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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

Vitamin DAdipocytokines

….and GDM pregnancies

objectives
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
vitamin d a few reminders
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
vitamin d a few reminders1
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
vitamin d recent oddities
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
vit d and gdm what do we know
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

slide11

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
does vit d status predict gdm risk
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
slide13

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]
does vitd predict adverse preg outcomes
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
what about interventional studies
What about interventional studies?
  • ………..wait……………………
what links vitd and insulin resistance
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)
links between vitd and insulin resistance
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
links between vitd and insulin resistance1
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
vitd and inflammatory markers
VitD and inflammatory markers
  • So:

holding onto VitD considerations

but

switching over to thinking about adipocytokines

what are adipocytokines
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
adipocytokines
Adipocytokines

You know some of these already:

  • leptin
  • adiponectin
  • TNF-α
  • interleukins
  • resistin

…etc….

just a few metabolic associations of adipokines
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
functions of adipokines
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
adipocytokines and gdm
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
so cooking up a study in london on
..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)?
psi grant
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.
methods
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]
methods1
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)
methods2
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)
do you want to guess
….do you want to guess?

Umbilical artery flows:

Umbilical vein flows:

slide36
So
  • umbilical arterial blood would reflect fetal chemistry
  • umbilical vein blood would reflect maternal AND placental chemistry
demographics
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
a few stats
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

r esults
Results
  • 73 women
  • 36 GDM; 37 C
  • Matched for week of gestation; present weight; pre-preg weight; maternal VitD intake
searching for correlations
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
searching for correlations cont
Searching for Correlations..cont
  • Neonatal VitD levels were not correlated with any of:
  • infant weight
  • placental weight
  • Apgar scores
  • labour duration/hospital stay
  • adipocytokines
admitting our limitations
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
so what
So…what…?

#1: As expected:

  • GDM women had lower adiponectin than Controls
  • however, this finding was present despite being matched for weight and pregnancy week
  • lower adiponectin levels would be consistent with increased GDM maternal inflammation…but….
so what 2
So what #2
  • GDM had lower resistin and PAI-1 levels [argues against inflammatory biochemical profile]
  • GDM leptin was not different from C
  • GDM CRP, ILs, TNFα, MCP-1 not different as well
  • overall, no conclusive evidence for inflammatory chemistry in GDM women
so what 3
So what #3:
  • GDM maternal VitD lower than Controls
  • But:
  • Umbilical arterial and venous VitD showed no difference between GDM and C offspring
so what 4
So what #4
  • Maternal GDM VitD levels were positively (not negatively as expected) correlated with some adipokines thought to be associated with inflammation (PAI-1; IL-8, TNFα)
  • Neonatal VitD levels did not correlate with inflammatory markers
so what 5
So what #5
  • Neonates born to mothers with GDM also manifested lower adiponectin and resistin levels
  • even in umbilical arterial bloods
  • suggesting that there are adverse adipokine profiles present at birth
so what 6
So what #6
  • We learned a very important life lesson:
  • Never ever again do a study where blood samples from babies have to be centrifuged and frozen at any time of day, night, holidays……
just an aside
Just an aside
  • Enthusiasm for VitD as THE miracle metabolic hormone has waned
  • Much of what our study was built upon (remember, grant applied for <2008) tantalizing hints and correlations around VitD effects
  • However, interventional studies have suggested perhaps some effect attributable to VitD, although final word not yet in…..
for instance1
For instance
  • 54 women with GDM (Iran)
  • randomized to placebo or cholecalciferol 50,000 u at study entry and day 21
  • fasting samples for BG and insulin taken at study onset as well as after 6 weeks
slide61

Results:

  • VitD supplementation:
  • was correlated with lower FG

(-17.1±14.8 mg/dl vs -0.9±16.6 mg/dl, p<0.001)

  • was correlated with lower serum insulin
  • was correlated with improved QUICKI index

Asemi. Am J ClinNutr 2013.98.1425

one more
one more…
  • 120 Iranian women <12 weeks of pregnancy
  • randomized to:
  • 200 u VitD OD;
  • 50,000 u VitD monthly
  • 50,000 u Vit D Q2 weeks

until delivery

measured
measured:
  • FBG,
  • insulin,
  • Ca,
  • VitD
  • before and after intervention
r esults1
Results
  • Group C receiving 50,000 u every 2 weeks had biggest rise in VitD level
  • FBG dropped 2.02 mg/dl in Group C (NS)
  • Insulin level in group C went up less than Group A (NS)
  • comparing all 3 groups: insulin and HOMA IR were improved with higher doses of VitD supplementation
  • SoheilyhkhahGynecEndocrinol 2013. 29. 396
one last london connection
..one last London connection
  • DALI study
  • Vitamin D and lifestyle intervention for gestational diabetes mellitus (GDM) prevention: an European multicentre, randomized trial-study protocol
  • 9 countries
  • <20 weeks gestation
  • 8 intervention arms (placebo, healthy diet, healthy activity, Vit D combos)
slide66
DALI
  • Vit D dose is 1600 u OD until delivery
  • primary outcome: gestational weight gain, fasting glucose and insulin sensitivity, OB outcomes
  • [biorepository blood is being stored at Lawson/David Hill]
  • Jelsma BMC Pregnancy Childbirth 2013. 13.124
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