Patogenecity of Low Vitamin B12

and Folate on Growth and Insulin

Resistance in the Offspring

Besari Adi Pramono

Maternal Fetal Medicine Department

Medical Faculty of Diponegoro University
Dr. Kariadi Hospital - Diponegoro National Hospital
Semarang
Diabetes Mellitus adalah penyakit metabolik
yang menjadi fenomena di abad 21

Resistensi insulin menjadi salah satu jalur

patofisiologinya.
Bayi kecil saat lahir mewakili 'hemat
fenotipe‘ yakni adaptasi intrauterin terhadap
asupan nutrisi yang kurang, yang dikemudian
hari saat pasokan makanan cukup hal ini
dikompromikan sehingga bermanifestasi
sebagai peningkatan kerentanan terhadap
penyakit kardiometabolik.
Pada tahun 1992, Nick Hales dan David
Barker mengusulkan bahwa gizi buruk
intrauterin menyebabkan peningkatan
kerentanan terhadap diabetes tipe 2 dan
penyakit kardiovaskular di kemudian hari

Idenya muncul diawali dengan berat badan

lahir rendah dikaitkan dengan risiko yang lebih
tinggi dari diabetes tipe 2 dan sindrom
metabolik.
Xie, et al, 2015 menyebutkan bahwa
suplementasi asam folat prenatal mungkin
memberikan proteksi tehadap obesitas dan
diabetes melitus pada keturunannya.

Penelitiannya sendiri bertujuan untuk

merangkum temuan yang menghubungkan antara
suplementasi asam folat / defisiensi asam folat
pada Ibu dengan kejadian obesitas/ resistensi
insulin pada keturunannya.
 Pregnancy is a period of increased
metabolic demand when nutritional
status directly influences the infant size
and also the main determinant factor for
the growth and development of the
offspring
 The fetus can be affected resulting in still birth,
preterm delivery, IUGR, congenital malformation,
reduced immunocompetence and abnormal organ
development
 The intrauterine environment, due to maternal
malnutrition and genetic factors affecting insulin
secretion, glucose sensing and insulin resistance
must also contribute
Vitamin B-12, also known as cobalamin, is a
micronutrient essential for cellular growth,
differentiation, and development
 Main functions:

• Essential growth factor

• Formation of blood cells and nerve sheaths
• Regeneration of folic acid
• Coenzyme-function in the inter- mediary
metabolism, especially in cells of the nervous
tissue, bone marrow and gastrointesti- nal
tract
Current recommendation
Pregnancy 2.6 µg
Lactation 2.8 µg
 Folic acid is a water soluble B vitamin that
serves a variety of functions within the cell.
Some of the most important functions are
associated within the developing fetus
 Tetrahydrofolic acid, which is the active
form of folate in the body, acts as a
coenzyme in numerous essential metabolic
reactions.
 The synthesis of the amino acid methionine from
homocysteine requires a folate coenzyme and, in
addition, vitamin B12.

Tetrahydrofolic acid is involved in the synthesis of

nucleic acids (DNA and RNA) – the molecules that
carry genetic information in cells
Pregnancy 600 µg
Lactation 500 µg
Folate coenzymes play an important role in
the metabolism of several amino acids, the
con- stituents of proteins.late coenzymes act
as acceptors and donors of one-carbon units in
these reactions.
 The micronutrients B-12 and folate are needed to
support the increased demands of the fetus in
pregnancy.
 Vitamin B-12 and folic acid are the two important
B vitamins which act as a cofactor for the
synthesis of DNA and RNA and in numerous
methylation reactions
 Homocysteine is a key metabolite in one-carbon
(1-C) metabolism, and homocysteine levels
influence several cellular processes including
DNA methylation and synthesis of nucleic acids
and proteins
 Homocysteine concentration is influenced by a
number of genetic polymorphisms and also by
dietary intake of ‘methyl donors’ (folate, vitamin
B12, choline and betaine)
 The association of elevated maternal
homocysteine with fetal growth restriction
suggests a role of maternal 1-C metabolism
in fetal growth and development, and a
potential for improvement by dietary
manipulations
 Vitamin B-12 plays an integral role in folate
dependent homocysteine metabolism as a rate
limiting cofactor in the conversion of
homocysteine to methionine
 Limited supply of vitamin B-12 during pregnancy
causes hyperhomocysteinemia which may have
very important consequences for fetal growth
 Higher maternal folate concentrations predicted
greater adiposity (fat mass and body fat per cent)
and higher insulin resistance, and lower vitamin
B-12 concentrations predicted higher insulin
resistance.
 Children born to mothers with low vitamin B-12
concentrations but high folate concentrations
were the most insulin resistant.
 The mechanisms that might link low
maternal vitamin B-12 status to offspring
insulin resistance
 Vitamin B12 deficiency will trap folate as 5-
methyltetrahydrofolate, prevent the generation of
methionine from homocysteine and therefore
reduce protein synthesis and lean tissue
deposition.
 Elevated methylmalonyl-CoA could contribute to
increased lipogenesis by inhibiting carnitine
palmitoyltransferase and thereby inhibit β-
oxidation
 The mechanisms that might link low
maternal vitamin B-12 status to offspring
insulin resistance
 Methionine is subsequently converted into S-
adenosyl methionine, a ubiquitous 1-carbon
donor to numerous methylation reactions,
including DNA methylation.
 A reduction in this important methyl donor may
have caused epigenetic modifications that
contributed to elevation in insulin resistance
 Mekanisme metabolik yg menggambarkan pembentukan adiposit,
resitensi insulin dan penyimangan gen pada defisiensi vitamin B 12
dan asam folat (Desmukh, 2013)

