and also each patient has more than one diagnosis, such as: 

Duchenne-syndrome, infantile autismus, moderate intellectual disability, dysgraphia, attention deficit, behavioural distuebance, sensory integration disorder, autismus, myocklonic epilepsy, stroke, balance disorder, vertigo, anxiety, synovitis, scoliosis, hypertonia, ragweed allergy, hypothyreosis, obesity, join pain, type 2 diabetes mellitus, lung tumor, breast tumor, skin cancer, spinal hernia, cardiomyopathy, colitis ulcerosa, reflux, autoimmune thyroid disease, prostate tumor, speech rythm disturbance, depression, deep vein thrombosis, gynecological tumor, sleeping disorder, EBV, pollen- and peanut allergy, neurasthenia, facial neuralgia, COPD, vaso-constcriction,  osteoporosis, dementia, ovarian cyst, hearing loss (80%), metabolic disorder, SIBO (Small Intestinal Bacterial Overgrowth), menopause, food allergy, multiple sclerosis, metastatic breast tumor, Traumatic Brain Injury, renal failure in final stage, benign skin tumor, panic disorder, spastic tetraplegy, perinatal injury, tinnitus, coordination disorder, migraine, Asperger syndrome, low back pain, chronic fatique, stress, Angelmann syndrome, pacemaker, torticollis, sciatica, pelvic tumor, dementia, earache, nervous exhaustion, Hashimoto thyreoiditis, hyperthyreosis, irritability, abdominal pain, nephritis, gravidity, nausea, weakness, fatty liver, arthritis rheumatica, Parkinson’s disease, extreme high blood pressure, asthma, Leiden mutation, COVID, colonic tumor, mixed disorder of the connective tissue, psoriasis, mitochrondial disease, Lyme disease, Bell-paresis, ADHD, immune deficit, Conn syndrome, autoimmune hepatitis.

Frequency and dosage

The dosage of C-peptide was started from type 0,5, than 1 and 2, according to age, than the dosage was changed according to the symptoms and the results.

The duration of appliance was 3-6 months.

Patients will continue taking C-peptide after 6 months as well.

Aspects of data collection and analysis

Each time of measurement the patients answered the items of the questionnaire, and the subjective observations were recorded as well.

Results

There was a great obstacle in the implementation of the investigation: the COVID-19 pandemic, therefore some of the measurement times were changed, and it also happened, that a measurement was skipped due to an infection.

The chart conains the patients’ age, sex, diagnosis, measured values and the changes in symptoms according to the questionaires. The type and dosage of C-peptide is also indicated.

The chart containing the data and results of each patient can be found in the Appendix.

Changes in HRV and RMSSD

In our investigation the HRV and RMSSD values were the following during the administration of C-peptide:

HRV and RMSSD was in the normal range according to age in 40 patients. In 43 patients both HRV and RMSSD values were low. The HRV and RMSSD values have been changed parallel to the administration of C-peptide.

Our measurements have also indicated that the HRV and RMSSD values were significantly influenced by the consumption of coffee, chocolate or cigarettes before the test. Patients under chemotherapy treatment had similar values. COVID infection also negatively affected HRV.

