WHILST THE USE OF INSULIN IS MANDATORY IN TYPE I PATIENTS, A JUDICIOUS USE OF INSULIN THERAPY MAY BE NECESSARY FOR OPTIMAL MANAGEMENT IN MANY NON INSULIN DEPDENT DIABETICS !

Non dependence does NOT imply that Type II's may never require insulin in order to obtain optimal control.

At the same time, there is increasing apprehension that raised levels of insulin in the blood may itself contribute to hypertension, lipid abnormalities and atherosclerosis.

In view of this, THE DECISION TO USE INSULIN IN NIDDM SHOULD BE TAKEN AFTER CAREFUL, JUDICIOUS CONSIDERATION.

• Patients manifesting OHA failure.

• Insulin should be considered in diabetics with significant complications like ischemic heart disease, CVA, peripheral artery disease, significant retinopathy, nephropathy and neuropathy, hepatic complications such as viral hepatitis.

• Any diabetic with an acute problem like several infection, injury, etc., should receive insulin.

• Diabetics with tuberculosis often do better with insulin.

• Any Type II patient who manifests ketosis for whatever reason.

• Diabetics undergoing most surgical procedures, especially those requiring general anesthesia, and where the patient will be on intravenous fluids for any significant period of time should be stabilised on insulin.

• Pregnant diabetics, if not "tightly" controlled with diet alone, must be managed with insulin.

• Any patient, even if optimally controlled with OHA's who shows evidence that may contraindicate the use of these oral agents, must be shifted to insulin.

• Many underweight patients and those with significant symptoms would do better with insulin therapy, possibly in combination with small doses of sulfonylureas;

• The insulins available for routine clinical use are the beef, porcine and human insulins.

• The insulins available now are the "pure" varieties and contain negligible amounts of contaminants.

• Beef insulins differ from human insulin in three amino acids, whilst porcine insulin differs from human insulin in only one amino acid. Thus, porcine amino acids are less immunogenic than beef insulins.

• But the beef insulins continue to be widely used in view of their relatively lower costs.

• Human insulins are pure and have the same amino acid structure as that of native insulin.

• They are made by genetic engineering or by transformation from porcine insulin by substituting alanine with threonine in the B30 position.

• Human insulins are replacing the other insulins in most developed countries, but its cost is the inhibiting factor to its widespread acceptability in most developing countries.

• All patients who are on beef or porcine insulins and manifest resistance due to the presence of antibodies;

• Patients requiring intermittent therapy, i.e. patients with gestational diabetes, those undergoing major surgery, patients with acute infections, etc., who otherwise may be controlled on diet, with or with out OHA's, should use Human insulins.

• Patients who require very large doses of beef or porcine insulins (>80 units/day), may benefit with change over to human insulins.

• In most patients with a significant degree of symptoms, or in whom the fasting blood glucose values are higher than 200-250mg%, insulin therapy, if indicate in a particular patient, may be started along with the diet and exercise prescription.

• There are no precise formulae by which the initial dose can be calculated; start with a small dose of an intermediate acting insulin (IAI), 8-12 units s.c. before breakfast; the therapy can be initiated with a mixture of a short acting insulin (SA) and IAI, in small doses.

• A thorough knowledge about the time action characteristics of the commonly used insulins will help in making the necessary changes in the insulin doses; this is discussed in detail in the section "Time-activity" of insulin (see below).

• The doses are usually increased by 2-4 units every 5-7 days, although this depends on the individual patient; dose adjustments should be based on multiple blood glucose measurements usually with the use of SMBG strips; adjustments based on occasional blood glucose results may lead to erroneous dosage; urine test results should rarely be used to adjust dosages;

• A reasonable daily dose is around 35-40 units per day; if more insulin is seen to be necessary, it would be worthwhile to re-assess the patient to rule out the presence of conditions which may interfere with insulin action.

• Some of the common conditions which reduce the insulin action include, infections, obesity, insulin receptor and post-receptor defects, ketosis, destruction of insulin at the site of injection, true immune mediated resistance, hormonal conditions associated with excess of cortisol, Growth hormone and thyrotoxicosis, associated use of drugs which increase glucose intolerance.

• MDR (Multiple Dose Regimen) may allow a more physiological control; it essentially consists of dividing the insulin requirements in two or more daily injections. Twice daily injection of a mixture of SAI and IAI is usually adequate in NIDDM and the single dose should be divided, once the daily insulin requirements reach 30-40 units. MDR is described in more detail later.

• The addition of a small dose of sulfonylurea (2.5 to 5 mg) per day along with a mixture of IAI and SAI, often permits smooth control in many patients, avoiding the need for two or more injection regimens; this combination therapy often used in insulin requiring NIDDMs and in early OHA failures.

• A few patients may benefit from addition of biguanides to the insulin therapy; small doses are to be used; all contraindications to the use of biguanides must be considered; care to be taken that normal weight patients do not lose weight; biguanides are better avoided in underweight patients or those normal or underweight patient who are continuing to lose weight.