CPT1 = Carnitine palmitoyltransferase; MCM = methylmalonyl-CoA mutase; MMA-CoA = methylmalonyl-

CoA; MTR = methionine synthase; R = methyl acceptor; R-CH3 = methylated compound; SAH = S-
adenosylhomocysteine; SAM = S-adenosylmethionine; THF = tetrahydrofolate
Pathways that involve vitamin B12 and the suggested mechanisms of increased adiposity and insulin resistance in maternal B12 deficiency
 Lower Circulating B12 Is Associated with Higher
Obesity and Insulin Resistance during Pregnancy in
a Non-Diabetic White British Population

Bridget Ann Knight, Beverley M. Shields, Adam Brook, Anita Hill, Dattatray S. Bhat,
Andrew T. Hattersley, Chittaranjan S. Yajnik

Results Higher 28 week BMI was associated with lower

circulating vitamin B12 (r = -0.25; P<0.001) and folate (r = -
0.15; P<0.001). In multiple regression analysis higher 28
week BMI remained an independent predictor of lower
circulating B12 (β (95% CI) = -0.59 (-0.74, -0.44) i.e. for
every 1% increase in BMI there was a 0.6% decrease in
circulating B12).
Relationship of Maternal Folic Acid and
Vitamin B12 with birth weight and body
proportion of newborn

Dr. Afsana Ahmed, Dr. Mahbooba Akhter, Dr. Shamim Ara, et al. Relationship of Maternal Folic Acid
and Vitamin B12 with birth weight and body proportion of newborn.
J. Dhaka National Med. Coll. Hos. 2011; 18 (01): 7-11
 Birth weight, length & OFC of newborns showed
significant positive correlation with maternal
serum folate & vitamin B12.
 The risk of lower serum folate was significant for
lower weight (OR11.00, 95% CI 4.81-25.15),
lower length (OR 3.67, 95% CI 1.42-9.47), lower
OFC (OR 6.96, 95% CI 2.47-17.87).
 The risks of lower serum vitamin B12 were
significant for lower weight (OR 4.09, 95% CI
1.67-10.00), lower length (OR 4.83, 95%CI 2.28-
10.22), lower OFC (OR 4.11, 95%CI 1.97- 8.54).
 Correlations of maternal serum folate with birth weight, length & OFC of newborn

Correlation of maternal serum vitamin B12 with birth weight, length & OFC of newborn
 Vitamin B12 and folate concentrations
during pregnancy and insulin resistance
in the offspring: the Pune Maternal
Nutrition Study

Yajnik CS, Deshpande SS, Jackson AA, et al. Vitamin B12 and folate concentrations
during pregnancy and insulin resistance in the offspring: the Pune Maternal
Nutrition Study. Diabetologia 2008;51:29–38.
 Higher maternal erythrocyte folate concentrations
at 28 weeks predicted higher offspring adiposity
and higher HOMA-R (both p<0.01).
 Low maternal vitamin B12 (18 weeks; p=0.03)
predicted higher HOMA-R in the children.
 The offspring of mothers with a combination of
high folate and low vitamin B12 concentrations
were the most insulin resistant.

Homeostatic Model Assessment of insulin resistance [HOMA-R]

Krikke, et al 2015 melakukan penelitian yang
prospektif kohort di Amsterdam ( the Amsterdam
Born Children and their Development study
(ABCD)) yang bertujuan mengetahui apakah
terdapat hubungan antara kadar vitamin B12 dan
folat Ibu pada saat hamil dengan resiko
cardiometabolik keturunannya saat berusia 5-6
tahun.

Kadar Vitamin B12 dan folate diukur dari serum

Ibu sejak kehamilan awal
 Pengukuran antropometrik, tekanan darah,
dan gula darah puasa diukur pada saat anak
berusia 5-6 tahun.

 Analisis multiple linear regression

digunakan untuk mengetahui hubungan
kadar serum ibu dengan kondisi anak.
 Kadar folat yang rendah pada ibu selama
kehamilan berhubungan dengan sedikit
peningkatan BMI pada keturunannya
[penurunan per 10 units: b 0.07 kg/m2, 95%
confidence interval (CI) 0.01, 0.13].

 Kadar vitamin B12 yang rendah pada ibu

berhubungan dengan denyut jantung tinggi
keturunannya [penurunan per 100 units: b 0.49
beats/min, 95% CI 0.11, 0.87].
 Hubungan antara 2 faktor utama ibu
(undernutrition & overnutrition) pada fetal
programming (Desmukh, 2013)
 The impact of ‘high folate/low vitamin B12’. Insulin resistance at 6 years of age is the
highest in children born to mothers who had the lowest vitamin B12 and highest folic acid
levels during pregnancy
Jurnal yang Membuktikan Hubungan Vitamin B12 dengan Pertumbuhan dan
Metabolisme Janin di Kemudian Hari (Rush, et al 2013)
 Key Messages
 Vitamin B-12 and folic acid are the two important B
vitamins which act as a cofactor for the synthesis
of DNA and RNA and in numerous methylation
reactions
 DNA methylation is one of the epigenetic
mechanisms resulting in foetal programming of
adult diseases
 Key Messages
 Vitamin B-12 and folate are related to normal fetal
development and fetal growth
 Birth weight, length & OFC of newborns significant
positive correlation with maternal serum folate &
vitamin B-12
 Maternal imbalance of ‘high folic acid and low
vitamin B12’ is associated with higher metabolic
risk (insulin resistance) in the offspring
 Terima Kasih
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