1. By Dr Sangeet Chadha

2. © 2004, John Walsh, P.A., C.D.E.
Before InsulinBefore Insulin
Before insulin was discovered in 1921,
everyone with type 1 diabetes died
within weeks to years of its onset
JL on 12/15/22 and 2 mos later

3. HISTORY
In 1869, a German medical student, Paul Langerhans, noted that
the pancreas contains two distinct groups of cells the acinar cells,
which secrete digestive enzymes, and cells that are clustered in
islands, or islets, which he suggested served a second function.
•
In the early 1900s, Gurg Zuelzer, an internist in Berlin, attempted
to treat a dying diabetic patient with extracts of pancreas.
Although the patient improved temporarily, he sank back into a
coma and died when the supply of extract was exhausted.

4. Frederick Banting, a young Canadian surgeon, convinced J.J.R.
Macleod, a professor of physiology in Toronto, to allow him
access to a laboratory to search for the antidiabetic principle of
the pancreas.
•Banting assumed that the islets secreted insulin but that the
hormone was destroyed by proteolytic digestion prior to or
during extraction. Together with Charles Best, a fourth-year
medical student, he attempted to overcome the problem by
ligating the pancreatic ducts. The acinar tissue degenerated,
leaving the islets undisturbed; the remaining tissue then was
extracted with ethanol and acid.

5. © 2004, John Walsh, P.A., C.D.E.
 In Jan, 1922, Banting and Best injected a 14-year-
old "charity” patient who weighed 64 lb with 7.5
ml of a "thick brown muck"in each buttock
 Abscesses developed and 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
 Leonard lived a relatively healthy life for 13 years
before dying of pneumonia (no Rx then) at 27

6. •The Nobel Prize in medicine and physiology was awarded
to Banting and Macleod with remarkable rapidity in 1923,
and a furor over credit followed immediately.
Banting announced that he would share his prize with Best;
Macleod did the same with Collip.

7. © 2004, John Walsh, P.A., C.D.E.
InsulinInsulin
Production BeginsProduction Begins
 First produced as “Connaught” by the Univ of Toronto
 On May 30, 1922, Eli Lilly signed an agreement to pay
royalties to the University to increase production
 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

8. © 2004, John Walsh, P.A., C.D.E.
mpact Of Insulin On.mpact Of Insulin On.
Life ExpectancyLife Expectancy
By The 1940’sBy The 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

9. In the post-absorptive period of a normal individual, low
basal levels of circulating insulin are maintained through
constant β cell secretion. This suppresses lipolysis,
proteolysis and glycogenolysis.
 After ingesting a meal a burst of insulin secretion occurs
in response to elevated glucose and amino acid levels.
When glucose levels return to basal levels, insulin secretion
returns to its basal level.

10. Type I:
depends on exogenous insulin to prevent hyperglycemia and
avoid ketoacidosis. The goal of type 1 therapy is to mimic
both the basal and reactive secretion of insulin in response to
glucose levels avoiding both hyper- and hypoglycemic
episodes
Type II:
The goal of treatment is to maintain glucose concentrations
within normal limits to prevent long term complications.
Weight reduction, exercise (independent of weight reduction)
and dietary modification decrease insulin resistance and are
essential steps in a treatment regimen. For many this is
inadequate to normalize glucose levels, the addition of
hypoglycemic agents is often required, often insulin therapy is
required.

11. Insulin secretion is regulated by glucose levels, certain amino acids,
hormones and autonomic mediators.
Secretion is most commonly elicited by elevated glucose levels;.
The influx of Ca+2 results in a pulsatile secretion of insulin;
continued Ca+2 influx results in activation of transcription factors
for insulin.
Oral glucose elicits more insulin secretion than IV glucose; oral
administration elicits gut hormones which augment the insulin
response.
Insulin is normally catabolized by insulinase produced by the
kidney.

13. Cell Types
Alpha (A) cell
Beta (B) cell
Delta (D) cell
G cell
F cell (PP cell)1
Approximate Percent
of Islet Mass
20 %
75 %
3–5 %
1 %
1 %
Secretory Products
Glucagon,
proglucagon
Insulin, C-peptide,
proinsulin, amylin
Somatostatin
Gastrin
Pancreatic polypeptide
(PP)
Pancreatic Islet Cells and Their
Secretory Products.

