life cycle of type 1 diabetes

AAEM Oct 14‐17, 2021

The Life Cycle of Type 1 Diabetes –

from environmental triggers to survival and beyond

Laura Neville, ND

Disclosure • Staff Physician at Doctor’s Data Inc (DDI)

Level of Evidence for Patient Care Recommendations unless otherwise stated, is B or C. The information, comments, and opinions expressed in this presentation are those of my training, clinical experience and interpretation of the literature and are for educational purposes only. Practitioners should evaluate the information, comments, and opinions using their own expertise coupled with an assessment for each patient.

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Beginning of your work day

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Where to start?

Analyze and regulate blood glucose

Optimize and diet and lifestyle (sleep, stress management, exercise)

Reduce inflammation

Improve gut microbiome

T reg immune support

Antioxidant support

Statistics

Globally, the incidence of type 1 diabetes started to increase in the 1950s with an average annual increase of 3–4% over the past three decades

This increase is too rapid to be due to genetic factors, suggesting that environmental factors may play a role

Norris JM, Johnson RK, Stene LC. Type 1 diabetes‐early life origins and changing epidemiology. Lancet Diabetes Endocrinol. 2020 Mar;8(3):226‐238. doi: 10.1016/S2213‐8587(19)30412‐7. Epub 2020 Jan 27. PMID: 31999944; PMCID: PMC7332108.

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Age‐sex standardized incidence rates (per 100,000 population per annum) of type 1 diabetes in children and adolescents aged 0–14

years, 2019

CHILDREN AND ADOLESCENTS

Statistics

• Data from the International Diabetes Federation on children ages 0‐14 found Finland to have the highest incidence at 57.6 cases per 10,000 people, followed by Sweden, Saudi Arabia and Norway.

• The US had the 6th highest incidence at 23.7 cases per 10,000 people.

• Venezuela has one of the lowest incidence rates at 0.1 out of every 100,000 people.

International Diabetes Federation. IDF Diabetes Atlas, 9th edn. Brussels, Belgium: 2019. Available at: https://www.diabetesatlas.org

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Etiology

• Type 1 diabetes (T1D) is an autoimmune disease caused the T‐cell mediated destruction of the pancreatic beta cells.

• T‐cells infiltrate the islet of Langerhans within the pancreas and destroy the insulin producing beta cells.

• How and why the immune system turns against otherwise healthy tissue, to cause an autoimmune disease, is currently not known.

Mannering SI, Rubin AF, Wang R, Bhattacharjee P. Identifying New Hybrid Insulin Peptides (HIPs) in Type 1 Diabetes. Front Immunol. 2021 Apr 30;12:667870. doi: 10.3389/fimmu.2021.667870. PMID: 33995402; PMCID: PMC8120023.

Etiology ‐ Genetic Predisposition

• HLA class II alleles• DQA1*0301 (DQ2), DQB1*0302 (DQ8), DRB1*DR301 (DR3) and several DR4 alleles

•HLA class I alleles

• Others• Insulin expression• Immune function• B cell function

Noble JA, Valdes AM. Genetics of the HLA region in the prediction of type 1 diabetes. Curr Diab Rep. 2011;11:533–542.Noble JA, Valdes AM, Varney MD, et al. HLA class I and genetic susceptibility to type 1 diabetes: results from the Type 1 Diabetes Genetics Consortium. Diabetes. 2010;59:2972–2979.

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More to the story . . .

• Only a small portion of individuals carrying those alleles will develop T1D

• No gender differences in prevalence• Sharp rise of T1D incidence in recent years= time frame not sufficient for genetic change

• Environmental factors may play a crucial role

• Prenatal influence, viral infections, dietary factors and “hygiene” can all affect the disease onset

Achenbach P, Bonifacio E, Koczwara K, Ziegler AG. Natural history of type 1 diabetes. Diabetes. 2005;54(Suppl 2):S25–31.Patterson CC, Gyurus E, Rosenbauer J, et al. Trends in childhood type 1 diabetes incidence in Europe during 1989–2008: evidence of non‐uniformity over time in rates of increase. Diabetologia. 2012;55(8):2142–2147.Knip M, Veijola R, Virtanen SM, Hyoty H, Vaarala O, Akerblom HK. Environmental triggers and determinants of type 1 diabetes. Diabetes. 2005;54(Suppl 2):S125–136.

Etiology ‐Microbiota

• Gut microbiota interact with innate immune cells to shape the immune system.

• Birth mode, breast‐feeding status, diet, water pH, infections and medication including antibiotics and PPIs all affect microbiome composition.

• In diseases with a multifactorial etiology, like type 1 diabetes, alterations of the microbiota have been shown to influence the incidence and onset of disease (animal models).

