CAUSES OF DIABETES

                 Diabetes mellitus is actually a chronic disorder related to abnormality of carbohydrate, fat and proteinmetabolism.this is due to defective or deficient insulin secretory response. This results into impaired glucose use, which is a characteristic feature of diabetes mellitus i.e.resultant hyperglycemia. Diabetes mellitus arises from primary disorder of the islet cell-insulin signalling system. In general this disease occure due to the diminished secretion of insulin by the beta cells of the islets of langerhans(Bonner-weir and ohci1982). Heredity is also a cause of diabetes. Heredity causes (Leahy, 1990) susceptibility of the b cells.this leads to the destruction of beta cells. Obesity is also a factor, which causes development of clinical diabetes. Obesity results in decrease in the number of insulin receptors in the insulin target cells, throughout the body. This results in decrease in the amount of insulin for its normal metabolic effects.(Atkinson et al..2001).

EPIDEMIOLOGY

                     The incidence of diabetes occurs in all age group. In USA 10% of all diabetes mellitus have IDDM or type I diabetes. The incidence of 18 persons per 1,00,000 inhabitants per year is observed. In UK 17 persons per 1,00,000 of population have got diabetes. In Europe the disease of IDDM varies with latitude in Europe. Statistical survey states that in Finland this disease is 43 people per 1,00,000 of population. The case is lowest in france, Italy,and Israeli.e. 8 person per 1,00,000 of population.statistical survey state that the majority of diabetes patients have NIDDM.In the US about 90% of all diabetic patients have NIDDM. In certain tropical countries, it has been observed that the cause of diabetes is chronic pancreatitis which is due to nutritional or toxic agent (chan et al..1987) Observed that diabetes some times results from point mutation in the insulin gene.mutation results in amino acid saubstitution .this sort of substitution produces insulin with low potency.this may also alter the processing of pro insulin to insulin.(Bennett et al..1997)

PHYSIOLOGY OF INSULIN

                    Insulin is a hormone related to energy abundance that is secretion of insulin is associated with energy abundance. Where excess quantity of carbohydrate is in diet. Insulin is secreted in large quantity. Insulin helps in storing the excess energy substances. If excess carbohydrate is in diet, insulin causes it to get stored as glycogen in liver and muscle. Insulin helps in storage of fat in adipose tissue. Excess carbohydrates, which cannot get stored as glycogen, get converted into fat under the stimulus of insulin. This fat is stored in adipose tissue. Insulin helps in uptake of amino acids by cells. Then the amino acids get converted into protein further. Insulin prevents the breakdown of protein present in the cells.

Liver has a role of blood glucose buffer system. this means when the blood glucose level reaches a high concentration generally after a meal then the rate of insulin secretion too rises. Maximum amount of glucose absorbed form the gut gets stored in the liver in the form of glycogen. After successive hours when the blood glucose concentration and the rate of insulin secretion fall then liver releases glucose back in to blood. A fall in glucose level stimulates glucagons secretions. Glucagon then functions in the opposite direction i.e. to increase the glucose level to normal. In normal persons, the blood glucose concentration is 80-90mg/dl of blood each morning before breakfast.

CHEMISTRY OF INSULIN

                                Insulin is a protein. Its molecular weight is 5808.insulin has two amino acid chains, connected to each other by di sulfide linkages.If the two amino acids chain are splits apart then insulin molecule looses its functional activty.

Beta cells of pancreas synthesize insulin firstly; translation of insulin RNA by (Raftel et al 1987) ribosome’s attached to the endoplasmic reticulum forms an insulin prepro-harmone. Its molecular weight is 11,500.this insulin prepro harmone is cleaved in the endoplasmic reticulum to form pro insulin. The molecular weight of pro insulin is 9000.most of the pro insulin cleaved in the Golgi apparatus to form insulin before getting into secretory granules.the pro insulin is inactive in nature. Insulin circulates in an unbound form in blood.a portion of insulin combines with receptor in the target cells.while thje remainder gets degraded by the enzyme insulinase mainly in liver to some extent in kidneys, muscles and slightly in other tissues.(Duckworth,1988)

In order to show effects in target cells,insulin binds with and activates membrane receptor protein.this membrane receptor protein has molecular weight of 3,00,00.this activated receptor causes subsequent effects.

The insulin receptor is made up of four subunits which are held together by disulfide linkages. two alpha sub units lie out side the cell membrane and two beta subunits that penetrate through the membrane, and it protrudes into the cytoplasm of the cell. firstly the insulin binds with the alpha subunits on the outside of the cell and then due to the linkages with the beta subunits the latter protruding into the cell become autophosphorylated. This autophosphorylation makes them an activated enzyme, a local protein kinase, (Denton,1986). This local protein kinase causes phosphorylation of multiple other intracellular enzyme.the consequence is to activate some of this enzyme and to inactivate the other. Thus insulin directs the intracellular metabolic machinery to yield the desired response.

