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Is There a Role for Testosterone and Anabolic Steroids in Adult Diabetes Mellitus?

ANDROGEN TREATMENT IN DIABETES, AUTO-IMMUNOLOGY and CARDIO-VASCULAR DISEASE

Edward M. Lichten, M.D., F.A.C.O.G., F.A.C.S.

Fellow, American College of Obstetricians and Gynecologists

Fellow, American College of Surgeons

600 West Brown Street Suite #202

Birmingham, MI 48009

Office phone: (248) 593.9999  

Cellular Phone: (248) 420.8726   

Fax: (248) 593.9037

Email: edwardlichten@gmail.com

Dr. Lichten’s focus for forty years has been the treatment of autoimmune and chronic diseases with natural, bio-identical androgenic anabolic steroids derived from testosterone.

ABSTRACT: (532)

Since antiquity, diabetes management has been integral to our level of medical knowledge. Symptoms were defined by Galen 2500 years ago when he elucidated the wasting and “sweet-tasting” of urine and treatment was pin-pointed by Banting and Best 100 years ago as insulin replacement.  In the 21st century with a new world of microscopic, immunologic, and intracellular biologic discoveries, causation of diabetes is still not clearly defined.  Without a singular causative agent, the plethora of present-day treatments are proof that, “we don’t understand diabetes disease at all.”

Science Magazine1-5 publish five articles in July, 2021 outlining healthcare objectives, future directives in diabetes management, and research toward the singularity of diabetes causation. TABLE I.  Absent was any reference to the use of testosterone/ androgenic-anabolic steroid even though half of insulin requiring diabetics are adult men. The FDA has approved 5 AAS. TABLE II.  EL Ding6 established that all diabetic men are hypogonadal and there is a plethora of scientific knowledge on testosterone treatments of diabetes, metabolic syndrome, and heart disease spanning 80-years.

Jens Möller, M.D.7 hypothesized that testosterone deficiency was causative for diabetes, metabolic and cardiovascular disease. He published his findings in Cholesterol in 1987 as the president of the 250-physician European Organization for the Control of Circulatory Disease (EOCCD). They successfully prescribed parenteral testosterone to 10,000 men and women with diabetes, insulin treatment, hypercholesterolemia, and cardiovascular disease. Malcolm Carruthers, M.D., a leading European endocrinologist, personally reviewed Moller’s clinic in-situ and affirmed his findings.7

MISSION:

Loyal to today’s epigenetic hypothesis of disease, we sought to integrate the microscopic, immunologic and recent observations from the diabetic and internal medicine literature with reports from our first-in-the-world, in-vitro cytokine and hormonal receptor laboratory.  We propose a new diabetes, immunologic, cardiovascular, and hormonal hypothesis. Scientific Method atolls that the hypothesis must encompass all known information. As Einstein stated, “No amount of experimentation can ever prove me right; a single experiment can prove me wrong.” Failure to incorporate testosterone and immunologic information into the present diabetes-insulin hypothesis about “insulin resistance” makes it null and void.

The hypothesis presented herein pinpoints hypogonadism as causative, loss of Estrogen Receptors homeostasis as intermediary, and inflammation as diseasepropagator by pro-inflammatory cytokines. Furthermore, the hypothesis states that remission may be achievable by reestablishing normal homeostatic levels of proinflammatory cytokines and hormonal receptors; i.e., thereby, clearing the inflammation. Observation from the in-vitro laboratory provide quantitative analysis of inflammation disease. The laboratory defines inflammation uniquely as increased levels of pro-inflammatory cytokines.  Decreased levels of anti-inflammatory cytokines, dysregulation of hormonal receptors, and correlation with non-specific serum inflammatory biomarkers are considered and included as secondary symptoms.

