INSULIN THERAPY IN

TYPE 2 DIABETES

Dharma Lindarto.
Div. Endokrinologi-Metabolik Bgn Penyakit Dalam FK USU/RSUP
HAM Medan

Secondar
y Failure

24-hr insulin profiles in normal, IGT

& late Type 2 diabetic subjects
160

Insulin (U/mL)

140
120
100
80
60

IGT
Early Type 2

40

Type 2 diabetes

20

Normal

0
0800

1200

1600
2000
Clock time (hours)

Polonsky KS et al. Horm Res 1998; 49: 17884.

2400

0400

Insulin Therapy in Type 2 Diabetes

Most patients with type 2 diabetes will eventually

need insulin.

As insulin deficiency progresses, a more

physiologic multi-component insulin regimen will
be required to adequately replace normal insulin
secretion.
- Basal insulin
- Meal-Related (prandial, bolus) insulin

Indications for Insulin Therapy

in Type 2 Diabetes
Severe hyperglycemia at glucose toxicity
To meet glycemic goals
Hyperglycemia despite maximum doses of
oral agents
Most patients with type 2 diabetes will
eventually need insulin

Profiles of Human Insulins and

Analogs
Aspart, lispro (46 hours)
Regular (610 hours)
Plasma insulin levels

NPH (1220 hours)

Ultralente (1824 hours)
Glargine (20-26 hours)

10

12

Hours

14

16

18

20

22

24

Sources of Insulin for Clinical Use

Human insulin produced by recombinant
technology has replaced bovine and porcine
insulin preparations

Available as 100 or 500 U/ml

labeled U-100 or U-500
Most available without prescription
exceptions- U-500, lispro, and glargine

Insulin Preparations

Insulin associates as hexamers in solution

The rate-limiting step for capillary absorption is the
subcutaneous dissociation into dimers and then
monomers

Insulin preparations are formulated to differ in

their peaks and durations of action on the
basis of factors which alter this rate of
dissociation

Bolus Insulin
(Mealtime or Prandial)
Limits hyperglycemia after meals
Immediate rise and sharp peak
at 1 hour
10-20% of total daily insulin
requirement at each meal

Basal Insulin
Suppress glucose production
between meals and overnight
Varying temporal levels based
upon individual physiology
50% of daily insulin needs

Protocol for adding insulin to

oral agent therapy

Continue oral agent but reduce SU to 50% maximum

dose if using NPH at bedtime or
premixed insulin at dinner, or to 25% if using
glargine at bedtime
Begin with single dose of 10 U in the evening
(or may go to 0,15 U / kg) :
NPH at bedtime
Glargine at bedtime
70 / 30, 30 min before dinner

Humalog mix 75 / 25 not more than 10 min

before dinner
Measure the morning (fasting) BG daily
Increase the insulin weekly by :
2 U if FBG is > 120 mg / dl
4 U if FBG is > 160 mg / dl
The goal is to have the morning glucose 90 130
mg / dl > 50% of the time if possible with no
symptomatic hypoglycemia

Basal Hyperglycaemia Contributes More to

Increased HbA1c Levels Than Does Postprandial Hyperglycaemia
Uncontrolled Diabetes HbA1c 8%
Basal hyperglycaemia
contributes ~2%

Plasma glucose (mg/dL)

300

Post-prandial
hyperglycaemia
contributes HbA1c ~1%

200

Post-prandial
hyperglycaemia
Fasting
hyperglycaemia

100

Normal
HbA1c ~5%

0
6

12

18
Time of day (h)

B=breakfast; L=lunch; D=dinner.

Adapted from Riddle MC. Diabetes Care. 1990;13:676-686.

24

Treating Basal Hyperglycaemia

Lowers the Entire 24-Hour Plasma
Glucose Curve
Meal

Meal

Meal

Diabetic (untreated)

300

20
15

200

10

100

5
Normal
0

0
6

10

14

18

22

Time of day (h)

Comparison of 24-hour glucose levels in control subjects vs patients with diabetes (P<0.001).
Adapted from Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.

Plasma glucose (mmol/L)

Plasma glucose (mg/dL)

400

Treating Basal Hyperglycaemia

Lowers the Entire 24-Hour Plasma
Glucose Curve
20
300
Meal

Meal

Meal

200

Diabetic
(after
treatment)
Diabetic
(after treatment)

100

15
10
5

Normal
0

0
6

10

14

18

22

Time of day (h)

Adapted from Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.

