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Sonam Chawla et al.

/ Journal of Pharmacy Research 2011,4(4),1118-1123

Review Article
Available online through
ISSN: 0974-6943 www.jpronline.info
Type 2 diabetes in the wake of Insulin Resistance: Molecular etiology and therapeutics
Sonam Chawla* , Deepesh Gupta, Archana Tiwari
School of Biotechnology, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Airport by-pass Road, Bhopal, Madhya Pradesh - 462033, India.
Received on: 05-12-2010; Revised on: 14-01-2011; Accepted on:09-03-2011
World-wide recognition of type 2 diabetes as an epidemic is a reality, despite the immense research, yielding in an increasingly complex signaling pathway network and consequent target-
specific sanative agents. The pathogenesis studies point to dual defect of insulin resistance in our body & insulin secretion by pancreatic cells. Herein, we discuss the central glucose-insulin
axis and the recently established signaling cascades from lipid metabolism in context of free fatty acids and the white adipose tissue, to delineate the molecular causes of insulin resistance.
Current pharmaceutical scenario target PPARs (Peroxisome Proliferator Activated Receptors) for insulin sensitization using thiazolidinediones, but recently these drugs have been amidst
controversy; PTP1B, a protein tyrosine phosphatase, offers hope in this case, its inhibition being restorative to the distorted insulin signal. These two strategies are discussed encompassing
their molecular action, current molecules being pursued and their future as a drug target. Herbal therapeutics though popular in masses lack the basis in terms of molecular players influenced
and this deficiency is illustrated, urging for research endeavors in this direction. Lifestyle modifications such as dietary restrictions and adoption of exercise are reported from a molecular

Key words:Anti-diabetic therapies; herbal therapeutics; Insulin resistance; PPAR; PTP1B; type 2 diabetes mellitus

Diabetes has been recognized by United Nations Assembly as a chronic, debilitating and Herein we begin by accounting for the molecular strays responsible for the defective insulin
expensive disease in resolution 61/225 passed on 20 December 2006. This resolution recog- signals i.e. insulin resistance in context of type 2 diabetes.
nizes diabetes as a global epidemic, leading to expenditure, high risk of cardiovascular
diseases, mortality, disabilities occurring from end stage retinopathy, nephropathy & limb 1.Pathogenesis of Insulin Resistance
wastage [1]. With a mortality rate equivalent to that of HIV-AIDS i.e. about 6% of total global Insulin resistance is defined as a reduced responsiveness of the insulin targeted organs to
mortality, we have amidst us a serious problem. The economic burden of this disorder is normal circulating levels of insulin in the plasma. It is a commonly observed feature in
projected to exceed US $ 302.5 billion, with appreciating treatment costs far exceeding the prediabetes conditions like impaired glucose tolerance and impaired fasting glucose, obe-
growth rate of world population [2]. sity, type 2 diabetes mellitus, certain other endocrinopathies as well as in cancer, infections and
autoimmune diseases. Interestingly, diabetes does not ensue in all people suffering from insulin
resistance. Impaired glucose tolerance progresses to type 2 diabetes mellitus when the beta
cells fail to compensate for peripheral insulin resistance by producing more than the usual
amounts of insulin. Hyperinsulinemia prevails in early stages of type 2 diabetes mellitus with
a progressive decline in insulin levels as the beta cell function is impaired due to exhaustive
production [4, 5]. A birds eye view of this disorder is summarized in figure 1.

2.1 Glucose-Insulin Axis

Insulin, an anabolic hormone, has varied functions involved in glucose & lipid homeostasis,
tissue growth and development. It is secreted from beta cells in response to elevated blood
glucose and amino acid levels. Metabolic control via insulin is mediated by tissue specific
actions like phosphorylation of involved proteins, changes in protein function, and differential
gene expression. Pathophysiology of type 2 diabetes mellitus, in light of insulin resistance,
involves pancreatic beta cells, liver, skeletal muscles, adipose tissue. A coupling of stimulus
(post-prandial higher blood glucose) and secretion (of insulin and suppression of glucagon) is
used by our bodies to maintain the plasma level of glucose around 5mmol [5, 6, 7]. The
mechanism of glucose-stimulated insulin secretion by cells is depicted in figure 2.

Figure 1 Bird's eye view of Insulin resistance and it's implications: Overview of homeostatic
insulin action and pathological defects in insulin signaling pathway culminating into Type 2
Diabetes Mellitus

Type 2 diabetes mellitus has rightly been described as a snake in the grass sneaking up on
afflicted and their physicians, as the disease progresses slowly without any noticeable symp-
toms and sudden but late diagnosis [3]. It accounts for 85%-95% of all diabetes. The gravity
of type 2 diabetes mellitus and its global implications with reference to health and economic
growth have led to various research programs and interventions. There is a volume of literature
available on the key molecular pathways which mar the homeostatic state of glucose and lipid
metabolism in conjunction with a subjects environment, triggering the manifestation of type
2 diabetes mellitus. The essence of these pathways holds peripheral insulin resistance (adipose
tissue and skeletal muscles) as the prime defect, setting in the larger implications of type 2
diabetes i.e. secretory defects of beta cells [4].

