Dr' M' Balasubramanyam

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Diabetes In search of an integrated management
and multidisciplinary research
Dr. M. Balasubramanyam Senior Scientist balusignal
_at_gmail.com
Madras Diabetes Research Foundation Chennai, India
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Diabetes World Scenario
Top Three Countries in the world
Wild S et al, Diabetes Care, 2004 27 1047 -
1053
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Diabetes - what you see is a tip of the iceberg
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Insulin Secretion
Glucose
Beta Cell
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Insulin Secretion
phosphate
Glucose
-
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-
6
2

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ATP
SUR1
-
ADP
K

2
Kir
6.2
Ca
5
-
70
mV
mV
-
30

Depolarization
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Voltage
-
dependent
2
2
Ca
Ca
channel
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Insulin binding
Phosphorylation of Insulin receptor substrate(s)
Insulin
IR ? subunit
Phosphoinositol glycans (PIGs)
IRS -1 to IRS -6 SH2B APS Shc Gab1 CBL
Activation
P -
- P
PI 3 kinase
Active IR Tyrosine kinase (IRTK)
P -
IR ? subunit (intrinsic inactive kinase)
P -
- P
Akt / PKB
Atypical PKC
PDK1
Dephosphorylation of IR
? IRTK activation Autophosphorylation
Endogenous PTPase(s) SHIP2, PTEN, PTB1B
Inhibition
Vanadium compounds
Insulin Signaling
Down stream Insulin signalling through
recruitment of appropriate signal transducers
Desired insulin-mediated biological effects
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Current anti-diabetic agents and their actions
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Problems of Present Day Diabetic Treatments
Problems
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Tissues are Issues here !
MOLECULAR CROSS-TALK
LIVER
Glucose production
Glucose uptake and utilization
MUSCLE
Type 2 Diabetes
Insulin Resistance
Glucose uptake and utilization
FAT
Insulin secretion
PANCREAS
?-cell dysfunction
Cardiovascular risk
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Insulin resistance and ?-cell dysfunction are
core defects of type 2 diabetes
Rhodes CJ White MF. Eur J Clin Invest 2002
32 (Suppl. 3)313.
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How do insulin resistance and ?-cell dysfunction
combine to cause type 2 diabetes?
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Insulin resistance reduced response to
circulating insulin
Insulin resistance
Adiposetissue
Liver
Muscle
? Glucose output
? Glucose uptake
? Glucose uptake
Hyperglycemia
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Commonly used techniques to assess insulin
sensitivity
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Then, why a sub-set of patients get diabetic
complications despite good control?
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Hyperglycemic memory
? Persistence or progression of
hyperglycemia-induced microvascular alterations
during subsequent periods of normal glucose
homeostasis ? Most striking example is the
development of diabetic retinopathy in dogs
during a post-hyperglycemic period of euglycemia
? It appears that hyperglycemia-induced
mitochondrial superoxide production and increased
advanced glycation end products (AGEs) may
provide an explanation for the development of
complications during post-hyperglycemic periods
of normal glycemia
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Progression of incipient diabetic retinopathy
during good glycemic control Engerman RL and Kern
TS Diabetes (1987)
Dogs were maintained in euglycemic status for an
additional 2.5 years
Dogs were maintained in hyperglycemic status for
2.5 years
No Diabetic Complications
Diabetic Complications
Retinal capillary aneurysms and other lesions
representing incipient diabetic retinopathy
?????
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Glucose memory from CURES study!
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Why clinical trial outcomes with Vitamin E were
unconvincing and inconclusive?
? None of the antioxidant trials to date has
measured markers of oxidation to assess the
degree of oxidative stress ? Vitamin E works by
concentrating in lipid bilayers whereas many of
the oxidative reactions occur in cytosol
and intracellular levels ? Oral intake of
Vitamin E only modestly increases its plasma and
tissue levels ? Vitamin E can work as a
pro-oxidant and thereby participate in radical
chain reaction ? In most clinical trials,
intervention made on a established disease state
?

The absence of epidemiological data on oxidative
damage in human populations represents a serious
gap in our knowledge about the distribution,
correlates, and causative factors of oxidative
damage

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Glycemic Variability or Glycemic Excursions !
Do fluctuating blood sugar levels increase the
risk of developing diabetic retinopathy and other
vascular complications? Consider a patient with
five blood glucose readings measuring 105, 110,
115, 104, and 116 will have an average (or
mean) blood glucose level of 110 Another
patient with readings of 50, 170, 40, 230 and 60
will also have an average blood glucose of 110
Obviously, this second patient has a great deal
of more fluctuation in his readings than does the
first patient, and researchers now believe that
this sort of difference places our second,
hypothetical patient at considerably higher risk
for diabetic complications
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So What Is The Significance of the Understanding
of GV?

• it suggests that different therapeutic
  strategies now in use should be evaluated for
  their potential to minimize glycemic excursion,
  as well as their ability to lower A1c.
• wider use of real-time continuous glucose
  monitoring in clinical practice would provide the
  required monitoring tool to minimize glycemic
  variability and superoxide overproduction.

