NUTRITION AND

HEALTH (CHRONIC
DISEASES)

OLEH:
DR. NI KETUT SUTIARI
PSKM, FK UNUD
 Micronutrient:
the Role in Type 2 Diabetes
 Micronutrients
Vitamins and trace elements

Micronutrients as components of the antioxidant network

Trace elements Role as antioxidant enzyme cofactor
Selenium Glutathione peroxidase
Iron Catalase
Zinc Cytosolic superoxide dismutase
Cooper Cytosolic superoxide dismutase and
ceruloplasmin
Manganese Mitochondrial superoxide dismutase
Antioxidant vitamins
Viamin A (retinol)
Beta-carotene (pre-vitamin A)
Vitamin C (ascorbic acid)
Vitamin E (tocoferol)
Vitamin K (quinones)

Opara and Rockway Dis Mon 2006; 52: 151-163

 Micronutrient status of diabetic patients

Status in diabetic patients

Micronutrient Type 1 Type 2

I. Trace elements
Zinc (Zn)  
Chromium (Cr)  NL*
Calcium (Ca)  NL
Magnesium (Mg)  
Copper (Cu) NL NL or 
Manganese (Mn)  or NL **
Iron (Fe) NL NL
Selenium (Se)  ?
II. Vitamins
A ? NL
Thiamin NL NL***
B-6 NL or  NL or 
B-12 NL or  NL
C NL or  NL or 
1,25-dihydroxycholecalciferol  NL
E  
* NL = neither increased or decreased.
** Type of diabetes not specified.
*** Increased in Japanese diabetics.
Mooradian and Morley. Am J Clin Nutr 1987; 45: 877-95
ZINC,
insulin and diabetes
• Zinc: insulin monomers assemble to a dimeric form for
storage and secretion as the zinc crystal
• Zinc:
– Improves insulin secretion
– Enhance binding of insulin to hepatocyte membrane
– Necessary factor in “antioxidant” enzymes (SOD, catalase,
peroxidase)
– Zn-metallothionien complex in the islet cell provides protection
against free radicals
– Necessary for adequate function of T-cell lymphocyte – foot ulcer

Chausmer. J Am Coll Nutr 17: 109-115, 1998

Mooradian and Morley. Am J Clin Nutr 45: 866-95, 1987
SELENIUM:
an insulin-mimetic

1. Glucose uptake 2. Glucose and FA metabolism

 GLUT-1, -2  Glycolysis
- Glucokinase
- L-type pyruvate kinase
3. Signal tranduction  Gluconeogenesis
- Phosphorylation insulin - PEPCK
receptor  Fatty acid biosynthesis
- Activates IRS-1 recognizes - FAS (fatty acid synthase)
and binds to SH2 domains  Pentose phosphate pathway
of various signal transduction - G6PDH
proteins such as PI3-kinase,  Glycogen synthesis
SH-PTP-2, Grb2 and Nck - Glycogen synthase

Stapleton. CMLS, Cell Mol Life Sci 57: 1874-1879, 2000

 CHROMIUM &
insulin action

Insulin
NH2
Alpha subunit
Cell membrane
Beta subunit
CooH
Cr activates
receptor kinase IRS-1
Cr inhibits
PI 3-kinase tyrosine phosphatase

Fig. Mode of action of Cr in potentiation of insulin.

Cr increases insulin binding to cells by increasing insulin receptor number.
Cr also increases insulin sensitivity by increasing insulin receptor
phosphorylation. Cr potentiation of insulin is inhibited by wortmanin,
which inhibits the enzyme, PI 3-kinase
Anderson. J Am Coll Nutr 17: 548-555, 1998
MAGNESIUM in
glucose homeostasis

• Cofactor in the glucose transfort system of plasma

membranes
• Has an important role in activity of various enzymes involved
in glucose oxidation
• May play a role in release of insulin
• Modulate the mechanisms of energy transfer from high-
energy phosphate bonds

