2. INTRODUCTION
Diabetes Mellitus is a syndrome complex of:
Hyperglycemia
Glycosuria
Hyperlipidemia
Negative nitrogen balance
India has largest no. of Diabetes pts. in world
No. of pts. with Diabetes Mellitus in India 40.9 millions
(2006)
Expected to rise to 69.9 million by 2025
Diabetes Mellitus.www. mohfw.nic.in/NRHM/STG/PDF%20Content/STG%20Select%20Conditions/
Diabetes%20Mellitus.pdf
3. INTRODUCTION : HISTORY
Word “Diabetes” first used in 250 BC
Apollonius of Memphis coined name "diabetes”
meaning "to go through" or siphon.
He observed: Disease drained more fluid than a
person could consume
Gradually Latin word for honey, "mellitus" was added to
diabetes because it made the urine sweet
4. INTRODUCTION
Two Types (Main):
Type I Diabetes Mellitus
Type II Diabetes Mellitus
Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on
the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;20:1183–1197
5. TYPE 1 DIABETES:
Impaired or absent ß cell function:
insulin secretion
Normal insulin action:
insulin sensitivity
Insulin deficiency results in unacceptable blood glucose
control
6. TYPE 2 DIABETES
Double Impairment
Impaired ß cell function:
insulin secretion
Impaired insulin action:
insulin resistance
Results in unacceptable blood glucose control
Alemzadeh R, Ali O. Diabetes Mellitus. In: Kliegman RM, ed. Kliegman: Nelson Textbook of Pediatrics . 19th
ed. Philadelphia, Pa: Saunders;2011:chap 583
7. SYMPTOMS
Type 1 Diabetes:
Develop over a short period of time
People may be very sick by time of diagnosis
Type 2 Diabetes
Develops slowly
Some people with high blood sugar & have no
symptoms
9. SCREENING
Recommended for:
Overweight children who have other risk factors for
diabetes, starting at age 10 and repeated every 2 years
Overweight adults (BMI greater than 25) who have
other risk factors
Adults over age 45, repeated every 3 years
10. DIAGNOSIS
Fasting blood glucose level:
> 126 mg/dl
100 - 126 mg/dL are called impaired fasting glucose or pre-diabetes
Oral glucose tolerance test :
Blood glucose level >200 mg/dl 2 hours after giving 75 mg of
glucose orally
Hemoglobin A1c Test :
Normal: Less than 5.7%
Pre-diabetes: 5.7% - 6.4%
Diabetes: 6.5% or higher
11. TREATMENT
Treatment of Diabetes is a combination of :
Nutrition therapy :
Exercise :
Pharmacotherapy
12. TREATMENT
Nutrition :
Carbohydrate Intake: 55-60% of total calorie intake
Fat Intake : Maximum 30% or total calorie intake
Protein Intake : 10-20% of total calorie intake
Physical activity:
Adviced in both type I & type II Diabetes Mellitus
13. TREATMENT
Pharmacotherapy
Treatment depends upon type of diabetes
Type I diabetes mellitus : Insulin therapy
Type II diabetes mellitus : Drug therapy
Drugs available to choose from
Sulphonylureas: Glimeperide, Glipizide,
Glibenclamide
Biguanides : Metformin
α Glucosidase inhibitors : Acarbose , Miglitol
Thaizolidinediones : Rosiglitazone, Pioglitazone
Gestational diabetes mellitus : Insulin therapy
15. EARLY DIABETES TREATMENTS
In 1000: Greek physicians recommended
horseback riding to reduce excess urination
In 1800s: Bleeding, blistering, and doping
were common
In 1915: Sir William Osler recommended
opium
Overfeeding was commonly used to
compensate for loss of fluids and weight
In early 1900s: a leading American
diabetologist, Dr. Frederick Allen,
recommended a starvation diet
16. EARLY RESEARCH
1798: John Rollo documented excess sugar in the blood
and urine
1813: Claude Bernard linked diabetes to glycogen
metabolism
1869: Paul Langerhans, a German medical student,
discovered islet cells in pancreas
1889: Joseph von Mehring and Oskar Minkowski
created diabetes in dogs by removing the pancreas
1910: Sharpey-Shafer suggested a single chemical was
