Skip to main content
  • More from ADA
    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care in Diabetes
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care
  • Subscribe
  • Log in
  • My Cart
  • Follow ada on Twitter
  • RSS
  • Visit ada on Facebook
Diabetes

Advanced Search

Main menu

  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • ADA Scientific Sessions Abstracts
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • ADA Scientific Sessions Abstracts
    • Diabetes COVID-19 Article Collection
    • Diabetes Symposium 2020
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Submit Cover Art
    • ADA Journal Policies
    • Instructions for Authors
    • ADA Peer Review
  • More from ADA
    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care in Diabetes
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care

User menu

  • Subscribe
  • Log in
  • My Cart

Search

  • Advanced search
Diabetes
  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • ADA Scientific Sessions Abstracts
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • ADA Scientific Sessions Abstracts
    • Diabetes COVID-19 Article Collection
    • Diabetes Symposium 2020
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Submit Cover Art
    • ADA Journal Policies
    • Instructions for Authors
    • ADA Peer Review
Commentaries

Going in Early: Hypoxia as a Target for Kidney Disease Prevention in Diabetes?

  1. Helen L. Barrett1,2,
  2. Kim C. Donaghue3 and
  3. Josephine M. Forbes1,4,5⇑
  1. 1Mater Research - The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
  2. 2Queensland Diabetes and Endocrine Centre, Mater Health, Brisbane, Queensland, Australia
  3. 3Children’s Hospital at Westmead and Discipline of Child and Adolescent Health, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia
  4. 4Faculty of Medicine, The University of Queensland, St Lucia, Queensland, Australia
  5. 5Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
  1. Corresponding author: Josephine M. Forbes, josephine.forbes{at}mater.uq.edu.au
Diabetes 2020 Dec; 69(12): 2578-2580. https://doi.org/10.2337/dbi20-0037
PreviousNext
  • Article
  • Info & Metrics
  • PDF
Loading

Diabetic kidney disease (DKD) begins early, which is pertinent to those diagnosed with diabetes during childhood and adolescence. The initiators of DKD are not fully defined, but hypoxia and metabolic abnormalities are important. With growing numbers of young people diagnosed with diabetes and concomitant risk for early mortality, this commentary examines the study by Vinovskis et al. (1) in this issue of Diabetes, which highlights renal hypoxia as an early phenomenon in diabetes associated with risk for DKD.

Many diabetologists and nephrologists consider DKD an affliction of late-middle age. Certainly, the proportion of affected individuals with diabetes escalates with age (2), and at least one-third of these will develop DKD, a major risk factor for cardiovascular disease and early mortality (3). Global estimates of people living with diabetes have tripled in the past 20 years (2), topping 463 million individuals, suggesting that 167 million of these already have or will develop DKD.

Perhaps less well known is the growing incidence of diabetes in children and adolescents, which is escalating by 3% each year, and at a higher rate in some ethnic groups (2). Another underappreciated fact is that many children and adolescents with diabetes develop complications in early adulthood, placing significant burden on the individual, the family, and society. Data from the International Diabetes Federation suggest that almost half (46.2%) of deaths associated with diabetes among the 20–79 years age-group are in people under the age of 60 years (2). Hence, because the average age of enrolment in phase 3 studies of diabetes-related mortality is 60 years of age, younger individuals who may have benefited from these interventions were excluded. Therefore, undertaking studies to understand and potentially intervene in early complications of diabetes in a much younger cohort than standard is crucial to potentially improving the outcomes of diabetes in our global population. Vinovskis et al. (1) have undertaken this important step by examining renal metabolic processes in a cohort of young people aged <21 years.

Evidence from a prospective study shows that 88% of future cases of DKD, at least in those with type 1 diabetes, can be predicted in childhood and adolescence, using elevations in urine albumin-to-creatinine ratio during puberty (4). Type 1 diabetes, where there is commonly a known diagnosis date, provides an opportunity to track kidney disease in real time to better understand early determinants of disease. Indeed, in the past, this led to the ascertainment of glomerular mesangial matrix expansion and basement membrane thickening as kidney structural markers of future DKD risk in biopsies (5). Recent clinical studies show that conventional therapies that slow kidney disease progression in adults, targeting dyslipidemia and hypertension, are not as effective in early kidney disease (6,7). This suggests that the factors at play early in DKD development are not well understood, which is hindering the discovery and translation of effective therapeutics for prevention.

