Characterised Impairment Of Carbohydrate Fat And Protein Metabolism Biology Essay

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Diabetes Mellitus is one of the most common types of metabolic disorders (Harrison). The disease is characterised by impairment of carbohydrate, fat and protein metabolism either due to lack of insulin production or reduced sensitivity of the tissue receptors towards the hormone, resulting in hyperglycaemia (gyton, who).

There are two main types of diabetes mellitus, Type I and Type II.

Type I: Insulin dependent diabetes mellitus(IDDM) ,also known as juvenile onset diabetes mellitus.

It is charecterised by the destruction of B-cells within pancreatic islets, which are concerned with insulin production, required for regulation of blood glucose level. As a result of the destruction of B-cells the insulin levels drop resulting in increased blood glucose levels, causing hyperglycaemia.

Type II:Non Insulin Dependent Diabetes Mellitus(NIDDM) also known as adult onset diabetes mellitus.

In this type there is no destruction of B-cells, however the insulin level in the blood may be low, normal or even high due to reduced sensitivity or abnormality of glucose receptors or due to excess of hyperglycaemic hormone, e.g. glucagon. (HARRISON n TRIPATHI).

INCIDENCE AND PREVALENCE

No of cases of diabetes is doubling every generation. Presently it affects 5% of the world population.

There are 1.8 million people suffering from diabetes mellitus which is equivalent to 3% of U.K. population. {The Handbook of Diabetes Mellitus and Cardiovascular Disease. Marso, S.P. (Editor) 2003 Remidica Publishing London. Diabetes Contemporary issues companion. Gerdes, L.I. (Editor) 2003 Greenhaven Press Maine}

According to Who prediction for 2030, it is expected that the 366 million people will be suffering from diabetes.

Prevalence of dm is higher in men than in women but however incidence of diabetes is higher in women than in men.

In India there are 31.7million people with diabetes(WHO2000), positioned right on top globally.

The incidence of Type II dm being on d rise is its close association with obesity. (Storing up Problems: The Medical Case for the Slimmer Nation. Report of a working party 2004.Storing up Problems: The Medical Case for the Slimmer Nation. Report of a working party 2004.)

Diabetes is on its rise among the developing countries mainly because of the changing lifestyle

Global prevalence statistics for diabetes

Year

Prevalence

1935

15 million

1955

55 million

1975

70 million

1995

135 million

2004

150 million

2010

220 million

2020

239 million

2025

300 million

UK prevalence statistics for diabetes

Year

Prevalence

1940

200,000

1960

400,000

1980

800,000

1996

1,400,000

2004

1,800,000

2010

3,000,000

PATHOLOGY

Intake of the carbohydrates increases the blood glucose level.

Due to decresed insulin secretion due to some defects in pancreatic β-cells or decreased peripheral sensitivity to insulin, this blood glucose cannot be utilised, resulting in increase blood glucose level.

Also, hyperglycaemic hormone like glucagon further increase glucose production resulting acute hyperglycaemic episodes.

Over a period of time ,it results in chronic complications of type 2 diabetes mellitus

SYMPTOMS

Polyurea (frequent urination)

Polydypsea (increased thirst)

Polyphagia(increased hunger)

Fatigue and weight loss

Blurred vision

Itchy skin

DIAGNOSIS

FPG-Fasting Plasma Glucose

2-h plasma glucose (PG)

COMPLICATIONS OF TYPE 2 DIABETES MELLITUS

Acute:

Hyperglycemic hyperosmolar state

Diabetic ketoacidosis

Chronic:

Macrovascular

Coronary artery disease

Peripheral arterial disease

Cerebrovascular disease

Microvascular

Eye disease Retinopathy (nonproliferative/proliferative), Macular edema

Neuropathy Sensory & motor (mono-& polyneuropathy), Autonomic

Nephropathy

Others

Glaucoma

Gastrointestinal

Genitourinary

Periodontal disease

Cataracts

TREATMENT

Figure for treatment and management harriaon 338-14

LIMITATIONS OF CURRENTLY AVAILABLE TREATMENT

There are at present many available treatments but not yet fulfilling the of the purpose of therapy, i.e is to maintain normal glucose levels. Hence here are some of the limitations pertaining to the current treatments.

Oral hypoglycaemic agent tends to lower the blood glucose level and at times it may result in hypoglycaemic episode.

Some of the available drugs have also resulted in weight gain, many of these drugs have also resulted in hypersensitivity reaction.