*Corresponding author.
Sonam Chawla Figure 2. cells of pancreas respond to high plasma glucose levels by secreting insulin.GLUT2
School of Biotechnology, transporter on the cells' membrane has a high Km and Vmax allowing rapid equilibration
Rajiv Gandhi Proudyogiki Vishwavidyalaya, of glucose on both sides of membrane. Glucokinase facilitates phosphorylation of glucose
Airport by-pass Road, Bhopal, and it's diversion into Glycolysis cycle,this is a key step in defining the glucose stimulated
Madhya Pradesh - 462033, India. insulin secretion [6].
Fax: 0755-2742006
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Sonam Chawla et al. / Journal of Pharmacy Research 2011,4(4),1118-1123
The released insulin binds the insulin receptor (IR). IR is a trans-membrane hetero-dimer of An increase in WAT biomass in the body, leads to display of inflammatory symptoms due to
two alpha and two beta subunits held by disulphide bonds. Two isoforms of IR are known - secretion of TNF a (tumor necrosis factor alpha), IL-6 (interleukin-6) and other cytokines from
IR-1 and IR-2, having varying affinities for binding insulin to their extracellular domain. This activated macrophages which form giant cells in obese mammals [16]. An important adipokine,
varying affinity for insulin though provides an attractive basis of insulin resistance, remains leptin, secreted in proportion to adipocyte biomass and nutritional status of the body, has
experimentally controversial. The binding of insulin brings about auto-phosphorylation of 3 important implications in energy homeostasis [17,18].
tyrosine residues in the regulatory domains and an enhanced tyrosine kinase activity. The
intracellular domains then phosphorylate insulin receptor substrate-1(IRS-1). IRS is an adap- Several of the adipokines have been accused of pathogenesis of obesity related-insulin resis-
tor protein with 4 isoforms, of which IRS-1 and IRS-2 are implicated in glucose homeostasis tance and eventually type 2 diabetes mellitus. TNF a interferes with insulin secretion as well
and type 2 diabetes mellitus [8,9]. In a study conducted on Wistar rats, a knockdown of IRS- as signaling [19]. Essentially, TNF a deranges insulin signaling by interfering with the
1 was achieved by administering antisense oligonucleotides over a period of 3 days. The rats phosphorylation of IR, IRS, and protein phosphatase-1. The stimulatory auto-tyrosine phos-
showed hyperinsulinemia, increased visceral adiposity, and insulin resistance mediated by phorylation of IR and downstream activation of IRS by tyrosine kinase activity are repressed
diminished phosphorylation of IR, IRS-1, and Akt (downstream signaling protein) [10]. IRS- on co-incubation of adipocytes with TNF a. The deactivating role of TNF a on tyrosine
1 is the major docking molecule in the normal state but in case of diabetic patients, expression phosphorylation is thought to be mediated via altered expression patterns of SH-PTP2 (Src
of IRS-1 is lowered and IRS-2 becomes the docking site. The major difference in IRS-1 and homology 2 protein tyrosine phosphatase), a protein tyrosine phosphatase [20, 21, 22, 23].
IRS-2 is the quantity of insulin required for activation; IRS-2 requires higher levels of insulin
for acting like a docking site [8,9]. Thus, we can conclude a crucial role as an interface between TNF also stimulates serine phosphorylation of IRS-1 (inhibitory in nature) via deactivation
insulin signaling and downstream responses for IRS. of serine phosphatases or activation of serine kinases. Serine phosphorylation of IRS-1 is
hindrance to its stimulatory tyrosine phosphorylation by interaction with the juxtamembrane
IRS-1 on phosphorylation looses its affinity for juxtamembrane domain of IR, and migrates to domain of the IR, in addition to triggering the degradation of IRS-1. Also, elevated serine
meet PI3-K (Phosphatidylinositol 3-kinase). PI3-K (isoform P110/p85) triggers a down- phosphorylation of IRS-1 is inhibitory for tyrosine kinase activity of IR. Such discrepancies
stream phosphorylation/ dephosphorylation cascade involving generation of PIP2 (Phosphati- in the phosphorylation status of key signaling proteins impair insulin signaling pathway [23,
dyl-inositol 4,5-bisphosphate) and PIP3 (Phosphatidyl-inositol 3,4,5-triphosphate). PIP3 ac- 24, 25, 26, 27]. Moreover TNF a suppresses the expression of GLUT4 transporter, as well as
tivates PDK1 (3-phosphoinositide dependent kinase-1), which in turn activates Akt/protein IR and IRS-1 to a lesser extent, and therefore interfering with insulin-mediated glucose
kinase B. Akt has varied effects on protein synthesis mediated by mTOR/RAPTOR (mam- transport [28].
malian target of rapamycin/ regulatory associated protein of mTOR), increases lipogenesis via
SREBP-c (sterol regulatory element binding protein-c), decreases hepatic gluconeogenesis, The molecular influence of IL-6 in pathogenesis of insulin insensitivity is observed to occur
raises glycogen synthesis via deactivation of glycogen synthase kinase-3, Akt also activates by a diminished tyrosine phosphorylation of IRS-1, interference in association of IRS-1 and
transcription factors belonging to Foxo family which activate genes involved in glycolysis and PI3-K and suppression of insulin-dependent Akt activation. IL-6 has also been seen to trim
gluconeogenesis. PDK and Akt enhance GLUT4 (Glucose Transporter4) mediated glucose down the activity of lipoprotein lipase in vitro & in vivo, lipoprotein lipase being responsible
uptake [8,9]. Any of the above listed proteins and their downstream targets can be held for rate-limited hydrolysis of triglyceride-rich lipoproteins [29, 30, 31, 32].
responsible for erroneous insulin signaling either via defective quantitative or qualitative
expressions. The morbid role of adipose tissue in implicating type 2 diabetes mellitus thus requires that it
be explored for the entire spectrum of adipokines and probed with functional analysis for
Protein tyrosine phosphatase 1B (PTP1B) has a critical role in regulating the above insulin assignment of role in pathogenesis of insulin resistance. The series of activation of various
signal. The expression of this phosphatase is observed to be increased in diabetes, and proteins and cross-talk with other pathways should be delineated for pin-pointing the links
functioning as a negative regulator of insulin signaling pathway it has been implied to play a between obesity and insulin resistance.
role in insulin resistance [5]. 2.Therapeutics Strategies against Insulin Resistance
We can now comprehend the complex biochemical and molecular interactions among the
Glucose-insulin axis has been researched over the years, but emerging evidences linking various proteins involved in pathogenesis of insulin resistance. Deficits in insulin action can
visceral obesity, and symptoms of dyslipidemia and elevated concentrations of free fatty acids hence be rectified by use of small molecule modulators of the involved protein for regulating
(FFA) strongly point towards involvement of discrepancies of lipid metabolism in type 2 its quantity and/or activity for a therapeutic response.
Current anti-diabetic therapies are centered on glycemic control. Initial phase of treatment
2.2 FFA and Insulin Signaling regimen involves monotherapy, but at later stages this scheme fails due to defective insulin
FFAs have been postulated to play a role in begetting insulin resistance. It has been experimen- secretion. Hence, combination therapies implying increased insulin action or enhanced insulin
tally observed by researchers that elevated plasma FFA has association with insulin resistance, secretion or mimetic of insulin secretion are employed.
specifically insulin-stimulated glucose uptake, in experimental animals as well as in humans
[11,12]. Randle hypothesis proposed in 1963 speculates a competitive mitochondrial oxida-
tion for FFA and glucose. A high plasma concentration of FFA increases transporter mediated
uptake of FFA into the cell which is oxidized in the mitochondria. The oxidation products
raise the ratio of [acetyl-CoA]/[CoA] and [NADH]/[NAD+] in the mitochondria. These high
ratios inhibit pyruvate dehydrogenase that eventually causes diminution of glycolysis due to
accrual of citrate. In time, glucose uptake is dwindled in the myocytes. An alternative
hypothesis suggests inhibited activities of GLUT4 to transport glucose into muscles [13].

Raised plasma FFA modulate insulin signaling cascade via mounting up of FFA metabolites
like diacyl glycerol, fatty acyl CoA, ceramide etc, which set off protein kinase C theta (PKC
). PKC interferes with insulin resistance through inhibitory serine phosphorylation of IRS-
1 and prohibiting its association with PI3-K to trigger downstream insulin response elements
involving uptake as well as metabolism of glucose [14,15].

Summarily, the high plasma FFA needs to be tackled for effective management of insulin
resistance. Protein targets involved in activation of lipolysis and release of FFA from liver or
adipose tissue can be modulated in activity or quantity for maintenance of normal plasma FFA
concentration. Modulators of PKC activity shall also serve the therapeutic purpose.