Hu Y, Wong FS, Wen L. Antibiotics, gut microbiota, environment in early life and type 1 diabetes. Pharmacol Res. 2017 May;119:219‐226. doi: 10.1016/j.phrs.2017.01.034. Epub 2017 Feb 7. PMID: 28188825; PMCID: PMC5392439.Wen L, Ley RE, Volchkov PY, Stranges PB, Avanesyan L, Stonebraker AC, Hu C, Wong FS, Szot GL, Bluestone JA, Gordon JI, Chervonsky AV. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature. 2008;455(7216):1109–1113.

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Microbiome Role

• Protect the host from pathogen infection

• Aid in nutrition derived from the diet and generate energy

• Keep gut epithelia intact/reduce permeability

• Promote development of immune system (gut epithelia + bacteria interaction)

Hu Y, Wong FS, Wen L. Antibiotics, gut microbiota, environment in early life and type 1 diabetes. Pharmacol Res. 2017;119:219‐226. doi:10.1016/j.phrs.2017.01.034


• High‐fat and high‐sugar diet affected the incidence of diabetes by causing dysbiosis of gut microbiota, particularly the decreased Bifidobacteria spp. (mouse model)

• In NOD mice, treatment with a broad‐spectrum antibiotic altered the composition of gut microbes and decreased the proportion of regulatory T cells (Tregs) in the intestinal lamina propria, resulting in an increased incidence of T1D.

Brown K, DeCoffe D, Molcan E, Gibson DL. Diet‐induced Dysbiosis of the intestinal microbiota and the effects on immunity and disease. Nutrients. 2012;4(8):1095‐1119.Candon S, Perez‐Arroyo A, Marquet C, et al. Antibiotics in early life alter the gut microbiome and increase disease incidence in a spontaneous mouse model of autoimmune insulin‐dependent diabetes. PLoS One. 2015;10:e125448.

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Etiology‐ Antibiotic Treatment

The earlier the NOD mice received antibiotics, the better the protection from diabetes development.

Hu Y, Jin P, Peng J, Zhang X, Wong FS, Wen L. Different immunological responses to early‐life antibiotic exposure affecting autoimmune diabetes development in NOD mice. J Autoimmun. 2016;72:47–56.


• MyD88 is a central adaptor in most innate immune Toll‐like receptor signaling pathways

• MyD88‐deficient NOD mice do not develop autoimmune diabetes in a clean, but not sterile, housing environment

• Germ‐free MyD88‐deficient mice develop full‐blown diabetes

Alkanani AK, Hara N, Gottlieb PA, Ir D, Robertson CE, Wagner BD, Frank DN, Zipris D. Alterations in Intestinal Microbiota Correlate With Susceptibility to Type 1 Diabetes. Diabetes. 2015;64(10):3510–3520.Burrows MP, Volchkov P, Kobayashi KS, Chervonsky AV. Microbiota regulates type 1 diabetes through Toll‐like receptors. Proc Natl AcadSci U S A. 2015;112(32):9973–9977.Hu Y, Jin P, Peng J, Zhang X, Wong FS, Wen L. Different immunological responses to early‐life antibiotic exposure affecting autoimmune diabetes development in NOD mice. J Autoimmun. 2016;72:47–56.

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• In animals, the incidence of T1D in disease‐prone mice could be dramatically reduced when cohorting with normal mice or orally gavage with faecal samples from healthy mice.

• Oral probiotic administration could also prevent diabetes development in NOD mice.

Tai N, Peng J, Liu F, et al. Microbial antigen mimics activate diabetogenic CD8 T cells in NOD mice. J Exp Med. 2016;213(10):2129‐2146.Calcinaro F, Dionisi S, Marinaro M, et al. Oral probiotic administration induces interleukin‐10 production and prevents spontaneous autoimmune diabetes in the non‐obese diabetic mouse. Diabetologia. 2005;48(8):1565‐1575.

Summary of bacteria studied in association

with T1D

Hu Y, Jin P, Peng J, Zhang X, Wong FS, Wen L. Different immunological responses to early‐life antibiotic exposure affecting autoimmune diabetes development in NOD mice.J Autoimmun. 2016;72:47–56.

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Microbiome Protection

• Colonization of specific bacteria in the gut can protect mice from developing type 1 diabetes:

• SFB (Segmented Filamentous Bacteria)

• Lactobacillus johnsonii N6.2• Some Streptococcal species• Glycoprotein extracts from Klebsiella pneumoniae

Hu Y, Wong FS, Wen L. Antibiotics, gut microbiota, environment in early life and type 1 diabetes. Pharmacol Res. 2017;119:219‐226. doi:10.1016/j.phrs.2017.01.034

Changes in gut microbiome and possible effects in T1D

Zheng P, Li Z, Zhou Z. Gut microbiome in type 1 diabetes: A comprehensive review. Diabetes Metab Res Rev. 2018;34(7):e3043. doi:10.1002/dmrr.3043

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• The composition of intestinal microflora is altered before the onset of T1D, including a reduced microbial diversity and increased Bacteriodetes in subjects with pre‐T1D.

• Specifically, the abundance of B.dorei in Bacteriodetes is increased and can be a useful predictor for T1D in Finland. Furthermore, those Bacteroides strains are resistant to common antibiotics and correlated with high‐protein and high‐fat diets.

