Insulin in patients not controlled on

Oral Medication

Asso Prof Wong YO

Natural History of Type 2 Diabetes
Severity of Glucose Intolerance
NGT IGT Frank
Diabetes Insulin
Resistance

Worsens with
Insulin Secretion Time
Postprandial Glucose
Fasting Blood Glucose

Normal Blood
Glucose
Risk of Microvascular Complications

Risk of Macrovascular Complications

Years to
Decades Typical Diagnosis of Diabetes
 ‘Diabesity’
Diabetes and obesity – ‘diabesity’ – are twin, interrelated
epidemics that threaten to engulf the world’s healthcare systems

90% of type 2 diabetes is associated with weight gain

in western countries1
This is driven further by childhood obesity
Diabetes and obesity together increase risk of death
by ~7-fold vs. those with no medical conditions2
58% of type 2 diabetes globally is caused by having
a body mass index (BMI) >21 kg/m2 2,3

1. Hossain et al. N Engl J Med 2007;356:213–5; 2. Oldridge et al. J Clin Epidemiol 2001;54:928–34;
3. IDF Diabetes Atlas. Second edition 2003
 The risk of type 2 diabetes increases
with BMI

Chan et al. Diabetes Care 1994;17:961; Colditz et al. Ann Intern Med 1995;122:481
Abdominal obesity increases the risk of developing type
2 diabetes

BMI, body mass index

Carey. Am J Epidemiol 1997;145:614–9

 Benefits of modest weight loss in
type 2 diabetes

BP, blood pressure; CVD, cardiovascular disease; HDL-C, high density lipoprotein cholesterol;
LDL-C, low density lipoprotein cholesterol; TC, total cholesterol; TG, triglycerides

1. Anderson and Konz. Obes Res 2001;9(Suppl. 4):326S–34S;

2. Anderson et al. J Am Coll Nutr 2003;22:331–9
 The Ominous Octet
Islet  -cell

Decreased
Incretin Effect
Increased
Impaired Lipolysis
Insulin Secretion

Islet  -cell

Increased Increased Glucose

Glucagon Secretion Reabsorption

Increased
Decreased Glucose
HGP
Neurotransmitter Uptake
DeFronzo Diabetes 2008
Dysfunction
The Ideal Regime is Basal Bolus but its
complexity can reduce adherence & lead to
suboptimal treatment
Basal insulin injection with pre prandial
injections:
 2 insulins, 2 devices, multiple injections at different
times of the day

Time
The rapid early rise of insulin secretion in
response to a meal is critical,

because
 it ensures the prompt inhibition of endogenous
glucose production by the liver
disposal of the mealtime carbohydrate load, thus
limiting postprandial glucose excursions.
 Types of Insulin
1. Rapid-acting (Analogs: Aspart, Lispro)
2. Short-acting (Regular Human Insulin)
3. Intermediate-acting (NPH, lente)
Neutral Protamine Hagedorn

4. Premixed (70/30) 70% intermediate-acting insulin and

30% short-acting insulin

5. Long-acting (UltraLente)
6. Extended long-acting (Lantus, Levemir)
7. Ultra long acting (Degludec) 24 hr
 Neutral Protamine Hagedorn

became interested in modifying the absorption rate of insulin. He was aware that contaminating proteins slowed the
absorption of insulin into the bloodstream, but these caused irritation and side effects. Thus he searched for a protein that
would not cause any irritation. He came upon protamine, a protein isolated from fish sperm. Hagedorn discovered that the
addition of protamine to insulin caused the insulin to form microscopic clumps. These clumps took longer to dissolve into the
bloodstream. This complex of protamine and insulin is known as NPH insulin.

Who or what does NPH stand for?

We stand on the shoulders of giants, never forget that!
So who or what is Hagedorn?
What i teach includes respect and honesty!!
Do NOT ever forget that
 All Type 1 diabetics should be on a
basal / bolus insulin regimen
to control glucose while minimizing hypoglycemia

LADA 4 years later

anti gad
 Indications for Insulin Use in Type 2 Diabetes
Pregnancy (preferably prior to pregnancy)
Acute illness requiring hospitalization

Perioperative/intensive care unit setting

Postmyocardial infarction

Inability to tolerate or contraindication to oral antiglycemic agents

Newly diagnosed type 2 diabetes with significantly elevated blood

glucose levels (pts with severe symptoms or DKA)

Patient no longer achieving therapeutic goals on combination

antiglycemic therapy
Why do people on insulin gain weight?

