INSULIN IN DIABETES

a. Insulin is required in all patients of diabetes-I if they become ketoacidodic without it.
b. Insulin is also helpful in management of diabetes-II along with oral hyperglycemic drugs.
c. Insulin replacement should ideally mimic B-cell function using two types of Insulin to provide basal and prandial
requirements that involves close monitoring of diet and exercise as well as time and dosing of Insulin.
d. Mostly insulins are available as human recombinant that eliminates its adverse reactions as compared to insulin
extracted from animal sources.
e. Majorly Insulin is administered as S.C but it is also administered as IV in hospitalized patients.
f. Types of Insulin is characterized by Onset and Duration of action that may vary in different patients with most
commonly factors as:-
 Site and technique of administration.
 Amount of sub-cutaneous fats.
 Rate of blood flow at site etc.
ONSET, PEAK AND DURATION OF ACTION OF HUMAN INSULIN PREPERATIONS
INSULIN ONSET OF PEAK DURATION
PREPERATIONS ACTION ACTION OF ACTION

1. RAPID ACTING INSULIN 5-15 mins 45-70 mins 3-5 hours

a. Lispro
b. Aspart
c. Glulisine

Rapid Acting Insulins have features as:

a. Rapidly absorbed because of reversal of Amino acid
pair prevents Insulin molecule from associating into
dimers and polymers.
b. They began to reduce Plasma glucose levels within
15 mins but have short duration of action.
c. These Insulins are best suited in meal times to
prevent Post prandial spikes of Plasma glucose
level.

2. SHORT ACTING INSULIN

Regular 30 – 60 mins 2-4 hours 6 – 8 hours

Regular Insulin have following features:

a. Have Slow on set of action but lasts longer.
b. Only available to be used in IV form.

3. NEUTRAL PROTAMINE HAGEDORN (NPH)

2 hours 4-12 hours 18-26 hours
Features of NPH are as:
a. Also called as “Insulin Isophane” or “NPH”
b. Intermediate action.
c. Mostly available commercially in combination with
following as:
 Insulin Lispro
 Lispro Protamine etc.

Some of combinations of NPH with other Insulins are as:

a. 70% NPH with 30% Regular Insulin 30 – 60 mins Dual 10 – 16 hours
b. 50% NPH with 50% Regular Insulin 30 – 60 mins Dual 10 – 16 hours
c. 75% NPL with 25% Insulin Lispro 5-15 mins Dual 10 – 16 hours
(NPL= Neutral Protamine Lispro)
d. 70% NPA with 30% Insulin Aspart 5-15 mins Dual 10 – 16 hours
NPA= Neutral Aspart

4. LONG ACTING INSULIN

a. Glargine 1-2 hours No peak 24 hours
b. Detemir 1-2 hours No peak 24 hours

g. Different Insulins can be drawn into same syringe but should not be mixed together in bottles except for the
manufacturer.
h. Mixing Insulins may affect “Rate of Insulin absorption” producing variable effects and making glycemic control
less predictable especially if mixed 1 hour before use.
“Insulin glargine should never be mixed with any other Insulin”
 i. Many Prefilled devices/pens are available commercially that eliminates need of syringe or vials and are holds
more compliance for the patients as can be used easily.
j. Lispro, aspart and regular insulin can also be given as in “Continuous sub cutaneous infusion pumps” that has
features as:
 Eliminates need of multiple dosing
 Provides maximum flexibility at times of meal.
 Substantially reduces variability in glucose levels.
 Costly and Mechanical failures leading to reduced supply of insulin are common disadvantages.
COMPLICATIONS OF INSULIN TREATMENT
a. “Hypoglycemia” is most common complication of Insulin treatment as patient tries to have a strict control
over his blood glucose levels.
b. Signs and symptoms of hypoglycemia in this regard are as:
Mild to Moderate Include:
Headache, Diaphoresis’s, Palpitations, Light headiness, Blurred vision, Agitation
More Severe Include:
Seizure and Lost of consciousness.
Geriatric Patients Include:
Stroke, MI and sudden death

