Diabetes Diabetes India

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INSULIN THERAPY

Dr. S.M.Sadikot.Hon. Endocrinologist,Jaslok Hospital and Research Centre,Mumbai 400026

11th January 1922 is a red letter day in the history of diabetes. Culminating a summer of hard work, epoch making

experiments, many failures and finally, what could be "success", Frederick Banting and Charles Best were convinced thatthey had isolated insulin. Now it had to be proved that what they had isolated would work in humans.

Leonard Thomson, was a 14 year old boy with insulin dependent diabetes. On 11th January 1922, the first injection ofinsulin, as prepared by the two doctors, was given to Leonard. Subsequently, other patients too were injected with insulin byBanting and Best. It would be worth while to quote the results in their own words. Writing in the Canadian MedicalAssociation Journal, Banting summarised his findings as follows:

"Following the production of what appears to be a concentrated internal secretion of the pancreas and the demonstration ofits physiological activity in animals, and under careful control, its relatively low toxicity, we are presenting a preliminaryreport on the pharmacological activity of this extract in human diabetes mellitus. Clinical observation at this juncture wouldappear to justify the following conclusions: (1) Blood sugar can be markedly reduced even to normal values. (2) Glycosuriacan be abolished. (3) The ace- tone bodies can be made to disappear from the urine. (4) The respiratory quotient shows

evidence of increased utilisation of carbohydrates. (5) A definite improvement is observed in the general condition of thesepatients and in addition the patient themselves report a subjective sense of well-being and increased vigor for a periodfollowing the administration of these preparations".

Euphoria accompanied the availability of insulin. It was hoped that we would be able to prevent the acute and also thechronic long-term complications of diabetes. To a certain extent, the hopes have proved true. There is no doubt that insulintherapy has allowed a number of people with diabetes to live a much longer and better life than it would otherwise havebeen possible.

In 1982, a banquet was held in New York attended largely by insulin dependent diabetics. The Chief Guest, one of the firstindividuals who had received insulin from the hands of Banting himself put matters in the right perspective, " If today, thishall resounds to the vibrant voices of living beings, and not to the ghoulish wailings of our ghosts, it is entirely due to thegreat courage and spirit of two radicals who had the confidence, some would call it obstinacy, to believe in themselves, evenin the face of adversity. If the world does make progress, it is due to such free thinkers, rather than those who would ratherfollow the straight, safe and well trodden path."

At the same time, we must accept that the initial euphoria that "diabetes had been defeated" was, and is, misplaced. Whilst ithas been possible to prevent, or adequately manage acute complications of diabetes like ketoacidosis, we have failed toprevent or treat some of the long term complications of diabetes.

Whilst it would be nave to feel that the longterm complications of diabetes are so simple that they would have a singleetiology, there is enough evidence to show that good control of diabetes can prevent, to a large extent, and definitelyalleviate most of these dreaded complications affecting the eye, kidneys, nerves etc. Then why is that in spite of havinginsulin in our therapeutic armamentarium, we are unable to offer optimal control and thereby prevent these verycomplications? Could it be that we have been unable to optimise the use of insulin thus far?

The most important stumbling block to the optimal use of insulin seems to be the inablity to define and understand theprecise role that insulin therapy should play in our management of diabetes. Very often, patients who should preferably beon insulin are treated with massive doses of oral agents without effective control of the blood glucose levels, whilst manyobese Type 2 patients, who have a fair amount of endogenous insulin, and should be managed with diet and exercise areadministered excessive doses of insulin in an attempt to bring about control. I think that it is this "abuse" of insulin with allits attendant problems that prevents us from offering our diabetics the best possible "use" of insulin therapy and as aconsequence, optimal management of their diabetes.

So which patients should receive insulin therapy?

Patients Who Should Receive Insulin Therapy 1 ) It is obvious that insulin therapy is mandatory for all Type 1 patients;


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Long acting;

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

This can be seen at a glance in the following chart This can be seen at a glance in the following chart

Insulin Begins Working Peaks At Ends Working Lows Occur At Lyspro 15-20 minutes 30-90 min 3-4 hours 2 to 4 hr Insulin- aspart 15-20 minutes 40-50 min 3-4 hours 2 to 4 hr Regular 30-60 minutes 80-120 min 4-6 hours 3 to 7 hr NPH 2-4 hours 6-10 hours 14-16 hours 6 to 12 hr Lente 3-4 hours 6-12 hours 16-18 hours 7 to 14 hr Ultralente 4-6 hours 10-16 hours 18-20 hours 12 to 24 hr Insulin Glargine 2-3 hours almost no peak 18-26 hours 4 to 24 hr

However, each person responds to insulin in his or her own way. That is why onset, peak time, andduration are given as ranges.

Fortunately, the picture becomes much more clear, if it is realised that from a practical and clinical viewpoint,insulins can be divided into two main groups, depending on their time course of action. These are the "short-acting (SAI)" and the "intermediate acting (IAI)" insulins. Within these two main groups, the insulins maydiffer in their source of origin and other details, but for all practical purposes, they are similar in their modeand duration of action.

The rapid acting insulin analogues are very useful for use in special circumstances and whilst they can be usedin place of the SAI's, this has not yet become standard practice. Longer acting insulins like Ultralente are veryrarely used in India.


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Traditionally, one starts with a dose of an intermediate acting insulin (IAI) given before breakfast; I am often asked whetherthere is any formula whereby one could calculate the dose that should be given. Let me make it quite clear at the outset thatthere is no such magic formula! When I was an undergraduate in medical college, I was taught that one should start with adose of intermediate acting insulin which was one tenth the level of the fasting blood glucose. In other words, if the FBGwas 250 mg%, then one should give 25 units of the IAI. This just does not work and frankly could lead to quite seriousproblems for reasons which I shall discuss below.

So, how much insulin should be given? I usually start with a small dose of IAI, unless there are adequate reasons forlowering the blood glucose levels very rapidly. In practice, this words out to an initial dose of an IAI of about 8-12 units.There are many valid reasons for starting with this small dose.

There is no method by which we can judge the sensitivity of the patient to insulin. Although it has been said that the thinpatients are more sensitive to insulin than normal weight or overweight patients, this is just a generalisation. There is a greatamount of difference in the sensitivity to insulin. Even patients with the same weight and similar blood glucose levels wouldtend to differ in the response that they show to a certain dose of insulin. As we are dealing with patients and not generalities,it would be prudent to start with a small initial dose, judge the response in the patient and adjust the dose accordingly. Thiswill allow the patients to escape from the hazards of hypoglycemia especially if the patient turns out to be very sensitive toinsulin injections and a large dose of insulin has been given. In fact, one of the commonest emergencies many of us arecalled to treat are patients who have gone into severe hypoglycemia when they have been given large doses of insulin due to

the fact that the fasting blood glucose levels were very high !

I have discussed how patients may differ in their individual characteristic with regards to the time course of action of theinsulin. There may be "early", normal or "late" activators. It is not possible to forecast how a patient would react. A highinitial dose may cause the patient to have hypoglycemic reactions at odd hours, which would be quite problematic. A smallinitial dose would not only protect the patient from these vagaries, but also allow us to judge the type of activator that thepatient is.

To sum up, I would once again like to emphasise that the dose of insulin is determined empirically and that it is alwaysbetter to start with a small dose and adjust according to the response, unless there are relevant reasons for the rapid loweringof the raised blood glucose levels.

After I start the patient on 8-12 units of IAI, given before breakfast at about 8 a.m., I ask the patient to do home bloodglucose monitoring. In the absence of home blood glucose monitoring, I ask the patient to estimate his blood glucose levelsevery 3-4 days and adjust the doses according to these reports. Many patients do not like testing their blood every 3-4 days.It is worthwhile to explain to them that this is required only till the blood glucose levels are normalised. This smallexplaination makes the patient much more willing to accept intensive testing of blood in the initial stages until his bloodglucose have stabilised to acceptable levels. Of course, IDDM patients, pregnant women etc., may have to continue to keepa close and frequent check in order to maintain good control.

Before we discuss the adjustments in the treatment, it would be worthwhile to be very clear in our minds about the aims ofthe treatment. We would like the patient to have "acceptable" blood glucose levels throughout the 24 hours of the day. Thismeans that the fasting blood glucose levels, the premeal and the postmeal blood glucose levels as also the levels in the

interim period should all be stabilised at these acceptable values. It goes without saying that this should not be accompaniedby frequent and/or severe episodes of hypoglycemia. Once, this aim of the treatment is clear, the adjustments in the doses ofinsulin will be much easier to understand.