Age
Sex
DiagnoseDosageHRVRMSSDLF/HFComments
67 FemaleIBS pain of unknown origin                 6 months0.5 1×1 1×2 2×4 2×6 2×667 41 stress 50 46 (coffee, cigarette mask 59 (coffee, cigarette)80.21 14.44 26.25 19.35 47.730.51 8.04 1.08 1.42 2.15takes several medicine smokes, stressful earlier suffered from herpes, during the investigation none occasional cough stopped d joint paine relieved depression due to COVID worsened, hard for her to cope with the lock down
59 Femalemalignant lung and breast tumor                     6 months1 2×1 2×2 2×252 45 36 (did not take for 4 days during chemotherapy) 52 48 (coffee)30.3 18.74 10.53 29.26 22.151.72 2.37 4.91 0.98 2.32takes several medicine, receives chemotherapy smokes after 6 months chemotherapy check-up arm itching remained, numb  toes, surgery after the 2. test she is in healing phase, feels well, joint pain ceased general health better, but feels week due to chemotherapy and radiation therapy
64 FemaleColitis ulcerosa reflux                 6 months1 2×2 3×2 2×247 53 53 49 stressful smoked 63  stressful21.52 30.69 30.73 23.46 58.516.15 1.21 3.17 1.13 1.17smokes (less, earlier 1 now half packet,) minor waist pain ceased colitis ulcerosa 1x recurrenced, had bloody stool for 1 day, (CU since 1977) earlier these episodes lasted for 2-3 weeks if the C-peptide dosage was raised, got mild headache learns easier (e.g. dance choreography) short-term memory improved a bit does not catch infections
60 Female  autoimmune thyroid disease               3 months0.5 1x 2×1 0.5 2×2 1 2×260 49 ate sweets 51 52 ate chocolate, stressful50.56 23.46 26.97 129.634.79 1.13 0.45 0.54smokes 15-16 cigarettes daily, her pulse rises, this did not change   Decreased the dosage of C-peptide because of severe anxiety   After initial improvement  a stressy  period amplified her symptoms   Very stressful, because her husband got into hospital
70 Femalefacial neuralgia, COPD, vaso-constcriction,  osteoporosis, dementia, depression   6 months0.5 1x 2×1 2×2 2×243 59 64 46 ate chocolate, 43 stressful, upset16.24 46.84 62.29 19.82 16.391.52 6.61 1.36 1.4 0.73takes several medicine smokes reflux got better after 3 months had fracture after 3 months, recovered feels more often cold does not really feel improvement depressed mood, upset

Changes in HRV

Among the patients having low HRV at the beginning, the values of 28 patients improved due to the administration of C-peptide, in 8 cases there was an initial improvement, but later a relapse was experienced. In the cases of 6 patients there was no significant change. The value of 1 patient was fluctuating.

Figure 3 – Changes of HRV and RMSSD values in patients with low values at the beginning

Our observations were in the changes of HRV, that in the initial phase a deterioration often occurred. A HRV változásában megfigyeltük, hogy a kezdeti időszakban előfordul egy rosszabbodás. The time period needed for the improvement to appear was investigated and also the duration of it.

In 16 cases the values started improving already in the first month and these increased values remained all through the time applying C-peptide.

In 5 cases the first improvement was noticed in the 3. months, while in 2 cases the first in the 6. months.

Figure 4 – The improvement of HRV over time
Age SexDiagnosisDosageHRVRMSSDLF/HFComments
3 MaleDuchenne0.5 1x 2x 2-3x61 68 72 72  53.02 81.16 110.01 106.40.73 1,2 7.2 0.57Face redness milder Immune system strengthened Healing faster when catching a cold Motor abilities improved a lot, sits up independently lot better adaptation abilities can walk up stairs not disturbed by the vacuum cleaner attention span longer says more and more words

Deterioration of HRV

In the cases of 10 patients the initial HRV was in the normal range, but when measured later, worse results were found.

Figure 5 – Deterioration of HRV

4 patients from these 10 got coronavirus infection.

3 patients received chemotherapy, one of them had improved values after 5 months. Another patient showed improvement in the 3. months, but before the measurement in the 6. month received chemotherapy again and the measured values got worse again. 1 patient received both chemotherapy and radiation treatment.

1 patient felt very stressful, had a coffee before the measurement, wore facial mask, had a really hard time emotionally due to the lock-down of the COVID pandemic.

The values of 1 patient were worse in the 3. and 6. month, he reported to be very stressful, exhausted, works a lot, takes several medicine.

The values of 1 patient got worse in the 5. month, smokes a lot, anxious.