c. Patient “should be educated to recognize symptoms of hypoglycemia” that usually responds as:
 By ingestion of Sugar involving Candy, Juice and Glucose tablets.
 Typically 15g of sugar should be ingested and should be evaluated 15 mins after for blood glucose
levels that should not exceed > 80 mg/dl (Only than patient can add 15g of more sugar afterwards).
 For Patients who are “Serious/unaware” Hypoglycemia can be treated immediately by:
 Glucagon 1mg S.C/I.M
 Dextrose solution 5 to 10% by IV
d. Hyperglycemia may also followed by Hypoglycemia as:
 Either too much sugar was ingested.
 Or Hypoglycemia caused surge in Counter regulatory hormones like Glucagon, Epinephrine, Cortisol
etc.
e. Too much dose of Insulin at bed time may cause Hyperglycemic episodes at next morning.

f. “Hypokalemia” (Less common) can be caused by “Intracellular shifts of K by Stimulation of Na-K ATPase
pump.

g. “Local Allergic Reactions” are very rare at site of administration especially for Human Insulin Preparations
but may occur at Site followed by “Pruritus, Irritation, Burning, Pain etc”

INSULIN REGIMEN FOR DIABETES-I V/S DIABETES-II

INSULIN REGIMEN FOR DIABETES-I INSULIN REGIMEN FOR DIABETES-II

 Regimen for Diabetes-I may vary as:
a. “Split mixed” (Split dose of Rapid and
Intermediate acting Insulin) ---- Twice daily
b. “Basal Bolus” (Single dose of Basal with Long
acting Insulin and Variable dose of Bolus with
Rapid Acting Insulin).
 Intensive treatment is required that involves:
a. Glucose monitoring >4 times a day.
b. Glucose injections >3 times a day.
c. Continuous injection of Insulin to prevent further
complications of Nephropathy, Neuropathy or
Retinopathy.
d. Intensive treatment may result in:
Hypoglycemic episodes with weight gain.
 Generally patients of Diabetes-I can start their dose of
Insulin from “0.2 to 0.8 units of Insulin per kg per
day”
 Obese patients requires more dose.
 Physiological replacement for Insulin involves:
40 to 60% of Long acting or Intermediate acting
Insulin to cover Basal needs with remaining 40 to
60% as Rapid or short acting Insulin.
Regimen for Diabetes-II may also vary as in many
patients blood glucose levels are adequately controlled by:
a. Life style changes.
b. By use of Single Oral hyperglycemic drug.
c. Combination of Oral hyperglycemic drugs.
Insulin is added only to Diabetes-II when “Blood glucose
level isn’t adequately controlled by:
a. Oral hyperglycemic drugs.
b. Life style (Diet and exercise) changes.
Insulin should replace “Oral hyperglycemic drugs”
especially in case of pregnancy and lactation.
Rational to use Insulin is strongly recommended along
with “Biguanides (Metformin etc) or Insulin sensitizers.
Regimen may vary from:
Single daily dosing of Long acting or Intermediate
Insulin (usually at bed time) to Multiple dose of
Insulin.
Because of Insulin resistance some patients may require
large doses of upto 2units of insulin/kg/day.
 Dose can be adjusted from 1 to 2 units for every Common complication observed in this regimen is
50mg/Dl or 2.7mmol/L above or below the target “Weight gain”
COMMERCIALLY AVAILABLE INSULIN PRODUCTS
S.NO PRODUCT GENERIC CONTENTS DOSAGE
NAME NAME

“SANOFI – AVENTIS”

1 APIDRA Insulin Available as: Adults and Children>6 yrs

Glulisine
1. APIDRA Inj 100 IU
(Per ml 100 UI of “Insulin glulisine is
present) in 10ml vial preparation.
2. APIDRA OPTISET Inj
(Available in 3ml Prefilled injection
device with range of 2 to 40 units that can
be adjusted allowing 2 units adjustments)
By s.c. route :
a. Immediately before meal
Or
b. Immediately after meal
(Target to achieve is 80 to 140
mg/dl of blood glucose between
pre-meal and bed time)