missing from the pancreas. He proposed calling this
chemical "insulin"
17. EARLY RESEARCH
In 1908, a young internist in Berlin, Georg Ludwig
Zuelzer created a pancreas extract named acomatrol
After injecting acomatrol into dying diabetic patient,
patient improved at first, but died when acomatrol was
gone
Zuelzer filed an American patent in 1911 for a "Pancreas
Preparation Suitable for the Treatment of Diabetes”
Disappointing results, however, caused his lab to be
taken over by German military during World War I
18. INSULIN DISCOVERY
American scientist E. L. Scott was partially successful in
extracting insulin with alcohol
A Romanian, R. C. Paulesco, made an extract from the
pancreas that lowered the blood glucose of dogs
Some claim Paulesco may have been the first to discover
insulin about 10 years before Banting & Best
Insulin was discovered by Banting & Best in 1921
1923 Nobel Prize for Medicine was awarded to Banting,
Best & Macleod for discovery of insulin
Abel, J. J. (1926) Crystalline insulin. Proc. Natl. Acad. Sci. U. S. A. 12, 132–136
20. BEFORE INSULIN
JL on 12/15/22 and 2 mos later
Before insulin was discovered in 1921, everyone with type
1 diabetes died within weeks to years of its onset
21. LEONARD THOMPSON
14 year old boy who first received Insulin injections in Jan
1922
Abscesses developed & he became more acutely ill
However, his blood glucose had dropped enough to
continue refining what was called "iletin” insulin
6 weeks later, a refined extract caused his blood glucose
to fall from 520 to 120 mg/dL in 24 hours
Lived relatively healthy life for 13 years before dying of
pneumonia (no Rx then) at 27
22.
23. INSULIN PRODUCTION BEGINS
First produced as “Connaught” by the University of
Toronto
First bottles contained U-10 insulin
3 to 5 cc were injected at a time
Pain and abscesses were common until purer U-40
insulin became available
24. IMPACT OF INSULIN ON
LIFE EXPECTANCY BY 1940’S
Age at start of
diabetes
50 30 10
Avg. age of death
in 1897
58.0 34.1 11.3
Avg. age of death
in 1945
65.9 60.5 45.0
Years Gained 8 26 34
Bliss, M. (1982) The Discovery of Insulin, The University of Chicago Press, Chicago, IL
26. INSULIN
Two chain polypeptide with 51 amino acid
Molecular weight - 6000
A chain – 21 amino acids
B chain – 30 amino acids
Goal of Insulin Therapy
Reach the target HbA1C level with a low rate of
hypoglycemic episodes and the least amount of weight
gain
Desired HbA1C level: < 7%
27. ENDOCRINE EFFECTS OF INSULIN
Effects on liver
Reversal of catabolic features of insulin deficiency
Inhibits glycogenolysis
Inhibits conversion of Fatty & Amino acids to keto
acids
Promotes glucose storage as glycogen
Increases triglyceride synthesis
Increases VLDL formation
28. ENDOCRINE EFFECTS OF INSULIN
Effects on muscle
Increased protein synthesis
Increased amino acid transport
Increased ribosomal protein synthesis
Increased glycogen synthesis
Increases glucose transport
Induces glycogen syntheses & inhibits
phosphorylase
29. ENDOCRINE EFFECTS OF INSULIN
Effects on adipose tissue
Increased triglyceride storage
Activation of lipoprotein lipase
Inhibition of intracellular lipase
Easterification of fatty acids
30. TYPES OF INSULIN
Short Acting
Regular ( Soluble ) Insulin
Intermediate Acting:
Neutral protamine hagedorn (NPH) or Isophane
Insulin
Insulin zinc Suspension (Lente)
32. SHORT ACTING INSULIN
Regular (Soluble) Insulin
Buffered solution of unmodified insulin stabilized by small
amount of zinc
Effect within 30 min, peak - 2-3 hrs & lasts for 5-8 hours
after subcutaneous injection
Self aggregation of molecules seen - delayed onset of
action
To be administered 30-45 min before meals d/t ↑ risk of
late postprandial hypoglyemia
33. SHORT ACTING INSULIN