2.3 Adipokines and Derangements of Insulin Signaling

Adipose tissue is the focal point of several investigations due to the observations linking
obesity (excess adipose tissue) and insulin resistance. The earlier status of adipose tissue only
as a passive energy storage organ has undergone a shift, it is now recognized that adipose tissue
secretes proteinaceous bioactive hormones known as adipokines. These adipokines function at
autocrine, paracrine and endocrine levels with respective roles in energy homeostasis and other
processes. The adipose tissue found in a mammalian body is of two types brown adipose
tissue (BAT) & white adipose tissue (WAT). Of the above, WAT is the pre-dominant type of
adipose tissue in mammals, composing of adipocytes encased in vascularized and enervated
connective tissue [16,17].

Figure 3. The current anti-diabetic therapeutic strategies are anchored to effective glycemic
control via various mechanism,as depicted in the figure.

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Sonam Chawla et al. / Journal of Pharmacy Research 2011,4(4),1118-1123
The oral therapeutic molecules can be broadly classified as, as in figure 3, insulin secreta- combination therapy with sulphonylureas or metformin. Profiled side effects of rosiglitazone
gogues (increasing insulin release from beta cells) e.g. sulphonylureas, meglitinide analogs, include respiratory tract infection, headache, edema, weight gain, and increased LDL (low
K+ channel openers, imidazoline compounds, insulin sensitizers (enhance insulin action) e.g. density lipids) cholesterol concentrations [43]. Pioglitazone, has been shown to improve
agonists of PPARs (peroxisome proliferator activated receptors) or molecules which modulate peripheral and hepatic insulin insensitivity, but has no role in prevention of insulin insensitiv-
the activity of proteins exerting negative pressure on insulin signal e.g. PTP1B inhibitors, ity as a consequence of exposure to non-esterified fatty acids [44]. Recently, rosiglitazone has
hormone analogs of amylin or glucagon-like-peptide1(GLP-1) - exendin 4, molecules sup- been shown to increase the risk of myocardial infarction and death from cardiovascular related
pressing hepatic gluconeogenesis e.g. metformin, or inhibiting intestinal glucose uptake e.g. causes by 43%. This has caused Food & Drug Association, USA, to issue warning about the
alpha glucosidase inhibitors and oral insulin itself. These therapies have noteworthy mecha- usage of Avandia [45].
nism based side-effects, limited efficacy and tolerability. Moreover, most of these therapies are
associated with weight-gain [32, 33, 34, 35]. Broadly, TZDs mediate insulin sensitizing effects by stimulating adipogenesis to increase
WAT biomass and prevent circulating FFA, down-regulate insulin desensitizing adipokines
Insulin insensitivity being the stepping stone to gravities of full fledged type 2 diabetes, such as TNF a, IL-6, leptin, plasminogen activator inhibitor-1 etc. Adiponectin, an adipokine,
insulin sensitizers are hence important therapeutic molecules. Two different strategies of expression is stimulated by transcriptional activation, eventually leading to lowered blood
insulin sensitization PPAR agonism and PTP1B inhibition are discussed here, the prior glucose levels. Certain other proteins expressed in adipose tissue implicated with low expres-
representing the present and latter a suggestion for future. Both strategies are yet to realize their sion rates in insulin resistant states are also upregulated e.g. c-Cbl associating protein [8].
full potential and are a challenge for molecular biologists and drug designers. Also, TZDs up regulate the GLUT4 transcription rate and its translocation to the cell surface,
increasing glucose uptake by the peripheral tissues [46].
3.1 PPARs as Therapeutic Targets
PPARs belong to nuclear receptor super family, acting as ligand activated transcription factors. Fibrates are another important class of PPAR agonists, activating PPAR alpha. Fibrates are
These ligands essentially activate transcription factors which are involved in regulating several employed to deal with dyslipidemia associated with type 2 diabetes mellitus. They mediate
genes responsible for lipid metabolism and factors associated with events downstream of their effects via enhancing lipoprotein lipase (LPL) activity and decreasing the expression of
insulin binding to its receptor, hence classified as insulin sensitizers [35, 36]. Since their apo III which is an endogenous inhibitor of LPL. They stimulate uptake of FFA and storage,
discovery in 1990 PPARs have been explored as potential anti-diabetic and anti-obesity agents enhance beta-oxidation of fatty acids and suppress fatty acid biosynthesis in the liver. Fibrates
[37]. The PPAR family consists of 3 members PPAR alpha, PPAR beta/delta, PPAR bring about a change in the quality of low density lipids by shifting towards HDL (high
gamma, each coded for by respective individual genes [38]. density lipids) from VLDL (very low density lipids) [47].

PPAR beta/delta, though neglected over the years, can serve as a valid and multifaceted drug
target in alleviation of insulin resistance and defective islet function. It is the most widely
expressed PPAR in the metabolically active tissues skeletal muscles, and controls the fate of
fatty acids & glucose in muscles as well as adipose tissue [48, 49, 50]. GW501516 developed
by GlaxoSmithKline, USA, is the most well characterized PPAR beta/delta agonist used in
various investigations [51]. GW501516 essentially activates PPAR beta/delta and AMPK
(AMP-activated protein kinase) in a PPAR delta - dependant and independent mechanisms to
enhance glucose uptake by myocytes and fatty acid uptake followed by oxidation [52].
Moreover, PPAR beta/delta stimulation by GW501516 has been observed to block the
excessive production of IL-6, and add to the therapeutic potential of this orphan receptor [53].
Several advancements in PPAR based therapeutic strategies include use of PPAR alpha/PPAR
gamma dual agonists, selective PPAR modulators (SPPARM), and PPAR antagonist.