3. APIDRA SOLO STAR inj

(Available as 3ml Prefilled injection
device with range of 1-80 units allowing 1
unit adjustment).
Insulin Glulisine?
Insulin Glulisine is Rapid acting Insulin Analogue with Onset of action to be 5-15 mins and Duration of action to be 3-5
hours.
2 LANTUS Insulin Available as: Adults and Children>6 yrs
Glargine
1. LANTUS INJ By s.c. route :
(Per ml 100 UI of “Insulin glargine is a. Immediately before meal
present) in 10ml vial preparation. Or
b. After meal
2. LANTUS SOLO STAR
(Available as Insulin glargine 100 UI in (Target to achieve is 80 to 140
Prefilled disposable injection device with mg/dl of blood glucose between
range of 1-80 units that can be adjusted pre-meal and bed time)
allowing 1 units adjustments)

Insulin Glargine?
Insulin Glargine is Long acting Insulin with Onset of action as 1-2 hours and Duration of action as 24 hours
3 TOUEJO Insulin Available as: Adults:
Glargine
Insulin Glargine 300 UI in 1.5ml Prefilled By S.C one time a day preferably at
pen. same time of each day.

Children:
Not recommended below <18 years
“NOVO- NORDISK”
1 ACTRAPID Human Available as: Adults:
Regular
Insulin 1. ACTRAPID HM INJECTION Effect of Actrapid HM Injection by
(Per ml 100 UI of “Human Regular Insulin S.C starts with in Half-hour with
is present) in 10ml vial preparation. maximum effect in 2-3 hours and
duration of action upto 8 hours.
2. ACTAPRID HM PENFILLS
INJ Children:
(Available as “Regular Human Insulin” (Target to achieve is 100 to 200
100 UI in 3ml Pen fill Cartages) mg/dl of blood glucose between
pre-meal and bed time)
Human Regular Insulin
Human Regular/Purified Insulin is Insulin having Regular/Intermediate Action with Onset of action to be 30 – 60 mins,
Peak Plasma Levels to be 1 – 4 hours and Duration of Action to be 6 to 8 hours
2 INSULUTARD Human Available as: Adults:
HM (Isophane
Insulin) 1. INSULUTARD HM Effect of Insulutard HM Injection
Or INJECTION by S.C starts with in One and Half-
Insulin NPH (Per ml 100 UI of “Human Regular Insulin hour with maximum effect in 4-12
(Neutral is present) in 10ml vial preparation. hours and duration of action upto 24
Protamine hours.
Hagedorn) 2. INSULUTARD HM PENFILLS
INJ Children:
 (Available as “Purified Human Insulin” (Target to achieve is 100 to 200
100 UI in 3ml Pen fill Cartages) mg/dl of blood glucose between
pre-meal and bed time)
3 LEVEMIR Insulin Available as: Adults and Children >5years:
Detemir By s.c. route :
LEVEMIR INJ a. Immediately before meal
Or
(having 300UI of Insulin Detemir in 3ml b. Immediately after meal
of Pre filled device with Range of 1-60
units allowing Dose adjustment of 1 unit) (Target to achieve is 80 to 140
mg/dl of blood glucose between
pre-meal and bed time)
Insulin Detemir
Insulin Detemir is Long acting Insulin with Onset of action as 1-2 hours and Duration of action as 24 hours
4 MIXTRAD 30 Premixed Available as: Adults:
HM 30%
Soluble 1. MIXTARD 30 HM INJECTION Effect of Mixtard 30 HM Injection
Human (Pre mixed Product having 30% of Soluble by S.C starts with in One and Half-
Insulin Human Insulin and 70% of Isophane hour with maximum effect in 4-12
Human Insulin) having 100 UI in 10ml hours and duration of action upto 24
And vial preparation. hours.

