The Traditional Systems Of Medicine And Diabetes Mellitus Biology Essay

Traditional medical specialty systems are portion of India ‘s civilization. Today the whole universe has become progressively interested in Indian Ayurveda and other traditional wellness systems. The demand for medicative workss is increasing in both developing and more-developed states as a consequence of acknowledgment of deficiency of side effects and easy handiness of many herbal drugs.

Ayurveda the traditional Indian system of medical specialty is every bit old as the Indian civilization and civilisation. The term Ayurveda means scientific discipline of life ‘s Ayur means life and Vedic literature agencies knowledge. The ayurveda trades with physical organic structure, herbal medical specialties, diet, surgery, pshycology, spiritualty and faith. Thr curative kingdom of Ayurveda is based on Tridhosa theory. They are vata, pitta and kapha harmonizing to Ayurvedic principles any perturbation in the above components may ensue to morbid province. Ayurveda has good classified Materia medica dwelling chiefly of drug of works beginning. Assorted portion of workss, roots, rootstocks, root, foliage, flowers, fruits, bark, extrudates have been employed for curative intent presently some 1250 workss find utilizations in Ayurvedic Materia medica. Earliest description of healing belongingss of medicative workss was found in Rigveda. Besides Charaka Samhita and susrutha Samhitas give extended description of assorted medicative herbs ( Kokate et al 2006 ) .

The antediluvian mending system from India has steadily increased its popularity in all over the universe. This 5000 twelvemonth old system of medical specialty recommends a combination of lifestyle direction and intervention with specific herbs to bring around assorted diseases. Plants have been the major beginning of medical specialty in Ayurveda. Indian common people medical specialties comprises legion prescription for curative intents which may be every bit varied as mending lesions, handling redness due to infections, skin lesions, Hansen’s disease, diarrhoea, itchs, veneral diseases, snake bites and ulcers etc. A complex upset like diabetes was small is talked about in facets of bar and curation, but instead direction. There are so many workss in Ayurveda, which are holding hypoglycaemic and antihyperglycemic activity. Because of leads provided by traditional medical specialty to natural merchandises that may be better than presently used allopathic medical specialty. The ancient doctors besides prescribed specific preparation for the intervention of diabetes, some of the drugs with a record of high safety and efficaciousness which have been validated late ( Bishwas NR et Al 1998, Majeed M and Prakash L 2006 ) .


The word siddha comes from siddhi, which means on object to be attained or flawlessness of celestial cloud nine. Siddhars were saintely personalities who attained proficiency in medical specialty through pattern of bhakthi and yoga. Siddha system originated from 18 siddhars Agastiar. this is the system of pre-vedic period and identified with Dravidian civilization and it is mostly curative in nature. Harmonizing to siddhantic doctors everything founds in nature have two qualities good and bad ; when they are utilised for any intent they have two actions in medical specialty. The good action is called “ Nalvinai ” and the bad action is called “ Theevinai ” . The universe originally consisted of atoms which contributed to five basic eliments, viz. Earth, H2O, fire, and ether which synchronize with the five senses of human organic structure. The designation of causative factors of diaseases is done through pulsation reading, coloring material of organic structure, survey of voice, urine scrutiny, position of digestive system and scrutiny of lingua. Siddha is essencially a psychometric system where in change as given to minerals and metals instead than works components. Herbs are used merely to triturate and calcinate metals into their bhasmam and sindooram. The deep frozen troubles in the siddha system are the deficiency of scientific proof of the curative claims based drugs utilizing standardise clinical theoretical accounts ( Kokate et al 2006 ) .


The roots of unani system go deep to the clip of good known Grecian philosophers Hippocrates and Aristotle Golen. It is known as Greco-Arabic systems of Islamic medical specialty. This system of medical specialty is originated in the 4th and 5th centuries B.C. the system is based on the two theories viz. the Hippocratic theory of four tempers and the pythagorian theory of four proximate qualities. The humoural theory of medical specialty signifiers the basic rules of unani system are blood, emotionlessness, xanthous gall and black gall, which represents the provinces of human organic structure like hot, cold, damp and dry. Many dietetic ingredients, veggies, fruits etc. are besides classified to Hot and cold.