Mooradian and Morley. Am J Clin Nutr 45: 866-95, 1987

 Select chromium clinical trials

Subjects Design Results

• 180 type 2 • RDBPCT • FBG decreased (P <0.05) at 4 months in the 1,000-mg group
• BMI 25 • Cr picolinate • HbA1c decreased at 2 and 4 months in the 1,000-g group,
• China • 200 or 1,000 g/day at 4 months in the 200-mg group (placebo 8.5%, 200 mg
• O, I, D • 4 months 7.5%, 1,000 g 6.6%, P <0.05%)
• HbA1c 9–12% • OGTT: 2-h glucose decreased in 1,000-mg group (P <0.05);
fasting, 2-h insulin decreased (P <0.05) in both groups
• Cholesterol levels decreased in the 1,000-mg group (P <0.05)
• 833 type 2 • Up to 10 months • FBG decreased from 10.0 to 8.0 mmol/l
• China • Non-placebo- • Postprandial BG improved from 12.0 to 9.9 mmol/l
• O, I controlled follow-up • 391 of 443 subjects who had reported symptoms of fatigue
• 500 g/day reported improvement; 287 of 334 reported improvement
• Cr picolinate in symptoms of thirst; and 282 of 322 reported a decrease
in incidence of frequent urination
• 24 IGT • DBPCT • BMI decreased in Cr group (P <0.05)
• Age 65–74 years • 6 months • No significant changes in HbA1c, FBG, fasting insulin levels, 1-
• BMI 30 • 160 g/day or 2-h postprandial insulin, or BG levels in Cr group
• Finnish • Cr-rich yeast • No significant changes in lipoprotein levels
• Trend to lower postprandial insulin levels in Cr group attributed
to weight loss

O’Connell BS. Diabetes Spectrum 2001; 14: 133-148

 Select magnesium clinical trials

Subjects Design Results

• 50 type 2 • RDBPCT • Mg supplementation slightly increased plasma Mg levels (P
• Netherlands • 15 mmol/day <0.05); no change in RBC Mg, which was not low
•I • Oral MgAspHCl • No change in FBG, HbA1c
• BMI 28 • 3 months • No change in lipids or hypertension
• HbA1c 8.7% • Intention to treat
and on-treatment
• 56 type 2 • RDBPCT • No effect of Mg on HbA1c, FBG, lipids, renal function, or blood
• Age 64±8 years • 15 mmol/day pressure
• D, O, I • Mg lactate citrate
• BMI~25 • 4 months
• HbA1c 7.3%

• 8 type 2 • RPCT crossover • Mg increased plasma (P <0.05) and RBC Mg (P <0.01) levels
• Age 72 years • 4-week treatment • Mg decreased FBG (P <0.05)
• 133% IBW • 2-week washout • Euglycemic hyperinsulinemic clamp: Mg increased acute insulin
• Italy • 2 g/day response to glucose pulse (P <0.05), glucose infusion rate (P
• HbA1c ? • Oral Mg <0.025)

O’Connell BS. Diabetes Spectrum 2001; 14: 133-148

 Select nicotinamide clinical trials

Subjects Design Results

• 173 postive ICA • Not placebo-controlled • Nic associated with significant decreases in the
• Age 5–8 years • 1,000 mg/day Nic development of type 1 diabetes (P<0.008), wide
• New Zealand • Mean follow-up 7 years confidence interval

• 211 type 1 • Meta-analysis • 1 year after diagnosis, baseline C-peptide levels

• Recent diagnosis • 10 randomized studies, significantly higher in Nic group (P <0.005), placebo-
• Ages 4–48 years 5 placebo-controlled controlled group (P <0.05)
• Dose 4–100 mg/kg/day • No differences in HbA1c or insulin requirements
• Up to 60 months follow-
up
•18 type 2 • Randomized, singleblind, • C-peptide release increased in two groups receiving Nic
• Negative ICA placebo compared to placebo (P <0.05)
• OHA failure • 6 months • No difference in HbA1c, FBG, or mean daily BG between
• BMI <25 • 1.5 g/day Nic groups
• I plus Nic, I plus placebo,
OHA plus Nic

Niacin (vitamin B3) occurs in two forms: nicotinic acid and nicotinamide. The active coenzyme forms (nicotinamide
adenine dinucleotide [NAD] and NAD phosphate) are essential for the function of hundreds of enzymes and normal
carbohydrate, lipid, and protein metabolism.