Different types of Diabetes mellitus and its path Physiology

Type I Diabetes mellitus

                            This is due to absolute deficiency of insulin, which is the result of an immune mediated destruction of pancreatic b cells .the autoimmune process is due to macrophages and T lymphocytes with circulating autoantibodies. These auto anti bodiesattack various b cells antigens. The islet cell antibody’s the commonly directed antibody.

Type II Diabetes mellitus-

                 These symptoms of this type include—

i-Defects in insulin secretion

ii-Resistanceto insulin involving muscle, liver, and the adipocyte.

Gestational Diabetes mellitus (GDM)

                   This is glucose intolerancebeing recognised during pregnancy.it can complicate pregnancy leading to prenatal morbidity and mortality, so clinical detection is important.

Other specific types of diabetes-

                Maturity onset diabetes of youth (MODY) is due to impaired insulin secretion with minimal or no insulin resistance so hyperglycemia is noticed at an early stage.genetic inability to convert pro insulin to insulin causes mild hyperglycemia.

Pathological features of diabetes mellitus are due to the following factors.

1. Decrease in utilization of glucose by the body cells. This results in increase in blood glucose concentration to 300-1200mg/dl.
2. Increase in mobilization of fats from the fat storage area. This results abnormal fat metabolism and deposition of cholesterol in arterial walls causing atherosclerosis.
3. Tissues get depleted from protein i.e. protein depletion in tissues.

PATHOLOGICAL PHYSIOLOGY OF DIABETES MELLITUS

1.Loss of glucose in the urine in Diabetes-

        If glucose entry inside the kidney tubules in the glomerular filtrate rise above a certain limit then a significant proportion of the excess glucose can not get reabsorbed. This gets into the urine and this type of condition occurs when blood glucose concentration rises above 180mg/dl.

2.Acidosis and coma in Diabetes-

       There is a shift from carbohydrate to fat metabolism in diabetes. Then the level of ketoacids acetoacetic acid andb hydroxybutyric acid in the body fluid rise to 10mEqlit.this extraacid results in acidosis. The direct increase in blood ketoacids causes a decrease in sidium concentration so sodium concentration in ECF decreases.this part of sodium is replaced by increase quantity of hydrogen ions.it leads to acidosis. This diabetic acidosis results into rapid and deep breathing known as “Kussmaul respiration”.it results in excessive expiration of carbon di oxide. This excessive expiration leads to a marked decrease in HCO3 content of the ECF. This condition leads to acidotic coma as blood PH falls below 7.0.

3.Dehydrating effect of elevated blood glucose level in Diabetes.

      Elevated blood glucose level causes dehydration of the tissue cells. As glucose does not diffuse easily through the pores of cell membrane and increased osmotic pressure of ECF caused osmotic transfer of water out of the cells.

4. Other diabetic symptoms or the pathological physiology of insulin lack:

·         Polyuria- this occurs due to the osmotic diuretic effects of glucose in the kidney tubules.

·         Polydipsia – this occurs due to dehydration resulting from polyuria.

·         Polyphagia and loss of weight- this occure due to failure of glucose and protein metabolism by the body.(American diabetes association,2004).

DIET

A well balanced diet is must for diabetic patient.Type I diabetics must take food at properly spaced interval.Type II diabetic patients are obese, so they need to follow a weight reduction diet.

Regulation of carbohydrate protein and fat is must.carbohydrate accounts for 45% -50%of total caloric intake, proteins account for 15%-20%. While fats account for 35%-40%.(Kotala, 1987).Type I insulin dependent diabetes needs life long diet modification.the diet should be in position to provide enough energy for growth and maintenance. But it must not cause weight gain. Smaller and more frequent meals is good for such patients.a bed time snack prevents hypoglycemia from occuring during night.Type II or non insulin dependent diabetes occurs in obese adults 90% of all diabetes in United State is type II or non insulin dependent diabetes .the best way to avoid this is to loose weight, exercise regularly and to avoid fat rich diet regularlyand to avoid fat rich diets. (Crapo and Vinik 1987)

TREATMENT OF DIABETES

                    Treatmen requires good achievement for glycemia, B.P. and lipid levels. regular monitoring for complication in this disease is needed. Medication, dietary, exercise modifications are needed.

             The principle behind the treatment of diabetes mellitus is to administer enough insulin. this is done so that the patients will have nearly normal state of carbohydrate, fat, protein metabolism.(Koffler,et al.1989).

        Previously insulin used for treatment was derived from animal pancreas. Recently human insulin produced by recombinnt DNA process is used as many patients develop immunity and sensitization againstanimal insulin. Insulin is available in the market in various forms. Regular insulin has duration of action from 3-8 hours.other forms of insulin, which are precipitated with zinc or with various protein derivatives are slowly absorbed from the site of injection.their effects last up to 10-48 hours.

