Diabetes may be associated with symptoms or without symptoms depending on the severity of the metabolic abnormality. Some common symptoms are thirst, polyurea and weight loss. It may also progress to ketoacidosis and coma. The treatment area of diabetes has been divided into three stages insulin treatment undesirable stage, insulin treatment desirable stage, insulin treatment is indispensable to prevent ketosis and to sustain life. The first two stages, insulin treatment undesirable stage and insulin treatment desirable stage are said to be etiological classification. They are also termed as insulin-dependent or type 1 stage and non-insulin dependent or type 2 stages ⁴

History :

Knowledge of diabetes date back to countries before Christ, the Egyptian papyrus ebres by physician hey-Ra (1552B.C.) described an illness associated with the passage of much urine. Celsus (30B.C. TO 50 AD) recognized the disease, but it was not until two centuries later that another Greek physician the renowned aretaeus of Cappadocia⁵gave the name diabetes (a siphon). He made the first complete clinical description, as it is “a melting down of the flesh and limbs into urine, In 160 AD the greed physician Galen of Pergamum⁶ mistakenly diagnosed diabetes as an ailment of the kidneys. In the 3rd to 6^th century AD scholars in china, Japan and India wrote as a condition with polyuria in which the urine was sweet and sticky. However, although it had been known for centuries that diabetes urine tastes as sweet, it remained for willis in 1674 to add the observation“ as if imbued with honey and sugar “. In 1869, the German medical student Paul Langerhans⁷ described the detailed microscopic structure of pancreas and explained about the nine different type of cells present in pancreas. The cells are small, irregular, polygonal cells without granules, which formed numerous “zellhaufen” literally⁸ cell heaps and he measured the cell 0.1 to 0.24mm in diameter throughout the gland Frederick Allen⁹ in 1919, he prescribed low calorie diets as little as 450 calories per day to 100 diabetes patients on a near “starvation diet” then he understood that reducing caloric intake caused diabetics to excrete less glucose in the urine. This diet could actually cure some overweight type 2 diabetes patients then he published, total dietary regulations in the treatmentof diabetes, In 1920, October 31, Frederick Banting¹⁰ conceives the idea of insulin after reading Moses Barrons “the relation of the islets of Langerhans to diabetes with special reference to the case of pancreatic lithiasis”and the work of Nanyn, Minkowski, Opie, Schafer, and other authors had indicated that diabetes was caused by the lack of a protein hormone secreted by the islets of langerhans in the pancreas, the hormone was named as insulin by Schafer¹¹. Based on the reference Dr. Banting and his assistant Charles Best continues his research using a murky concoction of canine pancreas extracts on de- pancreatized dogs.

DEFINATION:

A] Diabetes is a disease in which levels of blood glucose, also called blood sugar, are above normal. People with diabetes have problems converting food to energy. Normally, after a meal, the body breaks food down into glucose, which the blood carries to cells throughout the body. Cells use insulin, a hormone made in the pancreas, to help them convert blood glucose into energy. People develop diabetes because the pancreas does not make enough insulin or because the cells in the muscles, liver, and fat do not use insulin properly, or both.¹²

B] The term diabetes mellitus describes a metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. The effects of diabetes mellitus include long–term damage, dysfunction and failure of various organs. Diabetes mellitus may present with characteristic symptoms such as thirst, polyuria, blurring of vision, and weight loss. In its most severe forms, ketoacidosis or a non–ketotic hyperosmolar state may develop and lead to stupor, coma and, in absence of effective treatment, death. Often symptoms are not severe, or may be absent, and consequently hyperglycaemia sufficient to cause pathological and functional changes may be present for a long time before the diagnosis is made. The long–term effects of diabetes mellitus include progressive development of the specific complications of retinopathy with potential blindness, nephropathy that may lead to renal failure, and/or neuropathy with risk of foot ulcers, amputation, Charcot joints, and features of autonomic dysfunction, including sexual dysfunction. People with diabetes are at increased risk of cardiovascular, peripheral vascular and cerebrovascular disease.