The care of the humoural is based on the above hypothesis and medicines are given to rectify the humoural balance. The unani system of medical specialty purposes handling the cause of disease and non its symptoms. For this intent, through history the patient is recorded in add-on to his pulsation, piss, and stool scrutinies. The morbid status is considered to be due to the instability between tempers and consequently intervention is given. The unani medicative system advocates the use of of course happening herbal medical specialties ( Kokate et al 2006 ) .


Homeopathy system is newer when compared with other alternate systems and was introduced by the German physician Dr. Christian Frederick Samule Hehniman in the eighteenth century. This system is based on his rule of similar remedies like. It aims to excite organic structure ‘s critical force to such a point that the organic structure can get the better of the diseases and gets back to the normal wellness without doing any inauspicious side effects. The drug intervention in this system is non specified, but the pick of drug depends on symptoms and clinical status of patient. The symptoms are compared with similar symptoms and consequently the same infusion is given for intervention. During intervention the drug infusions are highly diluted, which is believed to do potentiation and sweetening of healing consequence. Homeopathic system in general is considerate as a slow procedure of remedy in homoeopathy ; nevertheless it ‘s the patient who is treated, non the disease ( kokate et al 2006 ) .


Naturopathy is non simply a system of intervention, but besides the manner of life, which is based on the Torahs of nature. The attending is peculiarly on feeding and life wonts, hydropathy, mud battalion, baths, massage, etc. The system of yoga is every bit old as Ayurveda. The eight constituents of yoga are restraint, observation of asceticism, physical positions, keeping of sense variety meats, take a breathing exercisings, contemplation, mediation and Samadhi. Yoga pattern have potential in betterment in better circulation of oxygenated blood in the organic structure, keeping the sense organs, betterment of societal and personal behaviour and initiation of repose and repose in the head ( kokate at al 2006 ) .


There are many drugs used in intervention of assorted upsets, most of the drugs are holding inauspicious reactions. Therefore there is a demand of more effectual and less toxic agents for the intervention of assorted complaints. Plants are some of most attractive beginnings and have been shown to bring forth promising consequence for the intervention of assorted upsets ( Joshi CS et Al 2007 ) .

Poly herbal preparations are the preparation which contains multiple ingredients of different herbal beginning. The works ingredients may hold broad spectrum of biological activities. In Ayurvedic system of medical specialty, poly herbal preparations were often used to heighten the activity or to antagonize the toxic effects of compounds from the other workss, but may besides move synergistically with other components from the same or other workss. Poly herbal therapies have interactive, potentiative, agonistic/antagonistic pharmacological agents within themselves that work together in dynamic manner to bring forth curative efficaciousness with minimal side effects. The curative end product may be due to the assorted active components with different mechanism, which can bring forth a combined action against assorted complaints including metabolic upsets ( Ebong PE et Al 2008, Chandrashekar CN et Al 2008 ) .

Diabetess MELLITUS


Diabetess mellitus is a metabolic upset characterized by hyperglycaemia, glycosuria, and negative N balance sometime ketosis. Resulting either unequal secernment of insulin, an unequal response of mark cells to insulin, or combination of these factors. Insulin lack is due to functional upset of the pancrease1.


pan-all kreas-flesh is ex post facto peritoneal duct gland and endocrinal secretory organ about 12 to 15 c.m. long and 2.5 c.m. in thickness and is connected normally by two canals, to the duodenum, pancreas divided into Head, Body and Tail. Head is ‘C ‘ form curve of duodenum, cardinal organic structure and tapering tail. As shown in Plate 1. Small canals of pancreas unite and form two canals that convey the secernment in to little bowel. In most people pancreas canals join the common gall canals from liver and saddle sore vesica and enters the duodenum as a common canal called hepatopancretic ampulla.

Pancreas is made-up of little bunchs of glandular epithelial cells, approximately 99 % of the cells are arranged in bunchs called acini, and constitute exocrine part of the organ. The cells with in the acini secrets the mixture of fluid and digestive enzymes, called pancreatic juice. And staying 1 % of the cells are organized into bunchs called islets ( islets of langerhans ) . They form endocrinal part of the pancreas. And consists of the cells that secret the endocrines Glucagon, Insulin, Somtostatin and Pancreatic Polypeptide.


1.1 Cells types in the pancreatic islets

Each pancreatic islets includes four types of endocrines, releasing cells.