The article by Vinovskis et al. (1) presents renal hypoxia, as estimated by blood oxygen–dependent magnetic resonance imaging (BOLD MRI) of renal oxygen availability as a ratio of ioxal measured GFR (RO2:GFR) in adolescents with type 1 diabetes, that was seen concomitantly with albuminuria, increased renal plasma flow, greater fat mass, and reduced insulin sensitivity measured during hyperglycemic clamps. The anatomical proximity to the heart delivers significant cardiac output to the kidneys ensuring adequate oxygen availability for metabolic processes including synthesis of hormones, amino acids, and glucose and maintenance of fluid balance where ions, solutes, and nutrients are reclaimed from the forming urine. The kidneys have disproportionately high oxygen consumption and mitochondrial numbers as compared with many other organs, which facilitates mitochondrial ATP production necessary for normal function (8). A number of pathways regulate stable delivery of renal oxygen, including metabolic control of Na+ transport and tubuloglomerular feedback, which are coupled to most molecular reabsorption pathways such as for glucose via sodium–glucose cotransporter 2 (SGLT2) and to the glomerular filtration rate (GFR) (9,10). Studies suggest increased metabolic ATP demand, driven by excessive reabsorption of glucose and other molecules, causes the kidneys to increase oxygen demand early in diabetes (11), resulting in hypoxia. Indeed, kidney damage is caused in the absence of diabetes, by phenocopying the excessive oxygen demand required for the reabsorption of high concentrations of glucose and lactate from forming urine via Na+ K+ ATPase coupling, as seen in diabetes (12). It is likely that this increased metabolic demand and concomitant insulin insufficiency and diuresis, both seen in the adolescent participants of the study by Vinovskis et al., are also contributing to early renal hypoxia. Insulin insufficiency would not adequately suppress endogenous glucose production and therefore exacerbate hyperglycemia and the glucose load needing to be salvaged from urine thereby increasing renal oxygen consumption. Similarly, diuresis also contributes to hypoxia due to the solute and ion load, which needs to be reabsorbed by the kidney tubules, increasing oxygen consumption while hyperfiltration decreases oxygen tension and therefore delivery (11).

However, other factors that were not studied may also be important such as breathing difficulties apparent in some young people with type 1 diabetes (13), oxidative stress, and decreasing electrolyte transport efficiency (8,11), which could also impact renal hypoxia. The real novelty of the study by Vinovskis et al. (1) lies in the fact that GFR was measured during a mild hyperglycemic clamp (170–190 mg/mL), ensuring that renal glucose reabsorption was fixed and that variations in GFR were not dependent on this factor.

One variable to consider, however, in this study is the population. The cohort comprised primarily female (50% type 1 diabetes, 70% control) participants. These individuals were 12–21 years of age with mean pubertal classification of Tanner stage 5 (4–5), but the age of menarche was not mentioned, which is potentially relevant since women with type 1 diabetes and delayed menarche in the Finnish Diabetic Nephropathy Study (FinnDiane) had a 2.3 times higher risk of DKD (14). Additionally, while excluding from participation those taking oral contraceptives, the investigators do not mention whether they controlled phase of menstrual cycle for the timing of investigations. There is evidence that insulin sensitivity changes across the menstrual cycle (15) as does estimated GFR (16), but less so for renal blood flow (17).

The study by Vinovskis et al. also included predominately White (92% diabetes, 95% control) participants. Data from the U.S. on the incidence of type 1 diabetes shows increases across all ethnic groups, but the annual increase is actually higher in non-White ethnicities including non-Hispanic White 1.2, non-Hispanic Black 2.2, and Hispanic 4.2 increases in cases/100,000 youth/year (18). It would be interesting for future studies to examine these changes in these emerging ethnicities affected by type 1 diabetes.