O’Connell BS. Diabetes Spectrum 2001; 14: 133-148

 Select vitamin E clinical trials

Subjects Design Results

• 53 type 2 • RDBPCT,crossover • VE supplementation in poorly controlled subjects did not improve
• Mexico • 400 mg VE FBG, HbA1c, fructosamine, cholesterol, LDL, HDL, TG, apo-A, apo-B
• Age 40 years • 2 months
• BMI 24 • 4-week washout
• HbA1c 11.9%

• 25 type 2 • RDBPCT, crossover • Decreased FBG (P <0.05), decreased HbA1c 7.8 to 7.1% (P
• Italy • 900 mg/day d- VE <0.05)
• Age 71 years • 3 months • TG (P <0.02), LDL (P <0.04), FFA, cholesterol, apo-B (P <0.05)
• BMI 27 • 30-day washout • Supplements increased plasma VE, GSSG/GSH ratio,
• HbA1c 7.8% decreased plasma oxygen production, no effect on fasting or
IVGTT insulin
30 • Group randomized, • Decrease in HbA1c 11.8 to 7.8% with 1,200 mg/day (P <0.01),
• Insulin-requiring blinded 11.5 to 8.9% with 600 mg/day (P <0.001)
• Age ~41 years • Placebo 600, 1,200 • No change in fasting or mean daily BG level or response to
• BMI ~28 mg VE/day hyperglycemic clamp
• HbA1c ~11.5% • Groups matched • VE may act in an early step of glycation, possibly glucose auto-
for age, duration, oxidation
and control of
diabetes
• 2 months

O’Connell BS. Diabetes Spectrum 2001; 14: 133-148

MICRONUTRIENT &
Diabetes

Micronutrient  Diabetes  Micronutrient

1. Intake
2. Absorption
3. Excretion

Micronutrient is a nutrient and not a drug, and it

will therefore benefit only those who are deficient
Vitamin D dan diabetes type 2
Fungsi Vitamin D klasikal ke fungsi
baru
• Th 2008, diperkirakan bahwa 1 miliar orang kekurangan vitamin
D dan jumlah ini meningkat dengan perkembangan tahun
(James 2008);
• Melamed et al (2008), bukti terbaru menunjukkan bahwa vitamin
D terlibat dalam beberapa mekanisme di samping metabolisme
tulang
• Perannya dalam metabolisme glukosa abnormal serta diabetes
tipe-2 telah dibuktikan (Chiu et al 2004; Polemer et al 2008)
• Defisiensi vitamin D dapat menyebabkan kerentanan terhadap
intoleransi glukosa, merubah sekresi insulin dan diabetes tipe-2
(Pittas et al 2010), baik langsung melalui tindakan aktivasi
reseptor vitamin D (VDR) ataupun tidak langsung melalui hormon
calcemic dan melalui peradangan (Thorand et al 2011).
• Beberapa penelitian cross-sectional telah mempublikasikan dan
menunjukkan keterkaitan terbalik antara 25 (OH)D dan risiko
diabetes yang tidak terdiagnosis, tetapi desain penelitian ini hanya
menyediakan bukti moderat mengenai penyebab karena
pengukuran 25 (OH) D yang simultan dan status diabetes;

• Epidemiologi status vitamin D terbalik dengan diabetes, karena

penurunan kadar 25(OH)D dengan usia dan lebih rendah pada
populasi dengan peningkatan pigmentasi kulit, seperti Afrika
Amerika dan Asia Selatan, dan pada orang dengan obesitas ,
sedangkan diabetes meningkat dengan usia dan obesitas dan lebih
tinggi pada kelompok-kelompok etnis tsb (Boucher 1998);

• Telah dihipotesiskan status vitamin D rendah dapat memprediksi

hiperglikemia dan hiperinsulinemia (Mattila et al 2007; Forouhi et
al 2008);
Hasil penelitian: vitamin D and insulin
resistance
• Vitamin D levels did not demonstrate any relation with insulin
resistance, and neither with parameters of glucose homeostasis
(glucose, insulin, diabetes duration and HbA1c), nor with
parameters of mineral homeostasis (serum calcium, phosphate and
alkaline phosphatase);
• it correlated significantly and inversely with parathyroid hormone
levels;
• Deficient levels of vitamin D in both the patients and controls in
this studies:
Reason: subjects were all obese , low 25(OH)D levels are
associated with obesity in Adults [14,19]; decreased sun exposure
due to sedentary lifestyle, poor diet, and increased clearance of
25(OH)D due to storage in adipose tissue[20];
Vitamin K dan resistensi insulin
 Potensi kesehatan yang sangat menarik ada pada
vitamin K terkait dengan perannya dalam koagulasi.