70% 2. MIXTARD 30 HM PENFILLS Children:

Isophane INJ (Target to achieve is 100 to 200
Human (Pre mixed Product having 30% of Soluble mg/dl of blood glucose between
Insulin Human Insulin and 70% of Isophane pre-meal and bed time)
Human Insulin) having 100 UI in 3ml Pen
fill Cartages)

5 NOVOMIX Premixed Available as: Adults and Children:

30%
Insulin 1. NOVOMIX INJECTION By S.C injection 10 mins before
Aspart (Pre mixed Product having 50% Insulin meal.
Aspart and 50% Insulin Aspart Protamine)
And having 100 UI per ml in 3ml pre filled Dose should be adjusted to maintain
disposable injection device with units Blood glucose levels between 80 to
70% Insulin ranging from 1-60 and dose adjustment of 140mg/dl and in children <5 years
Aspart one unit. between 100 to 200 mg/dl
Protamine
2. NOVOMIX PENFILLS INJ
(Pre mixed Product having 30% Insulin
Aspart and 70% Insulin Aspart Protamine)
having 100 UI per ml in 3ml pre filled
disposable injection device with units
ranging from 1-60 and dose adjustment of
one unit.

Insulin Aspart
Insulin Aspart is Rapid Acting Insulin with Onset of action 5-15 mins, Peak Levels between 45-70 mins and Duration of
action 3- 5 hours
6 NOVORAPID Insulin Available as: Adults and Children:
Aspart
NOVORAPID INJ By S.C injection immediately
(Having Insulin Aspart 100 UI in 3ml Pre before or after meal.
filled disposable injection device with
units 1 to 60 and dose adjustment of one Can be given as in IV Infusion/Inj
unit.
Dose should be adjusted to maintain
Blood glucose levels between 80 to
140mg/dl and in children <5 years
between 100 to 200 mg/dl
7 RYZODEG Premixed Diabetes-I Patients:
30% Recommended dosage is 60 to 70%
Insulin of daily Insulin requirements with
Aspart dose adjustments that can be
individualized.
And Should be used with meal- Once
daily with Short/Rapid acting
70% Insulin Insulin.
Degludec
Diabetes-II Patients:
 Recommended dosage is 10 units
per day with dose adjustment that
can be individualized.
Insulin Degludec
Insulin Degludec is Rapid acting Insulin with Onset of action 5-15 mins, Peak Levels between 45-70 mins and Duration
of action 3- 5 hours
8 XULTOPHY Premixed Available as:  Once daily via S.C route
Insulin  Can be administered at any
Degludec XULTOPHY time of the day.
 Administered as Dose steps
And (Having Insulin degludec and Liraglutide (One dose step contains one
3.6mg in 3ml cartridges with Pre filled unit of Insulin degludec and
Liraglutide Multi dose disposable pen) 0.036 mg of Liraglutide)
3.6mg Maximum dose is 50 steps
(Glucagon per day.
Like  Add on to Oral
Peptidase-I Hyperglycemic drugs
Agonist) or Dose adjustment for Oral
GLP-1 hyperglycemic drugs
agonist should be considered in this
regard as for the case of
Sulfonyl urea where
Recommended daily dose
in 10 steps per day
 Transfer from Oral GLP-
1 Agonist and Basal
Insulin
Oral GLP-1 Agonist and
Basal Insulin should be
discontinued while merging
to Xultophy with
Recommended daily dosage
of 16 steps per day.