Gülden E, Wong FS, Wen L. The gut microbiota and type 1 diabetes. Clin Immunol. 2015;159(2):143‐153Davis‐Richardson AG, Ardissone AN, Dias R, et al. Bacteroides dorei dominates gut microbiome prior to autoimmunity in Finnish children at high risk for type 1 diabetes. Front Microbiol. 2014;5:678.

The Role of Gut Microbiome in T1DM

Zheng P, Li Z, Zhou Z. Gut microbiome in type 1 diabetes: A comprehensive review. Diabetes Metab Res Rev. 2018;34(7):e3043. doi:10.1002/dmrr.3043

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Bacterial Role in Healthy State vs. T1DM

Brown CT, Davis‐Richardson AG, Giongo A, et al. Gut microbiome metagenomics analysis suggests a functional model for the development of autoimmunity for type 1 diabetes. PLoS One. 2011;6(10):e25792. doi:10.1371/journal.pone.0025792

Brown CT, Davis‐Richardson AG, Giongo A, et al. Gut microbiome metagenomics analysis suggests a functional model for the development of autoimmunity for type 1 diabetes. PLoS One. 2011;6(10):e25792. doi:10.1371/journal.pone.0025792

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Etiology ‐Viral Infections and Toxins

• T1DM is associated with coxsackievirus B, enteroviruses, mumps, rubella, and cytomegalovirus.

• Current pandemic• COVID‐19 and T1DM show a bidirectional relationship as diabetic patients are at an increased risk of COVID‐19 infection and vice‐versa.

Amutha A, Thai K, Viswanathan M. Childhood and adolescent onset type 1 diabetes in India.MGM J Med Sci. 2013;1:46–53.Desai S, Deshmukh A. Mapping of type 1 diabetes mellitus. Curr Diabetes Rev. 2020;16:438–441.Rodriguez‐Calvo T, von Herrath MG. Enterovirus infection and type 1 diabetes: closing in on a link? Diabetes. 2015;64:1503–1505.Rubino F, Amiel SA, Zimmet P, et al. New‐onset diabetes in COVID‐19. N Engl J Med. 2020;383:789–790.

Etiology – Viral Infections

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), binds to angiotensin‐converting enzyme 2 (ACE2) receptors ‐ expressed in many organs and tissues, including pancreatic beta cells.

Stress of a virus such as the flu or COVID‐19 can be the final catalyst to cause pancreatic beta cell destruction.

SARS‐CoV‐2 may cause alterations of glucose metabolism ‐ could complicate the established DM or lead to new mechanisms of this disease.

Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus: a first step in understanding SARS pathogenesis. J Pathol 2004;203:631‐637.

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Etiology ‐Environmental Risk Factors

• Oceanic climates

• Populations with low‐pigment skin type and/or blue eyes

• Reverse correlation between T1DM and the contact with the sunshine

• Vitamin D deficiency in early childhood

Chen YL, Huang YC, Qiao YC, et al. Climates on incidence of childhood type 1 diabetes mellitus in 72 countries. Sci Rep. 2017;7:12810.

Di Stasio E, Maggi D, Berardesca E, et al. Blue eyes as a risk factor for type 1 diabetes. Diabetes Metab Res Rev. 2011;27:609–613.

Ziegler AG, Baumgartl HJ, Ede G, et al. Low‐pigment skin type and predisposition for development of type I diabetes. Diabetes Care.

Desai SR, Deshmukh AA. A peripheral concept on etiology of type 1 diabetes mellitus. Pharm Reson. 2019;2:21–24.

Etiology ‐Nutrition and Dietary Risk Factors

• Undissolved gluten, lack of breastfeeding, early introduction of cow's milk, foods and water containing nitrates, nitrites or nitrosamines, and lack of vitamin D.

• Cow's milk albumin promotes autoimmunity of islet cells due to cross‐reactivity between the surface protein (ICA‐1) β‐cell and serum antibodies to albumin.

• Like cow's milk proteins, immune reaction against wheat proteins in T1DM could be the general result of an abnormal mucosal responserather than the specific driver of islet autoimmunity.

Amutha A, Thai K, Viswanathan M. Childhood and adolescent onset type 1 diabetes in India.MGM J Med Sci. 2013;1:46–53.Desai SR, Deshmukh AA. A peripheral concept on etiology of type 1 diabetes mellitus. Pharm Reson. 2019;2:21–24.

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Etiology ‐ Autoantigens and autoantibodies

• Islet cell cytoplasmic antibodies (ICCA)• 90% of TIDM patients

• Primary antibody

• Presence of ICCA is a precise analyst of TID future development

• Islet cell surface antibodies (ICSA)• 80% of TIDM patients

• Glutamic acid decarboxylase antibodies (Anti‐GAD )• 80% of TIDM patients

• Strongly predicts future TIDM in high‐risk population

• Antibodies decline over time in TIDM patients

Desai S, Deshmukh A. Mapping of Type 1 Diabetes Mellitus. Curr Diabetes Rev. 2020;16(5):438‐441. doi: 10.2174/1573399815666191004112647. PMID: 31584373.