PPAR alpha/gamma dual agonists combine the salutary effects of stimulation of PPAR gamma
by TZD to remediate insulin insensitivity and PPAR alpha by fibrates to cope with dyslipidemia.
These dual agonists belonging to glitzar class of drug molecules are in phase II and III clinical
trials. Ragaglitazar, muraglitazar, tesaglitazar are among the popular dual agonists, which
confer invigorating consequences by decreasing triglycerides and total cholesterol, raising
concentrations of high-density lipids, thereby diminishing insulin insensitivity. Their use,
though, has been suspended due to various safety issues ranging from mild side-effects like
weight gain & edema to grave complications like carcinogenicity, erroneous glomerular
filtration, anemia or leucopenia etc. [39, 54]. Muraglitazar was demonstrated to increase risk
of cardiovascular complications in patients prescribed this drug and hence its FDA approval
Figure 4. Peroxisome Proliferator Agonist Receptor has three isoforms-alpha(),gamma
() delta/beta (/). Each isoform has a distinct tissue distribution-PPAR is highly was suspended [54, 55]. A solution to deal with the ill-effects of the dual-agonist can be design
expressed in liver,heart,PPAR is highly expressed in adipose tissue,skeletal muscles,liver, of such molecules which stimulate PPAR alpha and PPAR gamma to equal extent and not
PPAR/ is uniformly distributed across the body with highest expression in keletal featuring higher proximities for any one receptor. As in case of muraglitazar, there was higher
muscle,intestines, brain, spleen, macrophages, lungs,adrenal glands [41,43] 3D structures affinity for PPAR gamma and in case of tesaglitazar an enhanced binding potentiality was
from RSCB PDB-PDBID 2ZNP,3K8S,3ET1 observed for PPAR alpha. Certain other dual agonists with co-stimulatory activities for PPAR
In cytosol, the PPAR is bound by chaperon proteins, holding the receptor in a conformation alpha/ delta and PPAR alpha/delta/gamma are also under development to deal with cardiovas-
permitting association with ligands, on availability. The ligands are usually hydrophobic and cular complications in diabetic patients. Benzafibrate is the first clinically tested pan-PPAR
translocated across the extra-cellular and intracellular fluids via iLBP (intracellular lipid alpha/gamma/delta agonist [56].
binding protein) by diffusion. Ligands of these diverse receptors can be naturally occurring
long-chain fatty acids or eicosanoids, or synthetic ligands developed for remedial measures. SPPARM is based on the hypothesis that each chemical ligand binding the LBD (ligand-
On encountering PPAR in cytosol a short-lived complex is generated which eventually sheds binding domain) of PPAR receptor brings about a distinct conformational change in the
the iLBP and the ligand is now held by the PPAR. The ligand bound PPAR hetero-dimerizes receptor, which eventually influences the transcriptional co-activators recruited. The net effect
with RXR (retinoid-x-receptor), unlike the other steroid receptors which are functional as of the above is a subtle difference in the extent of activation of target genes. nTZDpa is a partial
homodimers. RXR also has three isoforms alpha, beta and gamma, activated by endogenous agonist of PPAR gamma as established from in vitro studies, conferring limited conforma-
ligand 9-cis retinoic acid. It has been observed that ligands of RXR can also deactivate/activate tional stability to the receptor. When administered in vivo nTZDpa amends glycemic control
the PPAR-RXR complex and be explored as possible regulatory molecules. PPAR-RXR and insulin insensitivity without displaying ill-effect associated with a full agonist AD-5075
heterodimer now recruits suitable transcriptional co-activators, to bind the PPREs (peroxi- [54, 57].
some proliferator response element) in the promoter region of target genes to facilitate their
transcription [38, 39, 40]. PPREs are composed of single or multiple copies of hexanucleotide PPAR antagonist SR-202 combines the anti-diabetic effects of PPAR agonist with desirable
consensus sequence AGGTCA arranged as direct repeats separated by a single nucleotide anti-obesity characteristics by improving the lipid profile and interfering with adipocyte
(called as DR1). The PPAR-RXR is oriented such that the PPAR binds the 5 region of PPRE differentiation. This could be possibly due to generation of small adipocytes which produce
and RXR binds the 3 region [41]. lesser quantities of adipokines responsible for insulin resistance [58].

Thiazolidinedione (TZD) drugs are PPAR gamma agonists having a thiazolidine-2-4-dione An alternative to PPAR agonism as an anti-diabetic strategy was recently discovered, where
structure (active nucleus). Troglitazone, the earliest TZD introduced to the market was pulled regulating the cyclin dependent kinase-5 (CDK-5) phosphorylation of PPAR gamma at serine
out due to reported hepatotoxicity. Presently TZDs are represented by rosiglitazone (marketed 273 in adipocytes, enhances the expression of insulin sensitization genes. This could be a
as Avandia, by GlaxoSmithKline PLC, USA) and pioglitazone (marketed as Actos by Takeda novel route, and can be exploited via use of partial agonists such as INT131 (InteKrin
Pharmaceuticals, Japan) [33, 42]. Rosiglitazone is recommended for monotherapy or in Therapeutics Inc., USA) [59].