Plasma glucose (mmol/L)

Plasma glucose (mg/dL)

400

Insulin Preparations

Ultrafast/ultra short-acting: insulin lispro

lysine [B28], proline [B29]
Insulin
lispro

PRO
LYS
LYS
PRO

Ultrafast/ultra short-acting insulin

Insulin lispro
monomeric
not antigenic
the most rapidly acting insulin
used within 15 minutes of beginning a meal
short duration of action- must be used with
longer-acting preparation for Type 1 diabetes
unless used for continuous infusion

Short-acting insulin

Regular insulin (insulin injection)

denoted on vial by R

zinc insulin crystals in a neutral, nonbuffered,

suspending solution

can be given I.V.

Intermediate-acting insulin

NPH insulin (Neutral protamine Hagedorn,

isophane insulin suspension)
denoted on vial by N
stoichiometric mixture of regular and protamine
zinc insulin (complexed with excess of positively
charged fish sperm protamine)
LENTE insulin (insulin zinc suspension)
denoted on vial by L
30% SEMILENTE insulin (amorphous precipitate
of insulin with zinc in acetate buffer)
70% ULTRALENTE insulin

Long-acting insulin

ULTRALENTE insulin (extended insulin zinc

suspension)
denoted on vial by U
delayed onset
prolonged action
acetate buffer
excess zinc large crystals with low solubility

Ultra long-acting insulin

Insulin glargine
Recombinant insulin analog that precipitates in the neutral
environment of subcutaneous tissue
Peakless- prolonged action
Administered as single bedtime dose

Insulin
glargine

ASN
GLY

ARG
ARG

Insulin treatment regimens

Conventional insulin treatment

1 or 2 daily subcutaneous injections

mixture of short- and intermediate or long-acting
insulins

e
br

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a
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di
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total

ak
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br

s
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regular
lente
4

12

12

12

Other Factors Affecting Insulin

Pharmacokinetics

Method of injection
Standard- subcutaneous
Intradermal- poor absorption
Intramuscular - accelerated absorption
Rate of blood flow through injection site
Site of injection
absorption from abdomen or buttock faster
than from thigh or deltoid
Ambient temperature
Exercise

Guidelines for Starting Insulin

Insulin therapy is indicated if the following
measures fail to achieve glycaemic targets:

Maximum tolerated dose of Oral

Hypoglycaemic Agents (OHA)

Failure to reach glycaemic targets (6/12)

Remediable factors considered (e.g. food

and exercise plan, intercurrent problems)

Targets for glycaemic control

in Type 2 diabetes
Fasting/preprandial BG*
Postprandial BG*
HbA1c

< 6.0 mmol/L

< 7.7 mmol/L
< 7.0 %

* Self-monitored blood glucose

A Desktop Guide to Type 2 Diabetes Mellitus, European Diabetes Policy Group 1999

How to START insulin

therapy

If

more than 30-36 IU of insulin necessary to

obtain good metabolic control, consider stopping
insulin secretagogues and continue on same total
dose of insulin + metformin or actos
Divide

the dose into 2 daily injections:

2/3 before breakfast
1/3 at bedtime

Start insulin twice a day

Replacement TherapyTwice Daily Insulin

2/3 Daily dose given

in the morning

1/3 Daily dose given

in the evening

Continuous IV Insulin
In Hospital Setting

Why ?
Randomized prospectively design trials
Retrospective analysis of datae
Support the use of IV insulin
infusion
Reduced morbidity & mortality,
length of
stay, cost

INDICATION

Diabetic ketoacidosis
Nonketotic hyperosmolar state
Critical care illness
Myocardial infarction and Cardiogenic shock
Postoperative period (Cardiac surgery)
Type 1 DM (fasting)
General perioperative care (organ
transplantation)

Indication ( contd)

Total Parenteral Nutrition

Hyperglycemia due to high dose corticosteroid
therapy
Failure of SC insulin

When to Start ?