Several pathogenetic processes are involved in the development of diabetes. These include processes which destroy the beta cells of the pancreas with consequent insulin deficiency, and others that result in resistance to insulinaction. The abnormalities of carbohydrate, fat and protein metabolism are due to deficient action of insulin on target tissues resulting from insensitivity or lack of insulin^.13

C] It is metabolic disorder characterized by hypeglycemia glycosouria hyperlipaemia, negative nitrogen balance and sometime ketonaemia .A wildesread pathological change is thickening of capillary basement membrane, incease in vessel wall matrix and cellular proliferation resulting in vascular complication like lumen narrowing, early artherosclerosis, sclerosis of glomarular capillaries, retinopathy, neuropathy and peripheral vascular insufficiency. ¹⁴

DIGNOSIS:

The clinical diagnosis of diabetes is often prompted by symptoms as follows

1) Increased thirst and urine volume,

2) Unexplained weight loss

3) In severe cases, drowsiness and coma; high levels of glycosuria are usually present.¹³

4] Tiredness

5] Appetite often increases (especially in Type 1 diabetes)

6} Itchiness, especially around the genital

7] Recurrent infections on the skin eg boil ¹⁵

How is a diagnosis made?

The main diagnostic criteria for diabetes is taking a blood test to measure glucose, either when you have been fasting or at other times of the day.

Diabetes - diagnostic tests:

1] Oral glucosetolerance test(OGTT):

The diagnosis of diabetes can be made on the basis of individual response to the oral glucose load, commonly referred to as oral glucose tolerance test(OGTT)

A]Preparation of the subject for OGTT :

The person should have been taking carbohydrate-rich diet for at list 3 day prior to the test. All drug known to influence carbohydrate metabolism should be discontinued (for at least 2 day) .the subject should avoid strenuous exercise on previos day of the test. He/she should be in an overnight (at least 10hr) fasting state. During the course of OGTT, the person should refrain from smoking and exercise.¹⁶

B]Procedure for OGTT:

Glucose tolerance test should be conducted preferably in the morning (ideal 9 to 11am).a fasting blood sample is drawn and urine collected. The subject is given 75 g glucose orally, dissolved in about 300 ml of water, to be drunk in about 5 minutes. Blood and urine samples are collected at 30 minute interval for at least 2 hour. All blood samples are subjected to glucose estimation while urine samples are qualitatively tested for glucose ^.9 diagnostic criteria for oral glucose tolerance test (WHO1999) are shown in table no1. Diagnostic criteria for oral glucose tolerance test (WHO1999)¹⁶

Plasma glucose concentration as mmol/l (mg/dl)

Condition	Normal	Impaired glucose tolerance	Diabetes
Fasting	<6.1 (<110)	<7.0 (<126)	>7.0(<126)
2 hour after glucose	<7.8 (<140)	<11.1(<200)	>11.1(>200)

C] Other relevant aspects of OGTT :

1. for conducting OGTT in children , oral glucose is given on the basis of weight (1.5to1.75 g/kg)

2. in case of pregnant women , 100 g oral glucose is recommended . further , the diagnostic criteria for diabetes in pregnancy should be more stringent than WHO recommendation

3. In the mini GTT carried out in some laboratories, fasting and 2hrs. sample (instead of half hr. intervals ) of blood and urine are collected.

4. In individuals with suspected malabsorption intravenous GTT is carried out .

5. corticosteroid stressed GTT is employed to detect latent diabetes .¹⁶

2] Fasting blood glucose test – blood glucose levels are checked after fasting for between 12 and 14 hours. You can drink water during this time, but should strictly avoid any other beverage. Patients with diabetes may be asked to delay their diabetes medication or insulin dose until the test is completed.¹⁷

3] Random blood glucose test – blood glucose levels are checked at various times during

the day, and it doesn’t matter when you last ate. Blood glucose levels tend to stay constant in a person who doesn’t have diabetes.¹⁷

Diabetes diagnostic testing facing following problem

a]Feeling faint or nauseous at the sight of blood or needles

b]Bleeding and bruising at the injection site

c] Infection of the skin at the injection site

d]Multiple injection sites if collecting the blood is difficult

e] Rarely, a reaction following the oral glucose tolerance test if the patient has diabetes

mellitus or hypoglycaemia (low blood sugar levels) – medications may be needed¹⁷

Type of diabetes:

Two major type of diabetes mellitus are:

Type1 diabetes:-

Insulin dependent diabetes mellitus(IDDM),juvenile onset of diabetes mellitus ¹⁴.The process of beta cell destruction inpancreatis islets which may ultimately leads totype1 diabetes. In this type of condition insulin is required for the survival to prevent the development of ketoacidosis, coma and eventually death. The process of beta-cell destruction can be detected but before clinically manifesting type1 diabetes the patient may be metabolically normal. The presence of anti-GAD (Glutamicacid Decarboxylase), islet cell or insulin antibodies characterize the type 1 diabetes. This identifies the autoimmune process that leads to betacell destruction. Type1 diabetes occurs in young age with acute onset, but it may also occur in any age, sometimes with slow progression. It is amultifactorial disease in which environmental factors may also trigger an immune mediated destruction of the pancreatic beta-cells in genetically susceptible individuals. Type1 diabetes shows it’s presence in adult life in majority of cases though it is traditionally been considered a disease of childhood¹⁸. In the year of 2000 a study has been carried out to find the world wide prevalence of type 1 diabetes. The prevalence rate has been found to be 4.5% among 75.1 million of sample population.¹⁹This type is less common and has a low degree of genetic predisposition.¹⁴