14. Insulin is a peptide hormone synthesized as a precursor (pro-
insulin) which undergoes proteolytic cleavage to form a
dipeptide; the cleaved polypeptide remnant is termed protein C.
Both are secreted from the β-cell, normal individuals secrete
both insulin and (but much less) pro-insulin.
Type 2s are found to secrete high levels of pro-insulin (pro-
insulin is inactive) measuring the level of C-protein is a
more accurate estimation of normal insulin secretion in
type 2s.

15. Human insulin consists of 51 AA in two chains
connected by 2 disulfide bridges
T1/2 ~5-10 minutes, degraded by glutathione-insulin
transhydrogenase (insulinase) which cleaves the
disulfide links.
Bovine insulin differs by 3 AAs, pork insulin differs by
1 AA.
Insulin is stored in a complex with Zn+2 ions.

17. Synthesis & release of insulin is modulated by:
1. Glucose (most important), AAs, FAs & ketone bodies
stimulate release.
2. Glucagon & somatostation inhibit releases
3. α-Adrenergic stimulation inhibits release (most important).
4. β-Adrenergic stimulation promotes release.
5. Elevated intracellular Ca+2 promotes release.

18.  Insulin binds to specific high
affinity membrane receptors with
tyrosine kinase activity
 Phosphorylation cascade results in
translocation of GLUT-4 (and
some Glut-1) transport proteins
into the plasma membrane.
 It induces the transcription of
several genes resulting in
increased glucose catabolism &
inhibits the transcription of genes
involved in gluconeogenesis
.
 Insulin promotes the uptake of K+
into cells.

19. Insulin preparations

20. Regular insulin:
Short acting, soluble, crystalline zinc insulin is
usually given subcutaneously; it rapidly lowers
glucose levels.
All regular insulin is now made using genetically
engineered bacteria, cow & pig no longer used.
onset 0.5-1.0 hrs peak 2- 4 hrs duration 5- 7hrs

21. Insulin lispro.
 at positions B28 and B29, the sequence of the two residues has
been reversed to match the sequence in IGF-1, which does not self-
associate.
 Like regular insulin, lispro exists as a hexamer in commercially
available formulations.
Unlike regular insulin, lispro dissociates into monomers almost
instantaneously following injection. Results in the characteristic
rapid absorption and shorter duration of action compared with
regular insulin.
 Advantages. First, the prevalence of hypoglycemia is reduced by
20% to 30% ; second, glucose control, as assessed by hemoglobin
A1c, is modestly but significantly improved (0.3% to 0.5%) with
lispro as compared with regular insulin.

23. Insulin Aspart
Formed by the replacement of proline at B28 with aspartic acid.
This reduces self-association to that observed with lispro.
Like lispro, insulin aspart dissociates rapidly into monomers
following injection. Comparison of a single subcutaneous dose of
aspart and lispro in a group of type 1 DM patients revealed similar
plasma insulin profiles.
In clinical trials, insulin aspart and insulin lispro have had similar
effects on glucose control and hypoglycemia frequency, with lower
rates of nocturnal hypoglycemia as compared with regular insulin

24. Insulin Glulysine
In this compound, glutamic acid replaces lysine at B29, and lysine
replaces asparagine at B23.
Similar to the other two available rapid-acting analogs, this causes
a reduction in self-association and rapid dissociation into active
monomers.
The time-action profile of insulin glulysine is similar to that of
insulin aspart and lispro.
Similar to insulin aspart, glulysine has been approved by the Food
and Drug Administration (FDA) for continuous subcutaneous
insulin infusion (CSII) pump use.

25. Owing to their rapid onset, the fast-acting insulin analogs all
may be injected immediately before or after a meal, which may
confer considerable clinical advantages.
Many individuals with diabetes consume smaller amounts of
food than originally planned. This, in the presence of a
previously injected dose of insulin that was based on a larger
meal, could result in postprandial hypoglycemia.Thus, in patients
who have gastroparesis or loss of appetite, injection of a rapid-
acting analog postprandially, based on the amount of food
actually consumed, may provide smoother glycemic control.

26. 1. Lente insulin:
Amorphous precipitate of insulin with zinc ion combined with
70% ultralente insulin. Onset is slower but more sustained than
regular insulin. It cannot be given IV
( this has not been produced since 2005).
2. Isophane NPH insulin:
Neutral protamine Hagedorn insulin is a suspension of
crystalline zinc insulin combined with protamine (a polypeptide).
The conjugation with protamine delays its onset of action and
prolongs its effectiveness. It is usually given in combination
with regular insulin.

