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The selection and use of insulinSHALINI GOVIL, MOLLY THOMAS

The management of diabetes mellitus requires a clearunderstanding of the rationale behind the various treatmentmodalities. This article outlines the appropriate use ofinsulin, methods of dose determination and adjustmentsand the problems encountered in the long term use ofinsulin.

The insulin preparations commercially available arelisted in Table I. These are mixtures of insulin from thebovine and porcine pancreas. Porcine insulin is structurallyclosest to human insulin.

TABLE I. Classes of insulin and their effects

Class/ Onset of PeakPreparation action action Duration

(hours) (hours) (hours)

Rapid actingSoluble or plain { s.c. Yz-1 3-6 ~1O

or regular i.v. immediate V4-YZ 2Serni-lente s.c. V2-1 4-6 10-16

Intermediate actingNPHIlsophane s.c. 3 8-12 18-24Lente s.c. 3 8-12 18-28

Slow actingProtamine zinc s.c. 4 14-20 24-36

insulin (PZI)Ultra-lente s.c. 4 1~18 30-36

i.v. intravenous s.c. subcutaneous

Administration of insulin is indicated in diabeticswho have insulin dependent diabetes mellitus (IDDM),gestational diabetes, and those who have non-insulindependent diabetes mellitus (NIDDM) with complicationssuch as ketosis, acute infections, operation, an alteredsensorium, progressive retinopathy and poor control withsulphonylureas. Long standing cases of NIDDM andpatients who were discovered to have NIDDM before theage of 30 years may also require insulin.

tr1 CHOICE OF INSULIN-etr1 The choice of insulin type depends on the phase of,., therapy, patient compliance and ease of administration.><:tl In the initial phase, soluble insulin is useful because of its:I> rapid onset and short duration of action. The daily insulin><: requirement is ascertained quickly. The patient requires'1i hospitalization in this phase. Soluble insulin is given sub-,., cutaneously before each meal, titrating the dose with the~ blood glucose response to the previous dose (NB: blood..., should never be taken from an intravenous line adminis-o tering dextrose). For those patients who cannot affordtr1 frequent blood glucose estimations, doses are determined

THE NATIONAL MEDICAL JOURNAL OF INDIA YOL.2, NO.3

by the degree of glycosuria according to the 'sliding-scaletechnique' (Table II). The variation in the renalthreshold, however, limits the usefulness of this method.Dose increments early in therapy should be 4 to 8 unitsand later 2 to 4 units as control is reached.

TABLE II. The sliding scale technique of diabetic control

Percentageof glycosuria Urine colour

Insulin require-ment (units)

2-51-2

0.5-1

Orange -> RedYellow -> OrangeGreen -> Yellow

10-20~142-10

In the maintenance phase, the patient is switched ontoan intermediate acting insulin (usually lente) to reducethe frequency of insulin injection.

The totallente insulin dose is roughly two-thirds of thetotal soluble insulin dose per day. This dose of lente insulinmay be conveniently given as a single morning injectionwith breakfast or as a split-dose regime. Table III outlinesthe advantages and disadvantages of each method.

TABLE III. Single versus split dose of lente insulin

Single dose Split dose

- when tight control is desired,e.g. hyperglycaemia in IDDM

- low risk oflate afternoonhypoglycaemia

- when tight control of bloodglucose is not required

- high risk oflate afternoonhypoglycaemia, with glycosuriathrough much of the day andnight

- timing of evening meal cannotbe varied since insulinlevels are sustained

- daily insulin requirement greater - daily insulin requirement less

- timing of evening meal can bevaried

If the split-dose regime is used, the lente dose should begiven as two-thirds with breakfast and one-third withdinner. For smooth control, with little risk of hypo-glycaemia, soluble insulin can be added to the breakfastand dinner doses in a soluble to lente ratio of 1:2. Onthe split-dose regime, doses are adjusted as shownbelow:

i Blood glucose before meals or ~ i dinner lenteglycosuria before breakfast

,iRandom blood sugar or glyco- ~ i breakfast lentesuria before dinner

i Random blood sugar or glyco- ~ i breakfast solublesuria before lunch

i Random blood sugar or glyco- ~ i dinner solublesuria before bedtime

Often, a patient is found to have high blood glucoselevels despite a careful choice of insulin and rational