Overall, the purpose of this study was to increase understanding of DKD development so that it can potentially be prevented. There are already some approaches that target various aspects of hypoxia in clinical development, which are discussed below. The tissue expression of hypoxia inducible factor 1α (HIF-1α) is increased in response to hypoxia and stimulates angiogenesis and erythropoiesis and alters energy metabolism (19). Previous findings show that renal HIF-1α expression is too low to activate compensatory responses to hypoxia in DKD and that stabilizing HIF-1α activity is renoprotective in established DKD (20). Prolyl hydroxylase inhibitors, such as enarodustat (JTZ-951) and roxadustat (FG-4592) (21,22), stabilize HIF-1α and could be tested for their efficacy in primary and secondary prevention of DKD. These therapies are currently undergoing phase 3 clinical trials to determine their utility as activators of erythropoietin production and treatment of anemia in chronic kidney disease (CKD). One concern with this approach is that supraphysiologic doses of these agents can induce renal fibrosis. Thus, such agents need to be carefully evaluated for effects on renal fibrosis, given the presumptive need for chronic administration of these agents for the treatment of anemia in CKD. Indeed, HIF stabilization across the development and progression of DKD may be context and time dependent, which should also be given attention in future studies.

In their article, Vinovskis et al. suggest that SGLT2 inhibition would be a candidate for treatment in this population. While blocking SGLT2 is likely to alleviate some of the metabolic abnormalities including slowing of the oxygen consumed for glucose reabsorption from the forming urine, this may not come without some potential risk. A number of SGLT2 inhibitors have progressed to phase 3 clinical trials for use in type 1 diabetes, and dapagliflozin has been registered for use in Europe (23). There are yet to be formal cardiovascular outcome trials with SGLT2 inhibitors in type 1 diabetes, but early reductions in estimated GFR and urinary albumin excretion have been demonstrated (24). However, all of these trials (23) showed a rate of diabetic ketoacidosis approaching 4%. Clearly the risk–benefit for this group of medications in young people with type 1 diabetes will need careful consideration, given their generally poorer diabetes control and higher risk of DKA. Indeed, groups with poor glycemic control are often excluded from trials/studies, as was seen in the study by Vinovskis et al., which also excluded potential participants with HbA1c >11% (269 mg/dL), preexisting renal disease, and use of renin-angiotensin system–altering drugs. This limits the potential applicability of the findings to those young people with known renal disease but also to those with the poorest glucose control who are often at greatest risk for DKD.

Overall, it is likely that hypoxia is contributing to early kidney damage in diabetes. Hence, strategies that mitigate this risk should be considered as part of approaches to prevent the onset and progression of DKD and subsequent cardiovascular mortality.

Article Information

Funding. J.M.F. is supported by the National Health and Medical Research Council of Australia (GNT1102935, GNT1160428) and Mater Foundation (Equity Trustees and the Laurie Gertrude McCallum Estate and George Weaber Foundation Trust). The Translational Research Institute is supported by a grant from the Australian Government.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Footnotes

  • See accompanying article, p. 2700.

  • © 2020 by the American Diabetes Association
https://www.diabetesjournals.org/content/license

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www.diabetesjournals.org/content/license.