Age SexDiagnosisDosageHRVRMSSDLF/HFComments
59 Femalestiatica, palvic tumor
3 months
1 2×256 4437.83 17.243.08 4.34takes several medicine, recovered from COVID within 5 days   chemotherapy, radiation treatment   vitality improved, high pulse Due to covid changed for immunotherapy after 3 months
64 Femalecolon tumor, chemotherapy
0-3-5 months
 53 46 4932.33 19.4 24.253 46 49chemotherapy, medicine fluctuating health feels a lot more forceful  

Changes in LF/HF

The LF/HF rate was very high in a lot of patients according to our measurements. The changes were not so clear as those of HRV. A lot of patients had really high LF/HF rate, which refers to a dominating sympathetic functioning.   

The changes of values were also diverse.

Figure 6 – Changes of LF/HF rate

Changes of the LF/HF rate

The values of 4 patients were in the normal range and remained there as well.

The high values of 17 patients decreased and remained in the normal range while applying C-peptide.

In the cases of 8 patients az initial raising was found, than their values turned to be normal.

The values of 9 patients decreased, than raised back to high values. 2 of them received chemotherapy, 1 was infected by coronavirus, 1 patient had miscarriag, and 1 patient has inflammation in her body.

The values of 16 patients were very high, did not decrease. 5 of them received chemotherapy, 1 person had COVID infection as well, 1 patient receives radiation treatment. 2 patients take a lot of medicine. 3 patients suffer from severe anxiety and depression.  1 is a smoker, 1 has high blood pressure, 1 patient has autoimmune disease and 1 facial nerve palsy, as well as 1 patient has tetraplegia.

In 7 patients first raised, then very low values were experienced. 4 of them takes several medicines, 1 got COVID infection, 1 patient was under renal dialysis treatment, and 1 patient developed severe anxiety due to applying C-peptide, therefore the dosage could not be raised.

Very low value, the LF/LH rate below 1 was experienced in 1 patient, low values were found in 2 patients.

The LF/LH rate increased from a very low value, but did not reach the normal range in 8 patients. Interestingly, these patients had frequent herpes infection was found in their medical history.

The values of 4 patients became normal, starting from a very low value, their original diseases were earache, Bell-paresis, torticollis and epilepsy.

5 patients showed absolutely fluctuating values, each of them takes a lot of medicine regularly.

Changes depending on the dosage

The experience of our investigation pointed out that the changes both in HRV and the LF/HF rate dependent significantly on the dosage of C-peptide. In the cases of those patients, where the dosage was slightly or not changed at all, the values did not change. Therefore it is recommended in each case to change dosage according to symptoms and the results of the measurements.

Age SexDiagnosisDosageHRVRMSSDLF/HFComments
58 FemaleHypertension           6 months0.5 2×251 49 56 50 6027.99 24.83 38.94 26.11 48.692.62 3.93 2.28 2.26 4.18blood pressure stabilized in the normal range mood and sleeping improved copes with stressy situations better feels more forceful strain using the power improved a lot
20 MaleInfantile autismus     6 months0.5 2×163 68 58 47 4960.55 82.9 43.54 22.49 24.511.65 1.29 1.97 1.11 2.07calmer, sleeping became more restful started attending a college, tolerates more social life  concentration ability improved  
40 FemaleLatent hyperthyreosis Lyme disease0.5 2×155 52 53 52 5235.44 29.34 30.94 29.31 29.560.94 2.15 1.12 1.61 2.07Tolerates the hormonal changes due to the thyroid disease much better, the intensity of these significantly decreased Got pregnant but had a miscarrige, the cause of this is proved to be anti-cardiolipin positivity, investigation is going on Calmer, sleeps much better, became more forceful
61 MaleBell – paresis     6 months0.5 2×149 50 49 53 5124.15 26.04 24.03 30.86 26.750.48 0.88 0.29 1.37 1.26Bell paresis improved significantly, only a slight deviation of the mouth is experienced.
42 MaleFatty liver Autoimmune hepatitis0.5 2×159 67 55 4845.4 – 76.86 36.26 22.541.34 – 5.22 2.65 3.27values of laboratory test and general health improved strain using the power increased more restful sleep gained no weight.