Type2 Diabetes:-

Type 2 diabetes or non-insulin dependent diabetes mellitus (NIDDM),maturity onset diabetes mellitus ¹⁴ is most common form of diabetes and is characterized by disorders of insulin action, insulin secretion, either of which may be the predominant feature. Decreased insulin secretion and decreased insulin resistance are involved in pathogenesis of type 2 diabetes . Noticeable symptoms of diabetes often not serve enough to provoke it. This make the diagnosis of type2 diabetes undiagnosed for many years. Majority of patients with type 2 diabetes are obese and also obesity itself causes or aggravates insulin resistance ^20,21. A national study on 2000 AD has been predicted the prevalence of type 2 diabetes in India

Gestational diabetes (or gestational diabetes mellitus, GDM):-

It is a condition in which women without previously diagnosed diabetes exhibit high blood glucose levels during pregnancy (especially during third trimester of pregnancy). Gestational diabetes is caused when the body of a pregnant woman does not secrete excess insulin required during pregnancy leading to increased blood sugar levels.

Gestational diabetes generally has few symptoms and it is most commonly diagnosed by screening during pregnancy. Diagnostic tests detect inappropriately high levels of glucose in blood samples. Gestational diabetes affects 3-10% of pregnancies, depending on the population studied.²²As with diabetes mellitus in pregnancy in general, babies born to mothers with gestational diabetes are typically at increased risk of problems such as being large for gestational age (which may lead to delivery complications), low blood sugar, and jaundice. Gestational diabetes is a treatable condition and women who have adequate control of glucose levels can effectively decrease these risks.Women with gestational diabetes are at increased risk of developing type 2 diabetes mellitus (or, very rarely, latent autoimmune diabetes or Type 1) after pregnancy, as well as having a higher incidence of pre-eclampsia and Caesarean section;¹⁶ their offspring are prone to developing childhood obesity, with type 2 diabetes later in life. Most patients are treated only with diet modification and moderate exercise but some take anti-diabetic drugs, including insulin.²³

Table 2: Types of Diabetes

Diabetes type	Reason	Occurrence
Type 1	Destruction of beta cell in pancreas	Childhood age ,adult age
Type 2	Insufficient insulin action/secretion	Adult age ,young age
Gestestational diabetes	Hyperglycemia due to the carbohydrate in-tolerance in pregnancy	Pregnancy

Other type of diabetes:

Primary diabetes : classified in following sub group

(a) potential diabetic (prediabetic):- The individual with normal glucose tolerance test but with a family history of the disease .

(b) Latent diabetic (suspected diabetic):-the individual with a normal glucose tolerance test but he had a diabetic type of glucose tolerance curve after cortisone administration , pregnancy or severe infection.

(c) Asymptomatic diabetic ( chemical diabetic ):- The individual with a diabetic glucose tolerance curve but without signs of diabetes .

Secondary diabetes :

Damage to pancreas : in chronic pancreatitis and pancreatic carcinoma , the pancreatic destruction result in absolute insulin deficiency .

Presence of insulin antagonists: excess growth hormone secretion (acromegaly) or excess glucocorticoid secretion (cushing syndrome )act as antagonists to insulin .

Inhibition of insulin secretion : The secretion of insulin by beta cell is inhibited by the excess secretion of epinephrine and thyroxine resulting in the breakdown of liver glycogen .²⁴

Treatment of diabetes:

CLINICAL MANAGEMENT:

Diet is the cornerstone of the management of diabetes,regardless of the severity of the symptoms or the type ofdiabetes. Exercise is also an important component inmanaging diabetes, particularly in obese individualswith NIDDM who may have a component of insulin resistanceas a consequence of obesity. Treatment regimens that have proved effective include a calorierestricteddiet in combination with exogenous insulin or oral hypoglycemic drugs. However, since diet, exercise,and oral hypoglycemic drugs (Table 67.2), often becauseof noncompliance by the patient, will not always achieve the clinical objectives of controlling the symptomsof diabetes, insulin remains universallyimportantin therapeutic management. The administration of insulin is required for the treatment of type I (IDDM)and in cases of type II (NIDDM) that are refractory tomanagement with oral hypoglycemic drugsBecause the spectrum of patients with diabetes extendsfrom the totally asymptomatic individual to one with life-threatening ketoacidosis, therapeutic managementmust be highly individualized. An important objectiveis to maintain aglucose level as close to normalas possible without producing frequent hypoglycemiaor overly restricting the patient’s lifestyle.Many diabeticsaim to achieve an average blood glucose below 150 (hemoglobin A1c _ 7%). Unstable or ketoacidosispronediabetics are difficult to maintain with a singledose of either intermediate- or long-acting insulin; they usually require multiple injections of combinations ofshort-, intermediate-, and/or long-acting insulin preparations.

TABLE 3.Antidiabetic Drug:²⁵

Augment

Insulin Supply

Enhance

Insulin action

Delay Carbohydrate

Absorption

Sulfonylureas meglitinides

Insulins

Biguanides Thiazolidine-

diones

Glucosidase inhibitors

Insulin Preparations:

Commercially available insulins differ in their onset of action, maximal activity, and duration of action (Table67.3).They can be classified as rapid acting (0–5 hours), short acting (0–8 hours), intermediate acting (2 to 16hours), and long acting (4 to 36 hours). Human insulin(e.g. Humulin, Novolin) produced by rDNA technology is now widely available and has largely supplanted in-768 VII DRUGS AFFECTING THE ENDOCRINE SYSTEM67 Insulin and Oral Drugs for Diabetes Mellitus 769 insulins derived from beef and pork. Some insulins havebeen modified through genetic engineering to produceinsulin analogues, derivatives that possess novel pharmacokinetic properties (lispro, insulin aspart, and insulinglargine).The duration of action can vary with factorssuch as injection volume, injection site, and blood flow at the site of administration.Rapid-acting insulin analogues (lispro, insulin aspart [Humalog, Novolog]) have been engineered to containamino acid modifications that promote rapid entry intothe circulation from subcutaneous tissue. They begin to exert their effects as early as 5 to 10 minutes after administration.Lispro insulin, the first insulin analogue to be approved in Europe and the United States, is produced byswitching the positions of lysine-proline amino acidresidues 28 and 29 of the carboxy terminus of the _chain.Lispro insulin displays very similar actions to insulin andhas a similar affinity for the insulin receptor, but it cannotform stable hexamers or dimers in subcutaneous tissue,which promotes its rapid uptake and absorption.Insulin aspart is absorbed nearly twice as fast as regular insulin. In addition to binding to the insulin receptor,insulin aspart also binds to the insulinlike growth factor (IGF-1) receptor, which shares structuralhomology with the insulin receptor. However, at physiological and pharmacological levels, the metabolic effects of insulin aspart predominate. Both lispro insulinand insulin aspart have relatively fast onsets and short half-lives,making them ideal for controlling the upward glycemic excursions that occur immediately after mealsin diabetics.Short-acting or regular insulins (Humulin R,NovolinR) take 30 minutes to begin to exert their effect but have a longer duration of action than does either lisproinsulin or insulin aspart. Typically, regular insulin is administeredseveral minutes before a meal; it has a more gradual onset of action and is designed to control postprandialhyperglycemia. Regular insulin is primarilyused to supplement intermediate- and long-acting insulin preparations; however, it is also the preparation of choice for glucose management during surgery, trauma,shock, or diabetic ketoacidosis. Regular insulin can be given intravenously when emergency diabetes management is required (e.g., diabetes ketoacidosis). Promptinsulin zinc suspension (Semilente) is also a fast-actingform of insulin, but unlike regular insulin, it should bemixed only with Lente or Ultralente insulin preparations.Rapid-acting and short-acting insulins are often administered two to three times a day or more. Theseinsulins are also employed in sliding scale insulin regimens,which supplement a person’s glucose control based on blood glucose monitoring equipment.Intermediate-acting preparations (e.g., isophane insulin suspension [NPH insulin] or insulin zinc suspension [Lente insulin]) have a more delayed onset of action,but they act longer. Conjugation of the insulin molecule with either zinc or protamine or both will convert the normally rapidly absorbed parenterally administeredinsulin to a preparation with a longer duration of action. Isophane insulin suspension (Neutral protamine Hagedorn, NPH) has a rate of absorption that has been slowed by complexing insulin with protamine, a polyvalentcation. Both NPH and Lente insulin are used to control diabetes in a variety of situations except during emergencies (e.g., diabetic ketoacidosis). Intermediateactinginsulin preparations are usually given once or twice a day Protamine zinc and extended insulin zinc suspension(Ultralente) are often referred to as long-acting insulin preparations. These insulins have more protamine and zinc in the mixture than is found in isophane insulin suspension.Insulin zinc suspension, extended (Ultralente Insulin), is quite similar to the protamine zinc insulin suspension except that it does not contain protamine.Both of these long-acting insulins have an approximate duration of action of 36 hours.Insulin glargine (Lantus) is a long-acting insulin analogue that does not use zinc or protamine to modulate insulin solubility. The introduction of two positive arginine residues at the carboxy terminus of the _-chain shifts the isoelectric point of the peptide from 5.4 to 6.7, thus creating a molecule that is soluble at pH 4 but less soluble at neutral (physiological) pH (in subcutaneous tissue). A second modification of insulin, glargine, involves the substitution of a charge-neutral glycine for a negatively charged asparagine at the amino terminal end of the _-chain; this prevents deamidation and dimerization and enhances stability at physiological pH.Injection of insulin glargine forms microprecipitates in subcutaneous tissue as the pH is raised from 4 to physiological.A steady, sustained release of insulin from the site of injection mimics the basal secretion of insulin from the pancreas. Absorption of insulin glargine commences within a few hours of injection, and there is usually little or no peak or trough in the levels of insulin glargine as it dissolves from its site of injection. Because it is necessary to maintain its acidic pH prior to injection, insulin glargine must not be mixed with any other form of insulin during injection.²⁵Pharmacokinetic Properties of Insulin Formulations and Analogues