I review the patient every week until the patient is stabilized on the insulin therapy if I am seeing the patient in the clinicsituation. I do not feel that any person with diabetes, unless he has some complication, should be admitted into hospital justfor controlling his diabetes. Even if a patient is admitted, I do not think that the insulin doses should be changed morefrequently than every 2 days.


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Let us now discuss the various types of response that we would tend to see to the initial dose and our management of theseresponses.

SCENARIO 1

A few of the patients would show during the followup that their fasting and postmeal blood glucose levels are withinnormal, acceptable limits. This means that the patient is controlled and the dose of insulin should be continued. I try and

decrease the dose by about 2 units and see whether the control is still acceptable. If this is so, then I continue to graduallydecrease the dose of the IAI (about 2 units at a time) until I find that the blood glucose values are higher than acceptable.The dose is then increased by about 2 units and the patient called back after 15 days to see about his control. If he continuesto remain in control, then he is called for a routine followup after 6-8 weeks. I would like to make it clear that this scenariois rarely seen. SCENARIO 2

The more usual response is that both, the fasting and the post lunch blood glucose levels continue to remain high and thatthe urine, if tested, shows glucosuria throughout the day. In such cases, the dose of the IAI is gradually increased (again byabout 2-4 units at a time) and the patient examined every week. This would be repeated until either, the patient showsadequate control with the fasting and the post meal blood glucose levels within acceptable limits and no glucosuriathroughout most of the day, or one of the following scenarios would occur.

SCENARIO 3

Whilst, the fasting blood values would be within acceptable limits, the post lunch blood glucose values would be higher thannormal. This is often accompanied by high post breakfast blood glucose values, whilst the evening or the pre-dinner valuesare acceptable. This is quite commonly seen. The action of the IAI normally, starts after 3-4 hours, peaks about 8-12 hoursand lasts for 18-24 hours. Therefore, if the injection of the IAI is taken before breakfast, say around 8-8.30 a.m., then thepeak activity would occur in the evening or around the pre-dinner time. This peak activity could cause the blood glucosevalues at this time to be acceptable. As the activity of the IAI is supposed to start after 3-4 hours and then gradually increase,it may not show sufficient activity to cover the post breakfast and the post lunch levels which would occur within 1-2 hoursand 5-6 hours after the injection when the activity of the IAI would just be gradually starting.

If we were to increase the dose of the IAI, so that it would show stronger activity after 5-6 hours and may help in correctingthe raised post lunch blood glucose levels, but then it is quite possible that at the time of its peak activity, the action of theIAI would be strong enough to cause hypoglycemia which would be manifest in the evening or just before dinner. "Late"activators could go into hypoglycemia later in the night, possibly in sleep. Therefore, it may not be possible to increase thedose of the IAI in order to control the post lunch blood glucose values, without exposing the patient to hypoglycemia later.

The answer to this problem is to add a small amount of short acting insulin (SAI) along with the dose of the IAI, in themorning injection. The rational for this is that the SAI would help in controlling the post lunch values! At first sight, thismay appear doubtful. The action of SAI starts within about 30 minutes of the injection, peaks around 1-2 hours and lasts for4-6 hours. How could the addition of SAI under these circumstances, given before breakfast help to control the post lunchvalues? Clinically, this works!

It could help through various mechanisms. It could act on the glucose levels in the post breakfast period and lower them sothat the pre-lunch blood glucose values would be lower than before. This would lead to a lowering of the post lunch bloodglucose values. As an example, let us suppose that with the prescribed diet, the rise in the level of the blood glucose afterlunch would be in the vicinity of 80mg%. If with only IAI, the pre-lunch blood glucose values would be 150%, then thevalues seen after lunch would be 230mg%. But, if the addition of SAI causes the pre-lunch blood glucose levels to be about100mg% (this would be possible due to the fact that the early activity of the SAI would tend to lower the blood glucosevalues seen after breakfast and also before lunch), then the addition on the lunch increase of 80mg% would cause the postlunch blood glucose levels to be about 180mg%. This would be a definite improvement over 230mg%!


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More importantly, when the patient takes SAI regularly for a while, the time characteristics of its activity change somewhat.It has been shown that activity of the SAI starts slightly later, peaks later and also lasts longer. Therefore, activity of the SAIwould still be present to a significant extent after lunch, even if the injection is taken before breakfast. It should beremembered that in India, breakfast is usually taken at about 8-8.30 a.m., whilst lunch is at about 1 p.m. Therefore, evenwith a time action lasting 6 hours some of the effect of the pre-breakfast SAI would be seen in the post lunch period, Withthe prolongation of the time of activity of the SAI with prolonged use, this effect would be all the more significant!

Before adding the short acting insulin (SAI) to the morning injection of the intermediate acting insulin (IAI), I check theblood glucose levels of' the patient in the evening and also just before dinner, i.e. between 4-8 p.m. If these levels are seen tobe in the "well-controlled" range; then I slightly decrease the dose of the IAI whilst adding the SAI. This precaution isnecessary to protect the patient from the hazards of hypoglycemia occurring at these times. If this is not done, the decreasein the afternoon blood glucose levels, and consequently the evening blood glucose levels, brought about by the SAI, addedto the low in the blood glucose levels brought about by the peak activity of the morning IAI would make the patient prone toepisodes of hypoglycemia.

Often, this judicious use of an SAI along with the IAI brings about adequate control in a number of patients, with acceptablefasting and post prandial blood glucose levels and the absence of glucosuria (in a patient with a normal renal threshold forglucose).

SCENARIO 4

A situation which is less frequently seen than the one described above, is one where the morning, post lunch, and even theevening and pre-inner blood glucose levels are within acceptable limits. But, the fasting blood glucose levels areconsistently above normal and acceptable values. We have seen that the action of the IAI lasts for around 24 hours andtherefore an increase in the dose of the IAI could help, in theory, to control the raised fasting glucose levels. But, this wouldin clinical practice, lead to unwanted hypoglycemia during the day, as we have seen that in this case, except for the fastingvalues, the blood glucose levels are well controlled during the day. Therefore, if one is sure that one is not dealing with theSomogyi phenomenon or the Dawn phenomenon, then the treatment strategy would be to add a small dose of IAI to betaken by the patient before dinner, or at bedtime. This is basically putting the patient on a type of Multiple Dose Regimen(MDR).

This strategy would help in normalising the raised fasting levels. The peak activity of the IAI is normally seen after 8-12hours. As dinner is usually taken around 8-8.30 p.m. the peak activity of this would be seen the next morning in time to helpin normalising the fasting levels. Early activators who show a peak activity after 6-8 hours would be able to take theinjection around bedtime such that the peak activity would occur in the early morning hours (and help normalise the raisedfasting blood glucose levels) rather than in the middle of the night.

When adding an evening dose of IAI, I decrease the morning dose of the IAI injection. This would protect the patient fromhypoglycemia. We have seen that the morning dose of the insulin is sufficient to control the blood glucose throughout theday, but the waning of its overnight activity allows the blood glucose to rise to high fasting level. We have also seen thatadding more insulin would further depress the blood glucose levels and therefore, we cannot increase the morning dose ofinsulin. But, when the evening dose of insulin is given, it must not be forgotten that some of its activity will be present for

24 hours and would add to the insulin effect even during the day. As the blood glucose levels are already well controlled,this further insulin effect would tend to bring the blood glucose down further and possible depress them to hypoglycemiclevels! Therefore, even though the dose of the morning injection is reduced the additive activity of both the morning andevening insulin injections would bring about adequate control during the day and the night.

SCENARIO 5

This scenario is quite the same as that seen in scenario 4. Here, the addition of the evening dose of IAI helps in normalisingthe fasting blood glucose levels, But, in this case, the post dinner blood glucose levels tend to be higher than acceptable. The


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treatment strategy here is to add a small dose of SAI to be taken before dinner. This would help in keeping the post dinnerblood glucose levels down, whilst the two injections of IAI (taken at morning and evening) would, both, keep the bloodglucose levels in the well-controlled range throughout the rest of the 24 hour period.

Although, I have divided the response of the patient into these 5 distinct scenarios and have discussed the treatmentstrategies for each, it should be clear that one would rarely see such clearly demarcated responses. What we see in practice isoften a permutation and combination of the scenarios that we have discussed. Obviously, the treatment strategies would also

need to be adjusted to meet these variations,

But from the basic principles of dose adjustment seen in the 5 scenarios and an understanding of the time course of activityof the two groups of insulin, it should be quite easy to evolve a specific strategy to combat most of the various responsesthat patients would tend to show to the initial dose of the intermediate acting insulin.