Compensation for hypoglycaemia

by overeating1
Reduced glycosuria (reduced calorie
‘wastage’)2
Anabolic (fat- and muscle-building) effects
of insulin in peripheral tissue3
Insulin may have altered action on the
central nervous system (CNS) to influence
food intake4
diabetic baby pancrease produce a lot of insulin
Dissociation of Regular Human
Insulin

Regular Human Insulin

10-3 M 10-3 M 10-5 M 10-8 M peak time

2-4 hr

  

formulation hexamers dimers monomers

capillary membrane

www.diabetesclinic.c 22
Rapid-acting Insulin Analogues: Lispro and Aspart

400 500 Aspart

Lispro 450
350
Plasma Insulin (pmol/L)

Plasma Insulin (pmol/L)

400
300 350
250 300
200 250
Regular 200
150 Human
150
100 Regular
100 Human
50 50
0 0
0 30 60 90 120 150 180 210 240 0 50 100 150 200 250 300
Time (min) Time (min)

Meal Meal
SC injection SC injection

Heinemann, et al. Diabet Med. 1996;13:625-629; Mudaliar, et al. Diabetes Care. 1999;22:1501-
1506.
6-28
Rapid-acting Analogues: Clinical Features

• Insulin profile more closely mimics normal physiology

• Convenient administration immediately prior to meals
• Faster onset of action
• Limit postprandial hyperglycemic peaks
• Shorter duration of activity
– Reduced late postprandial hypoglycemia
– But more frequent late postprandial hyperglycemia

6-27
zinc
long acting
Limitations of Human NPH, Lente, and Ultralente

• Do not mimic basal insulin profile

– Variable absorption
– Pronounced peaks
– Less than 24-hour duration of action

• Cause unpredictable hypoglycemia

– Major factor limiting insulin adjustments
– More weight gain
Ultralente
Injected once or twice daily
Onset within 6–8 hours
Peak effect within 10–20 hours
6-30
 Types of Insulin Bi-aspart
Novomix 30 contains a mix of two types of insulin, 30%
soluble insulin aspart and 70% insulin aspart crystallised
with protamine. This combination of insulins is called
biphasic insulin aspart.
Soluble insulin aspart is a rapidly-acting insulin. It works
quickly, within 10 to 20 minutes, and its effects last for
about three to five hours.
Protamine-crystallised insulin aspart is an intermediate-
acting insulin. It takes longer to act, but its effects last much
longer.
The pre-mixed combination provides a rapid initial blood
glucose lowering effect, followed by a prolonged effect that
controls blood glucose throughout the day.
The dual-release insulin concept:
aspart and degludec
 The dual-release insulin concept:
NovoMix® 30 targets both PPG and FBG

Plasma insulin level

Physiological insulin
profile:2
 Basal component
 Meal-related peaks

NovoMix® 30 profile:2
 Basal component
 Meal-related peaks

Basal component
profile2 Time
Effect of Insulin on Triglyceride
and HDL-C Levels
2 0.34 mmol/l 1.5 0.22 mmol/l
(30mg/dl)
(19.4mg/dl)
Tryglyceride level (mmol/l)

p=0.07
p=0.07
1.8 1.85 n=15 1.4 n=15
1.39

HDL-C (mmol/L)
1.6 1.3

1.51
1.4 1.2

1.17
1.2 1.1

1 1
Baseline Month 9 Baseline Month 9
Triglycerides HDL-C

Adapted from Nathan DM et al. Ann Int Med 1988;108:334-40.

When Oral Medications Are Not Enough

• Watch for the following signs

•Increasing BG levels
•Elevated A1C
•Unexplained weight loss
•Traces of ketonuria
•Polydipsia
• Next steps
•Make a decision to start insulin

Remind the patient of disease progression…

 Step One: Initiating Insulin
• Start with
– Bedtime long-acting insulin in combination with Oral drugs
– BIDS
Adding basal insulin to oral agents is simple to implement, well
tolerated, and highly effective -- particularly for patients with A1C
levels between 7.0% and 10.0%

Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

Step One: Initiating Insulin, cont’d
• Check fasting glucose and increase dose until
in target range
– Target range: 3.89-7.22 mmol/l (70-130 mg/dl)
– Typical dose increase is 2 units every 3 days, but if
fasting glucose >10 mmol/l (>180 mg/dl), can
increase by larger increments (e.g., 4 units every 3
days)

Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

 Step One: Initiating Insulin, cont’d
• If hypoglycemia occurs or if fasting glucose
< 3.89 mmol/l (70 mg/dl)…
– Reduce bedtime dose by ≥4 units or 10%
if dose >60 units Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

Reduction in overnight and fasting glucose levels achieved

by adding basal insulin may be sufficient to reduce
postprandial elevations in glucose during the day and
facilitate the achievement of target A1C concentrations.