ELY LILY

1 HUMALOG
LISPRO
2 HUMALOG
MIX
3 HUMULIN
4 HUMULIN
70/30
5 HUMULIN N
6 HUMULIN R

ORAL HYPERGLYCEMIC DRUGS:

 Oral hyperglycemic drugs are indicated primarily for Diabetes-II but can be added with Insulin if there isn’t
control over with Mono/combinational oral hyperglycemic drugs along with control over diet and exercise.
 Oral Hyperglycemic drugs may:
A. Enhance Pancreatic Insulin Secretion (Called as “Insulin Secretagenous”)
B. Sensitize Peripheral Tissues for Insulin (Called as “Insulin Sensitizer”)
C. Impair GI absorption of Glucose.
 Drugs with different mechanism of actions may produce “Synergistic effect”
 Some of Oral Hyperglycemic drugs are evaluated as in Tabular form:
S.NO GENERIC DAILY DURATION COMMENTS
NAME DOSGAE OF
ACTION

A. INSULIN SECRETAGENOUS
“SULFONYL UREA”
Mode of Action:
Sulfonyl Urea are Insulin Secretagenous that “Lowers Plasma Glucose levels by Stimulating Pancreatic B cells Insulin
Secretion and Secondarily improves Peripheral and Hepatic Insulin Sensitivity by reducing glucose toxicity”

Drugs/Class Involved:
a. 1st Generation Sulfonyl Urea (Acetohexamide, Chlorpropamide, Tolbutamide, Tolazamide)
b. 2nd Generation Sulfonyl Urea (Glyburide, Glipizide, Glimepiride)

1st Generation Sulfonyl Urea

 Can be used alone or in combination therapy.
 Major Side effects are:
A. Hypoglycemia
B. Weight gain
1 ACETOHEXAMIDE 250mg O.D to 750mg 12-24 hrs
BID

2 CHLORPROPAMIDE 100mg O.D to 750mg 24-36 hrs May cause:

BID a. Hyponatremia
b. Flushing after alcohol
3 TOLBUTAMIDE 250mg O.D to 12 hrs
1500mg BID

4 TOLAZAMIDE 100mg O.D to 500mg 14-16 hrs

BID
2nd Generation Sulfonyl Urea
1 GLYBURIDE 1.25mg O.D to 10mg 12-24 hrs
BID

2 GLIPIZIDE AND 2.5mg O.D to 20mg 12-24 hrs

GLIPIZIDE ER BID

3 GLIMPRIDE 1-8 mg O.D 24 hrs

B. SHORT ACTING INSULIN SECRETAGENOUS
Mode of Action/Description:
 Stimulates Insulin Secretion is similar way as Sulfonyl Urea.
 Fast acting.
 Stimulates Insulin Secretion more during Meal times.
 Effectively reduces Post prandial Hyperglycemia.
 Have Low Risk of Hypoglycemia and Weight gain.
 Patients who have not responded to sulfonyl urea drugs are not likely to be responded from it also.

Drugs Involved:
a. Nateglinide
b. Rapaglinide
1 NATEGLINIDE 60 to 120mg TID 3- 4 hrs
with Meal

2 RAPAGLINIDE 0.5 to 5mg TID with 3-4 hrs

meal

C. INSULIN SENSITIZERS
“BIGUANIDES”

Mode of Action:
Biguanides are Insulin Sensitizers that “Lowers Plasma Glucose levels by Decreasing Hepatic Glucose
Production(Gluconeogenesis and Glucogenolysis)”
 Considered as “Peripheral Insulin Sensitizers”
 Lowers “Lipid Levels”
 Decreases GI absorption of Nutrients.
 Increase “B-Cells sensitivity to circulating Insulin”
 Decrease “Levels of Plasminogen Activator Inhibitor-I.
 Metformin is only Biguanide available that has features as:
a. As effective as Sulfonyl urea
b. Can be added with other oral hyper glycemic drugs as well as Insulin
c. Don’t cause increase in weight
d. Even promote weight loss by suppressing appetite
e. Produces Adverse effects as:
 GI adverse effects including Diarrhea.
 Vitamin B-12 Malabsorption
 Lactic Acidosis (rare)
 Contraindicated to be used in patients of:
 Renal insufficiency.
 Heart failure
 Metabolic Acidosis.
 Alcoholism