Etiology ‐ Autoantigens and autoantibodies

• Anti‐insulin antibodies (IAA)• 40% of young children with T1DM• Seen in T1DM patients as well as relatives who are at risk

• Chromogranin A (Chg A)

• Islet amyloid polypeptide (IAPP)

• Anti‐protein tyrosine phosphatase like protein (IA‐2A)• Zinc transporter 8 antibody (ZnT8A)

Stadinski BD, Delong T, Reisdorph N, et al. Chromogranin A is an autoantigen in type 1 diabetes. Nat Immunol. 2010;11:225–231Delong T, Baker RL, Reisdorph N, et al. Islet amyloid polypeptide is a target antigen for diabetogenic CD4+ T cells. Diabetes. 2011;60:2325–2330Desai S, Deshmukh A. Mapping of Type 1 Diabetes Mellitus. Curr Diabetes Rev. 2020;16(5):438‐441. doi: 10.2174/1573399815666191004112647. PMID: 31584373.

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Etiology‐ HIPs

Delong T, Wiles TA, Baker RL, et al. Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion. Science. 2016;351:711–714


• 2016 ‐ a new type of neoepitope formed by the fusion of two unrelated peptide fragments was discovered.

• These neoepitopes, called hybrid insulin peptides/HIPs, are recognized by pathogenic CD4+ T cells in the NOD mouse and human pancreatic islet‐infiltrating T cells in people with type 1 diabetes.

Etiology‐ HIPs

• Detailed knowledge of T1D‐associated HIPs will allow HIPs to be used in assays to monitor changes in T cell mediated beta‐cell autoimmunity.

• They will also provide new targets for antigen‐specific therapies for T1D.

• However, there are an ENORMOUS number of potential HIPs ‐technically challenging to identify.


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Symptoms of New Onset

• Polyuria• Polydipsia• Polyphagia• Weight loss

• Fatigue• DKA (15‐67%) – potentially life threatening

ClicDunger DB, Sperling MA, Acerini CL, Bohn DJ, Daneman D, Danne TP, Glaser NS, Hanas R, Hintz RL, Levitsky LL, Savage MO, Tasker RC, Wolfsdorf JI. European Society for Paediatric Endocrinology/Lawson Wilkins Pediatric Endocrine Society consensus statement on diabetic ketoacidosis in children and adolescents. Pediatrics. 2004;113:e133–e140. k to \

A Cure is Just Around the CornerA Cure is Just Around the Corner

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Lifesaving Insulin

• June 1921‐ physician Frederick Banting and medical student Charles Best injected isolated insulin into a diabetic dog ‐ lowered the dog’s blood glucose levels to normal.

• End of 1921 with chemist James B. Collipand physiologist J.J.R. Macleod, Banting and Best purified insulin, and the next year it was used to successfully treat a type 1 diabetic boy.

Madeb R, Koniaris LG, Schwartz SI. The discovery of insulin: the Rochester, New York, connection. Ann Intern Med. 2005;143:907‐912.

Rosenfeld L. Insulin: discovery and controversy. Clinical Chemistry. 2002;48:2270‐2288.

Lifesaving Insulin

• 1923 ‐Banting, Collip and Best awarded U.S. patents on insulin. They all sold these patents to the University of Toronto for $1 each.

• 1923‐ Banting and MacLeod shared the Nobel Prize in Physiology and Medicine.

Madeb R, Koniaris LG, Schwartz SI. The discovery of insulin: the Rochester, New York, connection. Ann Intern Med. 2005;143:907‐912.Rosenfeld L. Insulin: discovery and controversy. Clinical Chemistry. 2002;48:2270‐2288.Image by Image by @nicole.k.buchanan

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Types of Insulin LOE: A

Biosimilar Insulin

• June 2020 ‐ The US Food and Drug Administration (FDA) has approved the first interchangeable biosimilar insulin

• Semglee, which can be substituted for glargine (Lantus, Sanofi) at the pharmacy without the need for a separate prescription

• It has no clinically meaningful difference from the reference product

• The approval will allow Semglee to function like a generic drug in the market and may reduce insulin costs

https://www.medscape.com/viewarticle/955613?src=WNL_mdpls_210730_mscpedit_wir&uac=200835EV&spon=17&impID=3537418&faf=1

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Insulin Treatment Regimens

Insulin Pump + Continuous Glucose Monitor Data

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Promising research/treatments

Stem cells PMID: 33198288

Islet transplantation PMID: 30541144

Reprogrammed pancreatic alpha cells: PMID: 24843459

Peptide immunotherapies to ‘retrain’ killer T cells PMID: 29541078

Preventative vaccine PMID: 21524383

Artificial pancreas “closed‐loop control” – CGM + insulin pump PMID: 32846062

“Smart patch” – imitates that body’s beta cells by both sensing blood glucose levels and release insulin. PMID: 32015407

Fasting‐Mimicking Diet PMID: 28235195

Bovine serum albumin vaccine

• Bovine serum albumin is a serum albumin protein which is derived from cow's milk.

