AEGAEUM JOURNAL ISSN NO: 0776-3808 Dualism of Peroxisome Proliferator-Activated Receptor α/γ: A Potent Clincher in Insulin Resistance Mr. Ravikumar R. Thakar1 and Dr. Nilesh J. Patel1* 1Faculty of Pharmacy, Shree S. K. Patel College of Pharmaceutical Education & Research, Ganpat University, Gujarat, India. [email protected] Abstract: Diabetes mellitus is clinical syndrome which is signalised by augmenting level of sugar in blood stream, which produced through lacking of insulin level and defective insulin activity or both. As per worldwide epidemiology data suggested that the numbers of people with T2DM living in developing countries is increasing with 80% of people with T2DM. Peroxisome proliferator-activated receptors are a family of ligand-activated transcription factors; modulate the expression of many genes. PPARs have three isoforms namely PPARα, PPARβ/δ and PPARγ that play a central role in regulating glucose, lipid and cholesterol metabolism where imbalance can lead to obesity, T2DM and CV ailments. It have pathogenic role in diabetes. PPARα is regulates the metabolism of lipids, carbohydrates, and amino acids, activated by ligands such as polyunsaturated fatty acids, and drugs used as Lipid lowering agents. PPAR β/δ could envision as a therapeutic option for the correction of diabetes and a variety of inflammatory conditions. PPARγ is well categorized, an element of the PPARs, also pharmacological effective as an insulin resistance lowering agents, are used as a remedy for insulin resistance integrated with type- 2 diabetes mellitus. There are mechanistic role of PPARα, PPARβ/δ and PPARγ in diabetes mellitus and insulin resistance. From mechanistic way, it revealed that dual PPAR-α/γ agonist play important role in regulating both lipids as well as glycemic levels with essential safety issues. Certain clinical and epidemiological data showed beneficial effects and limitation of dual PPAR-α/γ agonists in insulin resistance lowering through regulation of diabetes mellitus with some safety precaution. Keywords: PPAR agonist, Dual PPAR α/γ, Type 2 Diabetes Mellitus, Insulin Resistance Introduction: Diabetes Mellitus is a chronic clinical complex, affiliated with hyperglycemia, T2DM initiated by either insufficiency in insulin release, insulin unable to generate its activity and/or both at cell level. Uninterrupted hyperglycemia damaged the diverse vital body organs specifically nerves, kidneys, heart, eyes and blood vessels that lead to complications namely stroke, neuropathy, renal failure, retinopathy, blindness, amputations, 1 Dr. Nilesh J. Patel Associate Professor, Head of Pharmacology, Faculty of Pharmacy, Shree S. K. Patel College of Pharmaceutical Education & Research, Ganpat University – 384012 Email Id:- [email protected] Page 1 of 27 Volume 8, Issue 3, 2020 http://aegaeum.com/ Page No: 965 AEGAEUM JOURNAL ISSN NO: 0776-3808 peripheral vascular diseases, cardiovascular diseases, etc. T2DM are categories into three types, IDDM (type 1), NIDDM (type 2) and Gestational diabetes. IDDM resulted by autoimmune destruction of the β cell of pancreas. NIDDM caused by insufficiency of insulin release and resistance towards the activity of insulin. [1,2] Worldwide current epidemiological data exhibits that approximately 366 million people had T2DM and 4.6 million deaths in 2011; it would have enhanced and reaches to 552 million in 2030. The numbers of people with T2DM living in low and middle-income countries is enhancing with 80% of people with T2DM.[3] The occurrence of T2DM diversifies from one geographical territory to the other through ecosystem as well as lifestyle predisposing factors.[4] India is the leader of the world with enormous number of diabetic patients earning the unreliable segregation of being designated the “World diabetes stock”. Honouring to the Diabetes Atlas 2006 circulated by the IDF, the number of population with diabetes in India currently around 40.9 million is predicted to uplift to 69.9 million by 2025 unless crucial preventive steps are taken. The “Asian Indian Phenotype” mentions that Indian has certain idiosyncratic clinical and biochemical deviations which encompass reduced insulin sensitivity, significant abdominal adiposity regardless of poor body mass index, lessen adiponectin and elevated high sensitive C-reactive protein levels. Elevated frequency of diabetes mellitus often outcome from in revises in food compositions and lack of physical functions in the urban population.[5] T2DM is fast capturing the status of a capable pandemic in India with greater than 62 million patients currently diagnosed with diabetic.