• Patients who show a significant rise in the posprandial blood glucose levels may do better with the addition of an alpha-glucosidase inhibitor.

• Once optimal control is reached, efforts should be made to try and reduce the dosages slightly to ensure that optimal control continues to be maintained at the smallest possible dosages.

Classification based on Time Characteristic of Activity.

This classification is based on

• how soon the insulin starts working (onset)

• when it works the hardest (peak time)

• how long it lasts in your body (duration).

Insulin analogs have been developed by modifying the amino acid sequence of the insulin molecule. This modification alters the time characterisitics of activity. The only insulin analog available in India is the rapid acting Lispro. It reaches the blood within 15 minutes after injection. It peaks 30 to 90 minutes later and may last as long as 4-5 hours.

Short-acting (regular) insulin usually reaches the blood within 30 minutes after injection. It peaks 2 to 4 hours later and stays in the blood for about 4 to 8 hours.

Intermediate-acting (NPH and lente) insulins reach the blood 2 to 6 hours after injection. They peak 4 to 14 hours later and stay in the blood for about 14 to 20 hours.

Intermediate-acting insulins include lente and NPH. Insulin preparations with a predetermined proportion of NPH mixed with regular, such as 70% NPH to 30% regular, or a 50/50 mix are called intermediate acting for purposes of classification, although their activity characteristics would be different from either only NPH/Lente or only Regular insulins.

Long-acting (ultralente) insulin takes 6 to 14 hours to start working. It has no peak or a very small peak 10 to 16 hours after injection. It stays in the blood between 20 and 24 hours.

THESE TIMINGS ARE AVERAGES AND INDIVIDUAL PATIENTS MAY WIDELY DIFFER IN THE TIMINGS OF INSULIN ACTIVITY.

INITIATING INSULIN THERAPY

There are no precise formulae by which the initial dose can be calculated; start with a small dose of an intermediate acting insulin (IAI), 8-12 units s.c. before breakfast; the therapy can be initiated with a mixture of a short acting insulin (SA) and IAI, in small doses.

• A knowledge of the time action characteristics allows a rational adjustment of the insulin doses; As an example, a patient has been initiated with 8-12 units of intermediate acting insulin (IAI); When the patient is seen on follow-up :

• In very rare cases, the patient may show control at the target values; in such cases, the dose may be reduced by 2-4 units to examine whether the patient continues to show the same level of control. The aim is to maintain control with the smallest dose.

• More often, all the blood glucose values are higher than acceptable. In these patients, the IAI can be increased. This increment should be gradual and in small amounts (2-4) units at a time. This dose adjustment can be continued till the target are achieved (Scenario 1), or,

• The blood glucose in the fasting may be acceptable, but the values the post breakfast and post lunch timings may be much higher than acceptable. If the dose of the IAI is increased further, there is a fear that when the blood glucose levels are fairly acceptable. The reason for this is that the IAI will have its maximum effect after 8-10 hours and the blood glucose levels at these times may be depressed further into hypoglycemic values.

• Since a greater effect is required in the morning and early afternoon, it would be better to add a small dose of a SAI to the morning injection. The time action characteristic of SAI will show that this will help in controlling the raised blood glucose values in the morning and in the early afternoon.

• It would be prudent to slightly decrease the IAI dose (by 2-4 units) to protect against the late evening and nighttime hypoglycemia.

• With the use of an IAI alone or a mixture of an IAI and SAI given pre-breakfast, the blood glucose levels throughout the day may be under fair control, but the fasting blood glucose levels may be higher than acceptable.

• The time activity characteristics of IAI show the activity to last about 14-20 hours and one could think of increasing the morning dose of the IAI. But this would expose the patient to daytime hypoglycemia. Thus, the best therapy would be to give an additional shot of an IAI to be taken pre-dinner. As the peak activity of the IAI is after 6-10 hours, this would help in reducing the fasting blood glucose levels.

• It would be prudent to reduce the morning dose of the IAI and the SAI by 2-4 units so as to protect against the daytime low blood glucose levels, now that the fasting blood glucose levels would be lower than previously.

• This is practically the same as in Scenario 4, but in this instance, in addition to the fasting blood glucose values, the levels post dinner are also higher than needed. In this case, a small dose of a SAI is added to the pre-dinner IAI so that both the post-dinner and the fasting blood glucose values are lowered. In this case, again, it would appear prudent to decrease the morning doses of the IAI and the SAI in order to avert the possibility of daytime hypoglycemia.

• It should be noted here that most NIDDMs, who have no contraindication to OHAs, may not need two insulin injections as they would do well with combination therapy.

• Most of the short acting and the intermediate/long acting insulins available here may be mixed in the same syringe.

• Insulins are presently available in strengths of U-40, and U-100; one must ensure that the syringes used by the patient are compatible with the strength of insulin used.

