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Diabetes is a chronic disease which metabolically effects the function of body systems. Diabetes is the disease which occurs n the pancreatic dysfunction which leads to decreased insulin production or when the body is not capable of using insulin effectively. Both the conditions relate to the insulin which was a hormone that regulates the glucose and sugar levels in blood. Uncontrolled diabetes leads to the conditions such as hyperglycemia and increased sugar level in blood. When untreated leads to nervous and blood vessels damage.
Diabetes mellitus is of two types
1.Type-1(Insulin dependent diabetes mellitus or Juvenile onset diabetes mellitus):
This type of diabetes occurs due to the condition of auto immune syndrome in which the body immune system destructs the beta cells in pancreatic islets by producing antibodies which leads to the decreased level of insulin in blood and might also leads to the very low level of insulin which do not comply with the demand required.
Symptoms: The symptoms include frequent urination, polydipsia, fatigue, blurred vision, weight loss, ketosis.
Type-1 diabetic patients has to be administered with insulin regularly
2. Type-2(Non insulin dependent or maturity onset diabetes mellitus)
This is the condition occurred due to the ineffective use of insulin by the body. Majority of the diabetic patients were of type-2. Type-2 diabetes occur because of different conditions.
(1). Delayed response of beta cells to produce insulin due to the abnormality of gluco- receptors.
(2). Due to the down regulation of insulin receptors and also low insulin receptors count leads to decreased response of peripheral tissues for insulin.
(3). High quantities of glucagon, obesity condition leads to beta cell fall back n producing insulin.
In many conditions type -2 diabetes was diagnosed years after the onset. The Hb1Ac gives the level of glucose in blood as used as main diagnostic tool.
Symptoms: Symptoms were similar to that of type-1 such as polyurea, polydipsia, constant hunger etc but were less prominent.
COMPLICATIONS OF DIABETES:
Microvascular diseases associated with diabetes were Retinopathy, Nephropathy occurred due to hyperfiltration and increased glomerular pressure, Neuropathy, diabetic ketoacidosis, non ketotichyperosmolarity
Blood sugar levels;
For adolescents the normal blood sugar level is between 70 to 115 per 100 ml of blood before meal and after meal is between 100 to 140 mg/dl. The blood sugar level exceeding 126mg/dl in a fasting individual is considered to be as hyperglycemic and considered as pre diabetic if the blood sugar ranges 100-125mg/dl. F the glucose level ranges to 700, 800 the patient may going to diabetic coma.(Medical records for Attorney, Laurence M.Deutsch)
According to glucose tolerance test the patient is said to be diabetic if the sugar level in blood is above 200mg/dl and pre diabetic if the range is between 140-199mg/dl.(Medical records for Attorney, Laurence M.Deutsch)
PRECALENCE OF DISEASE:
More than 220 million people worldwide have diabetes.In 2005, an estimated 1.1 million people died from diabetes.Almost 80% of diabetes deaths occur in low- and middle-income countries.Almost half of diabetes deaths occur in people under the age of 70 years; 55% of diabetes deaths are in women.WHO projects that diabetes deaths will double between 2005 and 2030.Healthy diet, regular physical activity, maintaining a normal body weight and avoiding tobacco use can prevent or delay the onset of diabetes.(WHO,2005)
Since past several years insulin was the main drug given to the diabetic patients which were administered intravenously. As insulin was the main component which on reduction results in diabetes. In type 1 patients the insulin was given intravenous as there was low production in insulin. Recent discoveries lights up the use of transdermal insulin patches were introduced in order to prevent painful intravenous infections.
The main drawback of insulin administration was it has to be given intravenously hence there was always a search for orally active drugs. The main condition of type-2 diabetes was the body does not utilize insulin impressive by improving the condition of the body to make effective use of insulin in a way of sensitizing beta cells, glucose uptake by tissues, improving calcium influx. In search of oral drugs during 1940's the tests on sulfanomides shows hypoglycemic condition as a side effect by using this as a base sulfonylureas(tolbutamide) was discovered in 1957 and subsequently thereafter. Keeping potency as the main aspect in 1970, the second generation sulfonylureas were developed and were much potent than previously discovered first generation sulfonylureas up to 90-150%. Biguanides were the other oral hypoglycemic drugs that were discovered subsequently along with sulfonylureas. Phenformine and metformine were the drugs in biguanides class among which phenformine was banded because of its lactoacedosis as a side effect.
During 1990's three more new classes of antidiabetic drugs were added on to the therapy (Î±-glucosidase inhibitors, meglitinidanloges and thiazolidinediones) were introduced. In practice many of the drugs in treating type-2 diabetes were not preferred to give alone, most of the drugs given in the form of combinations because they were more affect in combined form. The purpose of the combination is to counter act insulin resistant and side effects when used alone in monotherapy.
As mentioned risk on taking diabetic drugs alone was studied and proved. A study was conducted on "Once- and Twice-Daily Dosing With Rosiglitazone Improves Glycemic Control in Patients With Type 2 Diabetes" (Philips SL et al, 2001). The trial studied the treatment to hyperglycemia by measuring the change in the concentration of HbA1c. it was proved that Rosiglitazone when given 4 and 8 mg effectively decreased blood sugar level and helps glycemic control in type-2 diabetic patient and also proved that the drug is well tolerated.