It is fortunate that the vast majority of the patients that we see in clinical practice have a significant amount of endogenousinsulin secretion and are therefore much more easier to manage with these conventional methods of giving insulin. Onemodification, or "short-cut" of this conventional method which I have found to be quite useful in clinical practice is to startwith a small mixture of the short acting and the intermediate acting insulin given before breakfast. The response to this is

judged after 3-4 days. Depending on this, the dose is adjusted and the patient retested after a few days. When a stage isreached that the patient is receiving about 25-30 units of insulin in the morning injection, I do not increase the dose any

further, I examine the patient for the presence of any conditions which may be hampering the blood glucose control. Someof the common conditions which reduce the insulin action include, infections, obesity, insulin receptor and post-receptordefects, ketosis, destruction of insulin at the site of injection, true immune mediated resistance, hormonal conditionsassociated with excess of cortisol, Growth hormone and thyrotoxicosis, associated use of drugs which increase glucoseintolerance. If present, this is obviously treated. In the absence of any such associated condition, I add a small dose of aninsulin sensitiser such as a glitazone or metformin. If the postprandial blood glucose levels are in the very high range,acarbose would be an helpful addition. I usually would not add a sulfonylurea to the insulin, as these, especially the olderones, basically try and increase the endogenous insulin secretion. This is not too important once we are injecting insulin! Itis often seen that the addition of this small dose of oral agent tends to bring about quite an acceptable control!

I am often asked why I stop increasing the dose after about 25-30 units and add an oral agent in a patient with Type 2diabetes. This is absolutely empirical and based on the fact that the amount of insulin secreted by a normal person during theday is about 35-40 units. I also feel that when a dose of insulin taken as on injection reaches these levels, further increasesrarely help, but the patient may benefit from splitting the dose into two smaller injections taken before breakfast and beforedinner. Many patients would be extremely reluctant to take the second shot of insulin and in quite a few of these, theaddition of small dose of an oral agent to the morning injection of insulin does bring about control. It goes without sayingthat IDDM patients and pregnant women who need insulin are not given the oral agents but they may need to split theinjection or even go in for MDR.

Multiple Dose Regimens (MDRs)

Multiple dose regimens are not very commonly required for the routine management of most Type 2 patients, but may beimportant in special cases. Most Type 2 patinets who require insulin for optimal management do well with judicious useof combination therapy (insulin with OHA).

Regimens

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

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


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3) Injections of short acting insulin given before breakfast and before lunch and a mixture of short acting andintermediate acting insulin given before dinner.

SOME PRACTICAL ASPECTS IN INSULIN THERAPY

STORAGE

One of the commonest problem that patients seem to have is about the storage of insulin that they are using. Many of

them are under the impression that a refrigerator is essential for storing the insulin vial and since, many do not have a"fridge", they worry that the insulin will spoil and not be effective.

It should be made clear that refrigeration is not needed for storing the insulin vial that is in current use. Regular (plain)insulins are stable at room temperatures of about 750F for many months. This is true also of the longer acting insulins. Infact, the newer insulins that are being increasingly used these days are even more stable than the older insulins. This isdue to the fact that the newer insulins have a neutral pH whilst the older ones have a slightly acidic pH.

Occasionally, when the longer acting insulins are kept at room temperatures consistently above 100 F, they tend to formclumps, whilst this does not cause a significant loss of potency, it may be difficult to withdraw the insulin through theneedle and the vial may have to be discarded.

With the wide availability of insulin all over, the need to store large quantities of insulin by patients is no longernecessary. I usually advise the patients that they only keep one extra vial for use in an emergency like the currently usedvial breaking accidently. If for any reason vials of insulin have to be stocked for many months they may be stored at 40 Fin refrigerator, especially in those places where the room temperature would be high for many months in a year. The vialsshould NEVER be kept in the deep freeze or the freezer section of the refrigerator. In fact, any insulin vial that has beenkept in this freezer section should be thrown away.

This point is, unfortunately, not too well known and many patients do tend to stock the insulin vials in the deep freeze orthe freezer section under the mis- taken notion that this would ensure that the insulin would keep better. In fact, I havenoticed many chemists keep their stock of insulin in the deep freeze and only remove the number of vials which they feelthey would sell during the day, and then store these in the non-freezer section of the refrigerator.

If refrigeration facilities are unavailable, then the currently used vial can be stored at room temperature away from heatand direct sunlight.

If vials have to be stored for longer periods, a simple method is or the unopened vials to be stored in the earthen potswhich contain drinking water and are found in most homes where a refrigerator is not present.

The very fact that insulin can be kept at room temperature without loss of potency for many months, makes it easy tocarry along when travelling. There is no need to carry the insulin packed with ice in a thermos or carry along any othercooling apparatus like thermocole, etc. The insulin vial and the acces- sories can be carried in the travelling bag. I usuallysuggest to the patient that he carry the vial that is currently being used in the bag that he will take with him personallyrather than keeping it in the bag that would be put in the baggage compartment of the train or be checked in at the airport.This is due to fact that I am not convinced that the patient and his baggage would arrive at the same place and at the sametime! I also advise patients that they should always carry extra insulin vials and syringes etc., to face emergencies like astay of longer duration than expected, breakages, loss and other similar problems, especially if they are travelling toplaces where replacements may not be easily available.

STERILISATION

More and more patients are now using disposable syringes and needles. When these are used, the problems ofsterilisation do not arise. They are used once and then thrown away. New syringes and needles are used for the nextinjection. An added advantage is that due to the use of the new needles, these are always very sharp and thus easier andless painful during an injection. But the major drawback against the use of these disposable materials is the cost andmany of the patients do find the cost prohibitive in the long run. In order to circumvent this, it is now accepted that the"disposable" syringe and needle can be reused by the same person. After the injection is taken, the syringe and the needleis carefully placed back in the plastic cover in which they have been sold. They are taken out again, used and thenreplaced. How many times can the syringe and needle be reused. I usually tell the patient to use them till the patient feelsthat the needle has become blunt and needs more pressure to go in. This usually works out to 5-6 injections before


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Follow these steps when preparing two types of insulins to be given in the same injection:

1. Roll the insulin bottles (vials) gently between your hands. This will warm the insulin if you have been keeping thebottle in the refrigerator. Roll the cloudy insulin bottle until all the white powder has dissolved.

2. Wipe the rubber lid of both insulin bottle with an alcohol wipe or a cotton ball dipped in alcohol. If you are using abottle for the first time, remove the protective cover over the rubber lid.

3. Remove the plastic cap covering the needle on your insulin syringe (without touching the needle).

4. Pull the plunger back on your insulin syringe and draw air into the syringe equal to the number of units of cloudyinsulin to be given.

Illustration of step 4.

5. Push the needle of the syringe into the rubber lid of the cloudy insulin bottle. Push the plunger of the syringe to force theair into the bottle. This equalizes the pressure in the bottle when you later remove the dose of insulin. Remove the needlefrom the bottle.



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6. Pull the plunger of the syringe back and draw air into the syringe equal to the number of units of clear insulin to be given.

7. Push the needle of the syringe into the rubber lid of the clear insulin bottle. Push the plunger to force the air into thebottle. Leave the needle in place.

8. Turn the bottle and syringe upside down and hold them in one hand. Position the tip of the needle so that it is below the

surface of insulin in the bottle. Pull back the plunger to fill the syringe with slightly more than the correct number of units ofclear insulin to be given.


9. Tap the outside (barrel) of the syringe so that trapped air bubbles move into the needle area. Push the air bubbles backinto the bottle. Make sure that you have the correct number of units of insulin in your syringe. Remove the needle from theclear insulin bottle.


10. Insert the needle into the rubber lid of the cloudy insulin bottle. Do not push the plunger because this would force clearinsulin into your cloudy insulin bottle. If clear insulin is mixed in the bottle of cloudy, it will alter the action of your otherdoses from that bottle.

11. Turn the bottle and syringe upside down and hold them in one hand. Position the tip of the needle so that it is below thesurface of insulin in the bottle. Slowly pull back the plunger of the syringe to fill the syringe with the correct number ofunits of cloudy insulin to be given. This will prevent air bubbles entering the syringe. Remove the needle from the bottle.


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12. You should now have the total number of units for the clear and cloudy insulin in your syringe. For example, if 10 unitsof clear and 15 units of cloudy are needed, you should have 25 units in your syringe. Now you are ready to give theinjection.

GIVING THE INJECTION Injection sites include the abdomen, outer upper arms, the thighs, buttocks, or hip areas. Donot inject insulin near bony places or joints. Do not give injections closer than 1 inch apart. Insulin absorption can vary fromsite to site. The best absorption site is the abdomen. Try and rotate the injection site


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Your doctor will help you learn to inject insulin. This is an illustration of giving an insulin injection in your thigh.

