Research Interest My Laboratory is involved in
studying cell and molecular signatures with special reference to insulin
secretion, insulin action and vascular function. Our research integrates
physiological and pharmacological approaches with biochemical, molecular
biological and proteomics techniques to study mechanisms underlying development
and progression of diabetes, its complications and cardiovascular diseases.
This challenging multi-disciplinary research specialization dwells around the
following themes: Insights into biochemistry and
molecular biology of diabetes and its
vascular complications by studying nutrient-sensing pathways, redox signaling,
advanced glycation end products, calcium signaling and epigenetic mechanisms. Investigating the role of
organellar dysfunction (Endoplasmic reticulum (ER) stress and mitochondrial
mess) in insulin resistance and Type 2 diabetes utilizing the target tissue
specific (skeletal muscle, adipose, β-cell) microarray, proteomics, siRNA and
epigenetics studies. Bio-prospecting biomarker(s)
potential in body fluids and tissue biopsies (human skeletal muscle and
adipocytes) adapting to proteomic tools and identification of
prediabetes/diabetes/diabetic complications-specific molecular fingerprints and
protein post-translational modifications. Studying telomere biology and
test whether shortening of telomeres are related to inter-individual
differences in biological ageing that predisposes one to ‘lifestyle diseases’
and serve as a long-term biomarker. Demonstration of oxidative stress
as a therapeutic target, testing natural products (herbals, marine resources)
from the Indian biodiversity for their molecular actions beyond antioxidant
property and validation of their utility as novel insulin secretatgogues/insulin
sensitizers/vascular protectants. The department now serves as an
excellent 'interface' for biomedical/biotechnology/biopharmaceutical work with
translational applications. The goal of the department is set to evolve as a
‘Centre for Cellular and Molecular Medicine’ (CCMM) with state-of-the-art
facilities for preclinical research, biomarker(s) identification,
high-throughput cell-based assay systems, and to offer world-class contract
research and consultancy work in the areas of specialization. Important Findings One of the thrust areas of
research at the Madras Diabetes Research Foundation (MDRF) is to use the
biochemical and proteomic technologies for identifying novel biomarkers and
drug targets in the development and progression of diabetes and its associated
complications. In the sub-set of subjects from CURES, we have shown elevated
oxidative reactions (Sampathkumar et al 2005) and increased advanced glycation
end products (AGEs) (Sampathkumar et al 2004) in patients with Type 2 diabetes
and its vascular complications. Related to oxidative damage, our pilot
observations indicated that there was increased lipid and protein oxidation as
early in the stage of impaired glucose tolerance (prediabetes). In addition, we
have seen telomere shortening in prediabetes subjects and patients with Type 2
diabetes (Adaikalakoteswari et al 2005; Adaikalakoteswari et al 2007), arising
either from a cumulative burden of oxidative stress and/or other
phosphorylation or epigenetic post-translational mechanisms. Another study
(Adaikalakoteswari et al 2007) has demonstrated an association of oxidative DNA
damage with PARP and NFkB activation, indicating a role for poly
(ADP)-ribosylation in the pathogenesis of Type 2 diabetes. Moreover, a role for
oxidative stress in diabetes patients was also substantiated with differential
expression of NADPH oxidase and hemoxygenase gene (Adaikalakoteswari et al
2006). While these effects have been studied by classic biochemical and
molecular biology methods, the recent onset of proteomics methods are expected
to allow studying oxidative stress responses on a much wider scale with more
emphasis and focus on identification of biomarkers. In this direction, in
collaboration with Indian Institute of Science, Bangalore, we have recently identified
increased positivity for glutathionylated hemoglobin (HbSSG) as a specific
biomarker in diabetic patients with microangiopathy (Sampathkumar et al 2005b). As a prerequisite to study the
proteomics & genomics of Type 2 diabetes, we have standardized in-house,
the culturing of human skeletal muscle cells (HSMCs). Since insulin resistance
of skeletal muscle primarily results from impaired glucose uptake and glycogen
synthesis, these two metabolic read-out assays were first standardized in HSMCs
(Balasubramanyam, 2006). The fact that defects in these metabolic read-outs are
persisted in culture conditions of HSMCs obtained from patients with Type 2
diabetes, indicates that these cells are an excellent model system to study the
proteomics & genomics of Type 2 diabetes. From the clinical proteomics
view, our pilot studies also indicated protein spots with region-specific
differences in plasma samples of subjects exhibiting varying degrees glucose
tolerance. Other interesting studies which
yielded preliminary data include: convergence of ER stress and insulin
resistance in L6 skeletal muscle cells, palmitate-inudced impairment of
multimerization of adiponectin in 3T3 adipocytes, characterization of a novel
PTP inhibiting activity in prodigiosin, etc. As a part of the NMITLI diabetes
project on herbal medicine, both curcumin and gallic acid have been extensively
studied and scientifically documented for their specific molecular actions.
Gallic acid has been shown to possess novel (hitherto unknown) actions at the
interface of transcription factors, membrane transport, down regulation of
oxidants and upregulation of antioxidant enzymes etc. Specialized Training Dr.M.Balasubramanyam is a member
of the Asia-Pacific International Molecular Biology Network (A-IMBN) and had an
extensive post-doctoral training (1991-95) at the Hypertension Research Centre,
New Jersey Medical School, USA, in the areas of signal transduction in health
and metabolic diseases with special reference to molecular pathogenesis of Type
2 diabetes and vascular biology. Under the Scientific Investigator
training programme at AIIMS, New delhi,
he has learned both basic and advanced applications of Electron Microscopy
techniques. He is well-versed with transport assays, fluorescence imaging
techniques and flowcytometry applications. In the year 2003, he has visited the
University of San Diego and learned techniques related to human skeletal muscle
and adipose tissue culturing, differentiation protocols, and he is well-versed
with the insulin signaling assays such as, glucose uptake, lipolysis, tyrosine
phosphorylation, PTP inhibition, glycogen synthase activity, lipid
accumulation, palmitate oxidation etc. Dr.Balasubramanyam has
participated in several training programmes of frontier technologies including
microarray, siRNA, 2-Dgel electrophoresis and mass spectrometry and his team is
actively collaborating with Indian Institute of Science (Prof.P.Balaram &
Dr.Utpal Tatu) on body fluid and tissue proteomics profiling. He is
instrumental in setting up the basic science infrastructure in MDRF and with
his efforts the tissue culture facility at MDRF is now fully tuned to conduct
research on target-specific cells such as human skeletal muscle cells, human
retinal endothelial cells, 3T3-L1 adipocytes, L6 muscle cells, THP-1 monocytes
and RINm5F. The training offered at this department is considered unique in
that it is tailor-made for the students of biotechnology and pharmaceutical
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