Perioperative Care
Surgical ICU Care
Non Surgical illness
Pregnancy

> 140 mg/dl

> 110-140 mg/dl
> 140-180 mg/dl
> 100 mg/dl

Glucose Target Range

Critically ill surgical pts : 80-110 mg/dl

Other surgical + non surgical pts : 90

140 mg/dl

Woman during labor and delivery : 70

100 mg/dl

Protocol should be

Effective with minimal risk of

hypoglycemia
Easily used in all hospital units
Easily implemented
Cost effective

How To

Mixing Regular Insulin with 0,9% NS in 1

: 1 or 1 : 2 ratio (250 U / 250 ml or 125
U / 250 ml)
Peggybacked into IV fluid line, 40 ml/hr
Pump ~ 0,1 U / hr
Bedside monitoring (one hourly until
stable, then two hourly)

Protocol of Van den

Berghe

TEST

BG ON ENTRY TO ICU

MEASURE BG EVERY 1 2h
WITHIN NORMAL RANGE

BG RESULT

> 220 mg/ dl

110 220 mg / dl
< 110 mg / dl

> 140 mg / dl
110 140 mg / dl
APPROACHING
NORMAL RANGE

ACTION

START INSULIN 2 - 4 U / h
START INSULIN 1 2 U / h
DO NOT START INSULIN, CONTINUE BG
MONITORING EVERY 4 h
INSULIN DOSE BY 1 2 U / h
INSULIN DOSE BY 0,5 1 U / h
ADJUST INSULIN DOSE BY 0,5 1 U / h

TEST

BG RESULT

MEASURE GLUCOSE EVERY 4 h

APPROACHING NORMAL RANGE

ADJUST INSULIN DOSE BY

0,5 1 U / h

NORMAL

INSULIN DOSE UNCHANGED

DECLINING STEEPLY

INSULIN DOSE BY HALF

CHECK BG MORE FREQ.
INSULIN DOSE, CHECK BG
WITHIN 1 h
STOP INSULIN, ENSURE
ADEQUATE GLUC INTAKE,
CHECK BG WITHIN 1 h
STOP INSULIN, ENSURE
ADEQUATE GLUC INTAKE,
ADM 10 G GLUCOSE IV
CHECK BG WITHIN 1 h

60 80 mg / dl
40 60 mg / dl

< 40 mg / dl

ACTION

Risk

Hypoglycemia : < 40 mg/dl (2,6%-5,2%)

Correction :
(100 current BG) X 0,4 = ml D50
(D50 = 1,25 D40) X 0,5
Target : 100 mg/dl
Every 25 g Glucose, BG 125 mg/dl

Conversion from IV to
SC
Condition : volume resuscitation/

pressor support has been discontinued,

resume eating, stable BG in target
range (6 8 hrs)
Consist of :
Basal SC insulin
Nutritional SC insulin
Correction SC insulin

IV insulin continue 2 hrs ( to avoid

ketoacidosis)
SC total daily dose (TDD) = 80% total daily
iv insulin dose
Basal dose = 50% TDD
Bolus dose (nutritional) = part of 50% TDD
Correction dose = (current BG target BG)
: CF (correction factor)
CF = 1700 : TDD

Transition from IV to SC insulin

Average 2 U / h IV during previous 6 h.
Recommended doses are as follows :
SC TDD = 80% of 24 h insulin requirement :
80% of ( 2 U x 24 = 48 U ) 38 U
Basal dose is 50% of SC TDD :
50% of 38 U 19 U of long acting analogue
Bolus total dose is 50% of SC TDD :
50% of 38 U 19 U of total prandial rapid

acting analogue or ~ 6 U with each meal

Correction dose is actual BG minus target BG,
divided by correction factor (CF)
CF is equal to 1700 divided by TDD :
CF = 1700 : 38 ~ 40 mg/dl
Correction dose = ( BG 100 ) : 40

Future directions in insulin therapy

Inhalable insulin- Phase III

Oral insulin- modified with amphiphilic polymers to prevent

enzymatic digestion and facilitate uptake; Phase II

use for postprandial glucose load

in combination with ultralente or glargine for basal insulin

use in combination with ultralente or glargine as above

Gene therapy
glucose responsive promoters
glucose responsive cell types
Artificial pancreas: sensor, pump, control system

Summary

Early and aggressive treatment of Type 2 diabetes to

improve glycaemic control decreases the risk of long-term
complications
Type 2 diabetes is a progressive disease: progressive loss
of beta cell function is observed during the natural course
of the disease
Insulin treatment should be initiated when near
normalization of blood glucose cannot be achieved with
OHAs
Continuous IV Insulin,Reduced morbidity &
mortality, length of stay, cost