27. 1.Ultralente: a suspension of zinc insulin forming large particles
which dissolve slowly, delaying onset and prolonging duration of
action.
2.Insulin glargine: Precipitation at the injection site extends the
duration of action of this preparation.
3. Detemir insulin: has a FA complexed with insulin resulting in
slow dissolution.

28. Insulin Glargine
 Two arginine residues are added to the C terminus of the B
chain, and an asparagine molecule in position A21 on the A chain is
replaced with glycine.
Glargine is a clear solution with a pH of 4.0. This pH stabilizes
the insulin hexamer and results in a prolonged and predictable
absorption from subcutaneous tissues.
Owing to acidic pH, it cannot be mixed with currently available
short-acting insulin preparations (i.e., regular insulin, aspart, or
lispro) that are formulated at a neutral pH.
In clinical studies, insulin glargine results in less hypoglycemia,
has a sustained "peakless" absorption profile, and provides a better
once-daily 24-hour insulin coverage than ultralente or NPH insulin.

29. May be administered at any time during the day with
equivalent efficacy and no difference in the frequency of
hypoglycemic episodes. Glargine does not accumulate after
several injections..
Can be combined with various oral antihyperglycemic agents to
effectively lower plasma glucose levels.
Use of a long-acting basal insulin alone will not control
postprandial glucose elevations in insulin-deficient type 1 or type
2 DM.
Unlike traditional insulin preparations that are absorbed more
rapidly from the abdomen than from the arm or leg, the site of
administration does not influence the time-action profile of
Glargine. Similarly, exercise does not influence Glargine's unique
absorption kinetics, even when the insulin is injected into a
working limb.

30. Insulin Detemir
Insulin detemir (deh-TEE-meer) has a fatty-acid side chain.
The addition of the fatty-acid side chain enhances association
to albumin.
Slow dissociation from albumin results in long-acting
properties similar to those of insulin glargine.

31. Name Type Onset(1)
Peak(1)
Duration(1)
Lispro Rapid 5-15 minutes 30-75 minutes 2-3 hours
Glulisine Rapid 5-15 minutes 30-75 minutes 2-4 hours
Aspart Rapid 10-20 minutes 1-3 hours 3-5 hours
Regular (R) Short-Acting 30 minutes 2-5 hours 5-8 hours
NPH (N) Intermediate 1-3 hours 6-12 hours 16-24 hours
Lente (L) Intermediate 1-3 hours 6-12 hours 16-24 hours
Ultralente (U) Long-Acting 3-5 hours 8-14 hours 18 hours
Glargine Lantus
Very Long-
Acting
1 hour
Evenly for 24
hours
24-28 hours
NPH & Regular
Mixed in either
50/50 mix, or
70/30 mix
Premixed 30-60 minutes 2-12 hours up to 18 hours

32. Mixtures of Insulins
Because intermediate-acting NPH insulins require several hours to
reach adequate therapeutic levels, their use in diabetic patients usually
requires supplements of rapid- or short-acting insulin before meals.
 For convenience, these are often mixed together in the same syringe
before injection. Insulin lispro, aspart, and glulisine can be acutely
mixed (ie, just before injection) with NPH insulin without affecting
their rapid absorption.
 However, premixed preparations have thus far been unstable. To
remedy this, intermediate insulins composed of isophane complexes of
protamine with insulin lispro and insulin aspart have been developed.

33. These intermediate insulins have been designated as "NPL" (neutral
protamine lispro) and "NPA" (neutral protamine aspart) and have the
same duration of action as NPH insulin.
The FDA has approved 50%/50% and 75%/25% NPL/insulin lispro
and 70%/30% NPA/insulin aspart premixed formulations. Additional
ratios are available abroad.
Insulin glargine and detemir must be given as separate injections.
They are not miscible acutely or in a premixed preparation with any
other insulin formulation.

