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Q.I) What is proinsulin : Is it implicated in etiology of diabetes?
It is a precursor of insulin. Initially on the rough endoplasmic reticulum a large precursor-
preproinsulin is formed. It is cleared-immediately to form a long polypeptide chain proinsulin. It has 53 Amino acids and a single chain. Some diabetics have abnormal high proinsulin, which has low biological value. There is an aminoacid at C-peptide clevage point which prevents normal proteolytic conversion into insulin and C-peptide.
Q.2) What is C-peptide?
It is produced when proinsulin cleaves into insulin and C-peptide. It is secreted in
equimolar amounts with insulin. It has two practical importance. Measurement of C-peptide gives good index of insulin secretion as it is not metabolized. It can be used to measure endogenous insulin secretion even in insulin treated diabetics. It is excreted by kidney. Half life is 35 mts. C- peptide estimation can demonstrate remission phase in IDDM.
Q.3) How newer insulin differs from conventional Insulin?
a) Less Antigenic - Less chances of allergy, insulin resistance and lipodystrophy.
b) Neutral pH - i) Less chance of lipoatrophy
ii) More stable at room temperature half life is increased.
iii) Compatible with blood and tissue fluids.
iv) Possible to mix actrapid with NPH Insulin in any proportion.
v) Burning is reduced.
Q.4) Purity: More pure than conventional insulin?
Q.5) Could you tell us something about mixing of two types of insulin?
a) Majority of insulin requiring patients are managed with single injection of lente or NPH
or incombination with regular insulin.
b) Regular insulin is not added to PZI because excess of protamine will bind the regular
insulin.
c) Regular insulin which has acid pH cannot be mixed with lente. The rapid action of
regular insulin is blunted in syringe.
d) But regular insulin can be mixed with NPH ratio of regular -NPH 2/3 NPH (70%). 1/3
regular (30%).
e) Mixture are available mixtard/actraphan (novolin 70/30)30:70 (R:NPH) Intard 50:50R:
NPH.
f) Regular insulin with phosphate buffer, Humulin or velosulin can not be mixed with lente.
Because phosphate causes precipitation of insulin.
Q,6) What about Remission of Diabetes?
Seen in IDDM. It is an interval of declining insulin requirement .and improving metabolic
status. 10% of IDDM goes into complete remission meaning that glucosuria is absent and insulin is discontinued. This period is brief, for 6 wks. Remission represents a return toward normalcy of beta cell synthesis and release of insulin. In obese NIDDM permanent remission can occur with weight loss and OGTT may revert to normal.
Q.7) What is the initial dose of insulin in an uncomplicated IDDM?
Approximately, for child without ketosis the dose of insulin is 0.25 units per pound body
weight, if there is ketosis 0.5 to 1 units per pound. Another simple guide line will be 5 units year at per age 1 and at age 5,10 units.
Year Units
1 5
5 10
10 25
Teenage 20
Q.8) What is the Insulin regime in the management of diabetic ketoacidosis?
a) High dose of insulin was used in the past which carried of risk hypoglycaemia,
hypokalemia, fall of plasma magnesium, fall of phosphorus and induction osmotic
disequillibrium and late hypoglycemia.
Small dose of insulin 5-7 units/hour diminishes ketogenesis and glycogenolysis.
b) Route of administration insulin
(i) IV has half life of 4 or 5 mts, 100 units of IV bolus insulin disappears in 40 mts.
(ii) IV .continuous insulin 4/6 units/per hour is ideal.
(iii) IM 2 hour half life/high tissue depot/late hypoglycemia.
(iv) Subcutaneous 4 hour half life will not be absorbed in hypotensive patients.
c) Type of insulin: Regular or clear insulin is to be used.
d) Problem of absorption to plastics and glass while giving IV insulin is negligible when
given at higher concentration. No need to add albumin when 200 units of regular
insulin is added to 1 lit of 5% glucose in water less than 5% of insulin is'lost by
adsorption.
e) Both continuous insulin or intermittent insulin IM are safe, predictable and effective
alternate to IV insulin.
Q.9) What is a sick day rule?