PRECISION MEDICINE focuses on evaluation of a singular host. The term symptoms are not specific nor definitive of disease.  Rather, disease requires inflammation which is the quantitation of increased intracellular pro-inflammatory cytokines. Treatment is determined in-vitro where drugs are admixed with host’s T-lymphocytes:  the most potent drug is the one(s) that most reduces the quantity of proinflammatory cytokines.   Disease is the presence of inflammation defined by excessive proinflammatory cytokines and concomitant dysregulation of hormonal receptors. Remission is identified clinically and concurrently by return to homeostasis by the proinflammatory cytokines and hormone receptors. Disease is the physically manifested of the inflammation thrust upon specific organelles and their components.

HYPOTHESIS:

Diabetes Mellitus is an autoimmune inflammatory disease characterized by

  1. LOSS OF BIOAVAILABLE TESTOSTERONE.IS THE CAUSE8 Loss of bioavailable testosterone dysregulates and
  2. ESTROGEN RECEPTOR-β LOSS OF HOMEOSTASIS: on the nuclear membrane must down-regulate pro-inflammatory cytokines, otherwise
  3. PRO-INFLAMMATORY CYTOKINES. ESCAPE, PROLIFERATE, and PROPAGATE
  4. INFLAMMATION

The corollary is also proposed as true:   In diabetic states of

Bio-T9 can be corrected by

  1. ANDROGEN REPLACEMENT with appropriate dosages of mixed androgenic-androgen-anabolic steroids (MAAS) typified by testosterone, nandrolone, stanozolol,10 danazol and oxandrolone.
  2. The combination may be able t:o
  3. Bring Estrogen Receptor-beta into homeostasis
  4. Reduce proinflammatory cytokines
  5. Increase facilitative transport of glucose into skeletal miuscle
  6. Reduce inflammation and
  7. Bring disease into remission and
  8. Lower insulin requirements in diabetes.

That is the purpose of the Pilot Study enclosed herein.

BACKGROUND INFORMATION:

We have categorized the five articles from Science July 20211-5 to as to goal, author, natural physiology, observations of how the new science of mixed androgenic-anabolic steroids (MAAS) influences these goal, and key statements of the authors and potential benefits and side-effects of MAAS in Table I.  It is a recognized fact that the immune11 responses is modulated by anabolic androgenic steroids.

OBJECTIVE:

Reduce the dosage of insulin and reduce inflammation

Goals of these five articles are distilled into reducing the dosage of insulin and reducing inflammation. We quantitated these goals to insulin daily needs and concentration of proinflammatory cytokines present in-vitro.  The in-vitro laboratory also analyzes the drug-therapies for potential cytotoxicity to the anti-inflammatory cytokines.

 

5-Hour Insulin oral glucose tolerance Test

The glycosylated hemoglobin, HgB-A1c, is the singular screening tool for diabetes.  While obesity and BMI are the strongest risk factors, the physician must realize that in screening the African-American race there is increased insulin resistance.12

However, the 5-hour Insulin and Oral Glucose Tolerance Test may be the best screening tool the physician uses to diagnose and manage diabetes. The 5-hour Insulin and Oral Glucose Tolerance Test (I-OGTT) as proposed by R. Kraft13-14 is utilized to sub-classify the individual’s need for insulin. Normal insulin15 requirements increase 4-fold in the first hour while peak glucose and insulin should converge at one hour respectively at a glucose level of 140 mmol/L and an insulin of approximately 20 mIU/L. Worsening hyperglycemia often begins with an increase need and delay of insulin release15, the delay in peak glucose, and then prolonged insulin production that eventually fails to meet the host’s need. Exhaustion of insulin production defines insulin-requiring individuals.