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Sonam Chawla et al. / Journal of Pharmacy Research 2011,4(4),1118-1123
PPARs thus are an attractive molecular target to remediate insulin resistance. Active research 2,500 can be found in India. 800 plants have been reported to have anti-diabetic activities.
to elucidate the molecular mechanism of their action to complete transparency would amelio- Before the conventional insulin injections and anti-diabetic drugs, healers relied on the herbs
rate the ill-effects of current PPAR based drugs. Strategies like dual agonists mediated PPAR for treatment of diabetes and associated disorders. Herbals are advantageous to the effect that
activation, SPPARM have provided a foundation for further widening the stance of PPARs as 40% of the chemical scaffolds present in natural products are absent from the current drug
a suitable molecular target in type 2 diabetes mellitus. chemistry scenario. Also, these chemical scaffolds being synthesized in long biosynthetic
pathways have a history of interaction with various proteins and effectors of biological
3.2 Protein Tyrosine Phosphatase 1B as a Therapeutic Target response, this being an indispensible property for the future drug molecules. Various biological
Listing of PTP1B as a potential therapeutic target reinforces the importance of phophorylation/ assays can be employed to screen these plants for active principles responsible for hypoglyce-
dephosphorylation in regulation of metabolic pathways. mic or anti-hyperglycemic, anti-hyperinsulinemic activities. Besides use of direct crude
extracts from these plants, certain herbal formulations are also available such as Diabecon,
The inhibitory role of PTP1B, also known as PTPN1 (protein tyrosine phosphatase, non- Epinsulin, Diabetes Daily Care etc. [75, 76].
receptor type 1), on the insulin signaling pathway has been mentioned earlier. Briefly, PTP1B
dephosphorylates IR and IRS-1/2 at a tyrosine residues leading to interference of transmitting Several plants, crude extracts and active constituents have been investigated successfully for
the insulin signal. Also PTP1B interferes with GLUT4 mediated glucose uptake [60, 61]. their molecular targets, amongst them Gurmar leaf (Gymnema sylvestre), Neem (Azadiracta
indica), Jamun (Eugenia jambolana), Tulsi or holy basil (Ocimum sanctum), Stevia (Sweeten),
In obese (ob/ob) and diabetic (db/db) mice, absence of PTP1B attained by administration of Kalmegh (Swertia chirayita karst), Methi (Trigonella foenum-graecum) being the best in
antisense oligonucleotides, has been seen to improve glycemic control as well as insulin terms of safety and efficacy [77]. Azadiracta indica and Eugenia jambolana have been
sensitivity [62]. Similarly, PTP1B knock-outs generated by gene disruption exhibited en- established as insulin sensitizers in fructose-fed rats [78] and shown to have restorative action
hanced insulin sensitivity and when fed on high-fat diet showed resistance to weight gain mediated by PPAR agonism [79]. Elaborating on the significance of herbals, a recent study
besides retaining insulin sensitivity. The role of PTP1B in control of adiposity and genes confirmed 50 plant extracts, some of them being pomegranate, apple, clove, cinnamon, thyme,
involved in lipogenesis i.e. sterol regulatory element-binding protein 1 and their downstream green coffee, bilberry and bay leaves, were reported to bind in a PPAR competitive ligand
targets spot14 and fatty acid synthase, alongwith adipogenic genes PPAR gamma, lipoprotein binding assays. Five were reported to be trans-activators of PPAR gamma in chimeric GAL4-
lipase was evaluated in hyperglycemic ob/ob mice. The results implicate raised levels of PPAR gamma-LBD system, they being: nutmeg, licorice, black pepper and sage. These 5
PTP1B in obesity [63]. PTP1B is also implicated in leptin resistance as it is believed to extracts were hypothesized to function as SPPARMs, conferring insulin sensitivity without
dephosphorylate JAK2 (Janus kinase 2), a tyrosine kinase responsible for activation of leptin weight gain [80]. Similarly, corosolic acid, a triterpenoid compound widely existing in many
receptor. Specifically, neuronal PTP1B knockout mice have pointed towards neuronal PTP1B traditional Chinese medicinal herbs manifests its cellular and signaling effects by inhibition of
to interfere with leptins anti-obesity effects as well as linking it to pathogenesis of insulin several tyrosine phosphatases such as PTP1B, src homology phosphatase-1 and src homology
resistance [64]. Additionally, double knockouts of PTP1B and IRS-2 demonstrated limited phosphatase-2 and activating the insulin signaling pathway [81]. Berberine, mentioned above,
preservation of beta cell mass, indicating that PTP1B inhibition can compensate for IRS-2 mimics insulin action by increasing glucose uptake ability by 3T3-L1 adipocytes and L6
deletion to a fraction [65]. myocytes in an insulin-independent manner, inhibiting phosphatase activity of PTP1B, and
increasing phosphorylation of IR, IRS1 and Akt in 3T3-L1 adipocytes. The same has also
PTP1B inhibition is thus a key therapeutic approach to deal with pathogenesis of type 2 been tested and proved in vivo [82].
diabetes mellitus and related metabolic disorders. The therapeutic potential of PTP1B can be
tapped by employing inhibitors designed on the strategies of competitive and non-competitive Considering the immense potential exhibited by such herbal drugs, it would prove to be a
inhibition. boon to the medical practitioners and diabetic patients if intensive studies are conducted to
Certain compounds under exploration as competitive inhibitors are difluoromethylene consolidate the molecular mechanisms of these ancient therapeutics for suitable inclusion in
phosphonates, 2-carbomethoxybenzoic acids, 2-oxalylaminobenzoic acids. These active site regular anti-diabetic/insulin sensitization prescriptions. The investigations can evaluate the
inhibitors are plagued with problems of questionable selectivity and meager pharmacokinetics individual effects of active principles, as well in combinations in various bioassays against
due to charge and size of the ligands, thus there are no clinical candidates available despite individual molecular targets. The stress should though be on crude extracts or enriched
achievable potency. Selectivity issues arise due to high homology of active site among the fractions and herbal teas as they are simpler to prepare and do not involve the expenditure in
phosphatase family, and are being tackled by the development of bi-dentate inhibitors which terms of extraction and purification of individual active compounds. Moreover, the restorative
bind the active site and a second phosphate binding site adjacent to active site. Sunesis properties of an extract can have multiple benefits as against the singular and specific action of
Pharmaceuticals Inc, USA, is developing allosteric inhibitors with appropriate pharmacoki- an active constituent. As illustrated in case of Costus pictus, the methanolic extract exhibits
netics and selectivity over other phosphatases [66, 67, 68, 69]. Several inhibitory molecular anti-diabetic and anti-adipogenic potential by way of inhibition of PTP1B and reduced
leads have been discovered in fungi and plants e.g. berberine, diterpenoids etc. [70, 71, 72]. expression of adipogenic marker proteins such as PPAR, CCAAT/enhancer-binding proteins
Interestingly, rosiglitazone was found to depreciate the PTP1B levels and activity in diabetic (C/EBPs), and adipocyte determination and differentiation factor-1c/sterol regulatory element
patients and fat fed rats, thus acting through multiple targets to improve hepatic & peripheral binding protein 1c (ADD1/SREBP1c). But, the active compound methyl tetracosanoate,
insulin sensitivity [73]. isolated from the same methanolic extract only exhibited its anti-diabetic activity as a PTP1B
inhibitor [83].

