Archives of Medicine

Keywords

Diabetes; Nanotechnology; Stem cell therapy; Herbal therapy; Statin therapy; Gene therapy

Introduction

Diabetes is a most established issue it found by the Egypt doctor around multi year ago [1]. The term diabetes is originated from the Greek word siphon implies is that individuals with diabetes "passed water [2]. In everywhere throughout the world there are many number of people groups experiencing this issue it is a real existence treating jumble it cannot be fix just can be prevent [3]. The quantity of people groups with diabetes has expanded from 108 million out of 1980 to 422 million in 2014.

The worldwide pervasiveness of diabetes between grownups more than 18 years old has expanded from 4.7% in 1980 to 8.5% in 2014 [4]. A gathering of metabolic afflictions give you a thought regarding through hyperglycemia named as diabetes mellitus it is lack in insulin release, insulin accomplishment, or similarly [5,6]. Pancreas is the organ of stomach related framework it situated in the midriff and behind of stomach. In the pancreas pancreatic islets are available in which beta cell produces insulin and glucagon Hormones to control blood glucose level in the body [7,8]. Even however grouping of diabetes is significant undertaking in light of the fact that for their treatment is definitely not a basic assignment in the advanced way of life number of patient isn't fit on a solitary kind [9] from the all-out number of patients 74.75% experienced Diabetes Mellitus 1 and 25.25% experienced Diabetes Mellitus 2. 10% of patients had a progressive change in classification [10]. In the 1997 American diabetes affiliation grouped Type 1 and Type 2 different sorts Gastro-intestinal diabetes [11]. Type 1 diabetes, is immune system issue insulin subordinate Type 2 diabetes, cause by long haul harmed by some different issue while Gastrointestinal diabetes cause during the pregnancy it make genuine wellbeing hazard in mother and newborn children it additionally increment the hazard to create Type 2 diabetes [12] (Figure 1).

Figure 1: Top 10 Countries, total number of peoples with diabetes in percentage (%).

Data extracted from International Diabetes Federation Diabetes Atlas, 6^th edition, 2013 (Table 1 and Table 2).

Table 1: Top 10 Countries total number of peoples in the age of 20 to 79 years with diabetes [12].

Table 2: Number of subjects with type 1 diabetes in children (0-14 years), with diabetes in adults (20-79 years) and with hyperglycemia (type 2 or gestational diabetes) in pregnancy (20-49 years) [11,12].

Literature Review: Classification of Diabetes

Diabetes is classified into two types: Type 1 diabetes (Insulin dependent diabetes) and Type 2 diabetes (Non-Insulin dependent diabetes) [13].

Insulin dependent diabetes

It can develop at any age, but occurs most frequently in children and adolescents. In this type of diabetes our body cannot produce sufficient Insulin. It is a lifetime (incessant) affliction with raised force of sugar (glucose) in the blood [14]. The creation of insulin is flawed subsequently glucose can't travel inside the cells [15]. The pace of cell harm is to some degree conflicting in this sort of diabetes being hurried in certain people (mainly newborn children and kids) and thinks in others (essentially grown-ups). A few patients, mostly children and youths may start with ketoacidosis as the main manifestation of the ailment. Others include saved fasting hyperglycemia that can quickly modify to harsh hyperglycemia and additionally ketoacidosis in the inhabitance of disease or other strain [16]. There are approximately 10% peoples have type 1 diabetes. It is an autoimmune disease the actual causes are not known but by the genetic or environmental factors immune system of people ’ s attacks pancreatic cells which produces insulin. For their treatment administer external insulin into body.

Cause for Type 1 Diabetes: Gens play essential role for developing type 1diabetes. They are transferred biologically parents to children. They carry information for protein which is needed for functions of the body cells [17]. Certain gene variants that carry instructions for making proteins called human leukocyte antigens (HLAs) on white blood cells are linked to the risk of developing type 1 diabetes [18]. Some combinations of HLA gene variants predict that a person will be at higher risk for type 1 diabetes, while other combinations are protective or have no effect on risk. [19,20] Autoimmune damage of Beta Cells: In this form of diabetes, T cells hit and demolish beta cells. The course of action starts well earlier than diabetes sign emerges and persists following identification. Type 1 diabetes is not identified frequently until major beta cells have by now been damaged. At this peak, an individual wants every day insulin therapy to stay alive [21].

Ecological aspects such as foodstuffs, viruses and pollutants might play a part in the advancement of type 1 diabetes, although the precise character of their function has not been resolute. Few speculations propose that ecological features prompt the autoimmune damage of beta cells in people with a hereditary vulnerability to diabetes. Further hypothesis imply that ecological features play an enduring part in diabetes, yet subsequent to diagnosis [22] (Figure 2).

Figure 2: Pathophysiology of Type 1 diabetes.