Changes of symptoms

Subjective complaints and symptoms of our patients were also investigated. The patients reported general improvement of their symptoms, several patients described significant improvement in several symptoms.

3 patients felt that C-peptid was not beneficial for them, but in the answers of our questionnaire we could see that they are calmer, more balanced, they do not or less frequently catch infections.

Severe anxiety appeared in a patient with autoimmune disease, smoker, while applying C-peptide, therefore the dosage could not be raised.

25 patients felt more energetic.

Sleeping improved in 17 patients.

14 patients became less exhaustible.

In the cases of 12 patients infections were less frequent.

12 participants became more patient.

Speech improved in 11 patients, both in the cases of childhood disorder, and also adult problems.

Joint pain decreased in 11 patients.

Attention span became longer in 9 patients.

In 7 cases headache, migraine decreased.

6 patients feel less often cold since they apply C-peptide.

Motor skills improved, irritability decreased, depression  relieved, allergy or asthma got better, skin symptoms and memory improved, each of these in 6 cases.

Improvement of symptoms

Figure 7 – Improvement of symptoms

Deterioration of symptoms

There were rare cases, where the patients reported about deterioration of certain symptoms.

Anxiety increased in 3 patients.

In the cases of 2 patients differences between the pupils appeared.

Increased sweating, oversensitivity to scents, bad dreams, headache and feeling cold more often occurred, each symptom in 1 case. 

Figure 8 – Deterioration of symptoms

Anxiety, difference between pupils, increased sweating, oversensitivity to scents, bad dreams, headache and feeling cold more often 

Summary

Based on our present research it can be stated that the usage of intranasal C-peptide in a longer period (3-6 months) is secure, no serious side-effect or complication occurred during the application.  .

Both the objective, measurable values, such as HRV, RMSSD and the LF/HF rate indicated improvement in most cases, and also the subjective complains and symptoms of the patients significantly improved, and due to this their quality of life got better.

The symptoms and the measured values altered according to the dosage of the applied proinsulin C-peptide, therefore the dosage always has to be adjusted to the individual patient.

The patients were cooperating, they want to continue taking C-peptide in the future.

The exact effect, the more precise follow-up of symptoms and narrowing the patient groups in further research studies could provide more accurate image about the impact of intranasal C-peptide.

List of figures

Figure 1 – Mean HRV depending on age.
Figure 2 – Distribution of sexes.
Figure 3 – Changes of HRV and RMSSD values in patients with low values at the beginning
Figure 4 – The improvement of HRV over time.
Figure 5 – Deterioration of HRV.
Figure 6 – Changes of LF/HF rate.
Figure 7 – Improvement of symptoms.
Figure 8 – Deterioration of symptoms.

References

[i] Gidron Y, Deschepper R, De Couck M, Thayer JF, Velkeniers B. The Vagus Nerve Can Predict and Possibly Modulate Non-Communicable Chronic Diseases: Introducing a Neuroimmunological Paradigm to Public Health. J Clin Med. 2018;7(10):371. Published 2018 Oct 19. doi:10.3390/jcm7100371

[ii] Williams DP, Koenig J, Carnevali L, Sgoifo A, Jarczok MN, Sternberg EM, Thayer JF. Heart rate variability and inflammation: A meta-analysis of human studies. Brain Behav Immun. 2019 Aug;80:219-226. doi: 10.1016/j.bbi.2019.03.009. Epub 2019 Mar 11. PMID: 30872091.

[iii] Jarczok MN, Koenig J, Thayer JF. Lower values of a novel index of Vagal-Neuroimmunomodulation are associated to higher all-cause mortality in two large general population samples with 18 year follow up. Sci Rep. 2021 Jan 28;11(1):2554. doi: 10.1038/s41598-021-82168-6. PMID: 33510335; PMCID: PMC7844270.