[6,7]In the year of 2000, India exceeded the world with higher patients who have T2DM followed by China and the United States in second and third place respectively. Honouring to Wild et al. 2004, the universality of T2DM is expected to double ubiquitously from 171 to 366 million since 2006 to 2030 with a maximum rate in India. [8,9] IDDM is chiefly provoked by environmental factors. The important factors that play significant role in the development of T2DM comprise obesity[10],less physical activity and smoking. Obesity and poor socioeconomic level can convoyed enhancement of endemic of diabetes because of urbanisation, westernization and their affiliated lack of healthy food intake, lack of physical activity, unnutritional habits.[11,12]Weight of body is one of the most salient alterable etiologies in T2DM. Obesity is an unconventional etiology for dyslipidemia, elevated blood pressure, enhances the peril of CVDs and mortality in T2DM patients. [13] The pancreas of an elder’s individual doesn’t eject insulin as systematic as eject by adolescent. Higher blood pressure and inflated cholesterol level also contribute in T2DM.[14] INSULIN RESISTANCE: Insulin resistance is one of major factor for initialization of T2DM.It is referred as a clinical circumstances of diminished sensibility of tissues towards insulin, notwithstanding its balance or uplifted level into blood stream; the ailment principally materialize in adipose tissue, skeletal muscle cells, and liver.[15,16]After the induction of insulin resistance in body as a results of this diminished glucose uptake, elevated efficiency of gluconeogenesis, and enhanced lipolysis by tissues.[17] There are various factors have been recommended for the elucidation of insulin resistance mechanism, which incorporate obesity, inflammation, mitochondrial dysfunction, hyperinsulinemia, hyperlipidemia, genetic background, stress of endoplasmic reticulum, aging, oxidative stress, fatty liver, hypoxia, lipodystrophy and pregnancy. These factors are affiliated with obesity Volume 8, Issue 3, 2020 http://aegaeum.com/ Page No: 966 AEGAEUM JOURNAL ISSN NO: 0776-3808 that are crucial etiology for insulin resistance, have possible roles in the pathogenesis of insulin resistance.[18–20] Mechanism of insulin resistance at cellular level carried out by inadequate signaling is caused through diverse changes, which includes mutations and/or post-translational transformation in the receptors of insulin, IRS or in downregulating situated effect or molecules. Most common insulin resistance changes inclusive of a alleviate in insulin receptor numbers and their catalytic actions, an enhanced Ser/Thr phosphorylation phase in insulin receptor and IRS, an enhance tyrosine phosphatase action, mainly PTP-1B that take part in receptor and insulin receptor substrate dephosphorylation, a reduced in PI3K and Akt kinases effect, and defects in GLUT-4 expression and physiology.[21]Theses changes alleviate glucose uptake in adipose tissues, muscles and foster the changes at the metabolism level. An important factor play a central role for insulin resistance is Ser/Thr hyperphosphorylation of insulin receptor substrate and alleviates its phosphorylation in Tyrosine and lessen its interaction with PI3K, however changing Akt kinase phosphorylation and stimulation and IRS phosphorylation escalate its deterioration.Various agents likewise cytokines, saturated FAs, endothelin 1, angiotensin II, amino acids and states if elevated insulin levels in plasma.[22–24],It also enhance actions of kinases namely JNK stress kinase, mTOR, 70-kDa S6 ribosomal protein kinase, MAPK, diverse isoforms of PKC and PKA that phosphorylate insulin receptor substrate.[25] In addition, the development of ceramides because of saturated FAs metabolism enhanced likewise palmitate can control Akt action through modifying phosphor protein phosphatase 2A effect that dephosphorylate and immobilize it [26,27]and PKC effects that also phosphorylates it in Ser[28]and retards its translocation to the membrane in order to stimulated that mechanism control by at Akt level have been recognized.[29–31] PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS: In the journey of venturing, to particularize the methods via which few chemicals persuade peroxisome proliferation in experimental animals (rodents), as a receptor, peroxisome proliferator- activated receptor (PPAR) brought into light[32] and subsequently in short of time two others subtypes were identified that PPARβ/δ, PPARγ too. They diverse in expression, tissue allotment as well as ligand specificness.[33] PPARs synchronize a various biological actions in specific tissues that track down by specialism experimentation,[34] triggered by structurally numerous chemicals depends on as enlargement of size and/or quantity of peroxisome in the rodent liver acknowledged as peroxisome proliferators [35] The cloned receptor found that have structural