What Functional Medicine tell you about:

DM

Dr. dr. Amarullah H. Siregar, FAARM, FAAM, FABC, DIHom, DNMed, MSc, MA, PhD
CCPG
BPPT, 20 September 2014

43rd European Association for the Study of Diabetes Annual Meeting

17 21 September 2007

Diabetes is the fourth leading cause of death globally

Diabetes is estimated to reduce life expectancy by
12-14 years

Diabetics are 2 to 4 times more likely to develop

CVD than people without diabetes
Diabetes accounts for 35-45 percent of new cases
of endstage renal disease each year
10-20% of people with diabetes die of renal failure

May 5 - May 16, 2014

Amarullah Siregar, MD, PhD, Thanks for joining us at the 2014

Preventing and Reversing Diabetes World Summit!
Type 1 diabetes
Type 2 diabetes
Gestational diabetes
Juvenile diabetes
Type 3 diabetes
Alzheimer's
Type 1.5 diabetes
Latent Autoimmune Diabetes of Adults and Glutamic Acid Decarboxylase
Diabetes insipidus
symptom of Langerhans cell histiocytosis
Diabetes LADA
Latent Autoimmune Diabetes of Adults
Diabetes MODY
Maturity onset diabetes of the young

May 5 - May 16, 2014

Amarullah Siregar, MD, PhD, Thanks for joining us at the 2014

Preventing and Reversing Diabetes World Summit!
Brittle diabetes
diabetes is difficult to control and an inability to feel an elevated

Cystic fibrosis related diabetes

clogs the body's organs with thick sticky mucus and leave sufferers

Double diabetes
Drug induced diabetes
Glucagonoma
a rare form of pancreatic cancer.

Hemochromatosis
iron-storage disease

Secondary diabetes
effect of diabetes

Steroid induced diabetes

Diabetes Mellitus
impaired insulin secretion
peripheral insulin resistance
hyperglycemia.
- polydipsia,
- polyphagia,
- polyuria.
DM type 1 Juvenile & IDDM
DM type 2 Adult & NIDDM

LADA marker
Glutamic acid decarbox
(GAD-65)
PTP-1B
IA-2 (IA-2)
Islet Cell Autoantibody
(ICAs)
Insulin Autoantibody,
(IAA)
C-peptide

Journal of Advanced Nursing Practice. 2008 Volume 10 Number 1.

PHENOTYPE MECHANISM

PHYSIOGENESIS PROCESS

Cross-talk
Insulin is secreted from
the -cells of the
pancreas in response
to elevations in plasma
glucose. The hormone
decreases glucose
production from the
liver, and increases
glucose uptake,
utilization and storage
in fat and muscle. The
fat cell is important in
metabolic regulation,
releasing FFAs that
reduce glucose uptake
in muscle, insulin
secretion from the cell, and increase
glucose production
from the liver. The fat
cell can also secrete
'adipokines' such as
leptin, adiponectin and
TNF, which regulate
food intake, energy
expenditure and insulin
sensitivity.

mIRNA

PTP1B

BIOMOLECULAR MECHANISM

complex life of mRNA in eukaryotic cells

mRNA synthesized as precursor
heteronuclear RNA (hnRNA)
require complex process
form mature mRNA .
hnRNA processing in the nucleus
bind mRNA with numerous RNA
messenger ribonucleoproteins
(mRNPs).
Nuclear export of mRNPs
delivery of fresh mRNA transcripts
to cytoplasm for translation and
protein synthesis.
mRNPs stored in cytoplasmic RNA
act as regulated reservoirs
dictate metabolic conditions
translate activation or degradation

microRNAs (miRNAs)

key regulators
of
mRNA

Translational control
mechanisms in
cellular metabolism.

Am J Physiol Endocrinol Metab 2011;301:E1051-E1064

GENOTYPE MECHANISM

Metabolic alterations in diabetes

mellitus increase the generation of
microRNA (miRNA) and causes
translational repression or
degradation of mRNAs that encode
proteins needed for the endothelial
required for angiogenesis.

Circulation. 2011;123:236-238

mIRNA in insulin secreting cells

(pancreatic cells)

Normal condition
- following feeding: insulin produced in -cells
after release : reach target tissues (muscle, liver & adipose)
cause uptake of glucose,
reduce the production of glucose
activate fat production and storage.
MicroRNAs (miRNAs) affect insulin signalling
- miR-124a and miR-34a involved in pancreatic development
effects on: - FOXO2 (forkhead box protein O2),
[Transcriptional activator which triggers apoptosis]

- RAB27A (Ras-related protein Rab-27A)

[instructions for making a protein for membrane trafficking]

- VAMP2 (vesicle-associated membrane protein 2)

[participate in neurotransmitter release]

- and BCL-2 (B cell lymphoma 2).