The Timing of the Injection The interval between the injection and the following meal should be at least 30 minutes, although there is an excellentstudy which has shown that the optimal period is 45 minutes. This is an extremely important point as most of the patientsare under the misapprehension that unless they eat at once they will collapse with hypoglycemia. This is the reason weoften see the comical scene of indoor patients who sit with the food tray in front of them, an arm bare to take the injectionand then start to eat as soon as the nurse has given the injection!

Why should there be such a time gap? Under normal physiological circumstances, one sees that the insulin levels in thebody RISE even before the food is absorbed. In other words, the body does not wait for the food to get absorbed, theblood glucose to rise, and then start responding with insulin. It ANTICIPATES the rise of the nutrients and is ready to acton them. The time interval allows some of the injected insulin to get absorbed and thus the insulin levels in the bodywould be already raised to meet the postprandial demands.

THE ABSORPTION OF INJECTED INSULIN (BIOA VAILABILITY)

Insulin therapy does not end with the act of injection itself. If the injected insulin is to be effective, it must get absorbedfrom the subcutaneous site, enter the bloodstream and thus reach the insulin receptors where it would exert its activity.Unfortunately, not much attention is paid to this aspect inspite of the fact that it plays a crucial intermediate role in ourquest for optimal insulin therapy.

In clinical practice, one often comes across patients who show an odd or unexpected reaction to the insulin. This responsemay take several forms. Some patients show little, if any, response to insulin in spite of the fact that the insulin is potent,injected correctly and at doses where one would expect to find at least some response. There are patients who showerratic timing of the activity of insulin. As an example, a patient may show peak activity to an injection of theintermediate acting insulin after 8-12 hours, as is normally expected. But often he shows activity which is in keeping withthose who are "early" activators and at other times, the time of peak activity would classify him as a "late" activator!

Now a person does not change his characteristic activity pattern suddenly or often. There are patients who in spite of acorrect dosage of insulin continue to show a high 2-3 hour post prandial blood glucose levels and then go intohypoglycemia at a later period, say after 5-7 hours! One also comes across patients who are well controlled on a certaindose of insulin and are fairly stable. The patient may suddenly go into hypoglycemia even though the routine daily doseof insulin has been injected. Patients with Type 1 diabetes may even relapse into ketosis.

Faced with such patients, our first reaction is to put the blame squarely on the patient. One feels that the patient has notfollowed his diet regime or has made a mistake in the injection, either in the dosage or techniques. I do not deny that thismay be true in quite a few patients, but I feel that when one is confronted with a patient who often manifests such bizarreresponses, one should consider that the response could be due to factors that may affect the absorption of insulin from the


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the rDNA derived human insulins.

As with the case of localised allergy, it is more prudent to prevent the systemic allergy from occuring rather than intrying to manage it once this has occurred! Interrupted insulin therapy, especially with the animal insulins should beavoided and such patients should be preferably treated with rDNA derived human insulins. But if a patient taking animalinsulins does show systemic reactions, then again it would be better to shift to the rDNA derived human insulins.

This may help in the occasional patient. The reason why we see such a rare positive response, is that systemic insulin

allergy is due to the presence of antibodies and these are known to be directed against the insulin molecule itself ratherthan against any impurity contained in the insulin. Therefore, once the antibodies have been formed and the allergicreaction is manifest, a simple change over to the human insulin may not be effective. As I have shown before, the beefand the porcine insulin molecule differs from the human insulin molecule by three and one amino acid respectively.Whilst this discrepancy may have initiated the antibody formation, once the antibodies are formed, they would bedirected even against the other parts of the insulin molecule! Thus, removing the source of the antibody formation wouldnot stop the allergic reaction but may help in decreasing further progression.

When faced with a seemingly intractable problem of insulin allergy in a patient with diabetes in whom insulin therapy ismandatory, the only option left before us is to desensitise the patient. This is best left in expert hands.

Insulin Resistance True insulin resistance is usually defined as a situation in which the patient receives more than 200units of insulin per day for two or more consecutive days in order to try and achieve a control of the blood glucose levels.In my opinion, this definition is quite arbitrary, and as the amount of insulin secreted by the pancreas in a normal personis about 35-40 units per day, it is logical to assume the presence of some degree of insulin resistance when OPTIMALLYadministered insulin doses exceed a total of around 50-60 units daily, especially in a "compliant" patient.

I have purposely tried to highlight the point about optimal administration of the insulin, I have seen numerous patientswho were receiving around 100-120 units of insulin in a once a day dose and showed a poor control. When many of themare shifted over to a twice a day regimen (both times being given a mix of the short and intermediate acting insulins) theyshow an excellent control with the daily total insulin administration of around 40-50 units! Surely these patients are notreally resistant although one could say that they manifest "iatrogenic" resistance!

In any case, whenever we talk about insulin resistance, we need to be quite clear in our minds as to what exactly we arereferring to. From a purely theoretical viewpoint, true insulin resistance is a condition where there is an immunologicalbarrier to insulin action. This is due to the presence of specific antibodies that interfere with the action of insulin so thatmassive doses are required before any therapeutic response is seen.

At the same time, there are many other causes and conditions, which for varied reasons, manifest an antagonism toinsulin action such that more than normal doses of insulin are needed for a response. These conditions cannot beconsidered to be causes of "true" insulin resistance as there is no immunological barrier to insulin action involved.

These cause "relative" insulin resistance and from a purely clinical view, they constitute the vast majority of cases wherewe find the insulin requirements to be much larger than normal. I would therefore classify insulin resistance into: Trueinsulin resistance, caused by immunological mechanisms and relative insulin resistance caused by a variety of factorswhich manifest as increased insulin requirements, but which do not have an immunological basis.

As my approach is more clinical, and as cases of relative insulin resistance are so much more common and important, Iwould like discuss a few of the more common and important factors first. I feel that it is imperative to reiterate that theincreased insulin requirements are in spite of optimally administered doses in a compliant patient.

Infection

It is quite well know that in the presence of any infection, diabetic control deteriorates and the insulin doses may have tobe increased quite a bit. Con- versely, when faced with a clinical situation wherein the control deteriorates without anobvious cause, or where it is difficult to control the blood glucose levels in spite of optimal management, and relativelylarge doses are required, it is imperative that a thorough search be made for the presence of any obvious or occultinfection. In my experience, the most common infection in our country would be active tuberculous infections. Theassociation of diabetes with tuberculosis is frequent enough to justify routine ruling out of tuberculosis not only whenfaced with a case with "difficult" control but in all cases! The other common problem is caused by urinary tract infectionwhich may not cause symptoms or signs that would bring it into clinical diagnostic consideration. Thus, a routine urine


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examination is also mandatory to rule out a urinary tract infection.

Obesity

Type 2 patients who are overweight and especially those with a raised waist to hip ratio often manifest resistance to theaction of insulin. It is well documented that in most of these patients, the pancreas secretes more than average insulin.Yet they show a poor control and the situation may not become better even with the injection of additional doses ofinsulin. In such patients the problem seems to lie with the peripheral insulin receptor and the best management for such

patients would be to try to optimise the weight of the patient with diet, exercise and the possible use of a small amount ofsensitisers such as metformin and/or the glitazones.

Thyrotoxicosis

Another relatively common cause of relative insulin resistance is the presence of an increase in the activity of thosehormones that have an antagonistic effect to that of insulin. These are hormones like glucagon, growth hormone, cortisoland thyroid hormones. From a clinical viewpoint, the commonest condition that causes an increase in insulinrequirements in so far as these hormones are concerned is thyrotoxicosis. This conditions is not as rare as one mayimagine especially in the young. I have seen patients whose weight loss has been attributed to the diabetes itself andwhose diarrhea has been thought of as due to amebiasis or even autonomic neuropathy! When the thyrotoxicosis iscontrolled, one sees a good diabetic control with small doses of insulin.

Bioavailability

I have already discussed the factors associated with the bioavailability of insulin from the site of the injection. It isobvious that if the injected insulin is not properly absorbed from the site of injection, it would not reach the receptors insufficient amounts to be effective, thus creating a relative insulin resistance. Besides this, in the rare patient, the increasedinsulin requirement may be due to an increased amount of degradation of insulin at the site of injection.

Finally let us come to the problem of true insulin resistance. This is due to an immune based mechanism. All patientswho receive insulin therapy, especially with the older conventional insulin, do show a presence of antibodies, but thetiters of these antibodies are in such a low range that this seldom causes any clinical problem. These titers are usually inthe range of 10 units per liter of serum. In patients showing a true insulin resistance, these titers may range from 100 to ashigh as 50,000 units per liter of serum.