 Beberapa studi penelitian melaporkan fungsi klasik

vitamin K yaitu memelihara kesehatan tulang,
menurunkan risiko kalsifikasi (penyempitan) pembuluh
darah dan risiko pembuluh jantung.

 Sampai saat ini, bukti atau pun data-data pada studi

manusia dan hewan yang menunjukkan bahwa vitamin
K berbanding terbalik dikaitkan dengan resistensi
insulin adalah terbatas.
 Sebuah studi observasional (studi kohort)
menunjukkan asupan makanan dan
suplemen vitamin K yang lebih tinggi terkait
dengan meningkatnya sensitivitas insulin dan
status glikemik yang lebih baik pada
masyarakat laki-laki dan wanita.
 Namun fungsi dari vitamin K di luar fungsi
klasiknya adalah belum dimengerti dengan
baik, adapun fungsi klasik vitamin K adalah
berperan sebagai kofaktor enzim untuk
karboksilasi dari residu asam glutamate
tertentu pada vitamin K-dependent proteins.
• Studi in vivo dan in vitro menunjukkan bahwa vitamin K
menurunkan lipopolisakarida-menurunkan inflamasi
• Ada dugaan suplementasi vitamin K dan intake vitamin
K dari diet dapat memberikan efek menguntungkan
atau efek berlawanan terhadap resistensi insulin.
• Suplementasi vitamin K selama 36 bulan (3 tahun),
mempunyai efek menguntungkan pada insulin
resistensi pada lansia laki-laki dan bukan pada lansia
wanita.
• Penelitian selanjutnya: memerlukan replikasi studi
dengan desain spesifik untuk uji hipotesis bahwa
suplementasi vitamin K memainkan peran dalam
proteksi resistensi insulin pada kelompok lansia.
 Simpulan
• Mikromineral (trace element) diduga
berhubungan dengan kendali glikemik dan
glukosa homeostatis pada diabetes type 2.
• Terjadi defisiensi vitamin D pada masyarakat
dengan diabetes type 2 atau pun normal. Perlu
penelitian lanjutan terkait dengan status vitamin
D dengan diabetes type 2
• Vitamin K juga mempunyai potensi dalm
meningkatkan sensitivitas insulin kelompok usia
lanjut
Daftar Rujukan
1. Cockayne S, Adamson J, Lanham-New S, et al : Vitamin K and the
prevention of fractures: systematic review and meta-analysis of
randomized controlled trials. Arch Intern Med 166, 1256–1261,
2006
2. Beulens JW, Bots ML, Atsma F, et al: High dietary menaquinone
intake is associated with reduced coronary calcification.
Atherosclerosis 203, 489–493, 2009
3. Geleijnse JM, Vermeer C, Grobbee DE, et al: Dietary intake of
menaquinone is associated with a reduced risk of coronary heart
disease: the Rotterdam Study. J Nutr 134, 3100–3105, 2004
4. Sakamoto N, Nishiike T, Iguchi H, Sakamoto K: Relationship
between acute insulin response and vitamin K intake in healthy
young male volunteers. Diabetes Nutr Metab 12:37– 41, 1999
5. Sakamoto N, Nishiike T, Iguchi H, Sakamoto K: Possible effects of one
week vitamin K (menaquinone-4) tablets intake on glucose tolerance
in healthy young male volunteers with different descarboxy
prothrombin levels. Clin Nutr 19:259 –263, 2000
6. Yoshida M, Booth S, Meigs J, Saltzman E, Jacques P: Phylloquinone
intake, insulin sensitivity, and glycemic status in adult men and
women. Am J Clin Nutr 88:210–215, 2008
7. Sakamoto N, Wakabayashi I, Sakamoto K: Low vitamin K intake effects
on glucose tolerance in rats. Int J Vitam Nutr Res 69:27–31, 1999
8. Thijssen HH, Drittij-Reijnders MJ: Vitamin K status in human
tissues: tissue-specific accumulation of phylloquinone and
menaquinone-4. Br J Nutr 75:121–127,1996
9. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner
RC: Homeostasis model assessment: insulin resistance and cell
