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Vitamin D Adipocytokines

Vitamin D Adipocytokines. ….and GDM pregnancies. Objectives: . To review the role for Vit D as an insulin-sensitizing hormone, with particular reference to GDM pregnancy To review some of the roles for adipocytokines in insulin resistance and GDM pregnancy

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Vitamin D Adipocytokines

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  1. Vitamin DAdipocytokines ….and GDM pregnancies

  2. Objectives: • To review the role for Vit D as an insulin-sensitizing hormone, with particular reference to GDM pregnancy • To review some of the roles for adipocytokines in insulin resistance and GDM pregnancy • To review our local experience with VitD/adipocytokines in GDM women and their neonates

  3. But first….back to med school for a moment

  4. Vitamin D: a few reminders • Ergocalciferol(D2): provitamin form • Cholecalciferol(D3): inactivated, unhydroxylated form • 25(OH) Vit D3: this from is the least variable, and considered best measure of sufficiency. Therefore, most common form measured. • 1, 25(OH) Vit D3: this form is variable. Measured in odd rare conditions such as Vit D resistant rickets

  5. Vitamin D: a few reminders • Ergocalciferol(D2): provitamin form • Cholecalciferol(D3): inactivated, unhydroxylated form • 25(OH) Vit D3: this form is the least variable, and considered best measure of sufficiency. Therefore, most common form measured. This is the form that will appear in this talk as VitD • 1, 25(OH) Vit D3: this form is variable. Measured in odd rare conditions such as Vit D resistant rickets

  6. Vitamin D: recent oddities • We usually think of Vit D as promoting bone health • The last few decades have illustrated that Vit D has hormone properties • structural similarities with testosterone, steroids, cholesterol

  7. ….cholecalciferol

  8. …….cholesterol

  9. Vit D and GDM: what do we know? • Vit D deficiency suspected to be a risk factor for glucose intolerance • For instance: • 54 GDM, 39 IGT; 11 controls, matched for age, BMI, pregnancy week 24-28 • [NB: Iranian study] SoheilykhahNutrClinPract 2012. 25. 524

  10. CONCLUSIONS: • 83% GDM and IGT women had VitD <20ng/ml • vs • 71.2% Controls (p=0.03) • Lowest VitD levels were in GDM women compared to Controls

  11. Does Vit D status predict GDM risk? • 953 pregnant women in USA • Nested case/control study • VitD level taken at 16 weeks gestation • 57 women developed GDM • Zhang Plos One 2008.3.e3753

  12. CONCLUSIONS • VitD at 16 wks in women developing GDM: 24.2 ng/ml • vs • Controls: 30.1 ng/ml (p<0.001) • [Difference remained significant after adjusting for weight, age, race, family history of DM, prepreg BMI]

  13. Does VitD predict adverse preg outcomes? • Meta-analysis up to Oct 2012 • 24 studies fit criteria (Vitamin D/status/deficiency/insufficiency/pregnancy) • Outcome: women with VitD <50 nm/l: • OR 2.09 risk pre-eclampsia (CI: 1.5-2.9) • OR 1.38 risk GDM (1.12-1.7) • OR 1.57 risk preterm birth (1.08-2.31) • OR 1.52 risk SGA (1.08-2.15) • Wei .Mat-Fetal Medicine 2013.26.889

  14. What about interventional studies? • ………..wait……………………

  15. What links VitD and insulin resistance? • 1. No one really knows • BUT • 2. Perhaps: through inflammation: • VitD can be shown to be associated with anti-inflammatory properties; • and insulin resistant states are also pro-inflammatory states • inflammationendothelialdysfunctionpre-eclampsia • inflammationimmune modulation (IL-1 and IL-6 in particular)

  16. Links between VitD and insulin resistance • 3. Perhaps: • VitD receptors are present in the placenta and fetal tissues • VitD regulates genes involved in trophoblast invasion/angiogenesis

  17. Links between VitD and insulin resistance • 4. Perhaps: • pancreatic beta cells have VitD receptors • may regulate insulin secretion • Vit D stimulates insulin receptor expressionpromotes insulin sensitivity

  18. VitD and inflammatory markers • So: holding onto VitD considerations but switching over to thinking about adipocytokines