References

  1. ↵
    1. Vinovskis C,
    2. Li L-P,
    3. Prasad P, et al
    . Relative hypoxia and early diabetic kidney disease in type 1 diabetes. Diabetes 2020;69:2700–2708
    OpenUrlAbstract/FREE Full Text
  2. ↵
    International Diabetes Federation. IDF Diabetes Atlas, 9th edition, 2019. Available from https://diabetesatlas.org
  3. ↵
    1. Afkarian M,
    2. Sachs MC,
    3. Kestenbaum B, et al
    . Kidney disease and increased mortality risk in type 2 diabetes. J Am Soc Nephrol 2013;24:302–308
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Amin R,
    2. Turner C,
    3. van Aken S, et al
    . The relationship between microalbuminuria and glomerular filtration rate in young type 1 diabetic subjects: The Oxford Regional Prospective Study. Kidney Int 2005;68:1740–1749
    OpenUrlCrossRefPubMedWeb of Science
  5. ↵
    1. Chavers BM,
    2. Bilous RW,
    3. Ellis EN,
    4. Steffes MW,
    5. Mauer SM
    . Glomerular lesions and urinary albumin excretion in type I diabetes without overt proteinuria. N Engl J Med 1989;320:966–970
    OpenUrlCrossRefPubMedWeb of Science
  6. ↵
    1. Baigent C,
    2. Landray MJ,
    3. Reith C, et al.; SHARP Investigators
    . The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 2011;377:2181–2192
    OpenUrlCrossRefPubMedWeb of Science
  7. ↵
    1. Marcovecchio ML,
    2. Chiesa ST,
    3. Bond S, et al.; AdDIT Study Group
    . ACE inhibitors and statins in adolescents with type 1 diabetes. N Engl J Med 2017;377:1733–1745
    OpenUrlPubMed
  8. ↵
    1. Forbes JM,
    2. Thorburn DR
    . Mitochondrial dysfunction in diabetic kidney disease. Nat Rev Nephrol 2018;14:291–312
    OpenUrl
  9. ↵
    1. Epstein FH
    . Oxygen and renal metabolism. Kidney Int 1997;51:381–385
    OpenUrlCrossRefPubMedWeb of Science
  10. ↵
    1. Vallon V
    . The proximal tubule in the pathophysiology of the diabetic kidney. Am J Physiol Regul Integr Comp Physiol 2011;300:R1009–R1022
    OpenUrlCrossRefPubMedWeb of Science
  11. ↵
    1. Hansell P,
    2. Welch WJ,
    3. Blantz RC,
    4. Palm F
    . Determinants of kidney oxygen consumption and their relationship to tissue oxygen tension in diabetes and hypertension. Clin Exp Pharmacol Physiol 2013;40:123–137
    OpenUrlCrossRefPubMed
  12. ↵
    1. Friederich-Persson M,
    2. Thörn E,
    3. Hansell P,
    4. Nangaku M,
    5. Levin M,
    6. Palm F
    . Kidney hypoxia, attributable to increased oxygen consumption, induces nephropathy independently of hyperglycemia and oxidative stress. Hypertension 2013;62:914–919
    OpenUrlCrossRefPubMed
  13. ↵
    1. Bernardi L,
    2. Rosengård-Bärlund M,
    3. Sandelin A,
    4. Mäkinen VP,
    5. Forsblom C,
    6. Groop PH; FinnDiane Study Group
    . Short-term oxygen administration restores blunted baroreflex sensitivity in patients with type 1 diabetes. Diabetologia 2011;54:2164–2173
    OpenUrlCrossRefPubMedWeb of Science
  14. ↵
    1. Harjutsalo V,
    2. Maric-Bilkan C,
    3. Forsblom C,
    4. Groop PH; FinnDiane Study Group
    . Age at menarche and the risk of diabetic microvascular complications in patients with type 1 diabetes. Diabetologia 2016;59:472–480
    OpenUrl
  15. ↵
    1. Brown SA,
    2. Jiang B,
    3. McElwee-Malloy M,
    4. Wakeman C,
    5. Breton MD
    . Fluctuations of hyperglycemia and insulin sensitivity are linked to menstrual cycle phases in women with T1D. J Diabetes Sci Technol 2015;9:1192–1199
    OpenUrlCrossRefPubMed
  16. ↵
    1. Brøchner-Mortensen J,
    2. Paaby P,
    3. Fjeldborg P,
    4. Raffn K,
    5. Larsen CE,
    6. Møller-Petersen J
    . Renal haemodynamics and extracellular homeostasis during the menstrual cycle. Scand J Clin Lab Invest 1987;47:829–835
    OpenUrlCrossRefPubMedWeb of Science
  17. ↵
    1. Krejza J,
    2. Ustymowicz A,
    3. Szylak A,
    4. Tomaszewski M,
    5. Hryniewicz A,
    6. Jawad A
    . Assessment of variability of renal blood flow Doppler parameters during the menstrual cycle in women. Ultrasound Obstet Gynecol 2005;25:60–69
    OpenUrlPubMed
  18. ↵
    1. Mayer-Davis EJ,
    2. Lawrence JM,
    3. Dabelea D, et al.; SEARCH for Diabetes in Youth Study
    . Incidence trends of type 1 and type 2 diabetes among youths, 2002-2012. N Engl J Med 2017;376:1419–1429
    OpenUrlCrossRefPubMed
  19. ↵
    1. Gonzalez FJ,
    2. Xie C,
    3. Jiang C
    . The role of hypoxia-inducible factors in metabolic diseases. Nat Rev Endocrinol 2018;15:21–32
    OpenUrl
  20. ↵
    1. Nordquist L,
    2. Friederich-Persson M,
    3. Fasching A, et al
    . Activation of hypoxia-inducible factors prevents diabetic nephropathy. J Am Soc Nephrol 2015;26:328–338
    OpenUrlAbstract/FREE Full Text
  21. ↵
    1. Chen N,
    2. Hao C,
    3. Peng X, et al
    . Roxadustat for anemia in patients with kidney disease not receiving dialysis. N Engl J Med 2019;381:1001–1010
    OpenUrlPubMed
  22. ↵
    1. Forbes JM
    . Prolyl hydroxylase inhibitors: a breath of fresh air for diabetic kidney disease? Kidney Int 2020;97:855–857
    OpenUrl
  23. ↵
    1. Taylor SI,
    2. Blau JE,
    3. Rother KI,
    4. Beitelshees AL
    . SGLT2 inhibitors as adjunctive therapy for type 1 diabetes: balancing benefits and risks. Lancet Diabetes Endocrinol 2019;7:949–958
    OpenUrl
  24. ↵
    1. van Raalte DH,
    2. Bjornstad P
    . Role of sodium-glucose cotransporter 2 inhibition to mitigate diabetic kidney disease risk in type 1 diabetes. Nephrol Dial Transplant 2020;35(Suppl. 1):i24–i32
    OpenUrl
PreviousNext
Back to top
Diabetes: 69 (12)