EVERYDAY PRACTICE

dose adjustments. In such cases, it is wise to enquireinto the patient's adherence to the prescribed diet, hisor her ability to measure the dose of insulin accurately,performing the tests correctly (in cases of home-monitoring) and whether he or she is taking the correctamount of exercise. The presence of an intercurrent illnessor infection (urinary tract, tuberculosis), an abnormalrenal threshold, weight fluctuation, unsuspected preg-nancy, drugs (e.g. thiazide diuretics and steroids) andrarely endocrinopathies should be kept in mind. Theadvent of renal failure due to diabetic nephropathy maydecrease the insulin requirement. The Somogyi effect-rebound hyperglycaemia following an episode of hypo-glycaemia-is often forgotten and this leads to furtherincreases in insulin dose. This should be suspected ifurinetests negative for glucose are followed within a few hoursby marked glycosuria and ketonuria or if there are widefluctuations of blood glucose over a few hours, unrelatedto meals. Symptoms of nocturnal hypoglycaemia (sweat-ing, morning headaches, nightmares) together with a low3 a.m. blood glucose level usually confirms the presenceof a Somogyi effect and should be corrected by a loweringof insulin dose.

The preparations of insulin are fairly unstable andrequire care in storage and mixing. Refrigeration of thevial or storing it in a clay pot filled with sand and waterwill maintain its potency. Insulin should not be stored in adeep freeze as this will agglutinate the protein. Since theproperties of lente insulin are dependent on a neutral pH,soluble insulin should not be mixed with it unless theamount of lente is greater than the soluble insulin. Thesoluble insulin should be drawn into the syringe before thelente as the excess protein in lente insulin binds the solu-ble insulin and prolongs its action. The site of injectionshould be changed frequently to prevent lipodystrophy.Needles and syringes should be kept in a clean dry placeor in spirit. Disposable needles should not be reused but ifthey are, they should be cleaned, dried and boiled for halfan hour. They should be discarded when their tips showsigns of blunting.

SIDE EFFECTSThe side effects of insulin are hypoglycaemia, lipodys-trophy and immunological reactions.

Prolonged or repeated attacks of hypoglycaemia canlead to permanent brain damage. Since hypoglycaemiaresults from an excess of insulin, omission of meals orsudden strenuous physical activity; the patients should betold to take regular meals. His understanding of themarkings on an insulin syringe and the meaning of insulinconcentrations '40 U/ml' and '80 U/ml' should be re-checked. He should be instructed to eat a small snackprior to and after unusual activity and be familiarized withthe early symptoms and signs of hypoglycaemia and theirmanagement.

Lipodystrophy is of two types-the commoner Iipo-atrophy where fat is lost from the site of injection andlipohypertrophy which is the accumulation of fibrofattymasses of tissue at the injecting site. The latter disappears

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on giving that site a rest but lipoatrophy may require achange of insulin (NPH is more likely to cause lipoatrophythan lente while the newer insulins are less likely). Insulinallergy can manifest as a local irritation or systemicanaphylaxis. This can occur with interrupted insulin use,

Insulin resistance, thought to be due to circulating anti-insulin antibodies, is said to exist when the insulin require-ment exceeds 200 units/day for more than two days in theabsence of diabetic ketoacidosis. Addition of a sulphonyl-urea (acting via release of endogenous non-allergic insulin)or a change to one of the newer, purer insulins may help.

Patients may request a change from insulin to oralhypoglycaemic agents. This change is not advisable incases of IDDM, NIDDM with a past history of ketosis,previous failure of oral hypoglycaemic agents, hepatic orrenal dysfunction, during pregnancy and in those with aninsulin requirement of more than 40 U/day.

NEWER INSULINSThe newer insulins (Table IV) are purer and more stablethan the older ones. They are at a neutral pH and can bemixed with other preparations. They are less likely to

TABLE IV. Newer insulins

Type Remarks

NUSO BovineRapid actingPorcine (closer to human insulin)Rapid acting (faster than soluble)BiphasicIntermediate actingActrapid:Bovine = 1:3Faster onset than lenteHighly purified porcineZinc suspensionHuman insulin obtained by:a. recombinant DNA technology using E. colib. enzyme modification of porcine insulin

Actrapid

Rapitard

Monotard

Humilin

cause lipoatrophy and insulin resistance. However, theseare expensive and their use has to be restricted to patientswho have persistent insulin allergy, or when the use ofinsulin is likely to be for a short time (during pregnancy orsurgery). The requirement of insulin may fall when chang-ing to a newer preparation.

