Insulin Resistance in PCOS

Vitamin D and Omega 3: Are they useful ?

Budi Wiweko
budi.wiweko01@ui.ac.id
budi.wiweko@gmail.com

Academic Health System Universitas Indonesia - Indonesian Medical Education and Research Institute (IMERI)
Faculty of Medicine Universitas Indonesia - Dr. Cipto Mangunkusumo General Hospital

Jakarta

Inspiring and empowering society

Polycystic Ovarian Syndrome (PCOS) likely has long-term effects
It is a disorder that typically has its onset early in life.

Inspiring and empowering society

 2 GnRH frequency

1 Insulin Resistance

Hypersecretion of LH

Theca cells 3 Low FSH

Hyperinsulinemia
Increase of IGF-1

HYPERANDROGEN
Decrease IGFBP-1

Increase Free Androgen

Decrease SHBG Increase Free Estrogen
 INSULIN RESISTANCE AND METABOLIC SYNDROME

HYPERANDROGEN
Increase PAI-I
INSULIN RESISTANCE Hyperinsulinemia Increase VLDL
Decrease HDL

Cibula et al. Hum Reprod, 2000

Inspiring and empowering society

Recent evidence revealed extra skeleton activity of vitamin D, including prevention from cardiometabolic
diseases and cancer development as well as anti-inflammatory properties. It is worth noting that vitamin D
deficiency is very common and may be associated with the pathogenesis of insulin-resistance-related diseases,
including obesity and diabetes

Izabela Szymczak-Pajor and Agnieszka Sliwinska. Nutrients, 2019

Inspiring and empowering society

The regulation of synthesis and metabolism of
vitamin D.

• Under ultraviolet radiation (UVB, 290–315

nm) action, 7-dehydrocholesterol in
converted into previtamin D3 in the skin
• Previtamin D3 transformed into vitamin D3
as a result of heat-dependent process
• During excessive exposure to sun,
previtamin D3 and vitamin D3 are broken
down into inactive photoproducts to
prevent vitamin D3 intoxication

Izabela Szymczak-Pajor and Agnieszka Sliwinska.

Nutrients, 2019

Inspiring and empowering society

 INSULIN RECEPTOR
Insulin is major regulator of carbohydrate and lipid metabolism. Increase of blood glucose in
the blood will increase insulin production.

Izabela Szymczak-Pajor and Agnieszka Sliwinska. Nutrients, 2019

Inspiring and empowering society

 INSULIN RESISTANCE

Izabela Szymczak-Pajor and Agnieszka Sliwinska. Nutrients, 2019

Inspiring and empowering society

Vitamin D may play an important role in the regula*on and of pancrea*c β-cells func*on in T2D paIents since calcitriol
(1,25(OH)2D) acts as a chemical messenger by interacIng with calcium flux-regulaIng receptors on the β-cells . Moreover,
vitamin D can reduce hyperac*vity of the renin-angiotensin system and to improve the funcIon of β-cells.

On the other hand, vitamin D could influence the insulin secre*on regulated by the opening and closing of calcium channels
and 1,25(OH)2D may also improve insulin sensiIvity by s*mula*ng the expression of insulin receptors and acIvaIng
peroxisome proliferator-acIvated receptor delta (PPAR-δ).
Bolivar et al. Nutrients, 2021

Inspiring and empowering society

 How does Vitamin D Overcome Insulin Resistance and Related Disorders ?

Pancreatic B cell

Inspiring and empowering society

 How does Vitamin D Overcome Insulin Resistance and Related Disorders ?

Adipocyte

Inspiring and empowering society

How does Vitamin D Overcome Insulin Resistance and Related Disorders ?

Hepatocyte

Inspiring and empowering society

A normal level of vitamin D is able to reduce low grade inflammation, which is a major process in inducing
insulin resistance. It is also engaged in maintaining low resting levels of reactive species and radicals, normal
Ca2+ signalling, a low expression of pro-inflammatory cytokines but increased formation of anti-inflammatory
cytokines.

Vitamin D is also able to prevent hypermethylation (of DNA) and consequent functional inactivation of many
genes, as well as other epigenetic alterations in β cells and in other insulin-sensitive peripheral tissues, mainly
liver, adipose tissue and muscle.

Inspiring and empowering society

Characteristics of the included studies and study populations (n = 601).

Inspiring and empowering society

Mean changes in 25(OH)D (ng/mL) concentration after supplementation with vitamin D in the
supplemented and placebo groups of the selected studies.