Non-insulin dependent diabetes

Type 2 diabetes mellitus is the most commonly observed type of diabetes and is as of now an important global reason for nastiness and fatality. Diabetes was practically inaccessible 50 years backward and has suggested in approximately 40% of gains-ups. The IDF tested in 2014 that 387 million people have diabetes global and that by 2035 this number will escalate to 592 million. Of those with diabetes at performing, 77% work in low-and center income nations and 179 million are unexplored. This will presumably weaken, provided the rapidly developing proportion of this brainwashing; along these areas, an awareness of its etiology and pathogenesis is of extraordinary influence. Type 2 diabetes is absolutely not a singular malady process, however well speaks to a heterogeneous glorious body of illness conditions, all prompting the last primary channel of hyperglycemia. The illness involves a cluster of dysfunctions exemplified by hyperglycemia and resulting from the complement of safety from insulin activity, deficient insulin discharge, and unreasonable or inappropriate glucagon radiation [23]. Unusually regular and reports for 90-95% of all diabetes. Grown-ups have primarily influenced however recently Type 2 includes created in kids. There is a strong cooperation between Type 2 diabetes, physical latency and belatedness [24].

Cause of Type 2 Diabetes: Genes play a considerable part in affinity to type 2 diabetes. Containing distinct varieties or a combination of qualities may enhance or decrease a people’s uncertainty for having the illness. The role of conditions have showed by the established pace of type 2 diabetes in families and identical twins and broad variation in diabetes transcendence through rules. Learning has disclosed that modifications of the TCF7L2 quality improve disclosure to type 2 diabetes [25]. Physical laziness and largeness have forcefully connected through development of type 2 diabetes. At the time when these unsafe highlights have related by the people who are hereditarily powerless to type 2 diabetes are progressively defenseless. Contrast among caloric ingestion alongside physical development can prompt heftiness which produce insulin obstruction and is visit inside open with type 2 diabetes. Key greatness, inside which an individual have surplus stomach fat, is a predominant risk issue not merely for insulin obstruction just as type 2 diabetes anyway likewise for heart besides vain affliction moreover named Cardiovascular Disorder (CVD). This overflow “midsection strong” produces hormones alongside extra components that have the privilege to make risky unremitting outcomes inside the body like evil to veins [26] (Figure 3).

Figure 3: Pathophysiology of type 2 diabetes due to genetic or environmental factors insulin production will decrease that’s why glucose production will increase and it level of glucose in bloodstream will also increase.

A typical occurrence in public who is significant or overweight contains surplus stomach fat, just as are not real fiery. Muscle, fat, just as liver cells obstruct responding effectively toward insulin, affecting the pancreas to accommodate through creating pointless insulin. Blood glucose power lives inside the typical exhibit, since later than β-cells can produce satisfactory insulin. As insulin creation disappear since β-cell brokenness, glucose power expands chief to pre-diabetes or diabetes [27]. An abnormal increment in glucose production by the liver additionally adds to excessive blood glucose levels in particular entities with diabetes. Mostly, the pancreas releases the hormone glucagon when blood glucose just as insulin force is little. The liver has strengthened by glucagon and provides glucose which has released into the circulatory system. Glucagon levels drop, when blood glucose and insulin levels are high after a dinner and the liver stores surplus glucose proposed for some other time, varying. In a few peoples with diabetes, glucagon force lives raised than required. Raised glucagon power make the liver to generate undesirable glucose, which toss in to enhanced blood glucose force [28,29].

Recent Approaches for Management of Diabetes

Nanotechnology for diabetes

The merging of nanotechnology in the management of diabetes has given novel strategies for glucose estimation and insulin conveyance. Specialists have illustrated the advances of glucose sensors and shut circle insulin conveyance approaches in improving the diabetes management to carry out it [30] gainful in both sort 1 and type 2 diabetes. A Nano clinical tool is a microcapsule containing pores which has been a promising apparatus in the medication conveyance approach. These pores are massive to enable the passage of little atoms, for example, oxygen, glucose, and insulin yet are sufficiently little to enable the expansion of bigger safe framework atoms, for example, immunoglobulins and join bone infection particles. Microcapsules containing substitution islets of Langerhans cells, frequently obtained from swine, can embed underneath the skin of diabetes sufferers. This can incidentally reestablish the people’s fragile glucose control input circle without the need for amazing insusceptible suppressants that can leave the patient at genuine possibility for infection [31] the main issues associated with diabetes and the activity of nanomedicine in the management. The nanoparticle focused on tranquilize conveyance approach has huge improvements which integrate the increased bioavailability of drugs by concentrating on certain tissues, organs, and tumors along these areas leading the most extraordinary part of medication straightforwardly at the put on site. One of the highest mechanical complications is the adaptability of a nanoparticle. Assembling three dimensional nanostructures when varied with separate or two-dimensional layer-formed Nano surfaces is a perceived-boggling task since assembling procedures are still to placed. Another problem is that the delivery to nanoparticles may be toxic or hazardous. Worries about the potential sick effects of built nonmaterial, for example, carbon bulky balls and nanotube through inward breathing, ingestion, or consumption through the skin are developing [31]. Insulin structures an indispensable obligation for type 1 and type 2 propelled diabetes, and the rigid frameworks of insulin conveyance included diseases, agonizing organization, an poor consistence of patients. Ongoing small scale and nanotechnologies have developed the insulin organization Process through instruction of insulin conveyance establishing aspiratory, nasal, transdermal, and shut circle conveyance [32].