34. 10/90
20/80
30/70
40/60
50/50
Post-prandialhyperglycemia
Pre-prandialhyperglycemia
Pre-mixed insulin

35. Daily Requirements.
 Insulin production by a normal, thin, healthy person is
between 18 and 40 units/day or about 0.2 to 0.5 units/kg of body
weight per day
About half this amount is secreted in the basal state and about
half in response to meals. Thus, basal secretion is about 0.5 to 1
units/h; after an oral glucose load, insulin secretion may
increase to 6 units/h.
In non-diabetic, obese, and insulin-resistant individuals,
insulin secretion may be increased fourfold or more. Insulin is
secreted into the portal circulation, and about 50% is destroyed
by the liver before reaching the systemic circulation

36. In a mixed population of type 1 DM patients, the average
dose of insulin is usually 0.6 to 0.7 units/kg body weight per
day.
Obese patients generally require more (about 2 units/kg per
day) because of resistance of peripheral tissues to insulin.
Patients who require less insulin than 0.5 units/kg per day
may have some endogenous production of insulin or may be
more sensitive to the hormone because of good physical
conditioning.

37. 37
Insulin action
The action of insulin is to:
 Help movement of glucose into the cells.
 Stimulate cells to take up glucose from
the blood.
 Increase the storage of glucose, amino
acids and fatty acids.
 Increase glycogen formation and storage
in the liver.

38. Liver Muscle Adipose
↓ glucose production ↑ Glucose transport ↑ glucose transport
↑ glycolysis ↑ glycolysis ↑ lipogenesis&
lipoprotein lipase
activity
↑ TG synthesis ↑ glycogen deposition ↓ intracellular lipolysis
↑ Protein synthesis ↑ protein synthesis

39. 39
Insulin administration
 Sites: abdomen (preferable) & rotate site with
each injection.
 Timing: depends on the type of insulin.
 Storage: unopened stored in refrigerator.
Insulin in use, in cool, dark place <25º (not in
fridge).
 Expiry: use within 28 days of opening.
Discard after expiry date.
 Supply: prescription only.

40. 1. Hypoglycemia-
2. Hypokalemia: insulin draws K+ into the cell with glucose
(hyperglycemia with normal K+).
3. Anaphylaxis: when sensitized to non-human insulin gets non-
human insulin (now rare).
4. Lipodystrophy at injection site
5. Weight gain

42. Hypoglycemia
Commonly result from inadequate carbohydrate consumption, unusual physical
exertion, and too large a dose of insulin.
Manifested by signs of autonomic hyperactivity—both sympathetic (tachycardia,
palpitations, sweating, tremulousness) and parasympathetic (nausea, hunger)—and
may progress to convulsions and coma if untreated.
 "hypoglycemic unawareness." When patients lack the early warning signs of low
blood glucose. In patients with persistent, untreated hypoglycemia, the manifestations
of insulin excess may develop—confusion, weakness, bizarre behavior, coma, seizures
—at which point they may not be able to procure or safely swallow glucose-containing
foods. Hypoglycemic awareness may be restored by preventing frequent hypoglycemic
episodes.
An identification bracelet, necklace, or card in the wallet or purse, as well as some
form of rapidly absorbed glucose, should be carried by every diabetic who is receiving
hypoglycemic drug therapy.

43. Treatment of Hypoglycemia
Glucose administration. To expedite absorption, simple sugar or glucose should be
given, preferably in liquid form.
In mild hypoglycemia in a patient who is conscious and able to swallow, dextrose
tablets, glucose gel, or any sugar-containing beverage or food may be given.
If more severe hypoglycemia has produced unconsciousness or stupor, the treatment
of choice is to give 20–50 mL of 50% glucose solution by I.V infusion over a period
of 2–3 minutes.
If I.V therapy is not available, 1 mg of Glucagon injected either S.C or I.M may
restore consciousness within 15 minutes to permit ingestion of sugar.
If the patient is stuporous and glucagon is not available, small amounts of honey or
syrup can be inserted into the buccal pouch. In general, however, oral feeding is
contraindicated in unconscious patients.
Emergency medical services should be called immediately for all episodes of severely
impaired consciousness.