Non-Insulin Facilitated Transport (NIFT)

Hobbs16 elucidated the key role of anabolic steroids in glucose homeostasis. He showed that with 85% of glucose stored in muscle, glucose transport into muscle is dependent on anabolic steroids. Glucose transport occurs without insulin. As the transport of glucose takes energy and the anabolic steroids are key to ATP and aerobic metabolism, non-insulin facilitated transport (NIFT) is also key to the avoidance of hypoglycemia. Glycogen is moved out of the cell by non-glucagon facilitated transport to maintain serum glucose homeostasis.  Supraphysiological doses of anabolic steroids do inhibit gluconeogenesis and argumentatively are not applicable in daily diabetes management.17

The importance of NIFT cannot be overlooked. “Although poorly explored, insulin-independent glucose uptake might nevertheless represent a therapeutic target as an alternative to the clear limits of actual drug treatments.”18 Even long-term insulin use does not suppress non-insulin facilitative glucose transport in this population.19

STATUS of PHARMACEUTICAL PRODUCT DEVELOPMENT:

The pharmaceutical industry is focusing on non-insulin facilitated glucose transport system. They have included the classes of glucagon-like peptides-1 (GLP-1), sodium-glucose co-transporter-2 (SGLT2) and dipeptidyl peptidase-4 (DPP-4).20-21 The man-made drugs have side-effects, develop resistance, and complications of therapies that are not characteristic of the natural occurring host’s hormones.

Testosterone, Sex Hormone Binding Globulin and Diabetes in Men

EL Ding7 and others12 have strongly linked hypogonadism to adult-onset diabetes in men, Anderson8,9 stressed the importance of the bioavailability of testosterone as 98% was tightly bound to SHBG. SHBG is an independent factor that is statistically more important than total testosterone22 in development and monitoring of diabetes.

“After multivariate adjustment, men with low SHBG levels had a fourfold greater risk of T2D than men with high SHBG levels. Conversely, men with high estradiol levels had a 4-fold greater risk of T2D than men with low estradiol levels. Men with low SHBG and high estradiol had a 20-fold greater risk of T2D than men with high SHBG and low estradiol (odds ratio [OR] 20.23; 95% confidence interval [CI] 4.62-51.33). “22

Sex Hormone Binding Globulin (SHBG) is produced in the liver and is under the influences of estriol (in pregnancy), natural 17β estradiol and Endocrine Disrupting Chemicals (EDCs).23

“Together, this body of evidence indicates that sex steroids and SHBG should be routinely incorporated into clinical characterization of T2D patients, particularly in screening prediabetic patients, such as those with metabolic syndrome, using plasma levels of SHBG;”23 The physician should be “Using the sex steroids and SHBG as important biochemical markers in both clinical and population studies.23

 

METHOD:

Anabolic Steroids, Insulin, Diabetes and Risk of Disease

In clinical practice, as outlined in the hypothesis, the first step is to identify hypogonadism (low serum testosterone).  The Follicle Stimulating Hormone (FSH) measurement from the Hypothalamic-Pituitary-Gonadal (HPG) Axis will show dysregulation as either elevated (primary) hypogonadism) or secondary hypogonadism with normal FSH.   The ratio of the concentration of total testosterone [TT] to concentration of Sex Hormone Binding Globulin [SHBG] is the Free Androgen Index8 calculated as Bio-T = (3.47 x [TT}/ [SHBG]).  Ideal male value is 0.7 to 1.0.  Ideal woman’s rate is one-twentieth (0.04).

When the symptomatic male’s FAI is significantly reduced, the four MAAS are prescribed should he be without exclusive criteria of elevated Prostate Specific Antigen (PSA), or a history of prostate or testicular cancer. First prescribed is parenteral testosterone at week doses of 120 to 200mg or testosterone pellets of 600 to 900mg every 3 months. Secondly, intramuscular nandrolone 20 to 30 mg per week and stanozolol 10 to 20mg per week.  The goal is a serum testosterone 5 days after injection to remain stable at approximately 500 ng/dl and SHBG remain under 20 nmol/l. Oxandrolone is begun after his diabetes management has reached a steady state. The results of this protocol is a calculated FAI or Bio-T greater than 1.  Modifications to dosing are made to achieve the drug-therapy goal and clinical response appropriate for the patient.