Statin techniques for diabetes

Statins are expressed as inhibitors of 3-hydroxy-3- methylglutaryl coenzyme obstruct the fundamental procedure of LDL cholesterol in liver, along these lines diminishing its level in the blood other than expanding sound vein lining [33]. Since the drawn out impact of diabetes incorporate the great probability of cardiovascular diseases, statins (HMG-Co A reductase inhibitor) are an essential line of treatment in diminishing cardiovascular hazard in the patients experiencing type 2 diabetes [34,35]. The lipid bringing down specialists, prevalently known as statins, cause restraint of HMG-CoA reductase explicitly and reversibly. The protein catalyzes the transformation of HMG-CoA to malonic corrosive, the rateconstraining advance in the development of cholesterol. These mixes are exceptionally powerful in lessening cholesterol levels when contrasted with dietary enhancements [36]. Statin treatment diminishes low thickness Lipoprotein (LDL) Cholesterol to a noteworthy level in this manner extraordinarily diminishing the odds of building up a coronary course ailment [37]. National Institute for Health and Clinical Excellence (NICE) and Scottish Intercollegiate Guidelines Network (SIGN) diabetes rules showed lipid bringing down treatment as essential Prevention (when used consistently) for patients with type 2 diabetes, matured over 40 (Grade A proposal), just as its thought for patients matured over 40 with type 1 diabetes (Grade B suggestion) [37]. An ongoing data distributed at the gathering of the European relationship for the investigation of diabetes in Stockholm recommends that statin treatment is less investigated and applied in patients with type 2 diabetes among an enormous American gathering of over 100,000 subjects [37]. Statins have great viability and are interesting in bringing down cardiovascular occasions in individuals with humble degrees of cholesterol and without cardiovascular ailment. The HMG-CoA reductase inhibitors or statin treatment likewise has a few detriments. The treatment has some symptoms like real brokenness and muscle issue from myositis to forthright rhabdomyolysis and hepatic brokenness which is uncommon and can endure by the patient [37]. The preliminary led with 6422 patients showed that youthful individual and those showing nonappearance of ailment showed inadequate consistence with statin treatment [34]. The treatment ought centered on more established patients since in more youthful patients saw poor people consistence. Likewise, the patients with prime hazard components and side effects of heart issues ought managed with statins [38]. Reports have proposed that statins may raise the glucose levels decently and lead to diabetes mellitus [39].

Despite displaying great toleration and less antagonistic effects, statins may cause reactions like myopathies and increment in levels of liver chemicals in type 2 diabetes [40,41].

Stem cell technology: A novel therapeutic approach

The interest to detect a potential restorative for diabetes has in the great run investigated different new logical fields of exploration with the foundational microorganism innovation being one of them. I understand it that both type 1 and type 2 diabetes arise from the cell reduction of the pancreatic cells, contributing to about inadequate insulin emission. The techniques should direct on either eliminating the abnormalities in pancreatic cell or raising the affectability of the body cells to the action of insulin. cell substitution techniques provide a novel source while current procedures focusing on islet cells and pancreas transplantation have diminished because of shortage of benefactor organs [42]. In contrast in type 1 diabetes, which have contributed to about via immune system devastation of pancreatic cells, type 2 diabetes results from irregularities in cells move along with insulin obstruction in fringe organs [43]. Mesenchymal immature microorganism (MSC) management has grown as a suggested remedy in the therapy of type 1 diabetes because of its immunosuppressive nature. We have found MSCs to show immunomodulatory affects both in vitro and in vivo conditions because of present approach and establishment of solvent markers [44-47]. MSCs might break up into various mesenchymal cell genetics. The hematopoietic undeveloped cells are the multipotent immature microorganisms that can offer ascent to all the cell type in blood and furthermore have an immunomodulatory impact. The transplantation of hematopoietic undifferentiated organism has end up being a promising restorative, carrying about development in cell function in recently analyzed sort 1 diabetic patients [48]. Further researches have determined that the starter pluripotent stem (iPS) cells can be found from type 1 diabetic patients by reviving their grown-up fibroblasts with three interpretation factors (OCT4, SOX2, and KLF4). The cells identified as diabetes actuated pluripotent stem cells; (DiPS) are pluripotent and be adequate to break into insulin delivering cells. This is significant in type 1 ailment showing and cell substitution treatments [49]. Publication of Diabetes Research Some examinations have showed that bone marrow determined MSCs can split into insulin creating cells both in vitro and in vivo [50-52]. The hugeness of individual early stage immature microorganisms (ESCs) in the management of diabetes has got in great concern for their pluripotent nature and broad scope creation of different cell heredities in communities. The research has different confinements since there is nonattendance of good techniques for constructing explicit cell types, immunological dismissal of the emigrated cells, and concern in cleaning of explicit genealogies [53]. Further concerns cover the uncontrolled multiplication of transplanted undeveloped foundational microorganisms into a specific sort, when they have removed [54]. Regardless of its complex restrictions both necessary and proper, the application of immature microorganism innovation holds tremendous opportunities in management of diabetes.