IDDM patients are told not to stop insulin during febrile illness. If a patient is not eating or
taking only small amounts of liquid, regular insulin can be safely given on the basis of urine test at intervals of 4 hours. With illness and particularly if eating has stopped, the finding of glycosuria is always a grave situation. It becomes even more urgent for giving extra insulin.
Q.10) How to store insulin?
The storage is done best in refrigerator.
- Stable for several weeks at room temperature.
- Opened bottle can be kept out side.
- Not to be exposed to extreme temperatures. Should not be frozen, or heated or
exposed to direct sunlight.
Q.ll) Why long acting insulin is not given IV?
The particulate matter carries the critical risk of embolism with long acting insulin.
Q.12) What is meant by intensive insulin therapy?
a) It includes 3 or more injections of insulin per day (multiple daily injections) or
continuous, subcutaneous insulin infusion with an Insulin pump. Dosage is adjusted
frequently by self monitoring of glucose, which is performed 4 times a day.
b) When it is indicated? Women in pregnancy with diabetes, brittle diabetics, rapidly
developing hyperglycemia with ketosis.
c) What is the risk of such therapy? Hypoglycemia may occur if glucose self monitoring is
not done.
Q.13) What is insulin resistance? When it is encountered and how will you manage
it?
a) When insulin need in 24 hour is over 200 units in the absence of infection or coma the
condition is known as insulin resistance. In children if insulin requirement is over 2.5
units/day it is described as insulin resistance.
b) Prereceptor Receptor
a) Anti insulin anti-bodies a) Lipoatrophic D
IgG types
b) Anti insulin receptor b) Acanthosis nigricans
antibodies
c) Anti insulin Hormones c) Ataxia telengectasia
(Autoantibodies against receptor).
d) Growth Hormone, d) Obesity- Decrease in
Cortisone and thyroxine number of receptor.
c) Treatment of Insulin resistance:
1) Immunological type-Use pork insulin or human insulin.
2) Prednisone 60-80 rngm/10 day
3) Sulfated insulin
4) Oral hypoglycemic agents added to improve the receptor sensitivity.
Q.14) What factors modify insulin action?
Host factor Insulin factor
1) Site of injection 1) Type of insulin
2) Exercise 2) Route of administratio
-IV/IM/SC/
3) Temperature (Increase) 3) Insulin antibodies
4) Smoking 4) Timing of injection
5) Blood flow to food-30-60 mts before
rather than just prior to eating
Q.15) What are the adverse effects of insulin therapy?
a) Hypoglycemia
b) Insulin dystrophy
c) Insulin allergy
d) Insulin resistance
e) Insulin oedema (Resolves in 5/10 days spontaneously)
f) Refractive errors.
g) Sepsis (Inj. Abscess)
Q.16) Can we give Oral Hypoglycaemic Agents (OHA) and Insulin together? Is it
rational?
Not usually combined. If a patient needs insulin then give insulin alone if he needs, OHA
give OHA alone. During insulin resistance OHA are added to increase receptor sensitivity. In NIDDM with fasting hyperglycemia night dose NPH insulin can be added with OHA.
Q.17) How to know whether a patient has NIDDM or IDDM?
If a patient is obese, family H/O DM is there, there is no ketosis even after stopping
therapy and C-peptide secretion is adequate then the patient is NIDDM.
In IDDM C-peptide levels are low or absent, they are ketosis prone and no family H/O of diabetes is seen.
Q.18) Why oral Hypoglycaemic drugs are contraindicated in pregnancy?
a) OHA cross placenta and stimulate fetal pancreas to produce insulin. Which makes
neonatal hypoglycemia common.
b) Suphonylurea compete with Bilirubin for binding sites with albumin. This result in
increase in Bilirubin in neonates leading to Kernicterus.
c) Teratogenic effect.
Q.19) What is pseudoinsulin resistance?
In Somogii phenomenon this is seen. Patients are overtreated with insulin and get hypoglycemia. Hypoglycemia is followed by release of anti insulin hormone, resulting in hyperglycaemia in few hours. The situation is mistakenly interpreted as the result of inadequate insulin and more insulin is given. Such a situation is known as pseudo insulin resistance.