CASE REPORTS:

#1 EE is a 61-year-old African-American male whom developed IDDM even with an exemplary diet and exercise program. His HgB-A1c reached 11.9.  His random glucose approached 300 mg/dl. His initial evaluation showed a total serum testosterone greater than 500ng/dl and SHBG greater than 40 nmol/l. The first 3-hour I-OGTT was followed by one-month of testosterone cypionate, [TC] dosage of 300mg per week. The second I-OGTT was performed one month later and 30mg of nandrolone was added intramuscularly weekly. The third I-OGTT was performed and 10mg of Stanozolol was added intramuscularly weekly. The fourth I-OGTT was performed and 10mg of oxandrolone added orally daily.

His lowest reported HgB-A1c was 6.7%.  He had discontinued his evening Lantus dosage prior to beginning the MAAS protocol. His serum inflammatory biomarkers, in-vitro cytokine and hormone receptor analyses were within normal range for adult males without diabetes. CHART I and II.

#2 JP is a 53-year-old African-American male who unknowing recorded a random glucose greater than 400mmol/L and HgB-A1c of 17.9. His serum testosterone was approximately 200 ng/dl and SHBG greater than 40 nmol/l.  After 6-months of MAAS-4 drug-therapy, treatment he had lost 70 pounds, his HgB-A1c was 6.3 and I-OGTT within normal range. Chart III and IV. (pending)

#3 JA was 39-year-old African-American unemployed street-person who recorded a random glucose of greater than 400mg/dl. After a short emergency overnight stay, he returned for the mixed anabolic-steroid protocol. His glycosylated hemoglobin dropped to 7.9 in 7-months as he needed daily insulin. His death due to a drug overdose occurred 4 years later.

TABLE V. I.R.B.: Ascension Health: 706-97

Thirteen adult insulin requiring brittle diabetic men volunteered for the study. Each required more than 100iu of insulin daily. They had no exclusion criteria for testosterone or AAS use, had no major cardiovascular disease, or exclusion criteria. Their initial serum hormone assays, glucose, Hgb-A1c, inflammatory markers, and PSA were recorded. They each received 300mg of testosterone pellets and returned for repeat glucose assay the next morning. Two recorded asymptomatic hypoglycemic glucose levels below 40mg/dl. They did not require treatment with life-savers or glucose.

RESULTS:

As seen in GRAPHS I through IV, the serial Insulin-Oral Glucose Tolerance Tests (I-OGTT) can follow the individual’s transition back-and-forth from brittle insulin-requiring diabetes toward normalcy even without insulin.  The glycosylated hemoglobin, HgB-A1c, is used every 3 to 6 months to follows the 4 MAAS drug-therapy.  TABLE V shows the utilization of MAAS concurrent with insulin to maintain hemostasis in the most difficult insulin-requiring diabetic.

The six androgenic-anabolic steroids and their biologic characteristics available in the United State appear in TABLE II.   The list of diabetes medications arppearin Table III.

DISCUSSION:

The four key elements of the hypothesis are listed and reviewed in detail herein. In 1 to 4.  The in-vitro findings subsequently as to drug-therapy effectiveness and the cytotoxicity of man-made hypoglycemic drugs and natural insulin itself should cause an redirection into use of these products in lieu of in-vitro testing and MAAS.

#1 BIOIDENTICAL TESTOSTERONE:

Anderson in 19728 recognized that testosterone is bound tightly to Sex Hormone Binding Globulin (SHBG). When bound, testosterone is inactivated. SHBG becomes even more important to availability than testosterone itself. Free Androgen index (FAI) is used for calculated bioavailable-T or (Bio-T). Anderson’s FAI is recognized as the ‘gold standard’ for women’s bioavailable testosterone calculations and well-respected for men’s as well.

The failure of most published medical journal articles is that they relied upon total testosterone [TT] concentration rather than bioavailable testosterone concentrations [Bio-T].  This introduced a major error in determining the significance of outcome in published reports on testosterone and diabetes.  Graph III uses Anderson’s data to make this point: total testosterone, SHBG and bioavailable testosterone.