Gene technique for diabetes

The pattern of trials prompting cloning and diction of insulin in living cells during the 1970s was a gigantic revolution in treatment and application of quality approach in the management of diabetes have suggested as a dilemma. Managing the sugar levels is the most important perspective in the management, which additionally reduces the complications associated with the disorder [44-46]. Substantial quality management comprising the natural cells of the body incorporates two approaches for quality conveyance. It describes the first recognized as ex vivo quality management as the one in which it excludes the tissues from the body; the productive aspect has enclosed in vitro and later have fixed back in the body while the in vivo treatment comprises including quality treatment vectors legitimately to the patients by subcutaneous, intravenous, or intra bronchial courses, or by nearby infusion [55]. The utilization of ex vivo treatment concentrates on the growing of cells which have the properties of cells, for example, insulin delivering cells [56]. This medication has additionally applied to produce cells for transplantation. The problem lies in the separate of precisely expelling the tissue from the patient and re statement of the hereditarily changed tissues once again into the body of the patients [55]. We have considered type 1 diabetes results from auto resistant obliteration of insulin integrating pancreatic cells and islet transplantation as a potential claim for the treatment. The innovation of insulin quality treatment substitutes cell performance by producing insulin secretory non- cells, not defenseless against immune system returns, providing an immediate restorative process for type 1 diabetes [57]. The in vivo quality management is the approach for determination as a therapeutic procedure since it is less compound and the vector comprising the standard aspect has embedded into the patient, however the improvement of protected (not toxic to have) and successful vectors stays as a challenging task for quality professional. Directly, the approaches for in vivo treatment include three methods: hereditary transfer of glucose bringing down qualities which are non-insulin in character. By and by, the processes for in vivo treatment incorporate hereditary transfer of glucose bringing down qualities which are non-insulin in nature and purpose of glucose bringing down qualities: an enhancer of glucose control by liver or skeletal muscles and an avoidance of glucose Production by the liver [55]. For example, glucokinase as a transgene is getting to have glucose bringing down impact in the liver [58]. It was a possibility that the quality Gck improves glucose use by the body [59]. It had accepted the genetic change of glucokinase as an additional therapy in the management of diabetes [60]. In another method which have looked at leading the glucose production in liver, a condition recognized as “protein focusing to glycogen” (PTG) it was a help to reduce over glucose to glycogen [61,62]. The PTG protein has a place with the group of glycogen focusing on subunits of protein Phosphatase-1 which controlled the metabolism of glycogen. Examinations acted in rodents have showed that adenoviral intervened PTG move animates glycogen blend in the liver and diminishes blood glucose levels in rodents. This has been considered as a remedial methodology for diabetes [61]. Other territories of hereditary building incorporate exchange of qualities which demonstrate reaction to glucose and the utilization of quality treatment to prompt cells creation in the liver [55]. The glucose responsive qualities that have been controlled to improve transformation of proinsulin to insulin and those which after adjustment display articulation demonstrate reactions To blood glucose level [63,64]. The liver cells don’t deliver hormones which convert proinsulin to insulin; thusly, new proteolytic cleavage locales have been fused into the proinsulin atom, perceived by a protease, furin that is available in many tissue frameworks, including liver [65-67]. The insulin quality can be changed to encode insulin which has singlechain [68] having 20-40% action of ordinary develop Insulin. Research has additionally been done to actuate the union of cells arrangement in the liver. Kojima et al. [53] detailed that it is conceivable to initiate the development of cells by the endocrine cells by conveying islets explicit translation factors [69,70]. The guideline of insulin creation and its control stays as a troublesome undertaking since the information about insulin digestion is considerably less [71]. The system focusing on induced cells neogenesis is by all accounts a promising methodology as a helpful for diabetes, since it can offer an answer for the autoimmunity in type 1 diabetes [72-74].