1. Alpha- a cells constitutes about 20 % of pancreatic islets secretes glucagon,

2. Beta cells ( 70 % ) of pancreatic islets cells and secrets insulin.

3. Delta constitute about 5 % of pancreatic islets cells and secretes somastostatin.

4. F cells constitute the balance of pancreatic islets cells and secretes pancreatic polypeptides. Glucagon raises blood glucose degree, insulin lower blood glucose

degree, somastotatin inhibits the insulin release and pancreatic polypeptide inhibits the secernment of somastotatin.

1.2 Regulation of glucagon and insulin secernment

1. Hypoglycemia stimulate the release of glucagon and helps in transition of animal starch into

glucose in liver. ( glycogenolysis )

2. Hyperglycemia stimulate the release of insulin from beta cells of pancreatic islets.

Insulin facilitated diffusion of glucose into cells, particularly skeleton musculus fibres.

Conversion of glucose into animal starch.

Increase the aminic acids uptake by cells and increase protein synthesis.

Synthesis of fatty acids as a consequence of the blood glucose degree falls and low blood glucose degree inhibits the insulin release2.

1.3 Biosynthesis, storage, and katabolism of insulin

It is already stated that insulin is synthesized by the I?-cells of Isles of Langerhans but inside informations of the synthesis are unknown. After synthesis, insulin is stored in the I?-cells of the pancreas and the endocrine is released in a controlled and graded mode. The insulin in I? cells appears to be associated with granules of the cells. Insulin is released from the I? cells into the plasma by the action of glucose and certain other sugars. Growth endocrine appears to excite insulin secernment. Tolbutamide and other sulfonylureas enhance insulin secernment but C7 sugar, mannoheptulose, may deject its secernment. A figure of surveies suggests that glucose use in the I? cells is more or less related to insulin release. Insulin is inactivated in tissues by both enzymic and non-enzymic reductive cleavage of disulfide bonds and by proteolysis. The glutathione reductase enzyme system may be peculiarly involved in the reductive inactivation.

1.4 The function of insulin saccharide metamorphosis

By depancreatizing an animate being or in diabetes that occurs in human existences, the insulin inadequacy manifests itself in the undermentioned mode:

1. Hyperglycemia and glycosuria

2. Depletion of animal starch shops in the liver tissues

3. Lowered respiratory quotient bespeaking the deficiency of saccharide oxidization.

4. Addition in urinary N elimination declarative mood of the transition of protein into


5. The happening of propanone and I?-hydroxybutyric acid in the blood and urine owing to

faulty fat metamorphosis.

The injection of insulin will alleviate these symptoms and reconstruct to normal the deformed metabolic form.

The chief consequence of insulin is to increase the use of glucose by most organic structure tissues. In the whole animate being the most of import overall consequence of insulin quantitatively is to increase the rate of animal starch formation and oxidization of saccharide in musculuss. The primary consequence of insulin in increasing glucose use is to transport glucose across the cell membrane into the cell. Insulin has been shown to increase the incursion into the cell. Insulin has been shown to increase the incursion into cells of many monosaccharoses. Insulin appeared to advance the entry into cells of such sugars which possess the same chemical constellation at C atoms 1, 2 and 3 as does I?-glucose. The insulin consequence has been demonstrated in cats, Canis familiariss, rats, coneies and adult male and on stop, erythrocytes, bosom and skeletal musculuss, but non in encephalon. It is of involvement that insulin is non necessary in the metamorphosis of encephalon tissue.

In relation to the action of insulin in increasing the transition of sugar into the the construct of a membrane bearer system as the functional mechanism regulating the conveyance of glucose and other sugars is considered the most valid. Harmonizing to the theory, the sugar on the exterior of the cell membrane is postulated to organize a complex with a “ Carrier ” substance in the membrane. The complex so moves across the membrane. Within the cell the “ sugar-carrier ” complex dissociates and releases free sugar. The free bearer may either combine with free sugar in the cell and transport it to the extracellular fluid, or may travel back to the outside membrane to complex with free sugar and transport it into the cell.

Nothing is known about the chemical nature of the bearer. Presumably it may be a lipid character which combines reversibly with sugar molecules ; the composite formed possessing membrane solubility.

As primary action of insulin on Carbohydrate metamorphosis appears to cut down blood concentration by greatly heightening the rate of entryway of sugar to the intracellular compartment, and sing the bearer theory of sugar conveyance to be valid, the action of insulin may be implied to happen upon some constituent of the bearer system.