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Candidate Genes for Type 2 Diabetes its
Complications
PPAR-? PPARGC1A Adiponectin Resistin Uncoupling
proteins
Genes implicated in adipogenesis
Insulin receptor Insulin receptor
substrates Calpain-10 Glucose transporters
Genes implicated in insulin signaling
HNF-1? HNF-4? GCK IPF
Genes implicated in MODY
RAGE VEGF KDR Endostatin PEDF
Genes implicated in Diabetic retinopathy
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Biological function of T2DM candidate genes
arising from animal models and human association
studies
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Association of TCF7l2 Polymorphism( rs12255372)
with Type 2 Diabetes in Different Populations
p value for relative risk p value for Hazard
ratio for the TT genotype
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Genome-wide association studies provide new
insights into type 2 diabetes aetiology
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DNA Direct is now offering deCODE T2, a genetic
test that examines the presence of the T allele
of SNP rs7903146, located within the TCF7L2 gene
deCODE T2 is the first of several DNA-based
predisposition tests that are in development for
common diseases If the test is positive, ones
risk of developing type 2 diabetes is twice as
high as someone who does not have two copies of
the TCF7L2 gene variant Cost Several hundreds
of US !!!!!!
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Type 2 Diabetes Mellitus may result from a large
number of SNPs which impair modular domain
function and post-translational modifications of
proteins involved in signaling
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Post-translational modifications (PTMS)
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Skeletal muscle biopsy culturing and signaling
studies
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Human Skeletal muscle subjected to 2-D analysis
2D Gel Electrophoresis of human skeletal muscle
biopsy, pH 3-10, 18 Cm, 12 gel
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Translational Systems Biology

• Current state
• Extremely detailed information about highly
  simplified systems
• Simulations designed for in vitro validation
• omics information on clinically relevant
  situations, with no framework with which to
  interpret the data

• New approach
• Models structured for immediate translational
  utility
• Clinical trial simulations
• Diagnostics
• Rational drug design
• Basic insights are important but secondary
• Quantitative predictions

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Systems Biology at the Center for Inflammation
and Regenerative Modeling, McGowan Institute for
Regenerative Medicine
Research Biological Mechanisms
Develop Representative Models
Collect Biomarker Data
Calibrate Models to Data
Use Model for Predictions And Clinical Trial
Simulations
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Modeling Inflammation and Tissue Healing
(Dibetes Foot Ulcer)
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Novel PPAR-gamma Agonists Identified from a
Natural Product Library A Virtual Screening,
Induced-Fit Docking and Biological Assay
Study Chemical Biology Drug Design 2008
Peroxisome proliferator-activated receptor-gamma
(PPAR-gamma) plays an essential role in lipid and
glucose homeostasis. It is recognized as the
receptor of the thiazolidinedionesa synthetic
class of anti-diabetic drugsand is the target of
many drug discovery efforts because of its role
in disease states, such as type II diabetes
mellitus. In this study, structure-based virtual
screening of the PPAR-gamma ligand binding domain
against a natural product library has revealed 29
potential agonists. In vitro testing of this list
identified six flavonoids to have stimulated
PPAR-gamma transcriptional activity in a
transcriptional factor assay. Of these,
flavonoidpsi-baptigeninwas classed as the most
potent PPAR-gamma agonist, possessing low
micromolar affinity (EC50  2.9 µM). Further in
vitro testing using quantitative RT-PCR and
immunoblotting experiments demonstrated that
psi-baptigenin activated PPAR-gamma mRNA
(4.1  0.2-fold) and protein levels
(2.9  0.4-fold) in THP-1 macrophages. Moreover,
psi-baptigenins-induced PPAR-gamma enhancement
was abolished in the presence of a selective
PPAR-gamma antagonist, GW9662. Induced-fit
docking investigations provide a detailed
understanding on the ligands mechanism of
action, suggesting five of the active flavonoids
induce significant conformational change in the
receptor upon binding. Overall, these results
offer insight into various naturally derived
flavonoids as leads/templates for development of
novel PPAR-gamma ligands.
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Sample size for the whole country INDIA main
land 28
states 1 union territory has been calculated
using power calculations
INDIAB study
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Multi- and Interdisciplinary Research will be
Required to Solve the Puzzle of Complex
Diseases and Conditions
Genes Behavior Diet/Nutrition Infectious
agents Environment Society ???
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Molecular Medicine Lab
Hi Your score for risky biomarkers is very
high I am going to start therapy !
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Diabetes Needs Helping Hands !
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Acknowledgements
Dr. V. Mohan Dr. Rema Mohan Prof. P. Balaram,
IISc Dr. Utpal Tatu, IISc Dr. Tapas Kundu,
JNCASR R.Sampathkumar A.Adaikalakoteswari V.
Srinivasan V Sandhya Sameer Mohamed Finny
Monickaraj Aravind
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