Herbal therapy

Researchers have suggested the management of homegrown prescriptions to use insulin subordinate and non-insulin subordinate diabetes since the times of history. Plants having antidiabetic properties might be useful as extra to the present medications or as a planned wellspring of new hypoglycemic mixes. Since times of history, it becomes applied naturopathic treatments for individual wellbeing diseases and carry on picking up character in the present field ever. Old study uncovered that diabetes was a recognized illness since Brahmi period and gets a note in Ayurvedic writing, Sushruta Samhita written in fourth and fifth hundreds of years BC [75]. It described two types of diabetes: one genetic and the other because of dietary carelessness [75]. Herbal remedies are getting too well recognized among the bulk for being financially savvy and with comparatively few opinions. Although plant based remedies have used in dealing with infections throughout the world, the equipment of very of the herbs is even to identify and distributed [76]. Many new bioactive medications disconnected from plants having hypoglycaemic affects exhibit antidiabetic action comparable to and earliest in a while naturally more intense than related to oral hypoglycemic specialists, for example, daonil, tolbutamide, and chlorpropamide. Many other dynamic operators got from plants have been little portrayed [77]. Grover et al. [72] hypothesized that plants having antidiabetic exercises are of vital enthusiasm for Ethnobotanical people group as they have perceived to contain Valuable restorative properties in different parts and separate them have produced an altered level of hypoglycemic and antihyperglycemic movement. The bioactive constituents detected in many plants species have disentangled for intended use as medications, lead mixes, or pharmacological specialists. These customary methodologies may provide a characteristic key to open diabetic entanglements [78-80]. The synthetic constructions of a phytochemical assume an essential activity in its antidiabetic action. A few plants animal varieties being a significant wellspring of terpenoids, flavonoids, phenolics, Coumadin’s, and other bioactive constituents have showed a reduction in blood glucose levels as exhibited By Jung et al. [74]. A few plants like Allium sativum Linn. (Liliaceae), Gymnema sylvestre (Retz.) Schult (Asclepiadaceae), Murraya koenigii (L.) Spreng. (Rutaceae), Allium cepa (Liliaceae), Withania and Ferula foetida Linn. (they have found Umbelliferae to have antidiabetic properties when observed in test models of diabetes. The antidiabetic Somnifera dunal (Solanaceae), properties of G. Sylvester, had talked about [81,82] because of its influence in diabetes management and the executives.

Discussion

Lately, diabetes has developed into an important medical issue around the life, affecting individuals over all ages, sex, ethnicities, and races, and its frequency has been growing at a disconcerting rate. The related entanglements of manufactured medications have lead to a movement towards finding regular assets indicating hostile to diabetic movement. In this manner, numerous different plants have been applied separately or in explanations for management of diabetes and its complications.

Previous study determined it that around 1300 patients with type 1 diabetes get whole organ (pancreas) raft and appearn’t take insulin implantation anyway the passion for organs transplantation is higher than evenly. Another risk aspect is the excusal of transplanted organ; thusly, constant has produced strong immunosuppressive drugs which can lead to diverse real infirmities [83]. For the establishment of type 2 diabetes, an inside and out it requires watched glycemic control. The desire to manage the dynamic decomposition of β cell function is significant since it can lead to lost glycemic management. Common meds and insulin are active yet can’t resolve the relevant metabolic and glucoregulatory dysfunctions. The risk of diabetes is extending bit by bit and clear and focused on combinational treatment is the need for urgent, particularly incretin based management and peptide analogs. This may improve and spare β cell limit and interrupt the expansion of type 2 diabetes [84]. In the present time frame, the sufficiency and performing the new medication will depend upon its strength to treat/ease at any rate one of the metabolic disrupting affects whether extended construction of insulin or restore in glucose take-up and controlled by the periphery tissues particularly skeletal muscle. Other than other terms of medicine, two different classes have similarly represented as elective philosophies alone or in blends to give an Effective treatment to diabetes. The probable results of leptin treatment are one of the building patterns in the management of diabetes. It is a hormone released by adipocytes, which keeps up on the neurons inside the basic tangible structure. The individual exploits of this hormone recollect control of over the top addition for weight, by covering the confirmation of food and extending the utilization of essentialness [85]. Leptin moreover control glucose homeostasis through the authorization of leptin receptors (LEPRs) [86]. I have shown it the central tactile framework coordinates the sugar cutting down effect of Leptin; they acknowledged it the antidiabetic movement of Leptin could have influenced by neurons in the psyche concerning type 1 diabetes. Leptin treatment 8 Journal of Diabetes Research improves insulin-lacking sort 1 diabetes by CNS-subordinate parts in mice. Another zone of medicine insect joins arranging and usage of mucoadhesive microcapsules of various prescriptions like glipizide to achieve controlled appearance of the drug and its ground-breaking concentrating on. Muco adhesion has been a novel procedure in sedate movement organizing considering how it causes the moderate appearance of the drug at the action or osmosis site thusly improving the correspondence of the medicine with the basic tissue structures, overhauling the bioavailability of the prescriptions. There is no restriction to the prescription movement approaches which have followed as a potential answer for diabetes. The transdermal insulin association approach (which has made because of anguishing and obfuscated insulin treatment) keeps up reliable degrees of insulin without the stores of insulin in the skin visit with subcutaneous insulin imbuement. An investigation by Odegaard and partners revealed that established macrophages show an invaluable employment in the rule of sustaining homeostasis and suggests that polarization of the macrophages towards the elective state might be a useful possibility in the treatment of type 2 diabetes.