  19. What are Adipocytokines • Proteins produced by adipose cells • [note: adipose is not just unwanted insulation, but rather a large endocrine organ] • Many, many, many known and still unknown associations and effects

  20. Adipocytokines You know some of these already: • leptin • adiponectin • TNF-α • interleukins • resistin …etc….

  21. Just a few metabolic associations of adipokines • Low adiponectin levels have been associated with an increased incidence of Type 2 DM • Adiponectin increased insulin sensitivity, fatty acid oxidation and reduces liver glucose production • Leptin reflects total body adipose mass • Resistin levels increase with fat mass and correlate with insulin resistance • TNFα and IL-6 increased in obesity and are linked to insulin resistance and type 2 DM

  22. Functions of Adipokines? Endocrine; paracrine; autocrine roles in: • hemostasis • lipids metabolism • atherosclerosis • BP regulation • insulin sensitivity • angiogenesis • immunity • inflammation • Miehle. Clin Endocrinology 2012.76.2

  23. Adipocytokines and GDM • TNF-α correlates with insulin resistance in pregnancy • TNF-α is released from maternal side of placenta • Leptin rises during pregnancy and falls after delivery • Leptin correlates with insulin resistance in pregnancy • Adiponectin levels are lower in GDM than control preg women • Lacroix. CurrDiab Rep 2013. 13. 238

  24. For instance:

  25. ..So, cooking up a study in London ON INTERESTING UNKNOWNS: • What are VitD levels in offspring of GDM pregnancies? • What are the profiles of adipocytokines in GDM women AND their offspring? • Are maternal and neonatal VitD levels correlated? • Are maternal and neonatal adipokine levels correlated? • Do corralations exist between VitD and inflammatory adiokines (maternal and neonatal)?

  26. …..we had the following building blocks…

  27. PSI grant • Maternal, umbilical arterial and umbilical venous 25 hydroxyvitamin D and adipocytokine concentrations in pregnancies with and without gestational diabetes • R McManus, K Summers, B DeVrijer, N Cohen, A Thompson, I Giroux Clinical Endocrinology 2014; 80:635-641.

  28. Methods • Case control • GDM diagnosed before clinic referral • no recruitment during Nov-Mar months • GDM and Controls recruited at 31 weeks • Did 48 hour dietary and supplement recall [before GDM saw RD]

  29. Methods • Maternal blood taken/spun/frozen at 31 weeks for • Ca • Phosphate • BG • CRP • PTH • Adipocytokines (adiponectin, resistin, PAI-1, IL-6; Il-8, leptin, TNFα, MCP-1)

  30. Methods • On day of delivery: • Neonatal umbilical artery and umbilical vein bloods were taken for DR staff for: • Ca • Phosphate • BG • CRP • PTH • Adipocytokines (adiponectin, resistin, PAI-1, IL-6; Il-8, leptin, TNFα, MCP-1)

  31. ….do you want to guess? Umbilical artery flows: Umbilical vein flows:

  32. So • umbilical arterial blood would reflect fetal chemistry • umbilical vein blood would reflect maternal AND placental chemistry

  33. Demographics Maternal • age • pre-pregnancy weight • maternal weight at time of blood taking Infant • birth weight • infant gestational age • apgar scores • duration of hospital stay/complications

  34. A few stats Sample size of 24 X2=48 would allow for detecting a 30 nm/l difference between [VitD] in GDM women vs C

  35. Results • 73 women • 36 GDM; 37 C • Matched for week of gestation; present weight; pre-preg weight; maternal VitD intake

  36. Searching for correlations [we limited correlations to r>0.4 or r<-0.4; p<0.05] • Maternal Control VitD levels: + correlated with resistin only • Maternal GDM VitD: + correlated with PAI-1; IL-8; TNF-α

  37. Searching for Correlations..cont • Neonatal VitD levels were not correlated with any of: • infant weight • placental weight • Apgar scores • labour duration/hospital stay • adipocytokines

  38. Admitting our limitations • Big picture: no one knows what level of VitD is “ideal” for the non-osteomalacial actions of VitD • Our women were not as VitD deficient as in some studies so differing conclusions might occur if there was a wider range of serum levels • Our GDM women were generally only mildly hyperglycemic (ie) no one was on insulin when maternal bloods were taken: again a wider range of insulin impairement may have uncovered differing results

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