[iv] Rangon CM, Krantic S, Moyse E, Fougère B. The Vagal Autonomic Pathway of COVID-19 at the Crossroad of Alzheimer’s Disease and Aging: A Review of Knowledge. J Alzheimers Dis Rep. 2020 Dec 28;4(1):537-551. doi: 10.3233/ADR-200273. PMID: 33532701; PMCID: PMC7835993.

[v] Jarczok MN, Koenig J, Wittling A, Fischer JE, Thayer JF. First Evaluation of an Index of Low Vagally-Mediated Heart Rate Variability as a Marker of Health Risks in Human Adults: Proof of Concept. J Clin Med. 2019 Nov 11;8(11):1940. doi: 10.3390/jcm8111940. PMID: 31717972; PMCID: PMC6912519.

[vi] Jaiswal M, Urbina EM, Wadwa RP, et al. Reduced heart rate variability among youth with type 1 diabetes: the SEARCH CVD study. Diabetes Care. 2013;36(1):157-162. doi:10.2337/dc12-0463

[vii] Rickels MR, Evans-Molina C, Bahnson HT, Ylescupidez A, Nadeau KJ, Hao W, Clements MA, Sherr JL, Pratley RE, Hannon TS, Shah VN, Miller KM, Greenbaum CJ; T1D Exchange β-Cell Function Study Group. High residual C-peptide likely contributes to glycemic control in type 1 diabetes. J Clin Invest. 2020 Apr 1;130(4):1850-1862. doi: 10.1172/JCI134057. PMID: 31895699; PMCID: PMC7108933.

[viii] Gubitosi-Klug RA, Braffett BH, Hitt S, Arends V, Uschner D, Jones K, Diminick L, Karger AB, Paterson AD, Roshandel D, Marcovina S, Lachin JM, Steffes M, Palmer JP; DCCT/EDIC Research Group. Residual β cell function in long-term type 1 diabetes associates with reduced incidence of hypoglycemia. J Clin Invest. 2021 Feb 1;131(3):e143011. doi: 10.1172/JCI143011. PMID: 33529168; PMCID: PMC7843223.

[ix] Lam A, Dayan C, Herold KC. A little help from residual β cells has long-lasting clinical benefits. J Clin Invest. 2021 Feb 1;131(3):e143683. doi: 10.1172/JCI143683. PMID: 33529163; PMCID: PMC7843219.

[x] Johansson BL, Borg K, Fernqvist-Forbes E, Odergren T, Remahl S, Wahren J. C-peptide improves autonomic nerve function in IDDM patients. Diabetologia. 1996 Jun;39(6):687-95. doi: 10.1007/BF00418540. PMID: 8781764.

[xi] Schwartz MW, Sipols A, Kahn SE, Lattemann DF, Taborsky GJ Jr, Bergman RN, Woods SC, Porte D Jr. Kinetics and specificity of insulin uptake from plasma into cerebrospinal fluid. Am J Physiol. 1990 Sep;259(3 Pt 1):E378-83. doi: 10.1152/ajpendo.1990.259.3.E378. PMID: 2205107.

[xii] Okamoto S, Kimura K, Kitamura T, et al. Proinsulin C peptide obviates sympathetically mediated suppression of splenic lymphocyte activity in rats. Diabetologia. 2000 Dec;43(12):1512-1517. DOI: 10.1007/s001250051562.

[xiii] Derkach KV, Perminova AA, Buzanakov DM, Shpakov AO. Intranasal Administration of Proinsulin C-Peptide Enhances the Stimulating Effect of Insulin on Insulin System Activity in the Hypothalamus of Diabetic Rats. Bull Exp Biol Med. 2019 Jul;167(3):351-355. doi: 10.1007/s10517-019-04525-w. Epub 2019 Jul 26. PMID: 31346872.

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