TABLE 4.Pharmacokinetic Properties of Insulin Formulations and Analogues²⁵

Drug	Onset	Peak	Duration
Short acting Lispro(humalog)	10-20 min	1-2 hr	2-4hr
Insulin aspart (novolog)	10-20 min	1hr	3hr
Promt insulin zinc suspension (semi lent)	30-60 min	2-3 hr	5-7 hr
Intermediate acting Isophane insulin suspension (NPH)	1-2 hr	5-6 hr	13-18 hr
Insulin zinc suspension(lente)	1-3 hr	4-8 hr	13-20 hr
Long Acting Extended Zn Suspension (Ultralente)	2–4 hr	8-14hr	18-36hr
Insulin Glargine (Lantus)	2hr	NONE	Up to 24 hr

ORAL AGENTS FOR TREATING DIABETES MELLITUS:

Although insulin has the disadvantage of having to be injected, it is without question the most uniformly effective treatment of diabetes mellitus. Some milder forms of diabetes mellitus that do not respond to dietmanagement or weight loss and exercise can be treated with oral hypoglycemic agents. The success of oral hypoglycemic drug therapy is usually based on a restorationof normal blood glucose levels and the absence of glycosuria. Traditionally, the term oral hypoglycemic was used interchangeably with sulfonylureas, but more recently the development of several new drugs has broadened this designation to include all oral medications for diabetes. Because these drugs do not have to be injected, oral agents enhance compliance in type II diabetics. These classes of drugs are not generally used in type I diabetes. The pharmacokinetic profile of oralagents for diabetes is depicated

Sulfonylureas:

Sulfonylureas are the most widely prescribed drugs inthe treatment of type II diabetes mellitus. The initial sulfonylureas were introduced nearly 50 years ago and were derivatives of the antibacterial sulfonamides.Although their structural similarities to the sulfonamide antibacterial agents are readily apparent, the sulfonylureas possess no antibacterial activity.

Mechanism of Action:

The primary mechanism of action of the sulfonylureas is direct stimulation of insulin release from the pancreatic_-cells. In the presence of viable pancreatic _-cells, sulfonylureas enhance the release of endogenous insulin,thereby reducing blood glucose levels.At higher doses,these drugs also decrease hepatic glucose production, and the second-generation sulfonylureas may possess additional extrapancreatic effects that increase insulin sensitivity, though the clinical significance of these pharmacological effects is unclear. The sulfonylureas are ineffective for the management of type I and severe type II diabetes mellitus, since the number of viable _-cells in these forms of diabetes is small. Severely obese diabetics often respond poorly to the sulfonylureas, possibly because of the insulin resistance that often accompanies obesity.