Beef insulin differs from human insulin in three amino acids and the porcine insulin differs from human insulin in one

amino acid. Thus, beef insulin would have a greater tendency to give rise to the antibodies as compared to porcineinsulin. But once again I would like to make it clear that in most instances these antibodies do not reach a significantlevel. Higher antibody levels can also be seen in people who receive intermittent therapy especially with the olderinsulins. The reason why the antibody titers assume a clinical significance in only a relatively few patients is not quiteclear but may be due to differences in immune responsiveness of individual patients.

Although true insulin resistance can be managed in specialized centers it is a complex matter and the best way to avoidthis problem is to use the newer insulins which are now available, and also by avoiding needless intermittent insulintherapy.

Lipodystrophy and scar formation

Whilst injecting insulin, one should invariably rotate the site of the injection so that no area of the body about 3 cms. in

diameter, should receive the injection more than once every three to four weeks. One of the complications of notfollowing this rule, is that when the insulin is repeatedly injected into the same area, the skin and subcutaneous tissuemay become thickened and scarred with the formation of insulin lumps. As injections in this scarred area are relativelypainless, the patient keeps injecting the insulin into this area. This exposes the patient to bizzare reactions as theabsorption of insulin from such a site is delayed and wholly unpredictable.

Insulin lipodystrophy comprises both, lipoatrophy as well as lipohypertrophy. The insulin induced lipoatrophy isbasically a loss of subcutaneous fat at the site of the insulin injections. Insulin induced lipoatrophy may not seem to veryimportant from a purely clinical viewpoint but it may give rise to considerable cosmetic disfigurement and many of theyounger patients would rather discontinue the insulin therapy than accept these unsightly blemishes.


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It has been shown that rotating the site of the injection, using a slightly longer needle so that the injection goes deep intothe subcutaneous tissue, or even in- tramuscularly, are some of the simple manoevers to avoid lipoatrophy, as is theroutine use of the newer and purer insulins. In fact, if the newer insulins are injected into the site of lipoatrophic areas,these will fill out again! This is due to the new deposition of fat in the lipoatrophic areas and may take about 3-4 weeks.The areas which have thus filled out should get injections of insulin every three to four weeks or else it is possible thatthese areas may lose some of the fat again.

Of course, now that only the pure monocomponent insulins are available for use, one will see less and less of

lipoatrophy.Lipohypertrophy is much more rare than lipoatrophy. It basically means that the subcutaneous fat cell at the site of theinsulin injection undergo hypertrophy and is presumably a manifestation of the lipogenic action of insulin. One factorthat predisposes to lipohypertrophy is the repeated injection of insulin at the same site. Once slight hypertrophy develops,the patient may continue to inject his insulin at the same site as this is less painful than other normal areas. Sincelipohypertrophy is related to the inherent lipogenic action of insulin, it can occur even with the newer insulins. The bestmanagement of established lipohypertrophy would be to avoid using that site for the injection for a long time in order toallow the increased fat to resolve by itself.

DIABETIC NEPHROPATHY

Dr. S.M.Sadikot.Hon. Endocrinologist,Jaslok Hospital and Research Centre,Mumbai 400026

Renal dysfunction is fairly common in people with diabetes. Approximately 25% to 40% of patients with Type 1 diabetesultimately develop diabetic nephropathy (DN), whilst the corresponding figures for Type 2 diabetes are in 5% to 15%although some studies show that the figure may go as high as 40% even in this category of patients. Diabetic nephropathy(DN) progresses through about five predictable stages. Progression through these five stages is rather predictable becausethe onset of DM 1 can be identified, and most patients are free from age-related medical problems. The time line for Type 2patients is not too clear as the onset can be quite insiduos and some patients progress through the stages very rapidly.

The five stages are:Stage 1 (very early diabetes) Increased demand upon the kidneys is indicated by an above-normal glomerular filtration rate(GFR).

Stage 2 (developing diabetes) The GFR remains elevated or has returned to normal, but glomerular damage has progressedto significant microalbuminuria (small but above-normal level of the protein albumin in the urine). Patients in stage 2excrete more than 30 mg of albumin in the urine over a 24-hour period. Significant microalbuminuria will progress to end-stage renal disease (ESRD). Therefore, all diabetes patients should be screened for microalbuminuria on a routine basis.

Stage 3 (overt, or dipstick-positive diabetes) Glomerular damage has progressed to clinical albuminuria. The urine is"dipstick positive," containing more than 300 mg of albumin in a 24-hour period. Hypertension (high blood pressure)typically develops during stage 3.

Stage 4 (late-stage diabetes) Glomerular damage continues, with increasing amounts of protein albumin in the urine. Thekidney's filtering ability has begun to decline steadily, and the levels of blood urea and serum creatinine have begun toincrease. The glomerular filtration rate (GFR) decreases about 10% annually. Almost all patients have hypertension at stage4.

Stage 5 (end-stage renal disease, ESRD) GFR has fallen to approximately 10 milliliters per minute (


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dysfunction does not occur until diabetes develops; the worse and more prolonged the hyperglycemia, the greater the risk ofdiabetic nephropathy.

Whilst some people feel that renal dysfunction is a part and parcel of the diabetic scene and will invariably occur with time,it is also widely accepted that we can do quite a bit to delay the onset. In spite of this, if renal dysfunction does occur, earlydiagnosis and certain specific treatments can, if not reverse, at least slow down the rate of progression of the renaldysfunction so that it reaches its end stage at a very late age.

So how are we to avoid or the least delay the onset and rate of progression of renal dysfunction?

Diagnosis

Early diagnosis of the onset of complications is a crucial factor. However, early in the diabetic nephropathy, there are noclinical signs or symptoms of renal disease. Glomerular changes can be identified only by renal biopsy which is impracticalto carry out in every patient!

From a clinical viewpoint, every patient with diabetes who presents for the first time and regularly thereafter should betested for the presence of microalbuminuria. Aggressive intervention can delay and possibly stop progression through thestages of diabetic nephropathy (DN). Unfortunately, many patients often seek medical attention only after having progressedto stage 3 or 4.

I do not agree with those who feel that screening for microalbuminuria is not as useful in type 2 diabetes because it is not asclearly predictive of progression to overt nephropathy as in Type 1 diabetes. As we have discussed before, due to theinsiduos onset of Type 2 DM, one may not be able to see a distinct prediction of progression to end stage renal disease, buttreating the raised albumin levels is definitely helpful. Moreover, the presence of microalbuminuria is associated with anincreased risk of developing cardiovascular disease and retinopathy.

Even normally, a person excretes about 5 micrograms of albumin per minute in his urine. With incipient diabeticnephropathy, the amount of albumin that the patient excretes in the urine increases and this should alert us to the possibilityof diabetic kidney disease.

Incipient nephropathy is the stage of microalbuminuria;

Microalbuminuria is defined as albumin excretion rate:a) between 30-300mg per 24 hours, orb) an albumin excretion rate exceeding 20ug/minute and less than 200ug/minute.

Albumin excretion can be estimated through the following methods:1) 24 hour urine collection.2) Timed collection, say over a period of four hours.3) Spot urinary sample

The results are analysed as follows:24 hour collection Timed collection Spot collection

mg / 24 hours ug / min ug/mg Creatinine

Normal 300

Although dipsticks are available to detect microalbumin levels, they are costly. It may be worthwhile to do a spot or timedcollection of urine and then see the albumin to creatinine ratio to judge the level of renal involvement.

In the absence of methods to routinely look for the presence of microalbuminuria, the use of dipsticks to look for albumin inthe urine must suffice to warn of the presence of diabetic nephropathy, and it is essential that this test routinely and


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frequently be carried out in all patients.

Unfortunately, our routine method of detecting the presence of albumin in the urine is not very sensitive and by the timealbumin can be detected even by the use of the "dipstick", the amount of albumin excreted is around 150 micrograms perminute, which is too late to diagnose microalbumin excretion levels..