3.4 Modus Vivendi Interventions

Pharmacological interventions can be supplemented with lifestyle modifications involving
effective monitoring of body weight and switching to controlled energy diet, with special
emphasis on quality of carbohydrates and fats consumed [84]. Several nutritional substances
such as minerals (magnesium, calcium, potassium, zinc, chromium, and vanadium) and
amino acids (L-carnitine, taurine, and L-arginine,) have been suggested as remediators of
Figure 5. Activity of PTP1B can be supressed be active site inhibition and allosteric inhibition
as shown in the respective complexs (PDBID:1WAX & 1T4B). insulin resistance [85]. Commercial probiotic formulations composed of streptococci, lacto-
bacilli and bifidobacteria when administered to high fat-fed mice over a period of 4 weeks
Alternatives to small chemical inhibitors have also been explored, most successful of this non- brought about improvements in high fat induced obesity, insulin resistance, and steatosis by
conventional therapeutics being antisense oligonucleotides which knockdown the expression controlled inflammatory response [86].
of PTP1B post-transcriptionally.
It has been firmly established that exercise results in increased glucose uptake by the skeletal
Isis Pharmaceuticals is in second phase clinical trials of the antisense-oligonucleotide based muscles and post-exercise the insulin sensitivity of muscles in increased. This is mainly
drug like ISIS 113715 as a PTP1B inhibitor. When tested for treatment of nave diabetic mediated by an IR/IRS-1 independent pathway culminating in increased translocation of
patients in a monotherapy, they have obtained promising results on safety and efficacy. The GLUT4 transporter to the plasma membranes and hence enhanced glucose utilization by
ongoing trials are now awaiting results of a combination therapy with sulphonylureas. This muscle cells [87]. Exercise therapy has been shown to improve inflammation, hypertension,
antisense-oligonucleotide drug has been observed to have benefits of a weekly dosage and no and lipid metabolism. Major organizations across the world have recognized the salutary
side effects of weight gain as against PPAR based drugs which require daily doses and are effects of exercise therapy. Safety considerations like age, poor physical fitness, traditional
synonymous with gain in body weight and edema. A possible short coming may be the mode cardiac risk factors, retinopathy and other parameters prescribed by these organizations should
of delivery- subcutaneous injections, where as PPAR based drugs are available as oral formu- be considered before initiating exercise [88].
lations [74].
Conclusively, PTP1B is a persuasive target still unexplored and can provide an alternate to Insulin resistance, a crucial etiological aspect of type 2 diabetes mellitus, has a complex
cope with type 2 diabetes mellitus without a necessity to suffer from adverse-effects as in other molecular manifestation. A high resolution delineation of these underlying metabolic path-
therapeutic strategies. ways along with mapping the points of cross-talk with other pathways for e.g. inflammation
can help counter and manage insulin resistance, evading progression to diabetes. The current
3.3 Plant based Therapeutics knowledge suggests several drug targets PKC, PTP1B, TNF , PI3-K, some of them are
Synthetic drug molecules are costly and have severe side-effects. World Health Organization being actively researched. Overlooking the recent setback suffered by rosiglitazone, PPARs can
has recognized and compiled a list of 21,000 medicinal plants used around the world, of which be investigated in new light, considering the findings associating them with CDK-5 and
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SPPARM. These synthetic drug moieties can be supplemented in their insulin sensitizing 28. Stephens JM, Lee J, Pilch PF. Tumor necrosis factor-alpha-induced insulin resistance in 3T3-L1
action by herbals and natural products, but herbal therapeutics lacks the systematic evaluation adipocytes is accompanied by a loss of insulin receptor substrate-1 and GLUT4 expression without
a loss of insulin receptor-mediated signal transduction. J Biol Chem 1997; 272: 971-6
at molecular level to be included in medical practices, and same is urged for. Thus, the first 29. Bastard JP, Jardel C, Bruckert E, Blondy P, Capeau J, Laville M et al. Elevated levels of interleukin
generation of curatives for the global health concern of insulin resistance would therefore be 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss. J Clin
based on a perspicuous understanding of the underlying signaling cascades, safe and effective Endocrinol Metab. 2000; 85:3338-42.
30. Senn JJ, Klover PJ, Nowak IA, Mooney RA. Interleukin-6 induces cellular insulin resistance in
drug molecules, combined with co-operation from victims of the disease in terms of lifestyle hepatocytes. Diabetes 2002; 51: 3391-9.
modification. 31. Greenberg AS, Nordan RP, McIntosh J, Calvo JC, Scow RO, Jablons D. Interleukin 6 reduces
lipoprotein lipase activity in adipose tissue of mice in vivo and in 3T3-L1 adipocytes: a possible role
for interleukin 6 in cancer cachexia. Cancer Res 1992; 52: 4113-6.
4.ACKNOWLEDGEMENTS 32. Otarod JK, Goldberg IJ. Lipoprotein lipase and its role in regulation of plasma lipoproteins and
Corresponding author thanks faculty at School of Biotechnology, Rajiv Gandhi Proudyogiki cardiac risk. Curr Atheroscler Rep 2004; 6: 335-42.
Vishwavidyalaya, Bhopal, India for constant accompaniment, during the tenure of paper 33. Moller DE. New drug targets for type 2 diabetes and the metabolic syndrome. Nature 2001; 414:
writing. 821-7.
34. Lenhard JM, Gottschalk WK. Preclinical developments in type 2 diabetes. Adv Drug Deliv Rev
2002; 54: 1199-212.
ABBREVIATIONS 35. Nourparvar A, Bulotta A, Di Mario U, Perfetti R. Novel strategies for the pharmacological man-
ADD1/SREBP1c (adipocyte determination and differentiation factor-1c/sterol regulatory element agement of type 2 diabetes. Trends Pharmacol Sci 2004; 25: 86-91.
36. Terauchi Y, Kadowaki T. Peroxisome proliferator-activated receptors and insulin secretion. Endo-
binding protein 1c), AMPK (AMP-activated protein kinase), BAT (Brown Adipose Tissue), CDK- crinology 2005; 146: 3263-5.
5 (Cyclin dependent kinase-5), C/EBPs (CCAAT/enhancer-binding proteins), FFA (Free fatty acids), 37. Gilde AJ, Fruchart J, Staels B. Peroxisome Proliferator-Activated Receptors at the Crossroads of
GLP-1(Glucagon-like-peptide1), HDL (High density lipids), iLBP (intracellular lipid binding Obesity, Diabetes, and Cardiovascular Disease Journal of the American College of Cardiology
2006; 48: A24-A32.
protein), IL-6 (Interleukin-6), IR (Insulin receptor), IRS (insulin receptor substrate), JAK2 (Janus 38. Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med 2002; 53: 409-35.
kinase 2), LBD (ligand-binding domain), LDL (low density lipids), LPL (Lipoprotein lipase), 39. Cho MC, Lee K, Paik SG, Yoon DY. Peroxisome Proliferators-Activated Receptor (PPAR) Modu-
PDK1 (3-phosphoinositide dependent kinase), PI3-K (Phosphatidylinositol 3-kinase) , PIP2 lators and Metabolic Disorders. PPAR Res 2008; 2008: 679137.
40. Ziouzenkova O, Plutzky J. Retinoid metabolism and nuclear receptor responses: New insights into
(Phosphatidyl-inositol 4,5-bisphosphate), PIP3 (Phosphatidyl-inositol 3,4,5-triphosphate), coordinated regulation of the PPAR-RXR complex. FEBS Lett 2008; 582: 32-8.
PPARs (Peroxisome Proliferator Activated Receptors),PPREs (Peroxisome Proliferator Response 41. Murphy GJ, Holder JC. PPAR-gamma agonists: therapeutic role in diabetes, inflammation and
Element), PKC (Protein kinase C theta), PTP1B (Protein tyrosine phosphatase 1B), PTPN1 cancer. Trends Pharmacol Sci 2000; 21: 469-74.
(protein tyrosine phosphatase, non-receptor type 1), RXR (Retinoid-X-Receptor), SH-PTP2 (Src 42. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA 2002;
287: 360-72.
Homology 2 Protein Tyrosine Phosphatase), SPPARM (Selective PPAR modulators), SREBP-c 43. Malinowski JM, Bolesta S. Rosiglitazone in the treatment of type 2 diabetes mellitus: a critical
(Sterol Regulatory Element Binding Protein-c), TZD (Thiazolidinedione), TNF alpha (Tumor review. Clin Ther 2000; 22: 1151-68.
Necrosis Factor alpha), VLDL (very low density lipids), WAT (White Adipose Tissue). 44. Basu R, Basu A, Chandramouli V, Norby B, Dicke B, Shah P, et al. Effects of pioglitazone and
metformin on NEFA-induced insulin resistance in type 2 diabetes. Diabetologia. 2008;51:2031-40.
45. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from
5.REFERENCES cardiovascular causes. N Engl J Med 2007; 357:100.
1. Web URL: http://www.worlddiabetesday.org/files/docs/U4D/UN_Resolution.pdf. Accessed on 12 46. Lhrke B, Shahi SK, Krger B, Schmidt P, Renne U, Dietl G. Thiazolidinedione-induced activation
October 2009 of the transcription factor peroxisome proliferator-activated receptor gamma in cells adjacent to
