Treatment of Type 1 Diabetes mellitus involves lifelong insulin administration. Insulin is produced in the pancreas and regulates blood glucose levels. Type 1 diabetes results from autoimmune destruction of insulin-producing pancreatic beta cells leading to complete insulin deficiency. Various insulin preparations have been developed with differing durations of action to mimic normal insulin secretion. Treatment involves calculating total daily insulin dose and dividing into short and long-acting insulins administered multiple times daily. Adverse effects and methods to overcome insulin resistance are also discussed.

1. Treatment of
Type 1 Diabetes mellitus
(Insulin)
9 June 2017

2. Diabetes Mellitus
Hyperglycemia
Glycosuria
Hyperlipemia
Negative nitrogen
balance
Metabolic
disorder
Symptoms of diabetes plus Random blood sugar
≥ 200 mg %
or
fasting plasma glucose ≥ 126 mg %
or
2 hr plasma glucose ≥ 200mg % on oral GTT
WHO criteria

3. Diabetes mellitus - Types
Type 1 Diabetes mellitus
 Complete or near total insulin deficiency
Βeta cell destruction – immune mediated, idiopathic
Type 2 Diabetes mellitus
 Insulin resistance precedes insulin secretory defect
Diabetes develops only when insulin secretion becomes
inadequate
Other causes
Non pancreatic diseases, drug induced …
Gestational Diabetes mellitus

4. Why diabtetes mellitus needs to be treated?
1. Early atherosclerosis
2. Retinopathy
3. Neuropathy
4. Cardiovascular complications
5. Nephropathy
6. Peripheral vascular insufficiency

5. Pan c r e at ic h or m on e s
β cells (60-70%) Insulin,
Islet amyloid polypeptide
α cells (20%) Glucagon
δ cells (3-5 %) Somatostatin
PP cell (<2 %) Pancreatic polypeptide

6. Pro-insulin
Insulin
Pre-proinsulin
110 amino acids
86 amino acids
51 amino acids

7. Insulin is co-secreted with c-peptide
and it is more stable than insulin.
Clinical Implication :
C-peptide levels can be used to
differentiate between exogenous
insulin administration and insulin
secreting tumors

8. In su lin st r u c t u r e
 Mol. Wt. of 5808 in humans
 51 amino acids in two chains – A(21 AA) & B(30 AA)
 Linked by disulfide bridges
 Differs from porcine by one AA and from bovine by 3 AA

9. Insulin SecretionInsulin Secretion
Steady basal release of insulin
Response to increase in blood glucose
Rapid phase – release of stored insulin
Delayed phase – continued release and synthesis
Clinical implication:
While treating, two-thirds of total daily insulin
given to cover basal needs (by longer acting
insulin) and one-third to one-half should be short
acting given before each meal.

10. Phases of insulin SecretionPhases of insulin Secretion

11. Insulin storageInsulin storage
Synthesized & stored (bound to zinc) in
granules in the beta cells.
Clinical Implication :
Therapeutically used exogenous insulin is
also stored by adding small quantities of
zinc.
Addition of small quantities of zinc
increases the shelf life and all preparations
including regular insulin and insulin
analogs have small quantities of zinc.

12. In su lin ac t ion s
( m ain ly liv e r , m u sc le an d ad ip ose t issu e )
↑ triglyceride
storage
(adipose
tissue)
↑ uptake of
glucose
(skeletal
muscle & fat)
↑ protein &
glycogen
synthesis
(liver &
muscle)
↓ formation of
glucose from
glycogen,
protein & fat
(liver)

13. PharmacokineticsPharmacokinetics
Naturally secreted insulin enters portal vein
and half of it is taken up by liver
Rest enters systemic circulation
Circulating insulin has a short t1/2 (5 min)
Clinical implication :
Various preparations of insulin are available
for therapeutic use.