Regular (Soluble) Insulin
Only insulin to be adminstered intravenously
Delyed absorption
Dose dependent dution of action
Variability of absorption
Particularly useful in
t/t of Diabetic ketoacidosis
After Surgery
During acute infection
Use is declined
Martha S.Katzung basic & clinical Pharmacology; pancreatic harmones & antidiabetic drugs,Tata-McGraw
Hill Publication ; pg744-751
35. INTERMEDIATE ACTING INSULIN
Neutral Protamine Hagedorn (NPH) or Isophane
Insulin
Asorbption & Onset of action are delayed by :
Combining appropriate amounts of insulin & Protamine
Onset of action : 2- 5 hours
Duration of action : 4-12 Hours
Usually mixed with regular, lisipro, aspart or glulisine &
given 2-4 times daily
Clinical use waning d/t adverse pharmacokinetic profile &
variablity of absorption
36. INTERMEDIATE ACTING INSULIN
Insulin Zinc Suspension (Lente Insulin )
Two types :
Ultralente (Extended insulin zinc suspension)
Large particles → Crystalline
insoluble in water
Long acting than semilente
Semilente (Prompt insulin zinc suspension )
Smaller Particles → Amorphous
Short acting
Mixture of Ultralente & Lente in 7:3 ratio is Lente insulin
→ intermediate acting
37. LONG ACTING INSULIN
Protamine Zinc Insulin
Contains Excess of Protamine → complexed insulin
is released more slowly after s.c injection
Rarely used now
38. LONG ACTING INSULIN
Insulin Glargine
Soluble, peakless
first long-acting insulin analogue having amino acid
modifications in both chains
A-chain, the asparagine at position 21 is substituted by
glycine
B-chain is elongated at the C-terminus by addition of
two arginine residues
Slow onset of action – 1-1.5 hrs
Duration of action – 11- 24 hrs
Precipitates in subcutaneous tissue after s.c. inj.
39. LONG ACTING INSULIN
Insulin Glargine
E.G.Hagenmeyer, P. K. Sch¨adlich, A. D. K¨oster, F.-W. Dippel,& B. H¨aussler, “Quality of life and treatment
satisfactionin patients being treated with long-acting insulin analogues,” Deutsche Medizinische
Wochenschrift, vol. 134, no. 12, pp. 565–570, 2009
40. LONG ACTING INSULIN
Insulin Detemir
Most recently developed long acting insulin analogue
Characterized by:
Acylation of myristic acid to the lysine residue at
position 29 in the B-chain
Deletion of the last threonine (position 30) in the B-chain
Self –aggregation in subcutaneous tissue & reversible
albumin binding
Dose dependent onset of action – 1-2 hrs
41. LONG ACTING INSULIN
Insulin Detemir
Duration of action – 12 hrs
Given twice daily, Produces less hypoglycemia
J. Morales, “Defining the role of insulin detemir in basal insulin therapy,” Drugs, vol. 67, no. 17, pp. 2557–
2584, 2007
42. RAPID ACTING INSULIN
Insulin Lisipro
First genetically engineered rapid-acting insulin analogue
Approved for clinical use in 1996
Reduced capacity of self association in solution d/t
structural difference from human insulin in B chain →
Faster absorbed, with higher peak serum levels and
shorter action duration in comparison to regular insulin
43. RAPID ACTING INSULIN
Insulin Lisipro
Improves postprandial leptin and grehlin regulation of
type 1 diabetic patients
Needs to be injected immediately before or even after
meal
Dose can be altered a/c to quantity of food consumed
Can be used in Gestational Diabetes
K. Eckardt and J. Eckel, “Insulin analogues: action profiles beyond glycaemic control,” Archives Physiol
Biochem, vol. 114, no. 1, pp. 45–153, 2008
45. RAPID ACTING INSULIN
Insulin Aspart
differs from human insulin at position 28 where proline is
substituted with aspartic acid →inhibits insulin self
aggregation
absorbed twice as fast as human insulin
better glycaemic control when administered directly
before a meal
reduced risk of nocturnal hypoglycaemia in pregnant