Insulin peculiarly facilitates the conveyance of glucose into the skeletal and cardiac musculuss and perchance into the adipose tissues. In the conveyance of glucose into the tissues such as liver, encephalon, kidney, enteric mucous membrane etc. Insulin does non look to be involved. These tissues offer much less opposition to glucose incursion. Within the cell, glucose enters the metabolic watercourse. At the initial phase the metamorphosis of glucose by and large involves phosphorylation by ATP to the glucose-6-phosphate in a reaction catalyzed by the glucokinase enzyme in the hexokinase reaction.

On add-on of unabsorbable gel-forming, hydrocolloidal polyose fibres ( such as guar gum from the seeds of ‘cluster beam ‘ ) to the diet of diabetics, reduces carbohydrate soaking up and flattens the station prandial blood glucose curve, and demands of insulin and unwritten hypoglycaemic agents are reduced, which has been reported. But big sum causes discomfort due to flatulence6.


Man ‘s being on this Earth has been made possible merely because of the critical function played by the works land in prolonging his life.

The nature has provided a complete store-house of redresss to bring around all complaints of world. Since the morning of civilisation, in add-on to nutrient, harvests, adult male cultivated herbs for his medicative demands. The cognition of drugs has accumulated over 1000s of old ages as a consequence of adult male ‘s speculative nature7,8.

Emerging Approachs

The development grapevine for new unwritten curative agents for Type 2 Diabetes is encouraging and continues to spread out. These intensive research and development attempts are in response to the increasing prevalence of the disease and related co-morbidities, realisation by attention givers that successful glycemic control will probably necessitate combination therapy, a turning apprehension of the pathophysiology of the disease, and the designation and proof of new pharmacological marks. These marks include receptors and enzymes that: heighten glucose-stimulated insulin secernment, suppress hepatic glucose production, increase skeletal musculus glucose conveyance and use, addition insulin sensitiveness and intracellular insulin signaling, and cut down circulating and intracellular lipoids. Due to their promise for future clinical success and because they exhibit mechanisms of action distinct from current therapies, some of the emerging attacks will be highlighted here.

PPAR I±/I? double agonist

Glucagon like peptide-1 ( GLP-1 ) endocrine

Dipeptidyl protease IV inhibitors

HGO Inhibitor

I?3- Adrenoreceptor Agonist

I± – Lipoic acid

Liver selective glucocorticoid adversaries

PTP inhibitors

A. PPAR I±/I? double agonist 3

These agents are shown to better the hyperglycaemia and lipemia associated with Type 2 Diabetes. In add-on to their benefit on lipoids the activation of PPARI± may extenuate the weight addition induced by PPARI? activation.So this double agonist is supposed to supply linear and perchance interactive effects.

First literature study of a balanced PPAR I±/I? double agonist was KRP-297 ( MK-767 ) , a TZD derived function that was reported to adhere PPARI± and PPARI? with an affinity of approx. 0.230 and 0.33 I?M severally and to trans activate PPARI± and PPARI? with authorities of 1.0 and 0.8 I?M followed by phenylpropionic acid based PPAR I±/I? double agonists Tesaglitazar ( AZ-242 ) by Astra Zeneca, reportedly in stage III clinical test, Ragaglitazar ( DRF-2725 ) by Dr.Reddy ‘s Research Foundation, reportedly completed Phase I™I™ clinical test but clinical development being terminated due to an incidence of vesica tumours in gnawers. LY-510925 is a consequence of collaborative attempt of Ellily Lilly and Ligand Pharmaceuticals, Muraglitazar ( BMS -298585 ) is disclosed by Cheng et Al.

B. Glucagon like peptide-1 ( GLP-1 ) endocrine

It is the incretin endocrine moving via GLP-1 receptor ( a G-protein conjugate receptor ) . When blood glucose degrees are high this endocrine stimulates insulin secernment and biogenesis and inhibits glucagon release taking to cut down hepatic glucose end product. In add-on it serves as an “ ileal brake ” , decelerating stomachic voidance and cut downing appetite. GLP-1 has figure of effects on ordinance of I?-cell mass: stimulation of reproduction and growing and suppression of programmed cell death of bing I?-cells and neogenesis of new I?-cells from precursors. Therefore, GLP-1 therapy for the intervention of Type 2 Diabetes is an country of active research.