Conclusion

Great strides have been made clinically in the shirking, progression, and treatment of the contamination anyway no therapeutic method have been absolutely powerful till date. With new Technologies improving the treatment prospects, the mission for a feasible medication is certainly not far ahead. The expansive research provoking the revelation of the pathway characteristics adding to the progression of the illness and the sequencing of complete genomes have changed the diabetes ask about. The progression of the strategies like the PCRs, DNA microarray, and quality knockouts with quieting has opened up another domain in the conspicuous verification of the imperfect characteristics/changes in the genome of the living thing. The extending ordinariness of diabetes all around is making a financial load on the economy of the different country. Rather than some various diseases, treatment exists for diabetes, and at whatever point regulated precisely, it is incredibly effective in lessening complexities, for instance, coronary scenes, evacuations, visual impedance, and kidney disillusionment. With the consistent research, a right therapeutic for the treatment of diabetes isn’t unachievable.

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54. Ferber S, Halkin A, Cohen H, Ber I, Einav Y, et al. (2000) Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia. Nature medicine. 6: 568-572.
55. Halban PA, Kahn SE, Lernmark Å, Rhodes CJ (2001) Gene and cell-replacement therapy in the treatment of type 1 diabetes: how high must the standards be set?. Diabetes 50: 2181-2191.
56. Meier JJ, Bhushan A, Butler PC (2006) The potential for stem cell therapy in diabetes. Pediatr Res 59: 65-73.
57. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, et al. (2003) β-cell deficit and increased β-cell apoptosis in humans with type 2 diabetes. Diabetes 52: 102-110.
58. Abdi R, Fiorina P, Adra CN, Atkinson M, Sayegh MH (2008) Immunomodulation by mesenchymal stem cells: a potential therapeutic strategy for type 1 diabetes. Diabetes 57: 1759-1767.
59. Spaggiari GM, Abdelrazik H, Becchetti F, Moretta L (2009) MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: central role of MSC-derived prostaglandin E2. Blood 113: 6576-6583.
60. Wu J, Sun Z, Sun HS, Wu J, Weisel RD, et al. (2007) Intravenously administered bone marrow cells migrate to damaged brain tissue and improve neural function in ischemic rats. Cell transplant 16: 993-1005.
61. Tyndall A, Walker UA, Cope A, Dazzi F, De Bari C, et al. (2005) Immunomodulatory properties of mesenchymal stem cells: a review based on an interdisciplinary meeting held at the Kennedy Institute of Rheumatology Division, London, UK, 31 October. Arthritis Res Ther 9: 301.
62. Voltarelli JC, Couri CE, Stracieri AB, Oliveira MC, Moraes DA, et al. (2007) Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA 297: 1568-1576.
63. Maehr R, Chen S, Snitow M, Ludwig T, Yagasaki L, et al. (2009) Generation of pluripotent stem cells from patients with type 1 diabetes. Proc Natl Acad Sci U S A. 106: 15768-15773.
64. Tang DQ, Cao LZ, Burkhardt BR, Xia CQ, Litherland SA, et al. (2004) In vivo and in vitro characterization of insulin-producing cells obtained from murine bone marrow. Diabetes 53: 1721-1732.
65. Ianus A, Holz GG, Theise ND, Hussain MA (2003) In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion. J Clin Invest 111: 843-850.