women with type I diabetes
T. M. Chapman, S. Noble, and K. L. Goa, “Spotlight on nsulin aspart in type 1 and 2 diabetes mellitus,”
Treatments in Endocrinology, vol. 2, no. 1, pp. 71–76, 2003
47. RAPID ACTING INSULIN
Insulin Glulisine
Most recent rapid-acting analogue, launched in 2004
Difference from human insulin
Asparagine at position 3 is substituted by lysine
Lysine at position 29 by glutamic acid
Glycemic control comparable to insulin lisipro
Pharmacokinetic & pharmacodynamic profile does not
exhibit negative correlation with BMI & subcutaneous fat
thickness
R. H. A. Becker, “Insulin glulisine complementing basal insulins: a review of structure and activity,”
Diabetes Technology and Therapeutics, vol. 9, no. 1, pp. 109–121, 2007
51. ROLE OF INSULIN IN TYPE I DM
As individuals with type 1 DM partially or completely lack
endogenous insulin production,
Goal of insulin therapy is to design and implement insulin
regimens that mimic physiologic insulin secretion
Administration of basal, exogenous insulin is essential for
regulating
Glycogen breakdown
Gluconeogenesis
Lipolysis
ketogenesis
52. ROLE OF INSULIN IN TYPE I DM (CONTD)
Target: To achieve glycemic control (Hb1Ac : < 7.0) &
To promote normal glucose utilization & storage
Insulin replacement should be appropriate to
carbohydrate intake
Various insulin preparations available such as:
Short/Rapid/Long acting insulins
Mixed insulin preparations as described above
53. ROLE OF INSULIN IN TYPE I DM (CONTD)
Insulin Therapy
Doses:
0.5 units/kg = total daily dose
4x/day 40% NPH @ hs and 60% rapid acting
analogue ac meals
30/70 Dose Calculation:
Weight = 80 kg
80 kg x 0.3 U/kg = 24 U
2/3 in the AM = 16 Units
1/3 at supper = 8 Units
54. ROLE OF INSULIN IN TYPE I DM (CONTD)
Dosage Changes:
Corresponds to most abnormal Blood Glucose value
(pre-meal)
If all values are abnormal - start with fasting glycemia
followed by lunch, supper and bedtime
Change the dose by increments of 1-4 U
No change of dose more than twice/week
Monitor for PATTERNS in hypoglycemia
Harrisons principle of internal Medicine, 17 th edition , Chapter 332, Endocrinology and metabolism;
Diabetes mellitus: Tata McGraw Hill publication pg. 1324-386
55. ROLE OF INSULIN IN TYPE II DM
In type 2 diabetes mellitus, oral hypoglycemic agents &
analogues of glucagon-like peptide-1 provide adequate
glycemic control early in the disease
Insulin therapy becomes necessary for those with
advanced disease
Some experts recommend electively starting insulin
therapy in early diabetes
A common way to start is to add a once-daily dose of a
long-acting insulin at bedtime (basal insulin) to patient’s
antidiabetic regimen
56. ROLE OF INSULIN IN TYPE II DM (CONTD)
If Basal regimens do not control postprandial
hyperglycemia then,
Long-acting (basal) insulin along with a rapid-acting
(prandial or bolus) insulin before meals are given
In advanced stages of type II DM, Bolus insulin regimens
of Lisipro, Aspart, Glulisine insulin are preferred
Premixed insulin preparations are not recommended
Most commonly NPH, Glargine, Detemir insulin
preparations are used
Marwan Hamaty et al; Insulin treatment for type 2 diabetes: When to start, which to use; Cleveland clinical
journal of medicien; 2011;78;5;pg 332-42
57. INSULIN DELIVERY SYSTEM
Standard Delivery
Subcutaneous injection using conventional disposable
needles & syringes
Advantages:
Maximal ability to “freemix” & adjust to patient need
Disadvantage:
Multiple injections, need to carry inj. & bottles
Variable absorption
Difficult to distinguish between lisipro & glargine ( both
being clear)
59. INSULIN DELIVERY SYSTEM
Portable Pen Injectors
Developed to facilitate multiple subcutaneous inactions of