""Uf-<

INSULIN PUMPS ~An insulin pump refers to a battery regulated infusor ~

Il.which delivers insulin at a predetermined rate into thebody. Its main components are a syringe, a rechargeable ;;...battery and a small plastic catheter with an attached needle. <Insulin pumps permit a slow basal release of insulin ~throughout the 24 hour period with an additional bolus of ~insulin during meals. Patients have to be carefully ~selected since the care of the pump and monitoring of ""

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TABLE V. Recommended standards of blood glucose control

Measurement Fair PoorGood

Whole blood glucose (mg%)Before mealsTwo hours after mealsGlycosylated haemoglobinproportion (%)

110130

130150 {

Allothervalues

{Allothervalues5-8 8-9.5

Recent advances in diabeticmanagement

LILY JOHN

Diabetes is no longer considered to be a single diseaseentity but a clinical syndrome of metabolic abnormalitiesresulting from the deficiency of insulin. It is now recognizedto occur in two major forms: type I (insulin dependentdiabetes mellitus, 100M) and type II (non-insulin depen-dent diabetes mellitus, NIOOM).

100M occurs mostly in children, adolescents andyoung adults and is associated with progressivesymptoms. Survival of such patients depends on theadministration of exogenous insulin. NIOOM, the mostcommon form of the disease, occurs mostly in adults. Itsonset is insidious and relatively asymptomatic. Patientswith NIOOM tend to be obese and diabetes in them canoften be controlled with dietary modifications and oralhypoglycaemic drugs.

Between these two forms lie a wide range of clinicalpresentations with insulin dependency developing in laterlife and early onset of NIOOM in young adults, whichmakes clinical distinction difficult. Malnutrition relateddiabetes mellitus is recognized as a distinct clinical entitypresenting as non-ketotic hyperglycaemia. It is commonin certain parts of India where undernutrition poses pro-blems in the differentiation of protein deficient pancreaticdisease and 100M.

The diagnosis of fibrocalculous pancreatic diabetes istT1 made easy by the presence of abdominal pain and radiologi-<::tT1 cal evidence of pancreatic calculi. NIOOM presents a very~ heterogeneous clinical pattern ranging from mild glucose><tl tolerance to moderately severe fasting hyperglycaemia> which requires insulin for metabolic control. The major>< difference between 100M and NIOOM is the patient's'"Il dependence for survival on insulin. Such dependence can~ be judged when the classical symptoms of hyper glycaemia~ are associated with raised blood sugar levels and ketosis...., The aim of modern diabetic management is not only too maintain normal blood sugar and lipid levels and to givetT1 the patient a sense of well being, but also to prevent long-

THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 2, NO.3

blood sugar levels at home is difficult and complicated.Twenty-four hour euglycaemia is difficult to achieve

but 'good' to 'fair' (Table V) blood glucose levels can beobtained in most diabetics if insulin is prescribed in alogical way.

term complications. The diabetic must be provided withthe knowledge and motivation to livewith his or her disease.This can be achieved with improved methods of glucosemonitoring with target blood sugar levels, dietary adviceand the use of pure insulin and new insulin delivery sys-tems. Education of the patient and the family has beenaccepted to be a vital part of the treatment and diabeticsshould be encouraged to attend a clinic regularly and seekadvice early if any problem occurs.

OIETA proper diet is the cornerstone of treatment for allforms of diabetes and it must be planned according tothe individual patient's food habits. The calorie intake isadjusted to maintain his ideal body weight. The dietshould contain a high percentage of unrefined, high-fibrecarbohydrates which should provide 55% to 60% of thetotal calories. Fat intake should be in the form ofunsaturated fats.

INSULINInsulin is the essential treatment for all patients with100M while those with NIOOM can ordinarily be con-trolled with diet and oral hypoglycaemic agents. Insulinmay be required in NIOOM in the presence of infectionand during surgery. Whenever possible the preferenceshould be for pure insulin in view of its lower antigenicpotential. Patients requiring insulin for short periodsshould be given pure insulin. The introduction of highlypurified insulin preparations has been able to reduce theincidence of allergy and lipodystrophy besides increasingthe biological potency of insulin. Human insulin nowavailable is being synthesized in bacteria by the use ofrecombinant ONA technology .

Selected individuals with 100M are offered portableinsulin pumps. These pumps provide bolus doses of insulinwith each meal as well as a sustained infusion in between.