14. Insulin PreparationsInsulin Preparations
Insulin preparations are made by
 Physical modifications like adding protamine
or zinc to give amorphous or crystalline
suspensions
 Altering the amino acid sequence of non
receptor binding regions of insulin – insulin
analogs

15. Pr e p ar at ion s of In su lin
1. Conventional insulin preparations
- Beef and pork insulins
- Modified by adding zinc and/or protamine to form
slowly absorbed & longer acting preprations
2. Highly purified insulin preparations
- Single peak insulins – gel filtration & repeated crystallization
(50-200 ppm proinsulin)
- Monocomponent insulins- gel filtration & ion exchange
chromatography (<20 ppm)
3. Human insulin- recombinant DNA technology
4. Insulin analogues – Lispro, aspart, glargine, glulisine, detemir

16. Preparation Onset (h) Peak (h) Duration (h)
Rapid Acting
Insulin lispro, <0.25 0.5-1.5 3-4
aspart, glulisine
Inhaled (withdrawn) <0.25 0.5-1.5 4-6
Short Acting
Regular 0.5-1 2-3 4-6
Intermediate Acting
NPH 1-4 6-10 10-16
Premixed insulins
Long Acting
Glargine 1-4 ----- 24
Detemir 1-4 --- 12-20

17. Du r at ion of ac t ion of In su lin
p r e p ar at ion s
Rapid acting
Insulin lispro
Insulin aspart
Short acting
Regular insulin
Semilente
Intermediate acting
Lente (Ultra:Semi:7:3)
NPH or Isophane
Long acting
Ultralente
Protamine zinc
Insulin glargine

18. Lispro & Aspart
Glargine
Proline to aspartic acid at B28
Proline (B28 to B29) & lysine (B29 to B28)

19. Regular Insulin – contRegular Insulin – cont……
Injected 30 – 45 minutes before meals
Only type which can be given intravenously
Reason
 Dilution causes immediate dissociation of
hexameric forms
Time of onset, peak, duration of action increases
with size of dose

20. Neutral Protamine Hagedorn (NPH) insulinNeutral Protamine Hagedorn (NPH) insulin
In NPH insulin, neutral stands for pH,
protamine is the protein added,
What is Hagedorn?
The scientist who first formed this type of insulin.

21. Lente insulinLente insulin
Zinc is added in excess amount (10 times more)
Lente – intermediate acting
Semilente – amorphous suspension of zinc &
insulin, short acting
Ultralente – crystalline suspension of zinc & insulin,
long acting
Cannot be mixed with regular insulin because of high
zinc content
Not so popular, not manufactured from 2005 in USA

22. Insulin AnalogsInsulin Analogs
Rapid acting – lispro, aspart, glulisine
Long acting – glargine, detemir
Short acting analogs
Low propensity to self associate into dimers
Stabilized into hexamers to increase shelf life
After injection quickly dissociates into monomers

23. Advantages of insulin analogsAdvantages of insulin analogs
Closely mimic normal endogenous insulin
secretion
Insulin can be taken immediately before
the meal
Less risk for hypoglycemia
Lowest variability of absorption
Rapid acting analogs preferred for
subcutaneous pump infusion

24. Inhaled InsulinInhaled Insulin
(withdrawn?)(withdrawn?)
Administered in powder form by inhalation
Short acting
Bioavailability – 15%
Concerns of lung safety
(may cause acute bronchospasms or cough)

25. Glargine (20-26h)
Ultralente (18-24 h)
NPH (12-20 h)
Regular (6-10 h)
Aspart, lispro (4-6 h)

32. Acceptable levels of glycaemic control
• Overnight Fasting: 90-120mg %
• 1 hour after food: Not higher than 180mg %
• 2 hour after food: Not higher than 150mg %
• Glycohemoglobin value: No higher than 1%
above the upper limit of the normal range
for that lab.