#2 ESTROGEN RECEPTOR BETA:

Pierdomunici31 in 2015 showed that the flair of Crohn’s Disease could be linked directly to release of proinflammatory cytokine IL-06 precipitated by loss of signaling from the Estrogen Receptor-beta (ERβ) on the nuclear membrane. The loss of ERβ quantitation was present in the T-lymphocytes in the blood, colonic mucosa, and ubiquitous throughout every cell in the body. During remission, the ERβ returned to homeostasis levels. This was confirmed by Linares.32 The selectivity and specificity of these findings were 90% and 71% respectively.

The levels of the hormone receptors, estrogen receptor-beta, estrogen receptor-alpha and the androgen receptors are determined before and after 6-months. Correlation with serum assays of glycosylated hemoglobin (Hgb-A1c), 3-hour I-OGTT, levels of pro- and anti-inflammatory cytokines, and hormone receptors appear in TABLE V and CHART V.A correlation between HgB-A1c, proinflammatory cytokine propagation and hormone receptors should be evident in our volunteers.

#3 PROINFLAMMATORY CYTOKINES

Inflammatory diseases including diabetes Type I and Type II, show evidence of inflammatory cytokines. In diabetes disease, inflammatory cytokines likely contribute to the link between inflammation, oxidative stress, and skeletal muscle insulin resistance.33  There is correlation between worsening disease and elevated proinflammatory cytokines.34 There is a direct correlation between the severity of joint damage and the level of TNF-α and IL-6.35 β-cell destruction is one central means for enhancing their autoreactivity; done by the secretion of proinflammatory cytokines, such as IFN-γ, TNF-α, and IL-1.34 Activated innate immunity and inflammation are relevant factors in the pathogenesis of diabetes36  as activation of the innate immune system, itself, induces hyperglycemia and insulin resistance.37

In all likelihood, diabetes and chronic inflammation are inseparable and act as a reciprocal feed-forward loop.37

Researchers know that IL-6 and many cytokines can be pro-inflammatory and anti-inflammatory depending on the signaling. While the pharmaceutical companies seek “specific blockade of IL-6 trans-signaling rather than inhibiting both signaling pathways as a therapeutic strategy for the treatment of T2D and its associated macrovascular complications,”38-40 our authors believe that reestablishing the homeostatic levels of bioavailable testosterone to stabilize Estrogen Receptor-beta signaling is naturally the correct mechanism to reestablish homeostasis.

#4 GENDER-SPECIFIC MEDICINE:

  1. Legato41 has organized a new division of medicine practice called “Gender-Specific” Medicine. This international organization has identified that gender influences diseases. It is symptom and politically based to give women’s diseases more attention and discern the differences of sex and disease as for example, women have up to 6-fold more autoimmune diseases then men.

More specifically, our focus is on the immune system of men and women and how they differ.  In the Pierdominici study,31 both men and women with Crohn’s disease showed reduction in ERβ with the flair. However, diseases of women that originate within the reproductive Müllerian tract, such as endometriosis and breast cancer, show up to 100-fold increase in ERβ during a flair.  The Müllerian organs are the breast, ovaries, uterus, endometrium, cervix and upper third of the vagina. The lung may be included as a disease state with increased ERβ: our testing has not yet determined.  In endometriosis, resolution of disease occurs with the drop in ERβ which corresponds to resolution of the propagated proinflammatory cytokines. This is opposite to the ERβ direction seen in Crohn’s disease.  This is proof of Gender-Specific Medicine at the intercellular level.

The development of the in-vitro cytokine laboratory clarifies the roles of the cytokines and the Estrogen Receptors as they are different phylogenetically (Müllerian) and gender-specific; i.e., men and women.