Biguanides:

Biguanides are a group of oral hypoglycemic agentsthat are chemically and pharmacologically distinct from the sulfonylureas. One biguanide, phenformin, was briefly used in the United States more than 30 years ago but was withdrawn from the market because it produced severe lactic acidosis in some patients.Metformin (Glucophage) was used in Europe for many years before it was approved for use in the United States in 1995. Metformin is the only approved biguanide for the treatment of patients with NIDDM that are refractory to dietary management alone. Metformin does not affect insulin secretion but requires the presence of insulin to be effective. The exact mechanism of metformin’s action is not clear, but it does decrease hepatic glucose production and increase peripheral glucose uptake. When used as monotherapy, metformin rarelycauses hypoglycemia.Metformin works best in patients with significant hyperglycemia and is often considered first-line therapy in the treatment of mild to moderate type II overweight diabetics who demonstrate insulin resistance. The United Kingdom Prospective Diabetes Study demonstrated a marked reduction in cardiovascular comorbidities and diabetic complications in metformintreated individuals. Metformin has also been used to treat hirsutism in individuals with polycystic ovarian syndrome and may enhance fertility in these women, perhaps by decreasing androgen levels and enhancing insulin sensitivity. Adverse gastrointestinal symptoms (nausea, vomiting, anorexia, metallic taste, abdominal discomfort, and diarrhea) occur in up to 20% of individuals taking metformin; this can be minimized by starting at a low dose and slowly titrating the dose upward with food. Like phenformin, metformin can cause lactic acidosis, but its occurrence is rare except when renal failure, hypoxemia, or severe congestive heart failure is present or when coadministered with alcohol. Metformin is also contraindicated in persons with hepatic dysfunction, but it appears to be safe for use in the hepatic steatosis that often occurs with fatty infiltration of the liver in poorly controlled type II diabetics. Two relatively new formulations of metformin are available. Glucovance is a combination of metformin and glyburide that may be helpful for diabetics who require both a sulfonylurea and metformin, and Glucophage XR is an extended-release product of metformin that may be better tolerated in some patients who are prone to gastrointestinal side effects. Metformin is usually given two to three times a day at mealtimes Another oral agent for treating diabetes mellitus are Thiazolidinediones, Biguanides, Meglitinides, _-Glucosidase Inhibitors, etc²⁵

Complications of diabetes:

Both forms of diabetes ultimately lead to high blood sugar levels, a condition called hyperglycemia. Over a long period of time, hyperglycemia damages the retina of the eye, the kidneys, the nerves, and the blood vessels.

Damage to the retina from diabetes (diabetic retinopathy) is a leading cause of blindness.

Damage to the kidneys from diabetes (diabetic nephropathy) is a leading cause of kidney failure. Damage to the nerves from diabetes (diabetic neuropathy) is a leading cause of foot wounds and ulcers, which frequently lead to foot and leg amputations. Damage to the nerves in the autonomic nervous system can lead to paralysis of the stomach (gastroparesis), chronic diarrhea, and an inability to control heart rate and blood pressure during postural changes.Diabetes accelerates atherosclerosis, (the formation of fatty plaques inside the arteries), which can lead to blockages or a clot (thrombus). Such changes can then lead to heart attack, stroke, and decreased circulation in the arms and legs (peripheral vascular disease). Diabetes predisposes people to high blood pressure and high cholesterol and triglyceride levels. These conditions independently and together with hyperglycemia increase the risk of heart disease, kidney disease, and other blood vessel complications.

In the short run, diabetes can contribute to a number of acute (short-lived) medical problems.

Many infections are associated with diabetes, and infections are frequently more dangerous in someone with diabetes because the body's normal ability to fight infections is impaired. To compound the problem, infections may worsen glucose control, which further delays recovery from infection.

Hypoglycemia, or low blood sugar, occurs from time to time in most people with diabetes. It results from taking too much diabetes medication or insulin (sometimes called an insulin reaction), missing a meal, doing more exercise than usual, drinking too much alcohol, or taking certain medications for other conditions. It is very important to recognize hypoglycemia and be prepared to treat it at all times. Headache, feeling dizzy, poor concentration, tremors of hands, and sweating are common symptoms of hypoglycemia. You can faint or have a seizure if blood sugar level gets too low.

Diabetic ketoacidosis is a serious condition in which uncontrolled hyperglycemia (usually due to complete lack of insulin or a relative deficiency of insulin) over time creates a buildup in the blood of acidic waste products called ketones. High levels of ketones can be very harmful. This typically happens to people with type 1 diabetes who do not have good blood glucose control. Diabetic ketoacidosis can be precipitated by infection, stress, trauma, missing medications like insulin, or medical emergencies like stroke and heart attack.