It should be clear that there are numerous causes for the presence of albumin in the urine and diabetic nephropathy is only

one of these. Therefore, if albumin is found in the urine of a diabetic, it should not be taken to mean that the patient hasnephropathy. I usually ask my patients to repeat the test after a few days and only if this positive, then I investigate to ruleout the other more common causes of albuminuria. The most frequent cause of albuminuria is any infection in the urinarytract although any generalised infection in the body can cause albuminuria. Hypertension, cardiac failure and indeed drugsused in the management of these two conditions are also known to lead to albuminuria. Even in a diabetic, one shouldalways keep in mind that the renal involvement may be due to a non-diabetic cause. Even otherwise, a very poorlycontrolled diabetic may show an increased excretion of albumin in the urine without signifying diabetic nephropathy. Thisusually corrects itself after adequate control. Many people show a positive test after exercise and importantly, although thisis not well known, drinking a large amount of water may increase the albumin excretion. Many a patient when he has to gofor a test where he will need to give a urine sample, drinks a large amount of water so as to be able to give the samplewithout any problem, without realising that this act in itself may increase the amount of albumin in the urine. It should bementioned that this is usually seen if something like two or three big glasses of water are rapidly drunk. It should also be

remembered that many young people normally excrete albumin in the upright position.

In other words there are numerous causes of an increase in the urinary albumin excretion and all these have to be ruled outbefore one accepts the possibility that the albuminuria could be due to diabetic nephropathy.

POINTERS TO A "NON DIABETIC" CAUSE OF RAISED UAE1) a more rapid decrease in the GFR than is expected.2) sudden development of nephrotic syndrome.3) absence of retinopathy.4) presence of hematuria ; although red cell casts have been described in some patients.5) renal bruit.6) absent pedal pulses.7) disproportionately high serum potassium.8) sudden deterioration in renal function after starting ACE inhibitors.9) presence of cardiac failure, and the use of drugs, like diuretics, in its management.10) testing after heavy exercise.11) testing during acute illness.12) high protein intake.13) decompensation of metabolic control, including recent ketosis.

Diabetic nephropathy should only be diagnosed when seen to be present on repeat testing and when other causes of raisedurinary albumin have been excluded.I feel that checking for microalbumin levels and especially repeat testing is usually not feasible in most cases. I usually

start the patient on a small dose of an ACE inhibitor or an Angiotensin Receptor Blocker (ARB) or a combination ofboth irrespective of whether the patient has hypertension or not. There is overwhelming evidence to suggest that the useof these agents can reverse the early or incipient diabetic nephropathy or at the very least slow down significantly theprogression.


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Strict blood sugar control is important in the protection of kidney function.

Onset of diabetic nephropathy may be avoided with good glycemic control. Interventional and epidemiologic studies haveconfirmed the benefits of tight glycemic control in avoiding or delaying onset of diabetic nephropathy in patients with type 1diabetes. In one often quoted study, the DCCT, (average HbA1c level, 7.l%), in the primary-prevention group, who had hadtype 1 diabetes for less than 5 years and had no retinopathy, patients who received intensive versus standard insulin therapyhad a 34% decrease in the frequency of microalbuminuria and no significant decrease in the frequency of macroalbuminuria.In the secondary-prevention group, who already had mild retinopathy, patients who received intensive therapy had asignificant decrease in both microalbuminuria (43%) and macroalbuminuria (56%).

In patients with type 2 diabetes, a recent interventional study showed a decrease in the frequency of development of both


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microalbuminuria (57%) and macroalbuminuria (70%) with intensive insulin therapy. However, since type 2 diabetes isdiagnosed, on average, 8 years after onset, diabetic nephropathy may have already developed in many patients.

There are some who feel that once diabetic nephropathy has set in, the importance of optimal glycemic control is little ifany, in retarding the progression of the renal dysfunction. But this is far from true. Results from pancreatic transplantrecipients in which true euglycemia is restored suggest otherwise. In fact, optimal glycemic control in these patients led toeither an absence of albuminuria or a significant lowering of the urinary albumin excretion.

To sum up this aspect, optimal glycemic control is important in delaying the onset of diabetic nephropathy and is alsoimportant in retarding the progress of the nephropathy once it has set in.

Aggressive blood pressure control is by far the most important factor in protecting kidney function, regardless of the stageof DN. Even those who believe that there is a point of no return in so far as glycemic control is concerned agree that optimalcontrol of the blood pressure does retard the progression of diabetic nephropathy.

The goal of treatment is:

120 - 130 mm Hg systolic blood pressure and 70 - 80 mm Hg diastolic blood pressure.

We have already referred to starting an ACE inhibitor (ACEi) or an Angiotensin Receptor Blocker (ARB) even when the

patient does not have hypertesnion in order to delay the onset of nephropathy. These drugs continue to be the mainstay inoptimizing the raised blood pressure, but often combination therapy with other groups of blood pressure lowering drugs arenecessary. I have discussed the management of hypertesnion in a patient with diabetes in a separate chapter.

With an aggressive treatment approach, the decline in renal function can be reduced to half of the decline seen withouttreatment (ie, from 10% to 5% per year). Whilst this may not seem to be much, one should realize that this may mean thatthe patient reaches end stage renal disease state possibly 15-20 years later than he would without optimal management of thehypertension!

Aggressive treatment of dyslipidemias, surprisingly have been shown to be beneficial. Hyperlipidemia is common indiabetic patients, a tendency that is increased by the development of renal insufficiency.

In patients with type 1 diabetes, the incidence of myocardial infarction is not increased before age 35. However, after age

35, it is increased fourfold, and when proteinuria is present, it is increased by a factor of 140. The fourfold increase after age35 could potentially be due to the presence of microalbuminuria. In patients with type 2 diabetes, diabetic nephropathy, ormicroalbuminuria, the incidence of myocardial infarction is also increased.

Risk factors for ischemic heart disease, which occur in the presence of albuminuria, are hypertension, increased low-densitylipoprotein (LDL) cholesterol and triglyceride levels, a decreased high-density lipoprotein cholesterol level, and increasedplatelet aggregation and clotting factors. However, albuminuria is a significant independent risk factor. The presence ofalbuminuria suggests that large-vessel walls are more permeable to lipoproteins or damage from local release of growthfactors, as occurs in the glomerulus.

Aggressive treatment of dyslipidemia in patients with diabetic nephropathy may have beneficial effects on not onlymacrovascular disease but also diabetic microvascular disease (ie, retinopathy and nephropathy). Several studies oftreatment of dyslipidemia have shown improvement in retinopathy, and one double-blind study showed stabilization of renalfunction. Other studies have shown a positive effect of lipid lowering on other glomerular diseases.

Dietary protein restriction is minimally protective. A high-protein diet can further damage the kidneys in people withdiabetic nephropathy and/or chronic renal failure (CRF). Protein restriction must be cautiously implemented because of therisk for malnutrition. In general, dietary protein intake should be limited to 0.6 to 0.8 grams per kilogram (0.02 - 0.028oz/lb) of body weight each day.

A low-protein diet (0.6 g/kg of body weight) has the theoretical advantages of decreasing glomerular hypertension, reducingproteinuria, and slowing the decline in renal function. The efficacy of a low-protein diet in diabetic nephropathy has beenquestioned, but a recent meta-analysis found it to have a positive effect. Since high protein intake has the potential toaccelerate the decline in renal function, at least some degree of protein restriction is indicated.


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There are, however, potential problems associated with a low protein diet. In addition to difficulty with compliance due toconcurrent fat and simple carbohydrate restriction, diabetics are at increased risk for protein malnutrition because thereduction in intake may be associated with enhanced protein breakdown induced by insulin deficiency. Recent experimentalstudies also suggest that restricting all components of protein intake may limit the potential efficacy of this regimen. Theamino acid L-arginine is the precursor of the vasodilator nitric oxide (endothelium-derived relaxing factor). Theadministration of L-arginine to diabetic rats with nephropathy ameliorates both the glomerular hyperfiltration and the degreeof proteinuria. Thus, limiting L-arginine intake as part of a protein restricted diet may not be desirable.

Maintain hydration In patients with diabetic nephropathy, avoidance of dehydration is an important factor in maintainingrenal function, since a period of dehydration can cause an irreversible decline. Therefore, any acute illness that causesdehydration should be treated aggressively with intravenous fluids.

The most common cause of dehydration in patients with diabetic nephropathy is overuse of diuretics. Diuretic doses shouldbe adjusted so patients experience nocturnal ankle edema without morning ankle edema. All patients with diabetes should beexamined for physical signs of dehydration at each clinic visit.

It is absolutely essential that there should be adequate hydration. It is well known that dehydration can adversely affect thekidney. That is the reason why all diabetics should always be asked to drink an adequate amount of water so that normalquantities of urine are passed. I ask my patients to drink a glass of water at bedtime and to have some liquids on waking up.A problem that arises in our country is the fasts that people keep, especially those types of fasts where even water is notallowed. This in my opinion is harmful to some extent to a diabetic kidney, but one can only firmly advise in this matter asquestions of religion are involved.