There are two sub-classes of GLP-1 in clinical development.One is natural GLP-1 and the other is exendin-4, a peptide agonist isolated from the venom of lizard and is more powerful than natural GLP-1. Some of the compounds developed so far are: Exenatide ( AC2993 ) is under stage I™II clinical test developed by Lilly and Amylin, Liraglutide ( NN2211 ) , is under stage I™I™ clinical test by Novo Nordisk, CJC1131 is under stage I / I™I™ clinical test by Conjuchem, ZP10 is under stage I / I™I™ clinical test by Zealand.

C. Dipeptidyl protease IV inhibitors 8

The function of DPP IV enzyme is to split the N-terminal 2 aminic acids of active GLP-1 to give the inactive GLP-1 amide so this debasement of GLP-1 leads to diminish in insulin secernment and biogenesis. Thus the usage of DPP IV inhibitors increases the circulating degrees of endogenous GLP-1 taking to increase insulin secernment, biogenesis and inhibits glucagon release.

Preliminary clinical consequences have been disclosed on three DPP IV inhibitors ; Isoleucylthiazolidide ( P32/98 ) , DPP-728 and LAF-237. Novartis has late developed ( NBP-LAF-237, LAF-237 ) as vildagliptin, a potent, selective, stable orally active DPP IV inhibitor with antihyperglycemic belongingss, presently in stage III clinical tests as possible new intervention for Type II Diabetes. The promise of this intervention remains to be realized as a potent and selective DPP-IV inhibitors progress through clinical surveies. 9

D. HGO Inhibitors

Hepatic glucose end product is a effect of two distinct and extremely regulated procedures gluconeogenesis and glycogenolysis. Inhibition of assorted enzymes involved in these tracts can take to ordinance of glucose degree therefore pull offing Type 2 Diabetes. Metabasis-sankyo has GP3034, a F1, 6Bpase ( fructose-1, 6-bis phosphatase ) inhibitor in stage II clinical test. Aventis and Novonordisk have reported compounds that inhibit animal starch phosphorylase. Hoffmann La Roche has reported PEPCK ( phosphoenolpyruvate carboxykinase ) inhibitor that showed suppression of glucose production in the liver cell lines.

E. I?3-Adrenoreceptor Agonist 10

These shows marked selectivity for stimulation of lipolysis and hence O and energy ingestion in skeletal musculus and adipose tissue. An initial compound, which shows first-class activity in gnawers fail in human tests due to the difference in I?3 receptor isoforms in different species. Recent cloning of human I?3 receptor has enabled companies to develop compounds

selective for I?3 receptor. SR-58611 ( Sanofi-Synthelabo ) and TAK-677 ( Takeda ) are some of the compounds in this series undergoing phase II clinical tests.

F. I±-Lipoic Acid 11

I±-Lipoic acid ( LA ) is an eight-carbon fatso acid that is synthesized in hint measures in organisms runing from bacteriums to adult male. LA maps of course as a cofactor in several mitochondrial enzyme composites responsible for oxidative glucose metamorphosis and cellular energy production. LA has been prescribed in Germany for over 30 old ages for the intervention of diabetes-induced neuropathy. Consequences from several recent controlled clinical surveies indicate that this compound is safe, good tolerated, and efficacious.

Although the exact mechanism of action of LA is unknown, in vitro informations from the research labs of Rudich and others have indicated that LA pretreatment maintains the intracellularlevel of reduced glutathione ( the major intracellular antioxidant ) in the presence of oxidative emphasis, and blocks the activation of serine kinases that could potentially intercede insulin opposition. Therefore, one possible account for the protective effects of LA might be related to its ability to continue the intracellular oxidation-reduction balance, thereby barricading the activation of repressive stress-sensitive serine kinases including IKKbeta. This stress-sensitive kinase is a important regulator of the written text factor atomic factor-kappaB ( NF-kappaB ) , a major mark of hyperglycaemia, cytokines, reactive O species, and oxidative emphasis. The deviant ordinance of NF-kappaB is associated with a figure of chronic diseases including diabetes and coronary artery disease. Furthermore, LA and other agents that interfere with the relentless activation of the NF-kappaB tract appear to be promising attacks to increase insulin sensitiveness, and possibly even as interventions for complications of diabetes in which NF-kappaB activation has been implicated.