#5 ANDROGENIC-ANABOLIC STEROIDS AS ANTI-INFLAMMATORY and HYPERGLYCEMIA THERAPY

Missing in the cascade from health to inflammation is the epiphany that adequate levels of mixed androgenic-anabolic steroid (MAAS) are necessary to stabilize ERβ.  This is a second mechanism as the MAAS are able to reduce insulin requirements and hyperglycemia by NIFT.

Our unpublished I.R.B. from Ascension Health 1997-1999, reported a 50% drop in insulin requirements within 24 hours of 12 of 13 brittle diabetic men requiring more than 100 iu of insulin daily.  Two volunteers experienced serum glucose drops to below 40mg/gm, but remained asymptomatic. Reference: Ascension Health: IRB: 706-97.42

Forty years ago, McGuire43 predicted that there was a connection between hormones and autoimmune diseases as he used Danazol to reverse nephritis in women patients with lupus erythematosus. The mixed androgenic-anabolic steroids (MAAS), known to be anti-inflammatory, treatments for autoimmune diseases, and now are show in vitro and in-vivo to reduce not only the pro-inflammatory cytokines but to protect the anti-inflammatory cytokines from cytotoxic “insulins,” and the newest pharmaceutical hypoglycemic agents.

INSULIN AS AN INFLAMMATORY AGENT

Diabetes is an inflammatory state: the increase in inflammation is directly correlated with increases in pro-inflammatory cytokines. Domingueti40 and others identified endothelial, inflammatory and pro-coagulant biomarkers, such as VWF, IL-6, TNF-αD-dimer and PAI-1, as increased in diabetic patients. These have microvascular and macrovascular complications, including nephropathy or cardiovascular disease.

The rising concentration of IL-1Ra probably reflects a futile attempt to counteract IL-1.39 This will be a target of future in-vitro analysis. In our preliminary evaluation of our pilot case report, the observations of obesogens adipectin and resistin are noted.

Final note:  Menon reported in 1971 that the combination of stanozolol and metformin reduced PAI-I and fibrinogenesis.  This I another reason that the MAAS of nandrolone and stanozolol should play the initial intervention in the management of adult-onset diabetes in men.44

CONCLUSION

The symptoms of diabetes and its management has been the inherent characteristic of medical practice for 2500 years.  Banting and Best redefined the disease by discovering and manufacturing insulin.  Diabetes had a treatment, but life-expectancy never reached normal, non-diabetic parameters.45 It follows that reduced levels of bioavailable testosterone and the resultant increase in inflammation is a logical and established predictor state.46  It is unquestioned that glucose is inflammatory and when insulin is available to reduce glucose load, the body state becomes more anti-inflammatory. However, as shown in CHART I, the natural production of insulin in an insulin-requiring adult-onset diabetic man was mitigated in the 3-hour glucose tolerance test. NIFT,by reducing hyperglycemia and moving glucose into the skeletal muscle reduce the need for insulin.

However, when every one of the man-made hypoglycemic agents and man-made insulins were tested in the Lymphocyte Toxicity Assay, they all showed varying degrees of toxicity. Those closest to naturally occurring insulin, were less toxic than the newest pharmaceutical preparations. Seen in Table III. Surprisingly, naturally occurring ‘regular’ insulin was also toxic.  The 4-androgenic-anabolic steroids (AAS) sans oxandrolone, showed no toxicity.

This supports the concept that natural AAS promoted by exercise and a diet that is low in its inflammatory index promotes health in everyone:  normal, metabolic and diabetic.

The planned future I.R.B. will evaluate this observation just as we did in the pilot cases with special attention to the cytokines, hormone receptors including the androgen receptor, and lymphocyte cytotoxicity.

