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DRUG THERAPY FOR INSULIN RESISTANCE


Prof K M PRASANNA KUMAR
Prof & Head,
- Dept Of Endocrinology & Metabolism,
M S Ramiah Medical college, Bangalore

Insulin resistance (IR) is the subnormal response to the normal therapeutic dose of insulin. The therapy is either to improve insulin sensitivity or reduce insulin resistance.

Different Drugs used are:
Biguanides
Chromium
Vanadate
Beta 3 Adrenoreceptor Agonists
Troglitazone
Dichloroacetate analogues

Biguanides have been used for the past 2 to 3 decades & are well-established agents for treating obese Type 2 DM. However Metformin is more often prescribed than Phenformin. US FDA has banned Phenoformin since 1977 because of the high risk producing lactic acidosis.

Metformin also produces acidosis, but the incidence is less. Metformin increases glucose uptake in the peripheral tissues both in diabetics & non-diabetics.

In obese individuals, metformin induces weight loss by its anorectic effect.. Obesity itself contributes to IR, so therapy with metformin is beneficial whereas therapy with Sulfonylurea (SU) being an insulin secretogogue increases appetite and thus tends to increase body weight. Metformin may be combined with Sulfonylurea at the initiation of OHA therapy or may be added as secondary drug after sulphonylurea.

In non-diabetics like Polycystic ovarian syndrome(PCOS), therapy with metformin has been shown to increase fertility rate as it corrects the insulin resistance associated with PCOS. Metformin improves the level of tyrosine kinase & GLUT 4. The advantage with metformin is that it decreases weight and appetite & is the best drug for Type 2 Diabetic patient with dyslipidemia and obesity. In some studies metformin has found to have only marginal effect on hypertension. Thus by weight reduction, correction of dyslipidemia and reducing IR Metformin appears to correct many salient features of Syndrome-X.

B3 Adrenoreceptor agonist (B3AA) is a new drug. Atypical B3 adrenoreceptors have been identified in fat cells which determines the rate of energy consumption. B3AA leads to good energy consumption, which is supposed to reduce IR. BRL 35135 is another drug, which improves glucose tolerance by 25 - 30%. One of the clinical studies for 10 days showed 91% improvement in whole body insulin sensitivity. Further long-term clinical studies have been undertaken to assess the safety and efficacy of B3 AA in human beings.

Trolitazone

Troglitazone reduces insulin resistance and improves glucose tolerance and is useful in preventing Type 2 diabetes in insulin resistant subjects. Clinical studies have shown that Troglitazone reduces fasting insulin level by 12to 26%, fall in fasting plasma glucose by 20%, fall in Triglycerides by 20% and increases HDL levels by 10%. Troglitazone has been shown to increase the mean insulin sensitivity by 50-63% in Diabetics. These data show after metformin, Trolitazone is the drug, which increases the insulin sensitivity.

Troglitazone is available in 200, 300 & 400-mg tablet, single dose, 20 - 30% patients don't respond. There is no difference in insulin resistance, in responders vs. non-responders. It can be combined with SU, Biguanides &amp Insulin.

Insulin resistance may be inherited or acquired. Impaired glucose tolerance being a forerunner of Diabetes, drug therapy of IGT to reduce insulin resistance may prevent the conversion to frank Diabetes Mellitus.

The National Institute of Health (NIH) has undertaken a study in USA in persons with IGT to study the impact of life style modification versus drugs in preventing Diabetes.The DPPstudy (Diabetes Prevention Program) is being carried out at 26 centers in USA.The aim of DPP is to evaluate the result of intervention on prevention of diabetes in IGT patients. The study patients are divided into 4 groups.

Group 1 Intensive life style change
Group 2 Troglitazone 400mgm/day
Group 3 Metformin 850 mgm bid per day
Group 4 Placebo

It is essential to get a baseline liver function test (LFT) in-patients started on Troglitazone, every month thereafter for 6 months and later once in 6 months till the patient is on Troglitazone.

However because of hepatotoxicity, trolitazone has been withdraw in UK.

Autoimmune insulin resistance is not a very common phenomenon, unless the patient is on impure insulin. In type B Insulin resistance syndrome, there is remission after 2 - 3 yrs, & there is cyclical nature of this disease since antigen antibody reaction is not permanent. Antibody titre comes down, and insulin sensitivity improves. Plasmapheresis has been tried in some patients with autoimmune diseases. Immunosuppressive therapy with cortico-steroids quickly lowers the antibody level. Prednisolone 60-80 mgm/day or Cyclophosphomide 1mgm/kgbody wt/day to start with and titrate the dose. Once insulin antibody titre comes down careful follow up of the patient is necessary to adjust the insulin dose. However corticosteroids have anti-insulin effect which may be counter productive in the longrun.

Insulin Resistance and Glucosetoxicity

If a patient needs more than 2 units of insulin/Kg bodyweight/day, then he can be clinically considered to have IR. Several animal studies has shown that high blood glucose is itself toxic to Beta cells of the pancreas.Once the blood glucose is very high, it reduces the synthesis, secretion & release of insulin.This is known as glucosetoxicity. When the plasma glucose is brought down to euglycaemia, IR is overcome since euglycemia gives rest to Beta cells & the Beta cells starts performing better. Aggressive insulin therapy reduces IR. Once euglecemia is achieved, the patient needing 80 - 100 units of insulin may need less than 40 units of insulin per day. More than 40 units of insulin are not recommended for single administration. If more than 40 units are required per day it should be given in split doses. DCCT study has also showed it is better to take smaller doses of insulin 3 times a day. Large dose saturates the insulin receptors leading to down regulation of insulin receptors. Thus low doses of frequent insulin administration is more effective than large single dose of insulin. If a patient is not controlled on split doses then shift to IV insulin drip by infusing 2 - 4 units hourly for 24 - 48 hours.After IR is overcome switch over to Subcutaneous (SC) insulin. Thus with the availability of purified insulin and better insulin delivery system there is hardly any insulin resistance states which cannot be overcome in clinical practice. Tight & quicker control of hyperglycemia also delays Sulfonylurea failure.

Resistance to SC Insulin & not to IV Insulin

There are certain Diabetic patients and situations, where the patient responds to intravenous insulin but not to subcutaneous insulin. Euglycaemia can be achieved in these patients only by giving insulin through IV insulin pump. They dono't respond to S.C insulin infusion

The exact reason is not yet known although certain theories are proposed which are not yet proved, like local antibody to insulin in S.C tissue & altered kinetics of absorption in S.C tissue.

Conclusion

Metformin reduces IR & is particularly useful in the management of obese Type 2 diabetes; Troglitazone though showed promise in reducing IR, is under thorough scrutiny because of adverse events & hepatoxicity. Newer drugs like B3AA are efficacious but long term results are awaited .The results of NIH (USA) study, Diabetes Prevention program may prove the usefulness of Intensive life style modifications vs. drugs in IGT patients to prevent diabetes.


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