Inspiring and empowering society

Mean changes in fasting glucose concentration (mg/dL), fasting insulin level (μLU/L), and value of HOMA-IR index
before and after supplementation with vitamin D in the supplemented and placebo groups in the selected studies

Inspiring and empowering society

Vitamin D deficiency in this review was defined as serum 25-hydroxyvitamin D < 50 nmol / L,
whereas vitamin D insufficiency was defined as serum 25-hydroxyvitamin D between 50 and 75
nmol / L

Oktavius et al. Am J Obstet Gynecol, 2023

Inspiring and empowering society

Oktavius et al. Am J Obstet Gynecol, 2023

Inspiring and empowering society

 Oktavius et al. Am J Obstet Gynecol, 2023

Inspiring and empowering society

Oktavius et al. Am J Obstet Gynecol, 2023

Inspiring and empowering society

 IS AMH A REGULATOR OF FOLLICULAR ATRESIA ?

AMH inhibits granulosa

cells apoptosis

David B. Seifer & Zaher Merhi. J Assist Reprod Genet, 2014

Inspiring and empowering society

Effect of vitamin D on serum
antimullerian hormone (AMH) and
AMH / AMH receptor II gene
expression.

Irani. Vitamin D and ovarian physiology

Fertil Steril 2014.

Inspiring and empowering society

Role of vitamin D in human luteinized granulosa cells. Vitamin D down-regulates FSH receptor (FSHR) and antimu!llerian
hormone (AMH) receptor II (AMHR-II) mRNA levels. It also decreases Smad 1 / 5 / 8 phosphorylation and nuclear
translocation. Additionally, vitamin D induces 3-beta-hydroxysteroid dehydrogenase (3b-HSD) mRNA expression and
increases progesterone production and release.

Inspiring and empowering society

 AMH levels of the four groups based on PCOS-related phenotypes

Indonesian people tend to be less hyperandrogenic compared to Caucasians

• Ovulatory PCOS paZents had lower AMH levels compared to anovulatory PCOS paZents
• Increased androgen levels have also been related with the increased producZon of AMH

Wiweko et al. J Assist Reprod Genet, 2014

Inspiring and empowering society

n = 125

Phenotype 1 shows significantly higher AMH levels

(Kruskal–Wallis, p < 0.05) than other phenotypes.

Wiweko et al. BMC Res Notes, 2018

Inspiring and empowering society

 Int. J. Mol. Sci. 2021

Inspiring and empowering society

AssociaQon of vitamin D deficiency
with factors related to ovulatory
dysfuncQon in polycysZc ovary
syndrome (PCOS).

(Irani. Vitamin D and ovarian

physiology)

FerIl Steril 2014.

Inspiring and empowering society

Inspiring and empowering society
Crosstalk between advanced glycation end products and vitamin D:
A compelling paradigm for the treatment of ovarian dysfunction in PCOS

Merhi. Moll Cell Endocrinol, 2018

Inspiring and empowering society

 Int. J. Mol. Sci. 2021

Inspiring and empowering society

Inspiring and empowering society
Effect of adding Ca / Vitamin D to metformin on regularity of menses based on Odds ratio.
The horizontal lines denote the 95% CI.

Shojaeian et al. Caspian J Intern Med 2019

Inspiring and empowering society

Omega-3 faVy acids supplementaZon also has a beneficial effect on some cardiometabolic risk
factors in women with PCOS , which is achieved through reducing the synthesis of prostaglandins
by compeZZve inhibiZon of cyclooxygenase 2 (COX-2) and increasing the acQvity of anQoxidant
enzymes.

Inspiring and empowering society

Overview of possible routes of lipid oversupply-induced insulin resistances associated with
mitochondrial and endoplasmic reticulum (ER) stress

Inspiring and empowering society

Inspiring and empowering society
 HOMA-IR

TOTAL CHOLESTEROL

Inspiring and empowering society

 ADIPONECTIN

BMI

Inspiring and empowering society

FASTING INSULIN

FASTING GLUCOSE

Inspiring and empowering society

LDL - C

HDL - C

Inspiring and empowering society

 Take Home Messages
1. Vitamin D deficiency is very common and may be associated with the pathogenesis of insulin-
resistance-related diseases.

2. A normal level of vitamin D can reduce low grade inflammation, which is a major process in inducing
insulin resistance.

3. Vitamin D induces Akt phosphorylation and downregulated RAGE thus attenuating the effect of AGEs
and potentially reducing insulin resistance at the granulosa cell.

4. Indirect relationship between serum AMH and insulin resistance in PCOS patients leading them to
suffer from high risk of metabolic syndrome.

5. Supplementation of high dose vitamin D with insulin sensitizer will improve PCOS and metabolic
syndrome symptoms.

6. Omega-3 fatty acids supplementation reducing the synthesis of prostaglandins by competitive

inhibition of cyclooxygenase 2 (COX-2) and increasing the activity of antioxidant enzymes.

Inspiring and empowering society

 Acknowledgement
Julianto Witjaksono, Ali Baziad, Andon HesIantoro, Muharam Natadisastra, Kanadi Sumapraja,
Gita Pratama, Herbert Situmorang Eliza Mansyur, Tita Yuningsih, SiI Mariam, Endang Kurdiningsih,
Kresna MuIa, Prida Iffanolia, Deka

Inspiring and empowering society