• Consumption of cow's milk promote the cross‐reactivity between the surface protein (ICA‐1) β‐cell and serum antibodies to albumin.

• This leads to destruction of β‐cell and finally causes T1DM.

• Introducing a milder form of this protein in the form of vaccine may modulate the immune responses which is expected to occur later due to albumin from cow's milk.

Desai, Shivani et al. “Polyvaccine: joining the links in the cascade of type 1 diabetes.” Clinical and experimental vaccine research vol. 10,1 (2021): 1‐5. doi:10.7774/cevr.2021.10.1.1

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Etiological cascade for T1DM and targets for vaccines

Desai, Shivani et al. “Polyvaccine: joining the links in the cascade of type 1 diabetes.” Clinical and experimental vaccine research vol. 10,1 (2021): 1‐5. doi:10.7774/cevr.2021.10.1.1

Prevention‐ the Ultimate Goal for Type 1 DM

• Although regenerative medicine holds much promise, understanding of the causes of beta cell death and damage will lead to more effective prevention measures.

• We still don’t yet understand the cause

• Stem cell therapies do not represent a cure for diabetes.

• While transplantation methods are interesting, it doesn’t address the immune destruction side.

• Endogenous regeneration approaches that can be combined with a targeted immunotherapy to most effective therapies

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What to do in the meantime?

Estrogen – the Big Bad Wolf

• Epidemiological data indicates women with type 1 diabetes have 2‐3 times greater risk of cardiovascular disease than men with type 1

• Estrogen seems to be key in the early, rapid aging of the cardiovascular system.

• In diabetes the sex hormone estrogen produces a double whammy that increases levels of damaging oxidative stress while dramatically decreasing blood vessels' ability to dilate.

• More typically estrogen does just the opposite.

• Even isolated in a dish, when you put estrogen on a blood vessel, it dilates, and when you put it on a diabetic blood vessel, it contracts.

Codner E. Estrogen and type 1 diabetes mellitus. Pediatr Endocrinol Rev. 2008 Dec;6(2):228‐34. PMID: 19202509.

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Current Study via NIH

• 90 premenopausal women with T1DM studied alongside 30 healthy premenopausal women and 45 demographically matched men with type 1, all ages 18‐40 without diagnosed CVD or other known complications.

• Studying the natural high and low points of the sex hormone over the course of their natural cycle.

• They will look at vascular health before and two hours following treatment or placebo.

• Some women with type 1 will take ‐ vitamins C and E along with alpha lipoic acid• Other women will take resveratrol (found in red grapes, red wine, peanuts and berries ‐ thought to work as an antioxidant that can directly activate the protein Sirt1.

https://www.eurekalert.org/multimedia/686449Movahed A, Raj P, Nabipour I, Mahmoodi M, Ostovar A, Kalantarhormozi M, Netticadan T. Efficacy and Safety of Resveratrol in Type 1 Diabetes Patients: A Two‐Month Preliminary Exploratory Trial. Nutrients. 2020 Jan 6;12(1):161. doi: 10.3390/nu12010161. PMID: 31935938; PMCID: PMC7019753.

Sirt1

• Lowers the ROS produced by the endothelial cells that line blood vessels and increases the availability of nitric oxide, a powerful natural dilator of blood vessels.

• Also improves glucose homeostasis, lipid metabolism, and lowers blood pressure.

• Levels of Sirt1 naturally increase in the high‐estrogen days of the cycle, but it seems that diabetes decreases that healthy increase.

• Sirt1 levels are generally lower in people with diabetes‐ this has been implicated to increase inflammation

LOE: B

Biason-Lauber A, Böni-Schnetzler M, Hubbard BP, et al. Identification of a SIRT1 mutation in a family with type 1 diabetes. Cell Metab. 2013;17(3):448-455. doi:10.1016/j.cmet.2013.02.001Bartoli‐Leonard, F., Wilkinson, F.L., Schiro, A. et al. Suppression of SIRT1 in Diabetic Conditions Induces Osteogenic Differentiation of Human Vascular Smooth Muscle Cells via RUNX2 Signalling. Sci Rep 9, 878 (2019). https://doi.org/10.1038/s41598‐018‐37027‐2Lee JH, Song MY, Song EK, Kim EK, Moon WS, Han MK, Park JW, Kwon KB, Park BH. Overexpression of SIRT1 protects pancreatic beta‐cells against cytokine toxicity by suppressing the nuclear factor‐kappaB signaling pathway. Diabetes. 2009 Feb;58(2):344‐51. doi: 10.2337/db07‐1795. Epub 2008 Nov 13. PMID: 19008341; PMCID: PMC2628607.