But one area where doctors can definitely do something is regarding the advise we give the patient when they have to go fortheir blood tests. Often the patients are asked to go fasting and are told to have nothing from 10pm the previous night. Bythe time the patient finishes giving the blood it often happens that more than 12 hours have elapsed without any liquidintake. I have never understood the reason for not allowing the patient to have even water. I have come across no evidencethat having a glass of water in the morning would in any significant manner affect the test results! Unfortunately, thisstanding instructions to go completely fasting have become the "order of the day" and is accepted without question. Theproblem even gets worse when the patient has to go for an X-ray examination on a fasting stomach. By the time these testsare over, more than 12-14 hours may have elapsed without water. Whenever my patient is called for an X-ray in the fastingstage, I usually make it a point to inquire whether even a glass of water would affect the quality of the X-rays. If this is so,then I insist that my patient be taken up first in preference to other non-diabetics. I also instruct the patient to have more thanthe normal amount of water the previous night. I am not implying that one occassion that the patient stays without water forabout 12 hours will cause a renal shutdown, but when there is no need to be without water and when one knows thatdehydration can harm the diabetic kidney, is it not better to take all precautions to avoid even mild dehydration? If onethinks of the number of times that we ask patients to go fasting for something or the orther, and one can well imagine thethese small "insults" to the kidneys may well add up! And it is so simple to avoid these insults.

Infections of the Urinary Tract must be treated adequately and the urine should be tested repeatedly and regularly for thepresence of any infections which should be ruthlessly eradicated.

By itself, this may appear trivial but they may add up over the years and avoiding them may make the crucial differencebetween the patient who remains at a stage where there is just albuminuria as compared to reaching a stage of full blownrenal failure where life can be maintained only with dialysis or renal transplant.

UTIs are detrimental to the diabetic kidney and the best solution to this is early detection and adequate management.

Although such infections may be suspected from symptoms like burning micturation, dysuria, passing small but frequenturine, mild infections of the urinary tract may go unnoticed and may only be detected when the complete urine examinationis done. Urinary tract infections are more common in diabetics. Besides the fact that poorly controlled diabetics, in general,have a tendency to infections, long- standing diabetics, have some degree of autonomic neuropathy which leads to bladderatony, incomplete emptying and stagnation of some urine. This coupled with the presence of glucose in the urine of poorlycontrolled diabetics favors the growth of bacteria and infection. The stagnation of the urine also makes it that much moredifficult to eradicate any infection.

I usually ask my patients, especially women who are more prone to chronic urinary tract infections, to have a complete urineexamination done every three months or so irrespective of whether these have any signs and symptoms of urinary infection


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or not. If there is any evidence of infection, then I ask for a culture and sensitivity and treat the infection until the urine issterile. In patients who are prone to recurrent urinary infections, the antibiotic to which the organism is sensitive may becontinued in a small nighttime dose for a prolonged period. This often helps in avoiding frequent infections. The patient mayalso need to be taught methods which will help in a more complete emptying of the bladder. Occassionally drugs may be ofsome aid and in very severe case surgery may be required especially in male patients who may have some degree of anenlarged prostate that makes complete emptying of the bladder difficult.

Smoking worsens hypertension and albuminuria by increasing catecholamine levels in patients with diabetes without

autonomic neuropathy. Therefore, smoking cessation is imperative.Avoid renal damage from drug use. Some drugs should be avoided completely in patients with nephropathy whilst thedose of some other drugs needs to be carefully adjusted depending on the state of the renal function. It would be worthwhileto avoid the use of these drugs in cases with diabetic nephropathy especially if safer alternatives are available. Here againone may feel that occassionally taking a drug with a potential for renal toxicity may not have a significant effect on the finaloutcome of the renal disease, but these "minor" matters do add up and if one can avoid taking even these-minor risks, Ireally cannot find a valid reason for not doing so.

One area where I would like to draw special attention is the use of radio-contrast media in investigations. Wheneverpossible, radiocontrast material should be avoided, since patients with diabetic nephropathy are at increased risk ofradiocontrast-induced renal shutdown. Additional major risk factors for radiocontrast-induced renal shutdown are sepsis,dehydration, use of nephrotoxic antibiotics, use of antifungal agents or nonsteroidal anti-inflammatory drugs, and thepresence of cardiac or pulmonary disease or other causes of hypoxia. However, the most predictive factor is the volume ofiodinated radiocontrast material used. The risk of renal shutdown is minimal with intravenous urography or computedtomography of the head and greatest with coronary angiography. Coronary angiography is often considered in patients withdiabetic nephropathy because their incidence of ischemic heart disease is increased; however, it should be performed onlywhen absolutely necessary and with the lowest possible radiocontrast dose.

Renal Replacement Therapy. Once patients with DN progress to stage 5 (end-stage renal disease, ESRD), renalreplacement therapy (RRT) is implemented. The RRT options for DN patients include the following:

Hemodialysis, removal of the blood's waste products through filtration outside of the body Peritoneal dialysis , filtration through the membrane lining the abdominal cavity; fluid is instilled into the

peritoneal space, and then drained Kidney transplantation

MONITORING THE BLOOD GLUCOSE LEVELS Dr. S.M.Sadikot.Hon. Endocrinologist,Jaslok Hospital and Research Centre,Mumbai 400026One of the major aspects of a good diabetic management is that the blood glucose levels should be optimally controlled.Whilst there are a few who may still question the role that hyperglycemia plays in the pathogenesis of the dreaded long termcomplications, most of the authorities are of the view that an optimal control of the blood glucose level will definitely helpin retarding the progression of these complications even if one is not able to completely avoid the problems. By optimally, Iwould mean that they should be as close to normal as is possible without exposing the patient to the "peaks" ofhyperglycemia as well as the "troughs" of hypoglycemia.

But how are we to judge the adequacy, or otherwise, of the control of the glucose levels? What are the parameters availablewhich enable us to get a correct idea of the control?

Unfortunately, many of the so-called parameters which have traditionally been used to judge this control have so manyshortcomings associated with them, that they should have no place in the modern management of diabetes. At the sametime, one cannot accept all new methods of evaluating blood glucose control without inspecting their feasibility in ourcontext. Having made this point, what are the methods that we commonly use to judge blood glucose control.


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Presently, the following methods are in vogue :

1. Testing the urine for the presence of glucose;2. Occassional blood glucose test done in an laboratory ;3. Estimation of Glycosylated Hemoglobin and serum Fructosamine levels ;4. Self monitoring of the blood glucose levels.

URINE TESTING FOR THE PRESENCE OF SUGARS

This is still the most common method used for estimating the blood glucose control ! I feel that using this estimation is intoday's context mostly unacceptable, especially when other, better, parameters are easily available. Urine tests are associatedwith too many shortcomings to give any reasonable answer about the glucose control. At the same time, it would beworthwhile to examine the reason why urine testing for glucose was advocated as a means of evaluating blood glucosecontrol as a time when other methods were not routinely available.

When blood flows through the kidneys, glucose that is present in it is filtered by the glomerulii. When this filtrate flowsthrough the tubules, this glucose is reabsorbed back into the bloodstream and consequently, under normal circumstances, noglucose is found in the urine. The capacity of the tubules to reabsorb glucose is limited and if the amount of filtered glucose

is more than this capacity, the excess glucose would be found in the urine, which would then test positive for the presence ofglucose. As the amount of glucose found in the glomerular filtrate is dependent on the amount of glucose present in theblood, it follows that in cases where the blood glucose levels are increased, as in diabetes, more than normal amounts ofglucose would be filtered out and if this overwhelms the reabsorptive capacity of the tubules, glucose would be found in theurine.

This has lead to the concept of "renal threshold". This is the blood glucose level beyond which so much glucose would befiltered out by the glomerulii that the urine would test positive for the presence for glucose. The textbooks mention the renalthreshold for glucose to be 180mg%. In other words, if the blood glucose levels were to increase above 180mg% then theurine would test positive for the presence of glucose.

In view of this, it is easy to understand how testing the urine for the presence of glucose came to be used as a parameter to judge the blood glucose levels in the olden days. In the absence of wide availability to test for the blood glucose levels, itwas felt that if the urine showed the presence of glucose, then it could be surmised that the blood glucose were above 180%.This is where the first fallacy creeps in. One must realise that the figure of 180% is just an average approximation and thatthe threshold differs markedly in every individual patient. Thus, there are those non-diabetics who will show the presence ofglucose in their urine, even when the corresponding blood glucose level may be only 100mg% ! Conversely, some knowndiabetics may not show the presence of glucose in the urine, although their blood glucose levels may have reached as highas 300mg%. Most of the others would come in between these two extremes. Therefore, if urine testing is to have anyrelevance to judging the blood glucose control, then the renal threshold for every individual patient will have to be charted !Unfortunately, the method for estimating the renal threshold is quite cumbersome and one should not be under themisconception that it just a simple matter of checking the urine for the presence of glucose and estimating the correspondingblood glucose levels. This "simple" method will invariably give wrong idea of the renal threshold as we shall discuss later.