66. Ghannam S, Bouffi C, Djouad F, Jorgensen C, Noël D (2010) Immunosuppression by mesenchymal stem cells: mechanisms and clinical applications. Stem Cell Res Ther 1: 2.
67. Chien KR, Moretti A, Laugwitz KL (2004) ES cells to the rescue. Science 306: 239-240.
68. Hori Y (2009) Insulin-producing cells derived from stem/progenitor cells: therapeutic implications for diabetes mellitus. Med Mol Morphol 42: 195-200.
69. Thattet UM, Dahanukar SA (1989) Immunotherapeutic modification of experimental infections by Indian medicinal plants. Phytotherapy Research 3: 43-49.
70. Prasad SK, Kulshreshtha A, Qureshi TN (2009) Antidiabetic activity of some herbal plants in streptozotocin induced diabetic albino rats. Pak J Nutr 8: 551-557.
71. Bnouham M, Ziyyat A, Mekhfi H, Tahri A, Legssyer A (2006) Medicinal plants with potential antidiabetic activity-A review of ten years of herbal medicine research (1990-2000). Int J Diabetes & Metabolism 14: 1-25.
72. Grover JK, Yadav S, Vats V (2002) Medicinal plants of India with anti-diabetic potential. J Ethnopharmacol 81: 81-100.
73. Babu PA, Suneetha G, Boddepalli R, Lakshmi VV, Rani TS, et al. (2006) A database of 389 medicinal plants for diabetes. Bioinformation 1: 130.
74. Jung M, Park M, Lee HC, Kang YH, Kang ES, et al. (2006) Antidiabetic agents from medicinal plants. Current medicinal chemistry 13: 1203-1218.
75. Tiwari P, Mishra BN, Sangwan NS. Phytochemical and pharmacological properties of Gymnema sylvestre: an important medicinal plant. Biomed Res Int 2014.
76. Tiwari P, Sangwan RS, Mishra BN, Sabir F, Sangwan NS (2014) Molecular cloning and biochemical characterization of a recombinant sterol 3-O-glucosyltransferase from Gymnema sylvestre R. Br. catalyzing biosynthesis of steryl glucosides. Biomed Res Int 2014.
77. Tiwari P (2015) Recent trends in therapeutic approaches for diabetes management: a comprehensive update. J Diabetes Res 2015.
78. Campbell RK (2009) Type 2 diabetes: where we are today: an overview of disease burden, current treatments, and treatment strategies. J Am Pharm Assoc 49: S3-S9.
79. Elmquist JK, Elias CF, Saper CB (1999) Hypothalamic control of body weight. Neuron 22: 221-232.
80. Coppari R, Ichinose M, Lee CE, Pullen AE, Kenny CD, et al. (2005) The hypothalamic arcuate nucleus: a key site for mediating leptin’s effects on glucose homeostasis and locomotor activity. Cell metabolism 1: 63-72.
81. Huo L, Gamber K, Greeley S, Silva J, Huntoon N, et al. (2009) Leptin-dependent control of glucose balance and locomotor activity by POMC neurons. Cell metabolism 9: 537-47.
82. Morton GJ, Gelling RW, Niswender KD, Morrison CD, Rhodes CJ, et al. (2005) Leptin regulates insulin sensitivity via phosphatidylinositol-3-OH kinase signaling in mediobasal hypothalamic neurons. Cell metabolism 2: 411-20.
83. German J, Kim F, Schwartz GJ, Havel PJ, Rhodes CJ, et al. (2009) Hypothalamic leptin signaling regulates hepatic insulin sensitivity via a neurocircuit involving the vagus nerve. Endocrinology 150: 4502-11.
84. Fujikawa T, Chuang JC, Sakata I, Ramadori G, Coppari R (2010) Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice. Proc Natl Acad Sci U S A 107: 17391-17396.
85. Chowdary KP, Rao YS (2004) Mucoadhesive microspheres for controlled drug delivery. Biological and pharmaceutical Bulletin 27: 1717-1724.
86. Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, et al. (2007) Macrophage-specific PPARγ controls alternative activation and improves insulin resistance. Nature 447: 1116-1120.