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Sirt1 Support

• Fasting/Calorie Restriction: PMID: 25146190

• Resveratrol: PMID: 12939617

• NAD+ (under circadian control): PMID: 19262508

• Sauna/heat exposure (increases NAD+): PMID: 24435709

• Curcumin: PMID: 24755072

• DHA: PMID: 23806688

• Zinc: PMID: 19923004

• Exercise: PMID: 19549533LOE: B/C

Androgen Metabolism

• Total and free T, DHEA‐S, DHT, SHBG and 3α‐androstanediol glucuronide (3αdiol‐G) plasma concentrations were measured in 36 pubertal boys and 31 pubertal girls with T1DM and in 59 sex‐ and pubertal stage‐matched control subjects without diabetes.

• Significantly higher serum total testosterone (p<0.01) and free testosterone (p<0.05) levels were found in females and males with type 1 diabetes than in controls

Meyer, K., Deutscher, J., Anil, M. et al. Serum androgen levels in adolescents with type 1 diabetes: Relationship to pubertal stage and metabolic control. J Endocrinol Invest 23, 362–368 (2000). https://doi.org/10.1007/BF03343739

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Androgen Metabolism

• Hirsutism in 28.6% of type 1 diabetics compared to 0.0% of controls (P < 0.001).

• Biochemical hyperandrogenism was present in 23.8 % of the type 1s and 7.9% of the controls. .

• Polycystic ovarian morphology (PCOM) was present in 54.8% of type 1 diabetics and 13.2% of controls (P < 0.001).

• PCOS was 40.5% in type 1 diabetics 2.6% in the controls (P < 0.0001).

Codner E, Soto N, Lopez P, et al. Diagnostic Criteria for Polycystic Ovary Syndrome and Ovarian Morphology in Women with Type 1 Diabetes Mellitus, The Journal of Clinical Endocrinology & Metabolism, Volume 91, Issue 6, 1 June 2006, Pages 2250–2256, https://doi.org/10.1210/jc.2006‐0108

Case Study: 25 yo F, T1DM

• Low estrogen and low progesterone (suggestive of possible anovulatory cycles)

• Upper range testosterone and elevated DHEA, signifying PCOS/metabolic syndrome

• HPA axis dysfunction (phase I)

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Holistic Treatment Protocol

• Seed cycling: 2 tablespoons of ground flaxseeds days 1‐14, 2 tablespoons of ground sunflower seeds days 15‐28

• Limit carbohydrate intake to < 100 grams per day. Protein/fat intake with carbohydrates

• Evening primrose oil: 500 mg bid

• Vitamin D: 2,000 IU qd

• Cofactor combinations to support ovulation/progesterone:

• B complex daily

• Magnesium: 400‐600 mg daily

• Vitamin A : 5,000 IU per day (caution due to teratogenic effect at higher doses)

• Vitamin E: 200‐400 IU daily

• Vitamin C: 500‐1000 mg daily

• Zinc: 15 mg daily

• Turn off all electronics by 9 pm, in bed by 9:30 pm: 8 hours of QUALITY sleep per night

• Exercise: Resistance training 30 mins 2 times per week. Yoga, 60 mins, 1 day per weekLOE: C

LOE:C

25 yo F, T1DM: 8 month follow up testing

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Melatonin

• Regulatory role in sleep and reproduction

• Immunomodulatory effects

• Regulatory effects on autophagy, endoplasmic reticulum (ER) stress, and oxidative stress

• Direct free radical scavenging properties as well as inducing the production of other anti‐oxidant enzymes including glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT) and superoxide dismutase (SOD)

• Inhibits the expression of pro‐oxidant enzymes such as nitric oxide (NO) synthase (NOS), cyclooxygenase‐2 (COX‐2), myeloperoxidase and eosinophil peroxidase

Pourhanifeh, M.H., Hosseinzadeh, A., Dehdashtian, E. et al.Melatonin: new insights on its therapeutic properties in diabetic complications. Diabetol Metab Syndr 12, 30 (2020). https://doi.org/10.1186/s13098‐020‐00537‐z

LOE: B

Melatonin and diabetic complications

• Cardiomyopathy

• Diabetic Retinopathy

• Neuronal complications

• Cognitive dysfunction

• Depression

• Neuropathy

• Nephropathy

• Slow wound healing

Pourhanifeh, M.H., Hosseinzadeh, A., Dehdashtian, E. et al.Melatonin: new insights on its therapeutic properties in diabetic complications. Diabetol Metab Syndr 12, 30 (2020). https://doi.org/10.1186/s13098‐020‐00537‐z

LOE: B

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Melatonin: new insights on its therapeutic properties in diabetic complications

What influences blood sugar levels? • Food

• Insulin (dose, timing, expiration/heat)

• Hydration

• Stress

• Inflammation

• Allergies

• Hormones• Menses/puberty

• Illness

• Sleep

• Movement/exercise

• Caffeine

• Alcohol

• Medications (i.e. steroids, niacin PMID 18380993)

• Dawn phenomenon

• Infusion set issues

• Scar tissues

• Phenol at injection site

• Weather temps/humidity/Altitude

Goldberg RB, Jacobson TA. Effects of niacin on glucose control in patients with dyslipidemia. Mayo ClinProc. 2008 Apr;83(4):470‐8. doi: 10.4065/83.4.470. PMID: 18380993.