In this Issue

December 2020, 69(12)
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by Author
  • Masthead (PDF)
Sign up to receive current issue alerts
View Selected Citations (0)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word about Diabetes.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Going in Early: Hypoxia as a Target for Kidney Disease Prevention in Diabetes?
(Your Name) has forwarded a page to you from Diabetes
(Your Name) thought you would like to see this page from the Diabetes web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Going in Early: Hypoxia as a Target for Kidney Disease Prevention in Diabetes?
Helen L. Barrett, Kim C. Donaghue, Josephine M. Forbes
Diabetes Dec 2020, 69 (12) 2578-2580; DOI: 10.2337/dbi20-0037

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Add to Selected Citations
Share

Going in Early: Hypoxia as a Target for Kidney Disease Prevention in Diabetes?
Helen L. Barrett, Kim C. Donaghue, Josephine M. Forbes
Diabetes Dec 2020, 69 (12) 2578-2580; DOI: 10.2337/dbi20-0037
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Article Information
    • Footnotes
    • References
  • Info & Metrics
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Adipose Tissue Malfunction Drives Metabolic Dysfunction in Alström Syndrome
  • Staying Connected: Transcriptomics in the Search for Novel Diabetic Kidney Disease Treatments
Show more Commentaries

Similar Articles

Subjects

  • Complications-Nephropathy-Clinical and Translational Research

Navigate

  • Current Issue
  • Online Ahead of Print
  • Scientific Sessions Abstracts
  • Collections
  • Archives
  • Submit
  • Subscribe
  • Email Alerts
  • RSS Feeds

More Information

  • About the Journal
  • Instructions for Authors
  • Journal Policies
  • Reprints and Permissions
  • Advertising
  • Privacy Policy: ADA Journals
  • Copyright Notice/Public Access Policy
  • Contact Us

Other ADA Resources

  • Diabetes Care
  • Clinical Diabetes
  • Diabetes Spectrum
  • Scientific Sessions Abstracts
  • Standards of Medical Care in Diabetes
  • BMJ Open - Diabetes Research & Care
  • Professional Books
  • Diabetes Forecast

 

  • DiabetesJournals.org
  • Diabetes Core Update
  • ADA's DiabetesPro
  • ADA Member Directory
  • Diabetes.org

© 2021 by the American Diabetes Association. Diabetes Print ISSN: 0012-1797, Online ISSN: 1939-327X.