2. Web URL: http://www.boehringer-ingelheim.com/content/dam/internet/opu/com_EN/protected/ the murine skeletal muscle: implications for fibroblast functions. Pflugers Arch 2000; 439:2882-96.
document/01_news/02_Press_and_Informationpacks/diabetes.pdf Accessed on 13 October 2009 47. Chinetti-Gbaguidi G, Fruchart JC, Staels B Role of the PPAR family of nuclear receptors in the
3. Brower V. Like a snake in the grass. EMBO rep 2004; 5:555-8. regulation of metabolic and cardiovascular homeostasis: new approaches to therapy. Curr Opin
4. Poitout V, Robertson RP. An integrated view of beta-cell dysfunction in type-II diabetes. Annu Rev Pharmacol 2005; 5: 177-83.
Med 1996; 47: 69-83. 48. Muoio DM, MacLean PS, Lang DB, Li S, Houmard JA, Way JM. Fatty acid homeostasis and
5. Montecucco F, Steffens S, Mach F. Insulin resistance: a proinflammatory state mediated by lipid- induction of lipid regulatory genes in skeletal muscles of peroxisome proliferator-activated recep-
induced signaling dysfunction and involved in atherosclerotic plaque instability. Mediators Inflamm tor (PPAR)alpha knock-out mice. Evidence for compensatory regulation by PPAR delta. J Biol
2008; 2008: 767623. Chem 2002;277:26089-97.
6. Leibiger IB, Leibiger B, Berggren PO. Insulin signaling in the pancreatic beta-cell. Annu Rev Nutr 49. Winzell MS, Wulff EM, Olsen GS, Sauerberg P, Gotfredsen CF, Ahrn B. Improved insulin sensi-
2008; 28: 233-51. tivity and islet function after PPARdelta activation in diabetic db/db mice. Eur J Pharmacol.
7. Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest 2000; 106: 473-81. 2010;626:297-305.
8. Henry RR. Insulin resistance: from predisposing factor to therapeutic target in type 2 diabetes. Clin 50. Barish GD, Narkar VA, Evans RM. PPARd: a dagger in the heart of the metabolic syndrome. J Clin
Ther 2003; 25 Suppl B: B47-63. Invest 2006; 116: 590-7.
9. Guo L, Tabrizchi R. Peroxisome proliferator-activated receptor gamma as a drug target in the 51. Sznaidman ML, Haffner CD, Maloney PR. Novel selective small molecule agonists for peroxi-
pathogenesis of insulin resistance. Pharmacology & Therapeutics 2006; 111:145-73. some proliferator-activated receptor delta (PPARdelta)synthesis and biological activity. Bioorg
10. Arajo EP, De Souza CT, Gasparetti AL, Ueno M, Boschero AC, Saad MJ, et al. Short-term in vivo Med Chem Lett 2003; 13:1517-21.
inhibition of insulin receptor substrate-1 expression leads to insulin resistance, hyperinsulinemia, 52. Krmer DK, Al-Khalili L, Guigas B, Leng Y, Garcia-Roves PM, Krook A. Role of AMP kinase and
and increased adiposity. Endocrinology 2005; 146:1428-37. PPARdelta in the regulation of lipid and glucose metabolism in human skeletal muscle. J Biol Chem.
11. Hawkins M, Tonelli J, Kishore P, Stein D, Ragucci E, Gitig A et al. Contribution of elevated free fatty 2007; 282:19313-20.
acid levels to the lack of glucose effectiveness in type 2 diabetes. Diabetes 2003; 52:2748-58. 53. Rodrguez-Calvo R, Serrano L, Coll T, Moullan N, Snchez RM, Merlos M, Activation of peroxi-
12. Roden M. Non-invasive studies of glycogen metabolism in human skeletal muscle using nuclear some proliferator-activated receptor beta/delta inhibits lipopolysaccharide-induced cytokine pro-
magnetic resonance spectroscopy. Curr Opin Clin Nutr Metab Care 2001; 4: 261-66. duction in adipocytes by lowering nuclear factor-kappaB activity via extracellular signal-related
13. Randle PJ. Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle kinase 1/2. Diabetes 2008;57:2149-57.
after 35 years. Diabetes Metab Rev 1998; 14:263-83. 54. Fivet C, Fruchart JC, Staels B. PPARalpha and PPARgamma dual agonists for the treatment of
14. Boden G. Interaction between free fatty acids and glucose metabolism. Curr Opin Clin Nutr Metab type 2 diabetes and the metabolic syndrome. Curr Opin Pharmacol 2006 ;6:606-14.
Care 2002; 5: 545-9. 55. Stulc T, Ceska R. Is it safe to combine PPAR agonists? A lesson from muraglitazar. Med Hypotheses
15. Griffin ME, Marcucci MJ, Cline GW, Bell K, Barucci N, Lee D, et al. Free fatty acid-induced insulin 2006; 67: 669.
resistance is associated with activation of protein kinase C theta and alterations in the insulin signal- 56. Balakumar P, Rose M, Ganti SS, Krishan P, Singh M. PPAR dual agonists: are they opening Pandoras
ing cascade. Diabetes 1999;48:1270-4. Box? Pharmacol Res 2007; 56: 91-8.
16. Trayhurn P, Beattie JH. Physiological role of adipose tissue: white adipose tissue as an endocrine 57. Berger JP, Akiyama TE, Meinke PT. PPARs: therapeutic targets for metabolic disease. Trends
and secretory organ. Proc Nutr Soc 2001; 60: 329-39. Pharmacol Sci 2005; 26: 244-51.
17. Ahima RS. Adipose tissue as an endocrine organ. Obesity (Silver Spring) 2006;14 Suppl 5: 242S- 58. Rieusset J, Touri F, Michalik L, Escher P, Desvergne B, Niesor E, et al. A new selective peroxisome
9S. proliferator-activated receptor gamma antagonist with antiobesity and antidiabetic activity. Mol
18. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 2004; 89: Endocrinol. 2002 ;16:2745.
2548-56. 59. Choi JH, Banks AS, Estall JL, Kajimura S, Bostrm P, Laznik D, et al. Anti-diabetic drugs inhibit
19. Kubaszek A, Pihlajamki J, Komarovski V, Lindi V, Lindstrm J, Eriksson J, et al. Finnish Diabetes obesity-linked phosphorylation of PPARgamma by Cdk5.Nature 2010; 466:451-6.
Prevention Study. Promoter polymorphisms of the TNF-alpha (G-308A) and IL-6 (C-174G) genes 60. Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature
predict the conversion from impaired glucose tolerance to type 2 diabetes: the Finnish Diabetes 2001; 414: 799-806.
Prevention Study.Diabetes 2003; 52:1872-6. 61. Chen H, Wertheimer SJ, Lin CH, Katz SL, Amrein KE, Burn P, et al. Protein-tyrosine phosphatases
20. Hotamisligil GS, Budavari A, Murray D, Spiegelman BM. Reduced tyrosine kinase activity of the PTP1B and Syp are modulators of insulin-stimulated translocation of GLUT4 in transfected rat
insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-alpha. J Clin Invest 1994; adipose cells. J Biol Chem. 1997; 272:8026-31.
94: 1543-9. 62. Zinker BA, Rondinone CM, Trevillyan JM, Gum RJ, Clampit JE, Waring JF, Xie N, et al.PTP1B
21. Ragolia L, Begum N. Protein phosphatase-1 and insulin action. Mol Cell Biochem 1998; 182: 49- antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin
58. sensitivity in diabetic mice. Proc Natl Acad Sci U S A. 2002;99(17):11357-62.
22. Hotamisligil GS, Murray DL, Choy LN, Spiegelman BM. Tumor necrosis factor alpha inhibits 63. Rondinone CM, Trevillyan JM, Clampit J, Gum RJ, Berg C, Kroeger P, et al.Protein tyrosine
signaling from the insulin receptor. Proc Natl Acad Sci U S A 1994; 91: 4854-8. phosphatase 1B reduction regulates adiposity and expression of genes involved in lipogenesis.
23. Ahmad F, Goldstein BJ. Effect of tumor necrosis factor-alpha on the phosphorylation of tyrosine Diabetes 2002; 51:2405-11.
kinase receptors is associated with dynamic alterations in specific protein-tyrosine phosphatases. 64. Bence KK, Delibegovic M, Xue B, Gorgun CZ, Hotamisligil GS, Neel BG, et al. Neuronal PTP1B
J Cell Biochem 1997; 64: 117-127. regulates body weight, adiposity and leptin action. Nat Med. 2010;16:237.
24. Kanety H, Feinstein R, Papa MZ, Hemi R, Karasik A. Tumor necrosis factor alpha-induced 65. Kushner JA, Haj FG, Klaman LD, Dow MA, Kahn BB, Neel BG, et al. Islet-sparing effects of
phosphorylation of insulin receptor substrate-1 (IRS-1). Possible mechanism for suppression of protein tyrosine phosphatase-1b deficiency delays onset of diabetes in IRS2 knockout mice. Dia-
insulin-stimulated tyrosine phosphorylation of IRS-1. J Biol Chem 1995; 270: 23780-4. betes 2004; 53:61-6.
25. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM. IRS-1-mediated 66. Bailey CJ. Potential new treatments for type 2 diabetes. Trends Pharmacol Sci 2000; 21: 259-65.
inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin 67. Montalibet J, Kennedy BP. Therapeutic strategies for targeting PTP1B in diabetes. Drug Discov
resistance. Science 1996; 271: 665-8. Today Ther Strateg 2005; 2 : 129-35.
26. Paz K, Hemi R, LeRoith D, Karasik A, Elhanany E, Kanety H,et al. A molecular basis for insulin 68. Johnson TO, Ermolieff J, Jirousek MR. Protein tyrosine phosphatase 1B inhibitors for diabetes. Nat
resistance. Elevated serine/threonine phosphorylation of IRS-1 and IRS-2 inhibits their binding to Rev Drug Discov 2002; 1: 696-709.
the juxtamembrane region of the insulin receptor and impairs their ability to undergo insulin- 69. Sun JP, Fedorov AA, Lee SY, Guo XL, Shen K, Lawrence DS, et al.Crystal structure of PTP1B
induced tyrosine phosphorylation. J Biol Chem 1997;272:29911-8. complexed with a potent and selective bidentate inhibitor. J Biol Chem 2003;278:12406-12414.
27. Pederson TM, Kramer DL, Rondinone CM. Serine/threonine phosphorylation of IRS-1 triggers its 70. Oh H, Kim BS, Bae EY, Kim MS, Kim BY, Lee HB, et al. Inhibition of PTP1B by metabolites from
degradation: possible regulation by tyrosine phosphorylation. Diabetes 2001; 50: 24-31. Micromucor ramannianus var. angulisporus CRM000232. J Antibiot (Tokyo). 2004;57:528-31.