Biguanides causes Vit B12 deficiency due to its interference with its absorption especially with its high doses.

Current Insulin administered,is given prarenterally due to its incompatible nature when given through git, reducing patient compliance .With insulin therapy there is a lag time which is observed where after insulin administration a meal has to be taken or it may lead to severe hypoglycaemia or even death. Diabetes Care, the American Diabetes Association, June 1995

The current therapy targets the symptom and not its principal cause.

In many patients it is difficult to maintain the normal glucose level since it keeps fluctuating thus giving rise to co-morbidities.

Drugs belonging to thaiazolidindiones causes increased risk of heart disease as proved recently in case of Avandia (rosiglitazone)manufactured by Glaxo-Smith-Kline.

Drugs not being target specific leads to decreased effect and increased expenditure, also leaving the patient with worse complications.

There are chances of premature atherosclerosis due to hyperinsulinemia.

Since the currently available drugs are not lucrative enough, the medical expenditure incurred upon countries in the course of treatment are quite high and cost being further expected to rise, as per prevalence statistics calculated, leading to increased cost burden on to the shoulders of both the patient as well as the country's economy

NOVEL APPROACHES

Novel targets

1. Dipeptidyl peptidase IV enzyme inhibitor

Of the many novel approaches, one of the novel approach in treating T2DM is based on the benefiting action of incretins , glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide; GIP) and glucagon-like peptide-1 (GLP-1),This novelty of the treatment has proved to be beneficial towards improving glucose tolerance in case of type 2 DM in humans.

The major MOA however lies in the fact that improvement in the insulin secretion occurs by inhibiting dipeptidyl peptidase IV (DPP IV) enzyme, responsible for incretin metabolism.

Agents such as sitagliptin, vildagliptin and saxagliptin are developed as a therapeutic target for DPP IV

2. Incretine mimetics

Incretin mimetics are the analogues of naturally occurring icretins, which mimics its effect i.e induction of insulin release after ingestion of food, exerting antidiabetic effect.

Exenatide and Liraglutide are GLP-1 analogue which have been developed as incretin mimetics of which Liraglutide apart from stimulating insulin release not only improves insulin sensitivity but also recuperate islet morphology.

3. Interleukin-1-Receptor Antagonist

Interlukin-1 receptor is found on the pancreatic beta-cells which can be stimulated by high glucose concentration resulting in the production of interleukin-1β, a proinflammatory cytokine which cause beta-cell apoptosis and thus reduces insulin secretion.

In diabetic patient, the naturally occurring interleukin 1-receptor antagonist decreases and the balance between the interleukin 1-receptor antagonist and interleukin-1β is disrupted.

Thus, using a competitive interleukin 1-receptor antagonist (ankinara) will reduce the level of interlukin-1β and thus prevent the beta-cell destruction, enhancing insulin production.

Novel drug delivery system:

Advancement in insulin delivery system

Insulin used for type two diabetes, currently administered paraenterally, has poor patient compliance and also since being given parenterally requires patient administration skills making it tedious for use. Also due to its G.I.T. deterioration it cannot be administered orally. The above drawbacks have opened the doors to novel drug delivery approach.

Technosphere Insulin System:

Currently in phase III trials, it is a type of insulin made in the form of powder to be inhaled, involving ph sensitive carrier particle system which dissolves in the lung tissue. The insulin is in the monomer form, in bioactive form which upon inhalation have a rapid onset of action.

Oral Enteric Insulin System:

In this the insulin(hexyl insulin monoconjugate2) is made in capsule form with sodium N-[8-(2-hydroxybenzoyl)amino] caprylate, as the polymer to protect insulin from being destroyed by the git thus allowing insulin absorption from the intesting where the polymer dissolvation.

Transdermal Delivery:

The U-strip transdermal patches are coupled with ultrasonic and micro electronics which sends impulses through the patch. These signals result in widening of the skin pores, thus allowing a fixed amount of drug to be delivered through the skin into systemic circulation.

Oral Buccal:

Insulin in liquid form is administered in the buccal cavity using an oral spray which aerosolises it and is absorbed via oropharyngeal mucosa and enteres the systemic circulation. The absorption is rapid via oropharyngeal mucosa and there is a rapid onset of action with shorter duration of action compared to normal insulin.

There are number of alternative insulin delivery systems which have been developed, leaving us with better compliance and options in management of type 2 diabetes mellitus.

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