• Insulin vials should be preferably stored at 4-80C. If possible they should be kept in the refrigerator, but NOT in the freezer section. The insulin vial should be brought down to body temperature by gently rubbing it between the palms before withdrawing the insulin into the syringes. If refrigeration facilities are unavailable, then the currently used vial can be stored at room temperature away from heat and direct sunlight. If vials have to be stored for longer periods, a simple method is for the unopened vials to be stored in the earthen pots which contain drinking water and are found in most homes where a refrigerator is not present.

• It is advisable to use disposable syringes which are now increasingly available; the cost of the syringe is often a limiting factor to the routine use of these syringes; patients can reuse the same disposable syringe and decrease the costs; it would seem prudent to use the syringe for around 6-8 injections, or less if the needle feels blunt; the same syringe should NEVER be used on different patients.

• Injections are usually given 20-30 minutes before the meal; this may need to be individualised.

• The needle is to be inserted at a slight angle so that the injection is in the subcutaneous tissue; in patients with more subcutaneous fat, it would be correct to insert the needle vertically downwards;

The sites where the injections can be given are shown in Fig. . Efforts must be made to rotate the site of the injection throughout the permissible areas and not inject only into one region.

Parts of the body where injection can be made

• Multiple dose regimens are not very commonly required for the routine management of most NIDDMs, but may be important in special cases.

• Most NIDDMs who require insulin for optimal management do well with judicious use of combination therapy (insulin with OHA).

• Twice daily mixture of short, acting and intermediate acting insulins; one given before breakfast and the other before dinner. Once the daily dose at a single injection reaches around 30 units, it would be preferable to divide the insulin requirements into twice daily injections. This is the most commonly used MDR regimen in NIDDMs.

• The same as above, but with the addition of a short acting insulin injection given before lunch.

• Injections of short acting insulins given before breakfast and before lunch and a mixture of short acting and intermediate acting insulin given before dinner.

Many non insulin dependent diabetics are what has been termed as insulin "requiring" diabetics. This means that they have enough endogenous insulin to avoid ketosis under non stressed conditions, but this level of available insulin is not sufficient to attain optimal control. Such Type IIs can be optimally managed with a judicious combination of insulin and an OHA.

Combination therapy is also very useful in the management of early stages of secondary OHA failure.

A frequently advised regimen is the use of a long or very long acting insulin at bedtime along with the use of small amounts of an OHA at mealtimes. The rationale for this is that the insulin will lower the fasting blood glucose levels which is essential for glycemic control and will also maintain a basal insulin level. The OHAs will cause a bolus increase in the endogenous insulin to cover the mealtime rise in the blood glucose levels.

A regimen which has also been found to be practical and effective is the use of combination of a small doses of SAI and IAI in the morning along with an OHA at mealtimes, especially with dinner.

• Hypoglycemia: major side effect and to be guarded against stringently; start with small doses and adjust in small amounts; time activity characteristics should always be kept in mind when adjusting the doses.

• Allergy: usually seen with the use of the older insulins insulins; beef insulin differs from human insulin in three amino acids and this difference can give rise to antibodies causing local, and systemic, allergy; porcine insulin differs from human insulin in one amino acid and this may give rise to allergy, but rare; human insulins have same amino acid composition as endogenous insulin.

• Resistance: the impurities present in the older insulins insulins gave rise to antibodies which interfere with insulin action; newer insulins are purer and the chances of insulin resistance minimal.

• Edema: insulin has salt retaining properties and may cause fluid retention; in some patients it may be necessary to adjust the dose of diuretics and/or salt intake.

• Lipodystrophy: comprises, both, lipoatrophy and lipohypertrophy; lipoatrophy was seen with the use of older insulins; rare with the presently used insulins; best treated by changing over to the newer insulins and injecting the dose in the walls of the atrophic regions; Lipohypertrophy can be seen with the use of any insulin; no specific treatment, except to inject in parts of body which are usually covered.

• Recently, hyperinsulinemia has been implicated in leading to atherosclerosis, along with causing a propensity for high blood pressure, dyslipidemias and central obesity (Syndrome X).

• It is unclear whether this risk is due to the raised levels of insulin itself, or to related products such as pro-insulin and split pro-insulin products.

• Inspite of this ongoing controversy, this should NOT be taken to mean that insulin should not be used in a NIDDM, provided it is felt necessary to obtain optimal control.

• Meticulous control far outweighs any postulated cardiovascular risk.

• Thus, insulin must be used in any NIDDM in whom it is considered advisable, BUT the use of insulin should be judicious and in the smallest possible doses.

• Ultra short acting insulin analogues ( Lys-Pro) are now available in India.

• It is not recommended that these be used routinely as short acting insulins, but

• Their rapid onset and short duration of action make them of particular use in many clinical situations:

1. patients exhibiting high postprandial glycemia with late hypoglycemia.

2. brittle diabetics;

3. in the elderly and in children, especially in those with erratic eating habits.

4. perioperative period.

5. sick day therapy.

6. Renal and hepatic dysfunction where one sees low fasting blood glucose levels with high postprandial blood gluocse values and the fear of late hypoglycemia.