[cause immune unresponsiveness related to apoptosis]

- miR-29, miR-9 and miR-375 involved in insulin secretion

miR-29 activates insulin secretion,
miR-9 and miR-375 inhibit insulin secretion
acting through:
- MCT1 (monocarboxylate transporter 1)
[facilitates bidirectional monocarboxylic acid transport across
membranes]
- OC2 (one cut homeobox 2),
[binds to specific DNA sequences and stimulates expression]
- SIRT1 (sirtuin 1),
[regulate epigenetic gene silencing and suppress of rDNA]
- PDK1 (phosphoinositide-dependent kinase 1)
[signalling pathways activate by growth factors and hormones /IGF]
- and MTPN (myotrophin).
[regulation of the growth of actin filaments, NfkB and protein complex]
Nature Reviews Molecular Cell Biology 13, 239-250 (April 2012)

- miR-33, miR-34a, miR-29 and miR-143 act in the liver

(on targets involved in insulin signalling and its regulation)
acting through:
- IRS2 (insulin receptor substrate 2)
[mediates effects of insulin, IGF-1, and other cytokines]
- SIRT6,
[modulation of aging and other metabolic functions]
- AMPK1 (AMP-activated protein kinase- subunit 1),
[energy sensor protein kinase; role in regulating cellular energy]
- SIRT1,
[biological functions and characterized in metabolism]
- PIK3R1 (phosphatidylinositol 3-kinase subunit-)
[important role in the metabolic actions of insulins]
- and ORP8 (oxysterol-binding protein-related protein 8).
[sterol sensors that regulate the assembly of protein]
Nature Reviews Molecular Cell Biology 13, 239-250 (April 2012)

- Insulin signal in adipose modulated by miR-103 & miR-107

through CAV1 (caveolin 1)
[act as scaffolding proteins within caveolar membranes by compartmentalizing
and concentrating signaling molecules]
- miR-29 through INSIG1 (insulin-induced gene 1) and CAV2.
miR-29, let-7 and miR-223 miRNAs
act in muscle to modulate insulin signalling
- IGF1R (insulin-like growth factor receptor 1),
[Changes in glucose and insulin secretion result in counter-regulatory]
- INSR (insulin receptor)
[plays a key role in the regulation of glucose homeostasis]
- IRS2(Insulin receptor substrate 2)
[mediates effects of insulin, IGF-1, and other cytokines]
- glucose uptake GLUT4 (glucose transporter type 4).
[responsible for insulin-regulated glucose disposal]
Nature Reviews Molecular Cell Biology 13, 239-250 (April 2012)

 A microRNA (abbreviated miRNA)

small non-coding RNA molecule

(containing about 22 nucleotides)
transcriptional and post-transcriptional regulation

Encoded by eukaryotic nuclear DNA

function via base-pairing
no longer translated into proteins by ribosomes

actively disassembled by cell ("target degradation")

Human genome may encode over 1000 miRNAs
miRNAs well conserved in eukaryotic organisms

be a vital of genetic regulation.

 Plant miRNAs near-perfect pairing mRNA

induce gene repression
may bind their targets in both coding
miRNA revealed multiple roles
in negative regulation (transcript
degradation and sequestering,
translational suppression)
in positive regulation (transcriptional
and translational activation).
affecting gene regulation,
miRNAs are likely to be involved in most
biological processes.
Different sets of expressed miRNAs are
found in different cell types and tissues.

NATUROCEUTICAL
Molecular
Sites of action
TARGET
TARGET

TARGET TREATMENT FOCUS ON

DPP-4 INHIBITION
Oral glucose
stimulates
release of
Incretins
(GLP-1 & GIP)

DPP-4 rapidly
degrades incretin

NATUROCEUTICAL

inhibit DPP-4 to
increase active
incretin

NATUROCEUTICAL
DPP-4 (Gliptin): enzyme which destroys the hormone incretin
Incretins help the body produce more insulin

Medscape Education Diabetes & Endocrinology

CME Released: 06/30/2009

Low blood
Glucose

High blood
Glucose

ALGORYTHM
OF DIABETIC CARE

Glucose
from intestine

DPP4: Dipeptidyl Peptidase-4

GLPI: Glucagon Like Peptide-1

Glucagon release

Liver release
Glucose to blood

Insulin release

Fat & Muscle cell

remove Glucose from blood

Sites of action of the current and possible therapy

Hepatic glucose
output

Appetite control
Energy used

Lipotoxicity

Insulin & Glucagon

secretion

Glucose
reabsorption

Uptake
&
Utilization
Glucosidase

Nutrients for Blood Glucose Control: A Review and Clinical Guide. October, 2013

Diabetes 59.9 (2010): 2134-2144.

Research discoveries

References

Methode

Result

Int J Prev Med.

Aug 2012; 3(8):
531536

Cinnamon
DB RCT

T2DM

miRNA
HbA1c
Metabolic

S+

J Med Food. 2012

Feb;15(2):101-7.

Charantin
in-vitro

Induced

ADMc-1
AMPK
PTP-1B

S+

Journal of Diab
Res (2014),
Article ID 862473

Chromium
in-vitro

Induced

miRNA
HOMA-IR
PTP-1B

S+

J Ethnopharmacol.
2009 Nov 12;126(2):
339-44.

Gymnema
DB RCT

T2DM

C peptide
Cytosolic
HbA1c

S+

J Endocrinol. 1990
Sep;126(3):451-9

Vanadium
RCT

T2DM

Insulin
miRNA
HbA1c

S+

References

Methode

Result

Ann Intern Med.

2004 Jan 6;140(1):
1-8

Green coffee
RCT

T2DM

HbA1c
Insulin

S+

J Biosci. 2011
Jun;36(2):383-96

Fenugreek
RCT

T2DM

HbA1c
Insulin
GLUT

S+

J Clin Invest.
Oct 15, 2001;
108(8): 11051107

Galega
in vitro

Induced

AMPK
Glucagon
HMGCoA

S+

Endo Metab Imm

Lipoic
Disord Drug Targ. RCT
2009 Dec;9(4):392-8

T2DM

Insulin
HbA1c
ANA

S+

Eur J Biochem.
2002 Feb;269(4):
1050-9.

T2DM

HOMA-IR
PTP-1B
LAR

S+

Banaba
RCT