insulin
Contain cartridges of insulin & replaceable needle
Available for :
Regular insulin
Insulin lisipro
Insulin aspart
Insulin glulisine
Insulin glargine
Insulin detemir
60. INSULIN DELIVERY SYSTEM
Portable Pen Injectors
Well accepted by pts. As eliminates need to carry
syringes & needles
Advantages:
Convinient, Less to carry
Easy to distinguish (d/t different color of pens)
Improves dosing accuracy
Disadvantages:
Approximately 30% more costly per 1000 U bottle of
insulin
Jennings AM, Lewis KS, Murdoch S, Talbot JF, Bradley C, Ward JD. Randomized trial comparing continuous
subcutaneous insulin infusion and conventional insulin therapy in type II diabetic patients poorly controlled
with sulfonylureas. Diabetes Care.1991;14:738-744
61. INSULIN DELIVERY SYSTEM
Insulin Pumps
AKA Contineous Subcutaneous Insulin Infusion Devices
(CSII)
External open loop pumps for insulin delivery
Contains programmable pump → delivers individualized
basal & bolus insulin replacement doses based on blood
glucose level
62. INSULIN DELIVERY SYSTEM
Insulin Pumps
Reminders to :
Test blood glucose after a bolus
Warn when bolus delivery is not completed
Test blood glucose following a low or high BG
Give boluses at certain times of day
Change infusion site
Direct BG entry from meter
Eliminates errors in data transfer
G. Scheiner, R. J. Sobel, D. E. Smith, et al., “Insulin pump therapy guidelines for successful outcomes,”
Diabetes Educator, vol. 35, supplement 2, pp. 29S–41S, 2009.
63. INSULIN DELIVERY SYSTEM
Insulin Pumps
Advantages:
Fewer injections
Physiologic delivery with best glycemic control &
fewest hypoglycemic events
Eliminates variable injection site absorption
Disadvantages:
Expensive
Additional training needed
Pt. must be aware of technical problems
65. INSULIN DELIVERY SYSTEM
Inhaled Insulins
Marketed earlier , withdrawn later d/t deposition in
pharynx causing pharyngitis & pulmonary fibrosis
Two preparations approved by FDA earlier:
EXUBERA
AFREZZA
Both work like ultra short acting insulin
Inhaled at meal time to control rapid rise of blood glucose
level
Risk of hypoglycemia & weight gain
Justin Gillis (January 28, 2006). “Inhaled form of insulin is approved:.The Washington Post. Retrieved
2007-10-21
66. INSULIN REGIMENS
Intensive Insulin Therapy
Described to most of pts. with type I DM
Total insulin requirement (U) = weight in pouds/4
= 0.55 * weight in Kg
Meals, Snacks & high blood sugar corrections are
prescribed by formulas
Pt calculates amount of carbohydrate in meal/snacks,
current plasma glucose & target glucose
Diurnal variations in insulin sensitivity accomodated by
prescribing different basal rates & bolus insulin doses
throught day
67. INSULIN REGIMENS
Conventional Insulin Therapy
Prescribed only to some people with type II DM
Sliding Scale Regimen:
Regimen ranges from one injection per day to many
injections per day
Regimen mainly based on intermediate/long acting insulin
Based on plasma glucose level before injection, short or
rapid acting insulin can also be used
Action to control cardiovascular risks in diabetes study groups: Effects of intensive glucose lowering
therapy in diabetes . N Engl J Med 2008;358;2545
68. INSULIN TREATMENT OF SPECIAL
CIRCUMSTANCES
Emergency treatment of diabetic ketoacidosis
(Diabetic Coma)
Seen in type I DM pts
Treated by Bolus dose of 0.1 U/kg I.V. short acting
regular insulin f/b 0.1 U/kg/hr I.V. till glucose level falls
to 300 mg/dl till pt regains consiousness
Fluid & Electrolyte management
69. INSULIN TREATMENT OF SPECIAL
CIRCUMSTANCES
Treatment of Non ketotic hyperglycemic
(hyperosmolar) Coma
Seen in type II DM pts
Treated same as of Diabetic Coma with more
aggressive Fluid & Electrolyte management