Q.20) What do you understand by frosting and fibrillar insulin?
Frosting or floccluation where insoluble insulin precipitate is deposited on the walls of vial
as white clumped flocculate. This results in loss of potency. Occurs with NPH insulin, lente, more so with human NPH, accelerated in half used bottle. High temperature and agitation of vial increase frosting and lower pH, higher zinc reduce frosting.
Fibrillar insulin (large molecular weight aggregates) occur when subjected to motion or increased temperature, and in the presence of bicarbonate.
Q.21) Indications of newer insulin?
a) Insulin resistance
b) Insulin sensitivity
c) Insulin Lipodystrophy
d) Intermittent insulin therapy e.g. gestational DM/pregnant
D. During major surgery in NIDDM.
Q.22) Indications of insulin in NIDDM?
a) Long standing NIDDM not well controlled with maximum dosage of OHA + diet.
b) Prior to any major surgery patient has to be switched over to insulin.
c) Non healing ulcer lesions with infection.
d) When patient gets acute complications like diabetic ketoacidosis.
e) In the presence of chronic complications like diabetic retinopathy, nephropathy and
CAD it is advisable to start insulin for tight control.
Q.23) Obese diabetic and insulin
Obese diabetics as such have increased level of insulin in the | body. They save insulin
resistance due to receptor defect. Hence it is wrong to start insulin in obese uncomplicated diabetics. They become more obese and need more and more insulin. Diet alone is effective in controlling DM. If an obese diabetic gets acute infections which is not improving or goes into coma, then one can give insulin during that acute episode only.
Q.24) Could you tell us some thing about human insulin?
a) Human insulin source: One can get human insulin from many source like from human or
foetal pancreas, fully synthesised chemically by enzymatic conversion of porcine insulin, by use of recombination DNA technique. The last method is feasible. Human NPH differs from pork NPH in that its action is rapid in 1 hr. it's duration of action is shorter (11 to 15hrs).
b) Effect of human insulin on blood glucose.
There is a tendency for earlier and larger hypoglycemic effect with both soluble and
isopane forms of human insulin due to difference in absorption (more hydrophilic). Counter regulatory hormones - less secreted with human when compared to porcine
insulin.
c) Less immunogenic. Less antibodies are produced Immunogenicity depends on
proinsulin, Zn Protamine components of insulin.
d) Dose: The dose of Purified insulin has to be reduced by 20% in patients when a dose
of over 40 units of conventional insulin is used.
Q.25) What is insulin allergy and how to manage?
It can be local at the site of injection with read ness, swelling and formation of
subcutaneous nodule subsequently, occurring 15mts-2 hrs after insulin.
At times it progress to systemic allergy to insulin urticaria, angioneurotic oedema and
anaphylaxsis. History of intermittent use of insulin or allergy to penicillin is there. This is IgE mediated. How to Manage?
Use purified insulin-actrapid, or desentise the patient.
a) Patient should be off the insulin at least 12/24 hrs.
b) Stop antihistaminics and steroid-which will mask insulin allergy.
c) Epinephrine 1:1000-0.1 to 0.3 ml used if needed.
d) First desensitising doses are given in 0.1 ml vol. every 30 mts. 1/100 units, 1/50,
1/25, 1/10, I/5,2/5,1,2,5,units.
Q.26) Under which circumstances insulin need increases and when the need decreases in a IDDM?
a) Increasing need is seen with growth spurt, obesity actomegaly, pregnancy,
infection, stress and surgery.
b) Decreasing need is seen with remission of diabetes, with onset f CRF and after
delivery in pregnant D.M.
Q.27) How endogeneous insulin differs from exogenous insulin?
1) Basal secretion is there with endogenous secretion. Not seen with exogenous
insulin.
2) Meal related increase in secretion is not possible with exogenous insulin therapy.
3) Endogenous insulin goes into portal circulation whereas exogenous goes into
systemic circulation.
4) Exogenous is heterogeneous (Species)
Q.28) What impurities are there in conventional insulin?
Proinsulin, glucagon, Somatostain, VIP, Pancreatic, Polypeptide, Gastrin, Insulin
polymers.