44. Immunopathology of Insulin Therapy
There are two major types of immune disorders in these patients:
Insulin Allergy-
Insulin allergy, an immediate type hypersensitivity, is a rare condition in
which local or systemic urticaria results from histamine release from
tissue mast cells sensitized by anti-insulin IgE antibodies. In severe cases,
anaphylaxis results. Because sensitivity is often to noninsulin protein
contaminants, the human and analog insulins have markedly reduced the
incidence of insulin allergy, especially local reactions.
Immune Insulin Resistance-
A low titer of circulating IgG anti-insulin antibodies that neutralize the
action of insulin to a negligible extent develops in most insulin-treated
patients. Rarely, the titer of insulin antibodies leads to insulin resistance

45. Lipodystrophy at Injection Sites
Injection of animal insulin preparations sometimes led to
atrophy of subcutaneous fatty tissue at the site of injection.
This type of immune complication is almost never seen ever
since the development of human and analog insulin preparations
of neutral pH. Injection of these newer preparations directly into
the atrophic area often results in restoration of normal contours.
Hypertrophy of subcutaneous fatty tissue remains a problem if
injected repeatedly at the same site. However, this may be
corrected by avoiding the specific injection site or by
liposuction.

46. Unitage.
 For therapeutic purposes, doses and concentrations of
insulin are expressed in units. This tradition dates to the time
when preparations of the hormone were impure, and it was
necessary to standardize them by bioassay.
One unit of insulin is equal to the amount required to reduce
the concentration of blood glucose in a fasting rabbit to 45
mg/dl (2.5 mM).

47. The current international standard is a mixture of bovine and
porcine insulins and contains 24 units/mg. Homogeneous
preparations of human insulin contain between 25 and 30
units/mg.
Almost all commercial preparations of insulin are supplied in
solution or suspension at a concentration of 100 units/ml, which is
about 3.6 mg insulin per milliliter (0.6 mM).
Insulin also is available in a more concentrated solution (500
units/ml) for patients who are resistant to the hormone.

48. Insulin delivery devices
1. Insulin syringes
2. External insulin pumps
3. Implantable insulin pumps
4. Insulin pens
5. Insulin jet injectors
6. Insulin inhalers

49. Insulin syringes
Insulin syringes are to be used with 10ml insulin vials
Syringes are manufactured in 30 unit (0.3ml), 50 unit (0.5ml)
and 100 unit (1.0ml) measures. Its size will depend on
the insulin dose, for example, it is easier to measure a 10 unit
dose in a 30 unit syringe, and 55 units in a 100 unit syringe
Needles of the syringes are available in different lengths
ranging from 8mm to 13mm. You will be informed by your
doctor for its selection
Use each syringe only once.

50. Insulin Pumps
The insulin pump is a device that holds a reservoir of insulin.
The pump is programmed to deliver insulin into the body through
thin plastic tubing known as the infusion set
The pump is worn outside the body, in a pouch or on your belt.
The infusion set has a fine needle or flexible cannula that is
inserted just below the skin (usually on the abdomen) where it
stays in place for two to three days
Only short or rapid acting insulin can be used in the pump.
Whenever food is eaten, the pump is programmed to deliver a
surge of insulin into the body similar to the way the pancreas
does in people without diabetes. Between meals, a small and
steady rate of insulin is released

51. Pump Evolution
1970s1970s 1980s1980s
  

52. Pump Evolution
Modern Day Insulin PumpsModern Day Insulin Pumps

53. Insulin Used In Pumps
 Rapid-Acting Analogs are Preferred
 Aspart (Novolog)
 Lispro (Humalog
 Glulisine (Apidra)
 Modes of Delivery
 Basal
 Bolus

54. Basal Insulin
 Steady “Drip” of Insulin
 Matches Glucose Released by Liver
 Meets Body’s Basic Energy Needs
 May Need Different Settings at Different Times of Day
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
12:00AM
3:00AM
6:00AM
9:00AM
12:00PM
3:00PM
6:00PM
9:00PM
12:00AM
Units
per
hour

55. Bolus Insulin
 Given to “cover” carbs in meals and snacks.
 Used to “correct” high blood glucose levels
12:00AM
1:00AM
2:00AM
3:00AM
4:00AM
5:00AM
6:00AM
7:00AM
8:00AM
9:00AM
10:00AM
11:00AM
12:00PM
1:00PM
2:00PM
3:00PM
4:00PM
5:00PM
6:00PM
7:00PM
8:00PM
9:00PM
10:00PM
11:00PM
12:00AM

56. Insulin Infusion
(aka “getting under your skin”)
 Durable, clog-resistant tubing carries
insulin from the pump to the infusion set*.
 The infusion set delivers insulin into the
fatty layer below the skin.
 Set uses either a flexible plastic catheter
(canula) or a steel needle.
 Almost always disconnectable near the
infusion site.
* OmniPod does not have tubing; it* OmniPod does not have tubing; it
attaches directly to the skin.attaches directly to the skin.