The concept of insulin resistance now becomes as irrelevant as the urine tester for Galen and Hippocrates:  it is the lack of adequate levels of androgenic-anabolic steroids (AAS) that define diabetes mellitus and inflammation.  NIFT reduces insulin requirements by 50 percent so MAAS must be the first and foremost treatment for diabetes mellitus in men.   There is a problem though in menopausal women.  The AAS may increase cardiovascular disease.  Further research is planned to follow the role of MAAS in  the in-vitro laboratory to precisely determine the roles of MAAS in pre- and post-menopausal women,  The key is the in-vitro T-lymphocyte analysis before and after drug-therapy exposure.  It should correlate nearly 100% with the in-vivo findings.

CONCLUSION:

The medical and health perspective is that every doctor should order appropriate laboratory tests performed on every male over 35 years of age and especially those with suspected health issue. Without the glycated and bioavailable testosterone biomarkers, a physician would not suspect diabetes, low testosterone, or his patient’s health risks.

The safety of testosterone replacement has been unquestioned scientifically since World War II. The problem has been that naturally occurring hormone replacement is effective, natural, safe and not inflammatory.

Morganthaler47 has made it his work to promote the safety of androgenic-anabolic steroids especially in men. The topical creams are 30-times for expensive that the weekly injections of testosterone cypionate or the 3-months pellet implants.  These creams are metabolized by the skin to estrogens which increase SHBG and negate its positive effects.

Morganthaler47 clearly identified that a PSA greater than 3.0 with a low serum testosterone could increase the risk of prostate cancer by 9-fold.  By incorporating the Bio-T ratio of testosterone, [TT] to Sex Hormone Binding Globulin [SHBG] as the biomarker, the in-vitro MASS should increase both specificity and selectivity of glycemic control identified in the HgB A1c.

Medicine must return to the Scientific Methodology and explore from the depth of inflammation, the cytokines, the hormone receptors that suppress them to the drug-therapies that can reduce and reverse inflammation.

Forget not the physicians’ Hippocratic Oath; “Do NO Harm.”  Unfortunately, the pharmaceutical-Insurance-Government (P.I.G.s) are driven by Return on Investment (R.O.I.) instead of “Return to Health.,” (R.T.H).

May truth in research awaken mankind to health and Wellness!

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ADDENDUM

TABLE I. Science Magazine. 2021

Goal: Author: Natural Physiology: Scientific Observation in using MAAS: End Point/ side-effects:
Cost and availability Nusinovich Y.1 MAAS inexpensive and readily available “More work is needed to overcome this increasingly prevalent disease with the eventual goal of prevention or a cure.”
Childhood: prevent the islet specific auto-antibody Dayan CM.2 MAAS not applicable to children “…is recent successes in using immunotherapy to delay the progression.” Editor adds ‘although MAAS may not bev applicable to those who have not reached adult height”
Immunotherapy could reduce insulin needs: cyclosporin was toxic Bluestone JA3 if immunotherapy reduced inflammation/ cytokines

Individual MAAS11 may have different effects on pro- inflammatory cytokines (IL-01, TNFα) IL-6, etc.)

NEED IN-VITRO ASAAY

TABLE III

In-vitro lab can checks cyto-toxicity.  Drug-resistance does not usually develop to MAAS.  Results with 3-hr OGTT observable in lab confirm reduced insulin needs.

GRAPHS 1&2

Cyclosporin immunotherapy was cytotoxic.

MAAS is cyto-protective of anti-inflammatory cytokines [EML]

Reduce insulin needs

Brusko TM4;

if β-cell transplant

NIFT can reduce insulin requirements

GRAPHS 1&2

Β-cells subject to blood-mediated inflammatory reaction. Transplant increases risk for infection & cancer.  Tregs suppressà immune-regulatory cytokines.

MAAS reduces proinflammatory cytokines, reduces insulin required.