function from fasting plasma glucose and insulin concentrations in
man. Diabetologia 28:412–419, 1985
10. Booth SL, Tucker KL, McKeown NM, Davidson KW, Dallal GE, Sadowski
JA: Relationships between dietary intakes and fasting plasma
concentrations of fat-soluble vitamins in humans. J Nutr 127:587–
592, 1997
11. Gundberg CM, Nieman SD, Abrams S, Rosen H: Vitamin K status and
bone health: an analysis of methods for determination of
undercarboxylated osteocalcin. J Clin Endocrinol Metab 83:3258–
3266, 1998
12. Washburn RA, Smith KW, Jette AM, Janney CA: The Physical Activity
Scale for the Elderly (PASE): development and evaluation. J Clin
Epidemiol 46:153–162, 1993
13. Rimm EB, Giovannucci EL, Stampfer MJ, Colditz GA, Litin LB, Willett WC:
Reproducibility and validity of an expanded self-administered
semiquantitative food frequency questionnaire among male health
professionals. Am J Epidemiol 135:1114–1126; discussion 1127–1136,
1992
14. Bolton-Smith C, Price RJ, Fenton ST, Harrington DJ, Shearer MJ:
Compilation of a provisional UK database for the phylloquinone (vitamin
K1) content of foods. Br J Nutr, 83:389–399, 2000
15. Schurgers LJ, Vermeer C: Determination of phylloquinone and
menaquinones in food. Effect of food matrix on circulating vitamin K
concentrations Haemostasis, 30:298–307, 2000
16. Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, Dacquin R,
Mee PJ, McKee MD, Jung DY, Zhang Z, Kim JK, Mauvais-Jarvis F, Ducy P,
Karsenty G: Endocrine regulation of energy metabolism by the skeleton.
Cell 130:456–469, 2007
17. Ferron M, Hinoi E, Karsenty G, Ducy P: Osteocalcin differentially regulates
beta cell and adipocyte gene expression and affects the development of
metabolic diseases in wild-type mice. Proc Natl Acad Sci USA 105:5266–
5270, 2008
18. Reddi K, Henderson B, Meghji S, Wilson M, Poole S, Hopper C, Harris M,
Hodges SJ: Interleukin 6 production by lipopolysaccharide-stimulated human
fibroblasts is potently inhibited by naphthoquinone (vitamin K) compounds.
Cytokine 7:287–290, 1995
19. Ohsaki Y, Shirakawa H, Hiwatashi K, Furukawa Y, Mizutani T, Komai M:
Vitamin K suppresses lipopolysaccharide-induced inflammation in the rat.
Biosci Biotechnol Biochem 70:926 –932, 2006
20. Shea MK, Booth SL, Massaro JM, Jacques PF, D’Agostino RB Sr, Dawson-
Hughes B, Ordovas JM, O’Donnell CJ, Kathiresan S, Keaney JF Jr, Vasan RS,
Benjamin EJ: Vitamin K and vitamin D status: associations with inflammatory
markers in the Framingham Offspring Study. Am J Epidemiol 167:313–320,
2008
21. Pittas AG, Lau J, Hu FB, Dawson-Hughes B. The role of vitamin D and
calcium in type 2 diabetes. A systematic review and meta-analysis. J Clin
Endocrinol Metab 92:2017–2029, 2007
22. Ferrannini E, Natali A, Bell P, Cavallo-Perin P, Lalic N, Mingrone G: Insulin
resistance and hypersecretion in obesity: European Group for the Study
of Insulin Resistance (EGIR). J Clin Invest 100:1166 –1173, 1997
23. Abbasi F, Brown BW Jr, Lamendola C, McLaughlin T, Reaven GM:
Relationship between obesity, insulin resistance, and coronary heart
disease risk. J Am Coll Cardiol 40:937–943, 2002
24. Booth Sarah L: Roles for vitamin K beyond coagulation. Annu Rev Nutr 29:
89-110, 2009
25. Ferron M, Wei Jianwen, Yoshizawa T, Fattore Andrea D, et al: Insulin
Signaling in Osteoblasts Integrates Bone Remodeling and Energy
Metabolism. Cell 142, 296–308, 2010
Saya DENGAR, Saya LUPA;
Saya BACA, Saya INGAT;
Saya TULIS, Saya MENGERTI
 &
FUNGSI IMUN MANUSIA