57. Infusion Set Types
Infusion sets vary by:
 Angle of insertion
 Canula length
 Plastic vs. steel
 Tubing length

58.  Reduction in HbA1c1
 Less BG Variability2
 Reduction in duration, frequency and
severity of hypoglycemia3
 Better psychosocial outcomes & quality
of life4

59. Practical Benefits of Pump Basal
Delivery:
 Stable BG between meals & overnight
 Can skip/delay meals without dropping
 Can vary sleep & work schedules
 Fewer issues with travel/time zone
changes
 Can correct for dawn effect
 No long-acting insulins (more consistent
insulin action)
 Immediate, temporary basal adjustments
possible

60. Potential Drawbacks to Pump Therapy
 Cost
 Learning Curve
 Extra Testing
 Risk of Ketosis & DKA
 Skin Irritation
 Inconvenience
 Time/Discomfort of Set Changes
 Teaching & Follow-Up Required

61. Strategies for Success: DKA PreventionStrategies for Success: DKA Prevention
Unexplained
High Blood Sugar
Check for
Ketones
Ketones Ketones
Negative Positive
Bolus w/Pump BS Doesn’t Drop 1. Shot w/Syringe
BS Drops 2. Drink Water
3. Change Out Pump
O.K.

62. Insulin Pens
‘Pen’ is available in all shapes and sizes. An insulin cartridge
(3ml, containing 300 units of insulin) fits into the device.
When finished, a new cartridge is inserted. However, some pen
devices are pre-filled with insulin and the whole device is
disposable
Durable pen available are NovoPen 3, NovoPen Demi,
Innovo and HumaPen
Pre-filled disposable devices include Innolet, FlexPen and
Novolet

63. Types of Insulin Pens
 Rapid Acting Insulin
 Novolog FlexPen: Prefilled 300 units
 Humalog KwikPen: Prefilled 300 units
 Apidra SoloStar Pen: Prefilled 300 units (new April ’09)
 Humalog Memoir Pen: 300 unit cartridge
 Humalog Luxura Pen: 300 unit cartridge, can be dosed in ½ units
 Basal Insulin
 Lantus SoloStar Pen: prefilled 300 units
 Opticlick pen phasing out
 Levemir FlexPen : prefilled 300 units
 Many mixed Insulins and older insulins also come in pens

64. Pros/Cons to Insulin pens
 Advantages
 Easy to dial up dose
 Can “count” clicks
 Kept at room
temperature
 Portable
 More discrete
 Memoir Pen: good for
patients with multiple
care givers, able to
identify last dose
administered
 Disadvantages
 Only 300 units
 Pens look similar,
rapid acting and basal
could get mixed up
 Difficult to “plunge”
 Hold needle in for 5
seconds to ensure
administration

65. Insulin Jet Injectors
Insulin jet injectors are high-pressure air devices that deliver a
thin spray of insulin through and under the skin without any
perforation.
This method is not a first class option, since it may not be
extremely accurate, in terms of dose strength but it can be
used, if the patient is terrified with the idea of a needle.

66. Insulin Inhalers
Insulin inhaler for insulin delivery by the pulmonary route. The
patient presses the actuator to release the insulin from the
aerosol container, in the manner similar to the administration of
bronchodilators for the asthmatics.
 The hormone is provided as a spray or a dry powder.
When inhaled, insulin enters the blood stream through
the basic anatomic lung elements, called alveoli.
Eg-Exubera .