Journal of Pharmacy Research Vol.4.Issue 4. April 2011 1118-1123

Sonam Chawla et al. / Journal of Pharmacy Research 2011,4(4),1118-1123
71. Bustanji Y, Taha MO, Yousef AM, Al-Bakri AG. Berberine potently inhibits protein tyrosine phos- (Momordica charantia) improves insulin sensitivity by increasing skeletal muscle insulin-stimu-
phatase 1B: investigation by docking simulation and experimental validation. J Enzyme Inhib Med lated IRS-1 tyrosine phosphorylation in high-fat-fed rats. Br J Nutr 2008; 99: 806-12.
Chem 2006; 21: 163-171 80. Mueller M., Alois Jungbauer. Culinary plants, herbs and spices A rich source of PPARgamma
72. Na M, Oh WK, Kim YH, Cai XF, Kim S, Kim BY, et al. Inhibition of protein tyrosine phosphatase ligands Food Chemistry 2009;117:6607.
1B by diterpenoids isolated from Acanthopanax koreanum. Bioorg Med Chem Lett 2006;16:3061- 81. Shi L, Zhang W, Zhou YY, Zhang YN, Li JY, Hu LH, et al. Corosolic acid stimulates glucose uptake
4. via enhancing insulin receptor phosphorylation. Eur J Pharmacol 2008; 584:21-9.
73. Wu Y, Ouyang JP, Wu K, Wang SS, Wen CY, Xia ZY. Rosiglitazone ameliorates abnormal expres- 82. Chen C, Zhang Y, Huang C. Berberine inhibits PTP1B activity and mimics insulin action. Biochem
sion and activity of protein tyrosine phosphatase 1B in the skeletal muscle of fat-fed, streptozotocin- Biophys Res Commun. 2010; 397:543-7.
treated diabetic rats. Br J Pharmacol 2005; 146: 234-43. 83. Shilpa K, Sangeetha KN, Muthusamy VS, Sujatha S, Lakshmi BS. Probing key targets in insulin
74. WebURL:http://www.newbiomedicine.com/Revere/UploadFiles/file/ISIS_ISIS%20 signaling and adipogenesis using a methanolic extract of Costus pictus and its bioactive molecule,
113715%20Phase%20II.pdf Accessed on 14 November 2009 methyl tetracosanoate. Biotechnol Lett 2009; 31: 1837-41.
75. Modak M, Dixit P, Londhe J, Ghaskadbi S, Paul ADT. Indian herbs and herbal drugs used for the 84. Riccardi G, Giacco R, Parillo M. Lifestyle modification to prevent type 2 diabetes. International
treatment of diabetes. J Clin Biochem Nutr 2007; 40:163-73. Congress Series 2003;1253: 231-6.
76. Mller-Kuhrt L. Putting nature back into drug discovery. Nat Biotechnol 2003 ;21:602. 85. Kelly GS. Insulin resistance: lifestyle and nutritional interventions. Altern Med Rev 2000; 5:109-
77. Kosta S, Tiwari A. A Fusion Of Ancient Medicinal Plants With Modern Conventional Therapies on 32.
its Multifaceted Anti-diabetic Properties Pharmacologyonline Personal communication; 1: 64-77 86. Ma X, Hua J, Li Z. Probiotics improve high fat diet-induced hepatic steatosis and insulin resistance
78. Vikrant V, Grover JK, Tandon N, Rathi SS, Gupta N. Treatment with extracts of Momordica by increasing hepatic NKT cells. J Hepatol 2008; 49:821-30.
charantia and Eugenia jambolana prevents hyperglycemia and hyperinsulinemia in fructose fed 87. Goodyear LJ, Kahn BB. Exercise, glucose transport, and insulin sensitivity. Annu Rev Med 1998;
rats. J Ethnopharmacol. 2001; 76:139-43. 49: 235-61.
79. Sridhar MG, Vinayagamoorthi R, Arul Suyambunathan V, Bobby Z, Selvaraj N. Bitter gourd 88. Praet SF, van Loon LJ. Exercise therapy in type 2 diabetes. Acta Diabetol 2009; 46:263-78.

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