Q.29) What is a unit of insulin?
It is defined as the amount required to lower blood glucose of a fasting 2 kg. rabbit from
120 to 45mg/100ml/ when injected intravenously. Equivalent to activity of 24 units/mgm.
Now radioimmunoassay or bioassay are available.
Q.30) Why protamine zinc insulin is not used routinely?
It has prolonged action-duration of action is 36-40 hrs (Max 3 days). Increment cannot be
made every day. The protamine part may cause allergic reaction in some patients. It's peak action is between 8-12 hours. Unpleasant midnight reactions are common with this. It can not be mixed with crystalline insulin. Prolonged hypoglycemia for several days can occur.
Q.31) How human insulin differs from pork and beef insulin?
Type 'A'Chain 'B'Chain
8 9 10 30
Human Threonine Serine Isolucine Threonine
Pork -do- -do- -do- Alanine
Beef Alanine Serine Valine Alanine
Q.32) When is regular insulin preferred to long acting insulin?
1) In diabetic ketoacidosis
2) During surgery
3) Labour and Delivery
4) Acutely ill patients and ICCU patients
5) When IV route is preferred.
Q.33) Can you explain the difference between conventional insulin? Single peak insulin and monocomponent insulin?
Purity Impurity Proinsulin
content
1. Conventional 92% 8% 10,000/PFM
insulin
2. Single peak ion 99% 1% 50/PPM
exchange /
gelchromatography
3. Monocomponent 99.9% 0.1% 10/PPM
(Chromatograph)
Q.34) How surgery for a diabetic patient differs from a normal patient?
Surgery is a stress and leads to exaggerated hyperglycernia. A proper control is
necessary, otherwise there is greater morbidity and mortality.
Q.35) What insulin regimen you would recommend during emergency surgery?
Type of insulin to be used is regular insulin. In acute problems where surgery has to be
done rapid acting preparation and multiple doses of regular insulin along with fluid management has to be done. If they are on OHA then stop it, 12 to 24 hours prior to surgery. During post operative period multiple insulin regime to be given. Dose to be decided by frequent urine and/or blood glucose estimation. During operation 16 units of insulin in 500ml of 10% dextrose with 20 mmol of Kclat the rate of 100 ml per hr is given to prevent ketoacidosis and hypoglycemia (Albert's regime).
Q.36) Discuss timing of insulin injection and complexity of insulin regime.
Timing of insulin administration in patients with different responses to insulin
| Insulin |
Response Type |
Pre-Lunch |
Pre-Dinner |
|
| |
|
Breakfast
|
|
|
| 1.NFH |
I |
Administer |
- |
|
| 2.NPH/R |
II |
Administer |
- |
|
| 3.NPH |
III |
Administer |
- |
Administer |
| 4. NPH/R |
IV |
Administer |
- |
Administer |
| |
|
Administer |
- |
Administer |
Type I responses: One injection NPH at pre-breakfast and 24 hour control of blood sugar achieved.
Response Type II: Combination of NPH and regular insulin mixed and given before pre
breakfast gives a good control of blood sugar for whole 24 hours.
Type III: Here total 24 hour dose of NPH insulin, (intermediate insulin) has to be split in
equal amounts and is given before breakfast and before dinner. These patients if they take a single large doses.of NPH at pre breakfast they get hypoglycemia after 6 hrs. If the NPH dose is reduced then they are not controlled, show fasting hyperglycemia. Such patients need split does of NPH at pre- breakfast and an other pre-dinner. This response is known as response III.
Response IV: Where a mixture of NPH and regular insulin is given in 24 hrs twice. One at
prebreakfast time and one at pre-dinner time.
REFERENCES
1. V.A. Koivisto-Insulin therapy in type-2 diabetes mellitus Page 29-30 in Diabetes
Care. Supplement No. 3 published in American Diabetes Association.
2. Subhash S, Kale-Insulin Page 236-239 in Practice of Diabetes Mellitus 1983. Editor
MMS Ahuja Vikas Publishing House, New Delhi.
Type I responses: One injection NPH at pre-breakfast and 24 hour control of blood sugar achieved.
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