The patients were analysed for glycemic control serum lipid profile, HbA1c concentration and band that glycemia was controlled and HbA1c concentration was reduced but the serum lipid profile was not normal that is the free fatty acid levels were decrease "Small but statistically significant increases in total cholesterol and LDL cholesterol were observed in all treatment groups (individual placebo) as compared with baseline, as well as in rosiglitazone treatment groups compared with placebo"(Philips SL et al, 2001) and also an increase in HDL cholesterol was also observed.
The problem with Rosiglitazone that the study has resulted was there is marked increase in "LDL cholesterol and HDL cholesterol ratio is often considered a better predictor of cardiovascular risk than LDL cholesterol or HDL cholesterol alone" (Philips SL et al, 2001). Even though the increasing the cholesterol level is markedly less but on long run treatment with Rosiglitazone markedly increase the subcutaneous adipose tissue and intern leads to increase in cardiac heart failure.
A study was conducted on "Rosiglitazone treatment Increases subcutaneous adipose tissue glucose uptake in parallel with perfusion in patients with type-2 diabetes: a double blind, randomized study with metformin" (Viljanen APM et al, 2005). The study found that Rosiglitazone increase the body sensitivity to insulin but there is no significant glycemic control or any incidence of lowering plasma glucose levels despite of increase in the subcutaneous adipose tissue which may lead to weight gain and further increase in heart failure. The study also stated that " metformin when compared with rosiglitazone has better effects on glycemic control and lower plasma levels" (Viljanen APM et al, 2005). The problem with the study is subjects included were very less and needs more studies to get clear results.
Another study which was conducted on combination of drugs "adding insulin glargine versus rosiglitazone health related quality of life impact in type-2 diabetes" (Vinik AI, Zhang Q, 2007) showed that both insulin glargine and rosiglitazone were having significant improvmenting glycemic control. The study supported the fact that the oral hypoglycemic drugs when given in combinations improve the quality of life as well as much affective than given alone. Rosiglitazone shows minimal side effects when given with metformin and sulfonylureas or in other combined forms.
To overcome the problem of insulin resistant, less safety, efficacy, and tolerability a new treatment has been came that is treatment with anakinra, which is an recomibant human interleukin-1 receptor antagonist, which shows on positive effect on glycemic control and increased beta cells secretary function. "it also reduces the markers of systemic inflammation" (Larsen CM et al, 2007). The study was conducted on "interleukin-1 receptor antagonist in type-2 diabetes mellitus" (Larsen CM et al, 2007). And determine the effectiveness of anakinra (IM) in reducing the glycated hemoglobin level and their was marked increasing c-peptide secretion along with decreased conversion ratio to insulin from proinsulin. The study did not concentrate on the insulin sensitivity.
In this study there is no serious adverse effects observed. The anti-inflammatory action was beneficiary aspect of anakinara however which do not have an effect on increasing insulin release. "asanakinran is used in the treatment of Rheumatoid artheritis who underwent long trm treatment did not show infectious disease despite concomitant immunosuppression" (Larsen CM et al, 2007). The main limitation of the study is less number of subjects and lacks the dose regimen. The dosage used in the study were very low and increased dose might give the outcome more significant "high dosage of anakinara might improve insulin sensitivity" (Larsen CM et al, 2007). which was not determine in the study.
A detailed and clear understanding on the anakinara use in the treatment of type-2 diabetous is required based on the dose regimen, long run usage complications, insulin sensitivity in order to use anakinara more effectively in the diabetic treatment.
"A new trail was started by Novartis on dose finding safety and efficacy of monthly subcutaneous canakinumab administration in metformin monotherapy treated type-2 deabetic patients" (Novartis, 2009) started in 2009 conducting study on new interleukin-1 beta antagonist canakinumab in combination with metformin monotherapy which on success may leads to new therapy in treatment of type-2 diabetes.
The trail focused on monthly subcutaneous administration of canakinumab which after passing through the trail may decrease the frequent administration of the diabetic drugs. "The previous studies already proved the effectiveness of the interleukin-1 receptor anatagonist like anakinara" (Larsen CM et al, 2007). The study by Novartis 2009 on approval may add on the list of the best treatment for type-2 diabetes.
Mean while the recent studies on metformine had proved that the use of this drug is safe on regular monitoring of vitamin B12 concentration during long run metformin therapy was prescribed.
From the studies abserved above we can conclude that ant diabetic drugs were listed successful till the insulin sensitivity is not effected. Many oral hypoglycemic drugs were emerged in the treatment of diabetes but many of them were contraindicated in using them alone. Later on the combination forms of the drugs were prescribed to show the maximum effect in reducing HbA1c, glycemic control and efficient beta cell functioning. The new therapy of interleukin-1 receptor antagonist (anakinara) in treating diabetes was efficient to a greater extent in minimal doses further test has to be done on fixing the actual dose regimen of anakinara in diabetes treatment and long duration studies has to be conducted to find its effect on insulin sensitivity and its safety during long run of treatment. The dose finding of anakinara needs to be done by keeping the half-life of the component as the basis. This might improve the output of higher doses and long lasting anatagonism of interleukin-1.
Many studies has been proved that metafarmin is having minimal and curable side effects and therapeutic index was more then other oral hypoglycemic drugs like rosiglitazone in which the adipose deposition is more it leads to heart failure and weight gain hence it has been widely used either in combination or single. The most preferred combinations with metformin are sulfonylureas, meglitinides and glagrine.