Even if we were to take the trouble to estimate the renal threshold for every individual patient, we are then faced with theproblem that this value does not remain constant for that individual for all times. The threshold value changes with age,pregnancy, any kidney disease including diabetic nephropathy. More importantly, and this is not too well known, changes inthe blood glucose level themselves can effect a change in the renal threshold values ! It is now well accepted that when theblood glucose levels are very high, the renal threshold values tend to be lower and this then increases gradually as the bloodglucose levels are brought under control. In other words, the very parameter that we use to judge blood glucose control,itself undergoes changes as the blood glucose levels change !


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It should be obvious that such a labile renal threshold value should not have any important place to play in judging the bloodglucose control in the modern context.

There are many more reasons why we should not use urine glucose tests to evaluate blood glucose control. For the purposesof discussion, let us take a theoretical patient and accept that his renal threshold value for glucose is 180mg%. What thisimplies is that if the patients blood glucose values are below 180mg%, then no glucose would be found in the urine. Often,we test the urine in the fasting stage and feel gratified that is shows no glucose. But are we justified in accepting that this

signifies good control ? It is possible that the blood glucose levels may be 165mg% and this value in the fasting stage woulddefinitely be unacceptably high ! Looking at this from a slightly different angle, when the urine shows the absence ofglucose, it would mean that the corresponding blood glucose level could range, in theory, from 0mg% to 180mg%, acomplete range from the absurdly low to the unacceptably high. How is it possible to accept such a parameter to judge bloodglucose control, leave alone making treatment changes !

Thus, testing the urine for the presence of glucose as an indirect parameter to judge blood glucose control is, at best, a crudemethod and should be accepted as such.

Even if we are to accept that urine tests are only crude method and give us only a rough idea of the blood glucose levels, wewould be erring. It should be realised that urine test for the presence of glucose does NOT give an estimate of the bloodglucose levels at the very time of testing the urine. In simple terms, we test the urine for glucose, say, 2 hour after a meal, as

patients are often asked to do. Let us for the sake of discussion accept that the renal theshold of the patient is 180mg%, 1 +urine sugar corresponds to 200mg%, a 2 + to 250mg% and so on. The patient tests his urine after two hours of a meal andfinds that his urine shows a 2 + presence of sugar in the test. Can this be taken to mean that his blood glucose level 2 hoursafter the meal is 250mg% ? This could be completely off the mark. In this case, one may accept the blood glucose level atthat time to be 250mg%, only if the urine that we are testing is that which is passed by the kidneys precisely 2 hours afterthe meal. But the urine that we are, in reality, testing is NOT the freshly passed urine but a mix of all the urine that hasaccumulated in the urinary bladder since the last t ime that the patient had voided. In other words, urine testing cannot giveus a true idea of the blood glucose levels at the time that we test the urine. This point, though of utmost importance, is oftenforgotten by many of us.

One way out of this problem would be to ask the patient to completely empty his bladder, say, 5 minutes before the test anddiscard this urine. He would then pass a fresh sample of urine after about 5 minutes and this could then be construed to beakin to a freshly passed specimen from the kidneys and this may give an idea of the corresponding blood glucose levels inan ideal situation. To do this, that is to completely empty the bladder and then pass some more urine within 5-10 minutes ismore easily said than done. Most, if no all patients find this extremely difficult (not to say inconvenient) and many willrefuse to do the test at all. I always ask doctors who advise their patients to do this, if they have ever tried to do itthemselves. Only then they will realise how troublesome these instructions are ! Often, the patients are advised that afterthey have discarded the first urine completely, they should drink lots of water. This is done in the hope that it will help themoffer the second sample easily. Unfortunately, the very fact that the patient drinks a lot of water, makes him pass diluteurine, and this dilution in itself, changes the renal threshold !

More commonly, many diabetics have some amount of autonomic nerve involvement and this leads to an inability tocompletely empty the urinary bladder. Such patients, and there are quite a few of them, would find it impossible to offer a

second, fresh sample of urine, as any urine that they pass would invariable have been mixed with some of the urine that hasremained in the bladder due to incomplete emptying caused by the neuropathy. This inability to completely empty theurinary bladder caused by the neuropathy, leads to some urine stagnating in the bladder and this urine is particularly prone toget infected especially in diabetics with a high blood glucose levels who would pass an increased amount of glucose in theurine. The infecting bacteria will utilise the glucose that is present in the urine and when we test the urine, under suchcircumstances, one would find an absence of sugars. This would lead to a completely erroneous idea that the blood glucosecontrol is quite acceptable. In reality, the blood glucose may be very high but this would not be reflected in the urine tests

just at the time when it would be important to correctly assess the diabetic control so that adequate measures can be taken tomanage the blood glucose levels and help in the eradication of the urinary tract infection.


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Finally, let us briefly discuss the methods that are widely used in many parts of our country. The two most commonly usedmethods are the older Benedict's test and the "stick" test. The Benedicts test is the older test in which a certain amount ofurine is added to a measured quantity of the blue copper sulfate solution, and the mixture is boiled after which the change incolour of the solution and precipitate, if any, is noted. This change in the color is supposed to indicate varying levels ofsugars in the urine.

This test is still very widely used here, the main reason being its cheapness. But, it is also very non-specific and will show apositive reaction with many a reducing substance besides glucose. To give a common example, breast feeding mothersexcrete lactose in the urine and the Benedicts test will show a positive result even though the blood glucose of the motherare completely normal and she is not spilling any glucose in the urine. There are numerous drugs and medications that alsointerfere with the correct result as we shall discuss later.

The "stick" has a special paper attached to one end. This paper is impregnated with certain enzymes and when it is dippedinto the urine, the change in the color of the paper will denote the presence of, and the varying amounts, of glucose presentin the urine. It has the advantage that it is quite specific for glucose and also does not require all the paraphernalia that oneneeds for the Benedicts test like test tubes, dropper, a source for boiling the solution etc. At the same time, it is costlier thanBenedicts test, although the cost can be halved by cutting the strip longitudinally so that one can use each stick twice.

It, too, has drawbacks, the chief one being that there are many drugs and medications which interfere with the correct result.These drugs may interfere with false positive or false negative results. Just to show how common the problem can be, tworountinely used drugs which can interfere with the results are aspirin and Vitamin C. Thus, doing urine tests for the presenceof sugar when the patient is on any of these tablets would give a completely wrong result. These drugs are so commonlyused even by patients themselves that doctors are often unaware that the patient is on these medications. I do not think that itwould be possible to find a single diabetic patient who is not taking a vitamin tablet and aspirin is a common householdremedy for aches and pains and also now routinely prescribed as a preventive measure against atherosclerosis.

Does this imply that testing the urine for the presence of sugars has no role to play in the modern management of diabetes?Whilst, it would seem to be so, especially when other better methods are now available to judge blood glucose control, itshould also be remembered that many of these methods are not easily accessible or affordable to many of our patients. Theyalso have their inherent drawbacks. Therefore, I feel, that in spite of all the problems associated with the use of this mode oftesting, it will continue to be used by many patients. One of the main reasons is the relative cheapness of the method, butmore importantly, due to the fact that most of the patients are unaware of the useless results that one can get from suchtests.

Urine testing will continue to be important to look for the presence of ketones and albumin in so far as diabetes managementis concerned as well as to rule out mild, asymptomatic, urinary tract infection. Some authorities feel that urine testing forglucose may be an adequate parameter to judge blood glucose control in the elderly diabetic who does not have any othercomplication. The reasoning behind this is that elderly diabetics tend to have a higher threshold and are also quite averse tohaving the blood tested frequently. Under such circumstances, if the urine shows the presence of glucose, then it could besurmised that the blood glucose levels must be quite high and need to be brought down. Conversely, many young diabeticshave a low threshold and a consistent absence of glucose from their urine should be a pointer to the possibility that they

many be undergoing subclinical hypoglycemia. Frankly, I am not convinced about either of these aspects. From a practicalcompromise view point, a newly diagnosed patient with a blood glucose of 400mg% and a urine glucose of 4+, may bemonitored by testing the urine glucose till it comes down slightly, to say 2+, and then one must shift to monitoring the bloodglucose levels.

Finally, if one is going to utilise these tests to evaluate diabetes control it would be better to use the "stick" method, as this issomewhat specific for glucose. At the same time, it is essential that one be aware of the pitfalls

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