Hyperosmolar hyperglycemic nonketotic syndrome is a serious condition in which the blood sugar level gets very high. The body tries to get rid of the excess blood sugar by eliminating it in the urine. This increases the amount of urine significantly and often leads to dehydration so severe that it can cause seizures, coma, and even death. This syndrome typically occurs in people with type 2 diabetes who are not controlling their blood sugar levels, who have become dehydrated, or who have stress, injury, stroke, or are taking certain medications, like steroids.²⁶The main factors that increase your risk are:smokinghigh blood pressureraised levels of fats such as cholesterol in the blood. By taking measures to address these issues, you will reduce your chance of developing complications such as heart disease.²⁷

Recent development in diabetes treatment:

Insulin has been administered subcutaneous until now, although these parenteral routes are satisfactory in term of efficacy in great majority of cases, they can result in stimulation of smooth muscle cell proliferation, peripheral hyperinsulinemia and incorporation of glucose into the lipid of arterial walls. They might therefore be the causative factor in diabetic micro and macroangiopathy. Moreover, the burden of daily injection, physiological stress, inconveniences, pain, risk, cost, infection, handling problems and deposition of insulin in injecable site, lead to hypertrophy and fat deposition at the injection sites. In recent years, there has been a great deal of interest in the exploitation of non-invasive route for insulin delivery including oral²⁸, nasal^29. baccal³⁰, pulmonary³¹transdermal³², and rectal³³, ocular drug delivery³⁴.

Recent marketed insulin formulations:

A significant progress has been reported in recent past development in insulin delivery. The insulin delivery took a tremendous strep forward with approval of “Exubera” from Pfizer and Nektar therapeutics. Exubera was alternative insulin delivery system of eliminating needles. “Eligen” a oral insulin delivery system was developed by Emiphere technology. “Chisys” a chitosan based nasal delivery system developed by West pharmaceutical services to bypass degradation of insulin by oral route. There after “Exubera” a human insulin inhalation powder

developed by Pfizer and Sanofi-Aventis. Exubera weight about 115 Gms and produced a cloud of insulin powder in a clear chamber visible to the patient. This insulin powder was designed to pass rapidly into the bloodstream to regulate the body’s blood sugar level. Administration of liquid form of human insulin by microprocessor controlled inhaler (AERx) was developed by Novo Nordisk. It offers a high level of performances in a smaller and less expensive package. Finally in 2003 Alta therapeutics has announced “Passport” an insulin skin patch designed to provide continuously maintain the blood glucose level.

Future research on treatment of diabetes:

In the future researchers are looking at delivering insulin through the pulmonary system using a powder and an inhaler. Eli Lilly has just started a project with Dora Pharmaceuticals to formulate this alternative delivery system. Other researchers are examining ways of encapsulating beta cells in a semi-permeable membrane to protect them from immune attacks after transplantation. Bioengineers are working on creating artificial beta cells that secrete insulin in response to glucose. These are but a few of the roads that researchers are following to control and cure diabetes. Insulin, that complex three-D protein, holds the secrets, but wouldn’t the early researchers be astounded at the progress, and wouldn’t they jump in to continue the fight? We all continue the battle as we care for ourselves and others on a daily basis. Make sure you remain an active partner in the search for better treatments and a cure by contributing whatever and whenever possible to diabetes research. For further interesting information, mead The Discovery of Insulin by Michael Bliss (University of Chicago Press.)

REFERENCES:

1. Shukla, R., Sharma, S.B., Puri, D., Murthy, P.S. Indigenous drugs for diabetes mellitus. JK. Sci. (2000). 2(3):128-130.

2. Chandra, A., Mahdhi, A.A., Ahmad, S., Singh, R.K. Indian herbs result in hypoglycemic responses in streptozotocin-induced diabetic rats. Nutr. Res. (2007). 27:161-168.

3. Grover, J.K., Yadav, S., Vats, V. Medicinal plants of India with anti-diabetic potential. J. Ethnopharmacol. (2002). 81:81-100.