Anti diabetics can be classified as –

1.Oral hypoglycemic (Sulfonylureas)

Glimepiride, Gliclazide, Glipizide, Glibenclamide, Tolbutamide,Chlorpropamide.

2.Oral hypoglycaemics (Bi-guanides)

Metformin, phenformin, Combination preparations of phenformin and Metformin.

3.Others-

Acarbose, Repaginate, Guargum, and Herbal preparations.

4.Different types of insulin-

i)   Long acting insulin-Extended insulin zinc suspension (Ultralente)

ii)  Intermediate-acting insulin:Insulin zinc suspension (Lente insulin), Isophane insulin

iii) Short acting insulin-Neutral insulin (soluble)

      Premixed Biphasic insulin: Sulfonyl urea’s (Ferner and Neil 1988)

These drugs stimulate insulin secretion from b cells of pancreas. They induced increased activity of peripheral insulin ,intracellular receptor, also reduce glucagon secretion. Glibenclamide, Glipizide, Gliclazide, Tolbutamide, Chlorproramide are the drugs which act by the mechanism of sulfonyl urea.

Biguanides-

Biguanides such as Phenformin and Metformin act by increasing peripheral anaerobic glycolysis.they interface with absorption of carbohydrate in gut and suppress hepatic gluconeogenesis.

Other Agents-

1.Acarbose: Acarbose is a pseudo-tetrasaccharide.it is obtained from the fermentation process of the fungus Actinoplanesutahensis.

It acts by competitively inhibiting pancreatic alpha amylase and intestinal alpha glycosidase hydrolase enzyme.thus it slows down carbohydrate digestion. It prolongs digestion time and reduces the rate of glucose absorption. Thus it lowers postprandial hyperglycemia without producing hyperinsulinaemia.

2.Repaglinide: Repaglinide is novel insulin synagogue.it is used for the management of Type II diabetes mellitus. Repaglinide acts on the b cells of the pancreas. It lowers post prandial blood glucose and fasting blood glucose in patients with type II diabetes mellitus.

3.Nateglinide: It is a novel D-Phenyl alanine derivative used in the treatment of Type II diabetes mellitus. It specially targets post prandial hyperglycemia. Nateglinide inhibits ATP sensitive K+ channels in b cells of pancreas in the presence of glucoseand therapy simulation of parandial release of insulin takes place.

4.Rosiglitazone: It is a thiazolidinedione class of drugs, which improve insulin resistance patients with TypeII diabetesmellitus. Rosiglitazone is a potent and highly selective agonist for the nuclear receptor peroxisomes proliferator-activator receptor gamma (PPAR-gamma).the main function of PPAR- gamma is to increase the transcription of certain insulin sensitive genes,thus improves the insulin sensitivity.

5.Pioglitazone: Pioglitazone activates the nuclear peroxisomes proliferators activated receptors-gamma (PPAR-gamma) that results in increase transcription of a number of insulin responsivegenes,which are involved in the control of glucose and lipid metabolism.this drug  decreases insulin resistance in peripheri and in the liver which results in increased insulin dependents glucose disposal and decrese in hepatic gluconeogenesis.

6.Guargum:  Guargum is a high molecular weight hydro colloidal polysaccharides.it is available in granule form.Guargum on oral administration leads to viscous gel formation in intestine. This results in decreased carbohydrate absorption.thus blood glucose level is decreased. (Bolli,et al.1999).

NEW TECHNOLOGIES FOR INSULIN DELIVERY

1. Insulin inhalers- It is used in the treatment of both type I and type II diabetes. Inhaled insulin enhances patient satisfaction, quality of life and acceptance of intensive insulin therapy in a diabetic patient.
2. Insulin Spray-   This involves the buccal route. Buccal area has abundant blood supply. This route eliminates the destruction of insulin by first pass metabolism.
3. Insulin Pill- Azopolymer coated pellets deliver insulin to the colon.the Azopolymer protects the entrapped therapeutic agent until the pellets enter the colon.bacteria presentin colon secreteenzymes that can breakdown the azopolymer. So insulin release gets initiated once the pellets reach the large intestine.

Micro encapsulation of insulin in polymeric microspheres coated with PH responsive polymers like alginate is also available.Alginate coating protects the spheres from getting broken down in the acidic PH of the stomach.but dissolution is seen in the intestine where the ph increase to more than 7 and liberates the entrapped insulin. (Jain,et al.2006)

CONCLUSION

             Proper monitoring is an essential component of management of diabetes mellitus. This is the key to success of any diabetic treatment regimen.Those who are in high risk group but still not suffering from diabetes mellitus, should have a healthy life style. Thus include a prudent diet, regular aerobic exercise, avoidance of obesity and cigarettes further, avoidance of diabetogenic drugs is to be done.

REFERENCES

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