Drugs/Class Involved:
Metformin (Regular release and Extended Release)
1 METFORMIN 500mg O.D to 6-10 hrs
(Regular Release) 1250mg BID

2 METFORMIN 500mg O.D to 2g 24 hrs

(Extended Release) BID

“THIAZOLIDINEDIONES (TZD’S)”
Mode of Action:
Thiazolidinedione are Insulin Sensitizers that “Decrease Peripheral Insulin Resistance by Binding to specific Nuclear
receptor present at Fat cells (Peroxisome-Proliferator-Activated-Receptor Y)that is involved in Transcription of genes
involved in glucose and lipid metabolism”

 Considered as “Peripheral Insulin Sensitizers”

 Increase “HDL levels”
 Lowers “Triglycerides”.
 Anti-inflammatory and Anti atherosclerotic effect”
 As effective as Sulfonyl urea
 Produces Adverse effects as:
 Liver failure
 Peripheral Edema in Patients taking Insulin
 Weight gain due to increase in Adipose tissues.
 Increased risk of:
 MI.
 Heart failure
 Stroke

Drugs/Class Involved:
Metformin (Regular release and Extended Release)
1 PIOGLITAZONE 15 to 45mg O.D 24 hrs
2 ROSIGLITAZONE 2 to 8mg O.D 24 hrs  Produces Adverse effects as:
 Liver failure
 Peripheral Edema in
Patients taking Insulin
 Weight gain due to
increase in Adipose
tissues.
 Increased risk of:
 MI.
 Heart failure
 Stroke

“a- GLUCOSIDASE INHIBITORS (API’S)”

Mode of Action:
API’z are Insulin Sensitizers that “Competitively Inhibits Hydrolytic enzymes that are involved in Ingestion of dietary
Carbohydrates as result of which Carbohydrates are absorbed more slowly that helps in Lowering post-prandial blood
glucose levels”
 Least effective as any other Oral hyperglycemic drug.
 Can be used in Combination with other oral hyper glycemic drugs
 Produces Adverse effects as:
 Dyspepsia
 Flatulence
 Diarrhea
Drugs/Class Involved:
a. Acrabose
b. Miglitol

1. MIGLITOL 25-100mg TID with 6 to 10 hrs

meal
2 ACARBOSE 25-100mg TID with 6 to 10 hrs
meal

“DIPEPTIDYL PEPTIDASE-4 INHIBITORS (DPI-4)”

Mode of Action:
DPI’z are Insulin Sensitizers that “Blocks Glucagon Like Peptide-I Receptors(GLP-1) by Inhibiting the Enzyme
Dipeptidyl Peptidase-4 Inhibitor ”

 Low risk of hypoglycemia.

 Can be used alone or in Combination with other oral hyper glycemic drugs
Drugs/Class Involved:
a. Sitagliptin
b. Saxagliptin
1 SITAGLIPTIN 100mg O.D 24 hrs Dose reduced upto 25mg for patients of
Renal insufficiency.
2 SAXAGLIPTIN 2.5 to 5mg O.D 24 hrs Dose reduced upto 2.5mg for patients of
Renal insufficiency.
“GLUCAGON LIKE PEPTIDE-1 AGONIST (GLP-1 AGONIST)”

Mode of Action:
GLP-1’z are Insulin Sensitizers that “Blocks Glucagon Like Peptide-I Receptors(GLP-1) by Inhibiting the Enzyme
Dipeptidyl Peptidase-4 Inhibitor ”

Drugs/Class Involved:
a. Exenatide
b. Liraglutide

1 EXENATIDE 5-10 ug by S.C  Low risk of hypoglycemia

2 LIRAGLUTIDE
before meal BID  May reduce weight
 Used with Sulfonyl urea,
Metformin or both
 Increased risk of pancreatitis
 Starts with 5ug dose initially
 Nausea is most common side
effect.
1.2 to 1.8 mg by S.C  Increased risk of pancreatitis
O.D  Increased risk of Thyroid cancer