33. Principles of insulin
therapy When initiating insulin therapy, total daily dose
is calculated as 0.6 x body weight in Kg
 Two thirds of the total dose is given in the
morning and remaining one third in the evening
 Morning dose contains 2/3 longer acting insulin
and 1/3 rapid or short acting insulin
 Evening dose consists of 1/2 longer acting
insulin and 1/2 rapid or short acting insulin

34. In su lin u se s
1. Type 1 Diabetes mellitus – Life long maintenance
2. Type 2 Diabetes mellitus –
• Primary or secondary failure to OHD
• Underweight
• Infection, trauma, surgery, myocardial
infarction etc.
• Pregnancy
• Complications like gangrene
3. Diabetic ketoacidosis

35. A d v e r se r e ac t ion s t o in su lin
1. Hypoglycaemia
Hunger, sweating, anxiety, palpitation, tremor (sympathetic
stimulation)
Headache, dizziness, visual disturbances ( glucose deprivation
to brain)
Treatment : Glucose oral or i.v., glucagon 0.5-1mg i.v. or
adrenaline 0.2 mg s.c.
2. Lipoatrophy & lipohypertrophy
3. Insulin Allergy & resistance – Urticaria, angioedema,
anaphylaxis
4. Local reactions – Swelling, erythema, lipodystrophy

36. • Somogyi Effect:
• Dawn phenomenon: reduced tissue sensitivity to insulin
between 5AM and 8 AM
•Present in 75% of Type I diabetics
Higher blood glucose around 7AM
Blood glucose mg %
10 PM 3 AM 7 AM
Somogyi effect 90 40 200
Dawn
phenomenom
110 110 150

38. INSULIN RESISTANCE
FACTORS PROMOTING IR
Elderly
Obesity
Hypertension
Acromegaly
Pheochromocytoma
Cushing’s syndrome
ACUTE
RESISTANCE
Infection
Trauma
Surgery
Ketoacidosis

39. In su lin r e sist an c e
When insulin requirement in a diabetic patient is very high,
i.e. >200 U/day, he/she is regarded as insulin resistant
Types : Acute – Infection, trauma, surgery, ketoacidosis
Treatment : Correct precipitating cause & to give high
doses of regular insulin
Chronic- Antibodies to contaminating proteins
Treatment : Change over to more purified newer
preparations, Combine with sulphonylurea,
Corticosteroids, If extreme resistance - serine protease
inhibitor (aprotinin)

40. Diabetic ketoacidosis
Diabetic Ketoacidosis (DKA)
Medical emergency: Hyperglycemia, dehydration and acidosis
High glucose levels (>300 mg/dl), low bicarbonate (<15 mEq/l) and
acidosis (pH <7.30) with ketonemia and ketonuria
Treatment
Insulin : 0.1 – 0.2 U/Kg i.v. bolus, followed by 0.1 U/Kg/h infusion,
after 4-6 h reduce to 2-3 U/h (if BGL , 300 mg %)
i.v. fluids & supportive measures: Normal saline 1 l/h reduce to
0.5 l/4h when BSL reaches 300 mg%, 5% glucose in 1/2N saline
Potassium Chloride
Sodium Bicarbonate
Antibiotics

41. Drug Interactions
Potentiate insulin action
β blockers (↓compensatory
mechanisms through β2)
Alcohol (acute ingestion)
Salicylates,
Lithium
Theophylline
Inhibit insulin action
 Thiazides
 Furosemide
 OCP
 Salbutamol
 Theophylline
 Corticosteroids

42. EXAM POINT OF VIEW
Diabetic keto-acidosis- SAQ
Name few insulin preparations-
VSAQ
Name two novel drug delivery
mechanisms for delivery of
insulin- VSAQ

43. Thank you

44. History
• 1869 : Paul Langerhans (German Medical Student)
• 1911 : El Scott (Medical student)
• 1916 – 1920: Nicolas Paulesco
• 1921:
Banting F.B. (Canadian surgeon)
Charles Best (Medical student)
Macleod J.J.R. (Prof. of Physiology)
Collip J.B. (Chemist)
First Patient: Leonard Thomson (14 years)