67. www.diabetesclinic.ca 67
Non-diabetic InsulinNon-diabetic Insulin
and Glucose Profilesand Glucose Profiles
9.0
6.0
3.0
0
7 8 9 10 11 12 1 2 3 4 5 6 7 8 9
Insulin
Glucose
a.m. p.m.
Breakfast Lunch Supper
75
50
25
0 Basal insulin
Basal glucose
Insulin
(µU/mL)
Glucose
(mmo/L)
Time of Day

68. Insulin Preparations & Treatment
Various types of insulin are characterized by their
onset and duration of action

69. Examples of three
regimens that provide
both prandial and basal-
insulin replacement.
B = breakfast; L = lunch;
S = supper

70. Insulin Regimens
INTENSIVE INSULIN THERAPY
Intensive insulin regimens are prescribed for almost everyone with type
1 diabetes as well as many with type 2 diabetes.
Generally, the total daily insulin requirement in units is equal to the
weight in pounds divided by four, or 0.55 times the person's weight in
kilograms.
Approximately half the total daily insulin dose covers the background or
basal insulin requirements, and the remainder covers meal and snack
requirement and high blood sugar corrections. This is an approximate
calculation and has to be individualized.
Increased insulin requirements typically occur with obesity, during
adolescence, during the latter trimesters of pregnancy, and in individuals
with type 2 diabetes.

71. This newer approach contrasts with conventional insulinotherapy. Rather
than minimize the number of insulin injections per day (a technique which
demands a rigid schedule for food and activities), the intensive approach
favors flexible meal times with variable carbohydrate as well as flexible
physical activities.
The trade-off is the increase from 2 or 3 injections per day to 4 or more
injections per day, which was considered "intensive" relative to the older
approach.
In North America in 2004, many endocrinologists prefer the term Flexible
Insulin Therapy (FIT) to "intensive therapy" and use it to refer to any
method of replacing insulin that attempts to mimic the pattern of small
continuous basal insulin secretion of a working pancreas combined with
larger insulin secretions at mealtimes. The semantic distinction reflects
changing treatment.

72. Rationale for intensive or flexible treatment
Long-term studies like the UK Prospective Diabetes Study (UKPDS) and
the Diabetes control and complications trial (DCCT) showed that intensive
insulinotherapy achieved blood glucose levels closer to non-diabetic
people and that this was associated with reduced frequency and severity
of blood vessel damage. Damage to large and small blood vessels
(macro- and microvascular disease) is central to the development of
complications of diabetes mellitus.
This evidence convinced most physicians who specialize in diabetes care
that an important goal of treatment is to make the biochemical profile of
the diabetic patient (blood lipids, HbA1c, etc.) as close to the values of
non-diabetic people as possible. This is especially true for young patients
with many decades of life ahead.

73. A general description of intensive or flexible therapy
A working pancreas continually secretes small amounts of insulin into the
blood to prevent the body from shifting into "starvation metabolism." This
insulin is referred to as basal insulin secretion.
Most insulin used each day is produced during the digestion of meals.
Insulin levels rise immediately as we begin to eat, remaining higher than
the basal rate for 1 to 4 hours. This meal-associated (prandial) insulin
production is roughly proportional to the amount of carbohydrate in the
meal.
Intensive or flexible therapy involves supplying a continual supply of
insulin to serve as the basal insulin, supplying meal insulin in doses
proportional to nutritional load of the meals, and supplying extra insulin
when needed to correct high glucose levels. These three components of the
insulin regimen are commonly referred to as basal insulin, meal insulin, and
high correction.

74. Advantages and disadvantages of intensive/flexible insulin
therapy
The two primary advantages of intensive/flexible therapy over more traditional
two or three injection regimens are:
greater flexibility of meal times, carbohydrate quantities, and physical activities,
and
better glycemic control to reduce the incidence and severity of the
complications of diabetes.
Major disadvantages of intensive/flexible therapy are that it requires greater
amounts of education and effort to achieve the goals, and it substantially
increases the daily cost of diabetes care.
It is a common misconception that more frequent hypoglycemia is a
disadvantage of intensive/flexible regimens. The frequency of hypoglycemia
increases with increasing effort to achieve normal blood glucoses with any
insulin regimen. When traditional regimens are used aggressively enough to
achieve near-normal glycosylated hemoglobin A1c levels, hypoglycemia is at
least as frequent as with flexible regimens. When used correctly, flexible
regimens offer greater ability to achieve good glycemic control with easier
accommodation to variations of eating and physical activity.

75. CONVENTIONAL INSULIN THERAPY
Conventional insulin therapy is usually prescribed only for certain
people with type 2 diabetes who are felt not to benefit from intensive
glucose control.
The insulin regimen ranges from one injection per day to many
injections per day, using intermediate- or long-acting insulin alone or
with short- or rapid-acting insulin or premixed insulins.
Referred to as sliding-scale regimens, conventional insulin regimens
customarily fix the dose of the intermediate- or long-acting insulin,
but vary the short- or rapid-acting insulin based on the plasma glucose
level before the injection.