GRAPHS 1&2

Prevent hypoglycemia Perkins BA5 non-insulin facilitated transport (NIFT)

  mixed androgenic anabolic steroids (MAAS)

prevention of Somogyi effect: hypoglycemia

TABLE II. FDA Approved ANABOLIC STEROIDS

AAS Class III Aromatize to E2 Reductase to DHT Receptor affinity SHBG
Testosterone ü ü ü 10-fold E2 98% bound
Nandrolone ü 30-fold E2 5% bound
Danazol ü Reduces SHBG 80%
Stanozolol ü Reduces SHBG 80%
Oxandrolone ü Reduces SHBG41
DHEA Over-counter
  • TRT offers reductions in insulin resistance, total cholesterol, LDL cholesterol and triglycerides and improvement in glycemic control and anthropometric parameters.24
  • Danazolincreases the sensitivity of pancreatic insulin and glucagon secretion to glucose. Danazol-induced insulin and glucagon resistance could be due to receptor down-regulation resulting from hypersecretion of insulin and glucagon.25
  • Pharmacological doses of testosterone or 19-nortestosterone to normal men is not associated with increased insulin secretion or impaired glucose tolerance 26
  • Stanozolol reduces insulin requirements initially 27
  • DHEA supplementation has no effects on blood glucose levels.30

TABLE III.  Types of Diabetic Medications

Regular Insulin 30 minutes 3 to 6 hours >>Insulin regular Novolin R®
Intermediate- acting insulin 1 to 2 hours 12 hours

>>NPH

Novolin N®

Long lasting insulin 2 to 4 hours 24 hours

>>Insulin detemir/ Levemir®

>>insulin glargine/Lantus®, Basglar®

Ultra-long-lasting insulin 6 hours 36 to 42 hours

>>Insulin degludec Tresiba®

>>Insulin glargine U300 Toujeo®

Non-insulin drugs
(GLP-1) Glucagon-like protein Releases more insulin from pancreas

Semaglutide/ (Ozempic)®; Lixisenatide/ (Adlyxin)®;Dulaglutide (Trulicity)

Exenatide ER (Bydureon);Exenatide (Byetta)

Liraglutide (Victoza)

Dipeptidyl peptidase-4 inhibitors  (DPP-IV)

Releases more insulin from pancreas Sitagliptin (Januvia®) saxagliptin (Onglyza®) linagliptin (Tradjenta®) alogliptin     (Nesina®)
(SGLT2)  Sodium-glucose co-transporter 2 inhibitors release more sugar through kidneys Canagliflozin (Invokana®), dapagliflozin (Farxiga®), empagliflozin (Jardiance®)

TABLE IV. KRAFT 5 PATTERNS OF DIABETES INSULIN- GLUCOSE TOLERANCE TEST

Biochemical Patterns of Increasing Metabolic Syndrome >> Diabetes Mellitus

Pattern I: Glucose < 100 insulin <20 at 60min NORMAL
Pattern II: Glucose >140 insulin >40 at 60min Delay and increased peaks (In&G) at 60min
Pattern III; Glucose< 140 insulin <40 at 60min Delay and increased peaks (In&G) at 120min
Pattern IV: Glucose< 140 insulin <50 at 60min Hyperinsulinemia -Insulin >50
Pattern V: Glucose< 100 insulin <20 at 60min Insulin never rises above baseline
Reference Keys: Insulin (In) and Glucose (G): both (In & G)

TABLE IV.  CASE REPORT#3: AJ

ANDROGENIC-ANABOLIC STEROIDS with INSULIN to CONTROL IDDM

DATE

24-hr (Lantus®)

Glucose

HgbA1c

Testosterone serum mg/dl

SHBG nmol/ml

#/ week injections

7/18/2006

14 units

488

17.9%

643

38

2

7/29/2006

30 units

141

15.7%

2

8/06/2006

40 units

154

152

1.5

8/12/2006

50 units

13.5

953

1

9/02/2006

60 units

161

11.8

493

1

9/15/2006

70 units

165

11.2

522

1

9/22/2006

80 units

10.1

1

10/28/2006

75 units

308

9.5

894

1

11/14/2006

75 units

  47

8.3

1

12/18/2006

88 units

175

7.7

297

1.5

  1/ 27/2007

100 units

  65

7.4

792

1.5