4. Kuzuya, T., Nakagawa, S., Satoh, J., Kanazava, Y., Iwamoto, Y., Kobayashi, M., Nanjo, K., Sasaki, A., Seino, Y., Ito, C., Shima, K., Nonaka, K., Kadowaki, T. Report of the committee on the classification and diagnostic criteria of diabetes

5. The Greatest Doctor of Ancient Times: Hippocrates and His Oath. Science & Children, March, 2010.

6. Medical Antiques, the practice of phisick Lithotomy.GP: General Practitioner, June, 2009

7. P. Langerhans, Untersuchungen uber Petromyzon-Planery. Freiburg: C. Tromer, 1873

8. P. Langerhans, Zur Aetiologie der Phythise. Archives of Pathological Anatomy, 1884, 97, 289–306.56-89

9. Le Temps vécu. Étude phénoménologique et psychopathologique (1933, Delachaux), Ed.: PUF-Quadrige, 1995.

10. Vers une cosmologie, Fragments philosophiques, Aubier-Montaigne, Paris, 1936.

11. Traité de psychopathologie Intr. de Georges Lanteri Laura, Ed. Les empêcheurs de penser en rond, 1966

12. diabetes.niddk.nih.gov/dm/pubs/diagnosis/diagnosis.pdf

13. .http://whqlibdoc.who.int/hq/1999/who_ncd_ncs_99.2.pdf

14. Tripathi,K.D.,2009,essentials of medical pharmacology,sixth edition ,jaypee brothers medical publisher (p)LTD,new delhi ,254-255

15. .http://www.netdoctor.co.uk/diseases/facts/diabetes.htm

16. Satyanarayana,u ., 2005, biochemisty, second edition , book and allied .(P)LTD kolkata 597-598

17. http://www.betterhealth.vic.gov.au/bhcv2/bhcpdf.nsf/ByPDF/Diabetes_diagnostic_tests/$File/Diabetes_diagnostic_tests.pdf

18. Kyvik, K.O., Nystrom, L., Gorus, F., Songini, M., Oestman, J., Castell, C., Green, A., Guyrus, G., Ionescu-Trigoviste, C., McKinney, P.A., Michalkova, D., Ostrauskas, R., Raymond, N.T. The epidemiology of type 1 diabetes mellitus is not the same in young adults as in children. Diabetologia. (2004). 47:377- 384.

19. Karvonen, M., Viik-Kajander, M., Moltchanova, E., Libman, I., Laporte, R., Tuomilehto, J. Incidence of childhood type 1 diabetes world wide. Diabetes Care. (2000). 23:1516-1526.

20. Scheen, A.J. Pathophysiology of type 2 diabetes. Acta. Clin. Belg. (2003). 58(6):335-341.

21. Seshiah, V., Balaji, V., Balaji, M.S., Paneerselvam, A., Arthi, T., Thamizharasi, Manjula, D. Prevalence of gestational diabetes mellitus in South India (Tamil Nadu) – A community based study. J. Assoc. Physician. India. (2008). 56:329- 333

22. Thomas R Moore, MD et al. Diabetes Mellitus and Pregnancy. med/2349 at eMedicine. Version: Jan 27, 2005 update.

23. Donovan, PJ (2010). "Drugs for gestational diabetes". Australian Prescriber (33): 141–4.

24. Deb , A,C., 2004, fundamental of biochemistry ,eighth edition , new central book agency (P) Ltd ,kolkata,270.

25. Craig ,C.R., ,Stitzel, R..E.,modern pharmacology with clinical application ,sixth edition

26. http://www.emedicinehealth.com/diabetes/article_em.htm

27. http://www.netdoctor.co.uk/diseases/facts/diabetes.htm

28. P.L. Starokadomskyy, I.Ya. Dubey, New absorption promoter for the buccal delivery: preparation and characterization of lysalbinic acid, Int. J. Pharm, 308,2006, 149– 154.

29. N.G.M. Schipper, J. Verhoef, S.G. Romeijn, Absorption enhancers in nasal insulin delivery and their influence on nasal cilliary functioning, J. Control. Release 21 1992, 173–186.

30. A. Bernkop-Schnürch, S, Synthesis and characterization of mucoadhesive thiolated, Int. J. Pharm, 194 ,2000, 239–247.

31. Z.C. Shen, Y. Cheng, Q. Zhang, S.L. Wei, R.C. Li, K. Wang, Lanthanides enhance pulmonary absorption of insulin, Biol. Trace Elem. Res, 75, 2000, 215–225.

32. G.C. Chiou, B.H. Li, Chronic systemic delivery of insulin through the ocular route, J. Ocul. Pharmacol, 9, 1993, 85–90.

33. M.O. Yun, H.G. Choi, J.H. Jung, C.K. Kim, Development of a thermoreversible insulin liquid suppository with bioavailability enhancement, Int. J. Pharm. 189,1999, 137– 145.

34. http://exubra.com.

Received on 24.08.2011

Accepted on 11.09.2011

Research J. Pharmacology and Pharmacodynamics. 3(6): Nov.-Dec., 2011, 345-352