76. It is a 'conventional' therapy in which a mixture of short and long acting
insulin is given in the morning and then again before the evening meal.
Insulin is either drawn up from different bottles into the same syringe or
use the pre-mixed insulin (disposable pen injectors). One plus point of
this regimen is that there is no need of insulin shot at lunch and dinner
time, but it becomes very essential to maintain timings of each meal. And,
delaying or skipping of any meal will be oblivious cause of
hypoglycemia. Lack of flexibility is again a problem if, a pre-mixed
insulin is used as it is harder to vary the insulin dose according to the
changes in your daily routine. The doses of short and long acting insulin
cannot be varied independently of one another.
This regimen works as follow:
the morning short acting insulin takes care of breakfast
the morning long acting insulin takes care of lunch
the evening short acting insulin takes care of the evening meal
the evening long acting insulin takes care of overnight insulin needs

77. This older method (prior to the development home blood glucose monitoring)
is still in use in a proportion of cases.
Conventional insulin therapy has these characteristics:
Insulin injections of a mixture of rapid and intermediate acting insulin are
performed two or three times daily.
Meals are scheduled to match the anticipated peaks in the insulin profiles.
The target range for blood glucose levels is higher than is desired in the
intensive regimen.
Frequent measurements of blood glucose levels were not used.
The down side of this method is that it is difficult to achieve as good results of
glycemic control as with intensive insulinotherapy. The advantage is that, for
diabetics with a regular lifestyle, the regime is less intrusive than the intensive
therapy.

78. www.diabetesclinic.ca 78
0
10
20
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Cause:
Counter regulatory hormones response to
hypoglycemia at mid-night.
Increase in hepatic glucose production.
Insulin resistance because of the Counter
regulatory hormones.
Treatment:
Decrease pre-supper intermediate
insulin.
Defer the dose to 9 PM.
Change or start pre-bed snack.
Somogyi Phenomenon

79. 0
10
20
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Cause:
Less insulin at bed time.
More food at bed time.
Not using NPH at night.
Treatment:
Use enough dose.
Reduce bed time snack.
Add NPH pre-supper.
Dawn Phenomenon

80. Novo Nordisk announced on December 7, 2009, that it
had initiated its first phase 1 trial with oral insulin
analogue (NN1952).
Results from the trial, which is planned to enroll about
80 people, are expected to be reported in the first half of
2011.
Oral insulin

81. A Connecticut-based biopharmaceutical company called Biodel, Inc. is
developing what it calls VIAtab, an oral formulation of insulin designed to
be administered sublingually.
This therapy is a tablet that dissolves in minutes when placed under the
tongue. In a Phase I study, VIAtab delivered insulin to the blood stream
quickly and resembled the first-phase insulin release spike found in
healthy individuals.
Biocon, Asia's largest biopharmaceutical company, based in
Bangalore, India, is also developing an oral insulin product. It has
recently entered phase III trials; the company hopes to launch their
product, IN-105, in 2011.[29]

82. Pancreatic transplantation
Islet transplants had been highly experimental (read 'prone to failure') for
many years, but some researchers in Alberta, Canada, have developed
techniques with a high initial success rate . Nearly half of those who got an
islet cell transplant were insulin-free one year after the operation; by the
end of the second year that number drops to about one in seven.
 However, researchers at the University of Illinois at Chicago (UIC) have
slightly modified the Edmonton Protocol procedure for islet cell
transplantation and achieved insulin independence in diabetes patients with
fewer but better-functioning pancreatic islet cells.
Beta cell transplant may become practical in the near future. Additionally,
some researchers have explored the possibility of transplanting genetically
engineered non-beta cells to secrete insulin.

83. Oscillations
Insulin release from pancreas oscillates with a period of 3–6 minutes.
This is thought to avoid downregulation of insulin receptors in target cells and
to assist the liver in extracting insulin from the blood.
This oscillation is important to consider when administering insulin-stimulating
medication, since it is the oscillating blood concentration of insulin release,
which should, ideally, be achieved, not a constant high concentration.
This may be achieved by delivering insulin rhythmically to the portal vein or by
islet cell transplantation to the liver. Future insulin pumps hope to address this
characteristic.

84. THANK YOU