G. Liver Selective Glucocorticoid Antagonists 1

Glucocorticoids rise blood glucose degrees by functionally antagonising the action of insulin, thereby suppressing glucose disposal and advancing hepatic glucose production and

end product. So the attacks towards liver selective glucorticoid adversary have possible function in the direction of Type II Diabetes Mellitus. Mifepristone has shown glucocorticoid antagonist action and few other similar compounds have been tested in which A-348441 showed decrease in glucose degrees and improved lipid profiles in an carnal theoretical account of diabetes.

H. Protein Tyrosine Phosphatase 1 B Inhibitors ( PTP-1B )

Protein tyrosine phosphatase 1B emerged merely four old ages ago as a new drug mark for the intervention of diabetes and fleshiness.

PTP1B enzyme belongs to the household of tyrosine phosphatase which consists of 90 members. It contain a catalytic cystein residue and localized to the endoplasmic reticulam with its phosphate sphere directed towards the cytol. It play an of import function in the ordinance of signal transduction tracts and the phosphorylation of proteins. PTPase dephosphorylate the activated insulin receptor, rarefying the tyrosine kinase activity and therefore affect in Type 2 Diabetes.

PTP1B inhibitors have been shown to increase insulin receptors tyrosine phosphorylation. It exerts insulin like consequence invitro and invivo and decreases hyperglycaemia in insulin deficient animate beings. The recent presentation shows that mice missing PTP-1B have enhances insulin sensitiveness. Furthermore, when fed a high diet, these mice maintained insulin sensitiveness and were immune to fleshiness, proposing that suppression of PTP 1B activity could be a fresh manner of handling Type 2 diabetes and fleshiness. Discovery of small-molecule inhibitors has been pursued extensively in both academe and industry and a figure of really powerful and selective inhibitors have been identified.

PTPase have been inhibited by experimentation utilizing a assortment of mechanisms and chemical entities. PTPase can be inhibited by chemical inactivation of the active site cysteine residue common to all members of the household. This inactivation may happen via an oxidative mechanism initiated by reactive species such as pervanadate and peroxides e.g. , Bis -maltolato V. Most of early PTP1B inhibitors are phosphate-based and the most studied phosphate-based

PTP1B inhibitors are difluorophosphonates for example, Bis difluorophosphonate-phenylalanine. Thisdifluorophosphonate group was introduced as a nonhydrolyzable phosphotyrosine mimetic in 1992 by Burke and coworkers.2- ( Oxalylamino ) -benzoic acid ( OBA ) e.g. , Oxalylamino-benzoic acid was identified as a general, reversible and competitory inhibitor of several PTPase utilizing a scintillation proximity-based high throughput testing by workers at Novo Nordisk.

High-throughput showing has allowed the designation of several more PTP-1B inhibitor categories holding assorted mechanisms of action. Pyridazine derived functions such as Pyridazine parallel were identified at Biovitrum authorities in a low micromolar scope ( 5.6I?M ) and over 20 fold selectivity over TC-PTP. Hydroxyphenylazole derived functions such as Hydoxyphenyl azole, with IC50 value in the micromolar scope, were claimed by Japan Tobacco. A series of azolidinediones e.g. , Azolidinediones and phenoxyacetic acid based PTP1B inhibitors e.g. , Azolidinediones have been reported by American Home Products. More late a group at Hoffmann-LaRoche described fresh pyrimidotriazinepiperidine parallels e.g. , Pyrimidotriazinepiperidine with unwritten glucose take downing consequence in ob/ob mice. The suppression of PTP1B by this category of compounds presumptively involves the oxidization of the active site cysteine of PTP1B to the corresponding sulfenic acid

Bis -maltolato V Bis difluorophosphonate-phenylalanine

Oxalylamino-benzoic acid Pyridazine parallel

Hydoxyphenyl azole Azolidinediones

Azolidinediones Pyrimidotriazinepiperidine

Despite good biological mark proof, planing PTP-1B inhibitors as unwritten agent is disputing because of the extremely charged nature of the catalytic sphere of the mark. Furthermore the development of selective, powerful and bioavailable inhibitors of PTP-1B will be a formidable challenge although some of the basis has now been laid out.4