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49. Kojima H, Fujimiya M, Matsumura K, Younan P, Imaeda H, et al. (2003) NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice. Nat Med 9: 596-603.
50. Ferber S, Halkin A, Cohen H, Ber I, Einav Y, et al. (2000) Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia. Nature medicine. 6: 568-572.
51. Halban PA, Kahn SE, Lernmark Å, Rhodes CJ (2001) Gene and cell-replacement therapy in the treatment of type 1 diabetes: how high must the standards be set?. Diabetes 50: 2181-2191.
52. Meier JJ, Bhushan A, Butler PC (2006) The potential for stem cell therapy in diabetes. Pediatr Res 59: 65-73.
53. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, et al. (2003) β-cell deficit and increased β-cell apoptosis in humans with type 2 diabetes. Diabetes 52: 102-110.
54. Abdi R, Fiorina P, Adra CN, Atkinson M, Sayegh MH (2008) Immunomodulation by mesenchymal stem cells: a potential therapeutic strategy for type 1 diabetes. Diabetes 57: 1759-1767.
55. Spaggiari GM, Abdelrazik H, Becchetti F, Moretta L (2009) MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: central role of MSC-derived prostaglandin E2. Blood 113: 6576-6583.
56. Wu J, Sun Z, Sun HS, Wu J, Weisel RD, et al. (2007) Intravenously administered bone marrow cells migrate to damaged brain tissue and improve neural function in ischemic rats. Cell transplant 16: 993-1005.
57. Tyndall A, Walker UA, Cope A, Dazzi F, De Bari C, et al. (2005) Immunomodulatory properties of mesenchymal stem cells: a review based on an interdisciplinary meeting held at the Kennedy Institute of Rheumatology Division, London, UK, 31 October. Arthritis Res Ther 9: 301.
58. Voltarelli JC, Couri CE, Stracieri AB, Oliveira MC, Moraes DA, et al. (2007) Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA 297: 1568-1576.
59. Maehr R, Chen S, Snitow M, Ludwig T, Yagasaki L, et al. (2009) Generation of pluripotent stem cells from patients with type 1 diabetes. Proc Natl Acad Sci U S A. 106: 15768-15773.
60. Tang DQ, Cao LZ, Burkhardt BR, Xia CQ, Litherland SA, et al. (2004) In vivo and in vitro characterization of insulin-producing cells obtained from murine bone marrow. Diabetes 53: 1721-1732.
61. Ianus A, Holz GG, Theise ND, Hussain MA (2003) In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion. J Clin Invest 111: 843-850.
62. Ghannam S, Bouffi C, Djouad F, Jorgensen C, Noël D (2010) Immunosuppression by mesenchymal stem cells: mechanisms and clinical applications. Stem Cell Res Ther 1: 2.
63. Chien KR, Moretti A, Laugwitz KL (2004) ES cells to the rescue. Science 306: 239-240.
64. Hori Y (2009) Insulin-producing cells derived from stem/progenitor cells: therapeutic implications for diabetes mellitus. Med Mol Morphol 42: 195-200.
65. Thattet UM, Dahanukar SA (1989) Immunotherapeutic modification of experimental infections by Indian medicinal plants. Phytotherapy Research 3: 43-49.
66. Prasad SK, Kulshreshtha A, Qureshi TN (2009) Antidiabetic activity of some herbal plants in streptozotocin induced diabetic albino rats. Pak J Nutr 8: 551-557.
67. Bnouham M, Ziyyat A, Mekhfi H, Tahri A, Legssyer A (2006) Medicinal plants with potential antidiabetic activity-A review of ten years of herbal medicine research (1990-2000). Int J Diabetes & Metabolism 14: 1-25.
68. Grover JK, Yadav S, Vats V (2002) Medicinal plants of India with anti-diabetic potential. J Ethnopharmacol 81: 81-100.
69. Babu PA, Suneetha G, Boddepalli R, Lakshmi VV, Rani TS, et al. (2006) A database of 389 medicinal plants for diabetes. Bioinformation 1: 130.
70. Jung M, Park M, Lee HC, Kang YH, Kang ES, et al. (2006) Antidiabetic agents from medicinal plants. Current medicinal chemistry 13: 1203-1218.
71. Tiwari P, Mishra BN, Sangwan NS. Phytochemical and pharmacological properties of Gymnema sylvestre: an important medicinal plant. Biomed Res Int 2014.
72. Tiwari P, Sangwan RS, Mishra BN, Sabir F, Sangwan NS (2014) Molecular cloning and biochemical characterization of a recombinant sterol 3-O-glucosyltransferase from Gymnema sylvestre R. Br. catalyzing biosynthesis of steryl glucosides. Biomed Res Int 2014.
73. Tiwari P (2015) Recent trends in therapeutic approaches for diabetes management: a comprehensive update. J Diabetes Res 2015.
74. Campbell RK (2009) Type 2 diabetes: where we are today: an overview of disease burden, current treatments, and treatment strategies. J Am Pharm Assoc 49: S3-S9.
75. Elmquist JK, Elias CF, Saper CB (1999) Hypothalamic control of body weight. Neuron 22: 221-232.
76. Coppari R, Ichinose M, Lee CE, Pullen AE, Kenny CD, et al. (2005) The hypothalamic arcuate nucleus: a key site for mediating leptin’s effects on glucose homeostasis and locomotor activity. Cell metabolism 1: 63-72.
77. Huo L, Gamber K, Greeley S, Silva J, Huntoon N, et al. (2009) Leptin-dependent control of glucose balance and locomotor activity by POMC neurons. Cell metabolism 9: 537-47.
78. Morton GJ, Gelling RW, Niswender KD, Morrison CD, Rhodes CJ, et al. (2005) Leptin regulates insulin sensitivity via phosphatidylinositol-3-OH kinase signaling in mediobasal hypothalamic neurons. Cell metabolism 2: 411-20.
79. German J, Kim F, Schwartz GJ, Havel PJ, Rhodes CJ, et al. (2009) Hypothalamic leptin signaling regulates hepatic insulin sensitivity via a neurocircuit involving the vagus nerve. Endocrinology 150: 4502-11.
80. Fujikawa T, Chuang JC, Sakata I, Ramadori G, Coppari R (2010) Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice. Proc Natl Acad Sci U S A 107: 17391-17396.
81. Chowdary KP, Rao YS (2004) Mucoadhesive microspheres for controlled drug delivery. Biological and pharmaceutical Bulletin 27: 1717-1724.
82. Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, et al. (2007) Macrophage-specific PPARγ controls alternative activation and improves insulin resistance. Nature 447: 1116-1120.