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It has been estimated that life with type 1 diabetes requires an astonishing number of health‐related decisions, even estimated at about 180 per day

Tack CJ, Lancee GJ, Heeren B, et al. Glucose Control, Disease Burden, and Educational Gaps in People With Type 1 Diabetes: Exploratory Study of an Integrated Mobile Diabetes App. JMIR Diabetes. 2018;3(4):e17. Published 2018 Nov 23. doi:10.2196/diabetes.9531

Type 1 Diabetes is not just about insulin replacement and carb counting

• Glycosylation

• Cardiovascular disease

• Infections

• Neuropathy

• Nephropathy

• Retinopathy, cataracts, glaucoma

• Cavities/Gum disease

• Infertility, preeclampsia, miscarriage, stillbirths, birth defects

• Depression/Anxiety

• Loneliness

• Fear of hypoglycemia/death

• Eating disorders/obsessive compulsive patterns

• Financial difficulties/inability to purchase sufficient insulin/supplies

Chiang JL, Kirkman MS, Laffel LM, Peters AL, Type 1 diabetes through the life span: a position statement of the American Diabetes Association. Type 1 Diabetes Sourcebook Authors Diabetes Care. 2014;37(7):2034.Zoffmann V, Vistisen D, Due‐Christensen A cross‐sectional study of glycaemic control, complications and psychosocial functioning among 18‐ to 35‐year‐old adults with type 1 diabetes. M Diabet Med. 2014 Apr;31(4):493‐9. Epub 2013 Dec 6.

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Insulin Costs – average retail price for 30day supply

https://www.goodrx.com/blog/wp‐content/uploads/2020/04/Diabetes‐Cost‐White‐Paper.pdf

Insulin Costs – average retail price for 30day supply


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Supplies Supplies Supplies

• Insulin (expensive!) • Back‐up long acting and short acting insulin (outside of insulin pump)

• Syringes• Sensors for CGM (expensive!) $610 per month

• Reservoirs (holds insulin) $42.90 per month

• Tubing for insulin pump “infusion sets”(fairly expensive) $112 per month

• Tape ‐ $119.99 for 50 • Glucometer

• Lancets• Test strips (expensive!) $45 for 100 • Glucagon• Ketone Sticks• Medical Identification • AAA batteries• Glucose tabs• Alcohol swabs• Sharps container


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Sensory overload

Work life

Family life

Social life

Insulin dosing calculations

Financial challenges

Pings and dings

• insulin pump alarms – day and night

Burnout

• ICD‐10 Z73.0

• Emotional and physical exhaustion resulting from a combination of exposure to environmental and internal stressors and inadequate coping and adaptive skills.

• 3 classic symptoms:• emotional exhaustion (feeling drained and hopeless)

• depersonalization (becoming detached and uncaring)

• reduced feeling of accomplishment

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HPA Axis

• HPA dysregulation in diabetes ‐ impaired glucocorticoid negative feedback sensitivity + hypoinsulinemia, hyperglycemia and/or hypoleptinemia, that may increase central drive of the axis. PMID: 12717340

• Hyperactivation of the HPA axis ‐ increased expression of hypothalamic corticotrophin‐releasing hormone (CRH) mRNA and hippocampal mineralocorticoid receptor (MR) mRNA. PMID: 12625483

• Although insulin replacement restores ACTH and corticosterone levels to normal, likely through glucocorticoid‐mediated suppression of ACTH secretion, CRH and MR mRNA expression remain elevated. PMID: 12625483

Beyond Survival

• Treatment strategies beyond exogenous insulin therapy is essential to help patients live a life above survival.

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Ancient Ayurveda

Originated in India, Ayurveda is one of the ancient health traditions.

Ayurveda is commonly referred as ‘science of life’ because the Sanskrit meaning of Ayu is life and Veda is science or knowledge.

Life in Ayurveda is conceived as the union of the body, senses, mind and spirit.

The concept of Prakriti or individual nature has a central role in Ayurveda therapeutics. (aka ‘naturopathic constitution’)

Ancient + Modern Medicine

Banerjee S, Debnath P, Debnath PK. Ayurnutrigenomics: Ayurveda‐inspired personalized nutrition from inception to evidence. J Tradit Complement Med. 2015 Mar 24;5(4):228‐33. doi: 10.1016/j.jtcme.2014.12.009. PMID: 26587393; PMCID: PMC4624353.

Bredesen D.E., Rao R.V. Ayurvedic profiling of alzheimer's disease. Altern Ther Health Med. 2017;23(3):46–50

Jnana A, Murali TS, Guruprasad KP, Satyamoorthy K. Prakriti phenotypes as a stratifierof gut microbiome: A new frontier in personalized medicine?. J Ayurveda Integr Med. 2020;11(3):360‐365. doi:10.1016/j.jaim.2020.05.013

Sethi TP, Prasher B, Mukerji M. Ayurgenomics: a new way of threading molecular variability for stratified medicine. ACS Chem Biol. 2011 Sep 16;6(9):875‐80. doi: 10.1021/cb2003016. PMID: 21923095.