OLEH:
NI KETUT SUTIARI
PSKM, FK UNUD
Kuliah Dasar Ilmu Gizi
 Pendahuluan
• Dalam waktu 5 tahun terakhir ini, fungsi
vitamin dan mineral secara klasikal sudah
mengalami perkembangan
• Vitamin D  memelihara kesehatan tulang,
mencegah osteoporesis, penentu
metabolisme mineral, seperti kalsium (Ca)
• Vitamin D  Fungsi Imun
 Sistem imun manusia
• Sistem imun sistem imun alami dan didapat.
• Sistem imun non spesifik / alami telah
berfungsi sejak lahir.
• Sistem imun alami merupakan perlindungan
terdepan dari sistem imun, meliputi fisik (kulit,
selaput lendir dan silia), biokimia
(komplemen, interferon), seluler ( makrofag,
polimorfonuklear, natular killer cell, mast cell)
dan larutan (asam lambung, enzim).
• Sistem imun spesifik berkembang kemudian
setelah kontak dengan lingkungan 
membutuhkan perkenalan  waktu untuk
berkembang.
• Sistem imun spesifik tidak efektif untuk
mencegah serangan awal, namun umumnya
mampu mencegah infeksi lanjutan dan
membantu menghilangkan infeksi yang
berkepanjangan.
• Sistem imun ini meliputi sel B (humoral) yang
membentuk sel T (seluler) yang terdiri dari
sel T cytotoxic /CTL , sel T helper, sel T
delayed hypersensitivity /TDH.
 Hasil riset: vitamin D menurunkan
infeksi
• There have been a number of other cross-
sectional studies looking at vitamin D levels
and rates of influenza (Cannel et al, 2006)
• Rates infections including bacterial vaginosis
(Bodnar et al., 2009), HIV (Villamor 2006;
Rodriguez et al 2009).
• All have reported an association of lower
vitamin D levels and increased rates of
infection.
 Vitamin D dan sistem imun
• Vitamin D has important functions beyond
those of calcium and bone homeostasis which
include modulation of the innate and
adaptive immune responses.
• Vitamin D has numerous effects on cells
within the immune system.
• It inhibits B cell proliferation and blocks B cell
differentiation and immunoglobulin secretion
(Lemire et al 1984; Chen et al 2007).
• In vivo data from animals and from human
vitamin D supplementation studies have shown
beneficial effects of vitamin D on immune
function, in particular in the context of
autoimmunity.
• Review: currently available data are summarized
to give an overview of the effects of vitamin D on
the immune system in general and on the
regulation of inflammatory responses, as well as
regulatory mechanisms connected to
autoimmune diseases particularly in type 1
diabetes mellitus.
Kalim et al 2015)
Kalim et al 2015)
• Vitamin D mampu menghambat respons limfosit
Th-1 (Fatmah 2006)
• Gizi merupakan faktor utama dalam pengaturan
respon imun.
• Secara umum, zat gizi mempengaruhi sistem
imun melalui mekanisme pengaturan ekspresi
dan produksi sitokin.
• Pola produksi sitokin merupakan hal penting
dalam merespon infeksi.
• Ketidakseimbangan gizi yang serius pada akhirnya
akan mempengaruhi perkembangan respon imun
dimasa yang akan datang.
 Simpulan
• Kekebalan tubuh atau imunitas manusia ada
yang alami dan spesifik
• Gizi seimbang untuk meningkatkan
keseimbangan imunitas tubuh
• Konsumsi makanan yang bergizi, imbang dan
beragam serta sehat  pola gizi seimbang