Wallace RK. Ayurgenomics and Modern Medicine. Medicina (Kaunas). 2020 Nov 30;56(12):661. doi: 10.3390/medicina56120661. PMID: 33265906; PMCID: PMC7760374.

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Abhyanga

• Abhyanga is the anointing of the body with oil. Often medicated (herbs added to the oil) and usually warm, the oil is massaged into the entire body before bathing.

• Used for thousands of years to maintain health, improve sleep patterns, increase longevity and reduce the effects of aging.

• Thought to relax the central nervous system – oil helps to pacify Vata dosha (the bus driver of the nervous system)

Rao RV. Ayurveda and the science of aging. J Ayurveda Integr Med. 2018;9(3):225‐232. doi:10.1016/j.jaim.2017.10.002Bredesen D.E., Rao R.V. Ayurvedic profiling of alzheimer's disease. Altern TherHealth Med. 2017;23(3):46–50

LOE: B

Pilot study investigating the effects of Ayurvedic Abhyanga massage on subjective stress experience

Clinical Trial J Altern Complement Med. 2011 May;17(5):435‐40.doi: 10.1089/acm.2010.0281. Epub2011 May 13.

• Researchers studied how abhyanga affects stress in 20 healthy adults.

• Before receiving a 1‐hour abhyanga massage, the participants completed a stress‐related questionnaire and had their heart rate measured. Both tests were repeated after the session.

• Subjects showed high statistically and clinically significant reductions in subjective stress experience.

• After massage, the participants’ heart rate decreased.

• After abhyanga, blood pressure decreased in those with prehypertension.

LOE: B

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Rhythmical massage improves autonomic nervous system function: a single‐blind randomised controlled trial. PMID: 29598986

• The study determined rhythmical massage led to long‐term heart rate variability stimulation, a sign of relaxation. The aromatic oil also helped, but its effect was temporary.

• This suggests that abhyanga, which also involves massage and oils, could potentially offer similar benefits.

LOE: B

Shirodhara: A psycho‐physiological profile in healthy volunteers. PMID: 23741161

• Ayurvedic procedure of slowly and steadily dripping medicated oil on the forehead

• Significant improvement in mood scores and the level of stress (P <0.001).

• Significant decrease in rate of breathing and reduction in diastolic blood pressure along with reduction in heart rate.

• Increase in alpha rhythm in EEG.

• Leads to a state of alert calmness similar to the relaxation response observed in meditation.

• The clinical benefits observed with Shirodhara in anxiety neurosis, hypertension, and stress aggravation due to chronic degenerative diseases could be mediated through these adaptive physiological effects.

LOE: B

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Image by @nicole.k.buchanan

Burnout Treatment• Chronic illness thrives in anxiety, depletion, rigidity, overstimulation, burnout

• Nourish the opposite• Encourage patients to ”make space”• Don’t expect perfection• Be careful not to shame blood sugar swings/spikes/lows• Support the long game – this is a marathon, not a sprint• Encourage whole foods/NOT low carb (focus on complex carbs)• Watch for OCD‐like behaviors• Support to soothe anxieties• Encourage positive support groups• Add in creativity• Allow for laughter• Respect the illness, but don’t let override the human in front of you

LOE: C

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Abhyanga

• Simple

• Can be done at home

• Opposes depletion and burnout• Encourages time away from electronics and the “to‐do” list

• Inexpensive• Decreases subjective stress• NOT on the typical treatment protocol for type 1 diabetics

LOE: C

Make Space

• Treat any aspect of your patient’s health other than type 1 diabetes in order to treat their type 1 diabetes most effectively

LOE: C

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While waiting for a cure. . .

• Encourage vaginal birth/ breastfeeding

• Vitamin D, sunshine

• Whole foods diet/diversity = diverse gut bugs, avoid simple carbs

• Improve digestive strength/avoid gluten, diary

• Address estrogen dominance and elevated/upper range androgens

• Treat viral infections – olive leaf, oregano, coconut, garlic, elderberry,

licorice root, ginger

• Improve microbiome (butyrate)

• Provide antioxidants such as vitamin C,E, ALA or Arjunolic acid

• Resveratrol and others to increase Sirt1 (slide 50)

• Consider melatonin to reduce risk of complications

• Community – encourage “diabuddy” support network

• HPA Axis support – Abhyanga

LOE: C

Manna P, Sil PC. Arjunolic acid: beneficial role in type 1 diabetes and its associated organ pathophysiology. Free Radic Res. 2012 Jul;46(7):815‐30. doi: 10.3109/10715762.2012.683431. Epub 2012 May 3. PMID: 22486656.

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life cycle of type 1 diabetes

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