While using basal insulin alone, continue ongoing oral therapy

Starting With Basal Insulin: Advantages

• 1 injection with no mixing

• Slow, safe, and simple titration
• Low dosage
• Limited weight gain
• Effective improvement in glycemic control

6-37
Starting with Basal Insulin
• Continue oral agent(s) at same dosage
• Add single, evening insulin dose (around 10 U)
– Glargine/ Levemir (bedtime)
or
– 70/30 (evening meal) or 75/25
• Adjust dose by fasting BG
• Treat to target (usually <120 mg/dL, 6.6mmol/l)

6-59
 After 2-3 Months…
• If HbA1c is <7%...
– Continue regimen and check HbA1c every 3 months

• If HbA1c is ≥7%...
– Move to Step Two…

Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

With the addition of basal insulin and titration
to target FBG levels, only about 60% of
patients with type 2 diabetes are able to achieve
A1C goals < 7%.

In the remaining patients with A1C levels

above goal regardless of adequate fasting
glucose levels, postprandial blood glucose levels
are likely elevated.
Managing PPG from the start is important

Patients spend 50% of the 24-hour day in the

postprandial state
Targeting both PPG and FPG is an important
strategy for achieving optimal glycaemic control
 Advancing Bolus/ Adding Prandial Insulin
• Indicated when FBG acceptable but
– HbA1c not at goal and/or
– Postprandial BG not at goal (<140mg/dl)
• Insulin options
– To eg Glargine, add 1 to 3 mealtime Regular or
Lispro/Aspart
– Basal plus 1 to Start with largest Meal

– IF suppertime 70/30 or 75/25, add morning 70/30 or 75/25

• Oral agent considerations
– Usually stop secretagogue when Basal plus 3 (it is redundant to be on insulin and
secretagogue)
– Continue metformin, DPP4i, SGLT2i and TZD for additional glycemic and
other benefits 6-60
Starting patients on NovoMix® 30
or Rysodec is simple
 How much Insulin do we need?
First calculate the estimated total
daily requirement of insulin

Body weight in kgs / 2

• e.g. an 80 kg person will require roughly about

40 units / day; but start Low
Keeping in mind that stress, infection, insulin
resistance, all affecting this value.
 Dose adjustment…contd.
• Once the fasting blood glucose has been controlled,
check 6-Point blood sugar as follows:

– Fasting.
– 2 hours after breakfast.
– Before lunch (and noon insulin)
– 2 hours after lunch.
– Before dinner (AND EVENING INSULIN)
– 2 hours after dinner
Dose adjustment…contd.

• For example in Basal Bolus regime:

a high post lunch reading will require
adjustment of the pre-lunch regular
insulin on the next day to bring down
raised reading to the required levels.
 Pre Mixed Insulin BD
• Problem: Remember that BD dosing may fail
to cover lunch, especially if it is heavy.
• So Always check for post lunch hyperglycemia
when using this regimen.
• Solution:
1. Patients can be advised to take their lunch
(heavier meal) at breakfast; and breakfast
(lighter meal) at lunch.
2. Adding Glucobay with lunch some times provides
a reasonable control.
I

N Insulin Use
S
• Regular/Analog and NPH used twice daily the commonest
U
regimen used.
L
• Lunch is a big meal usually but no insulin dosing.
I

N 25 0

I 15 0

N
50
6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5

E Diabetic week day

25 0

T
15 0

I
50
6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5

N
I

N Hyper-glycemia window
S
Hyperglycemia
U
25 0
Diabetic week day
Window
L

I 15 0

N
50
6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5

Cause:
I
Lack of insulin
N
Lunch effect
J afternoon snacks
E

C
25 0

I
15 0

O
50
6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5

N
 Somogyi phenomenon
• Due to
– excess dose of night time insulin, or
– Night insulin taken early
• Peaks at 3:00 a.m: hypoglycemia
• Counter regulatory hormones released in excess:
• Resulting in over correction of hypoglycemia:
• Fasting hyperglycemia
• Solution:
– Check BSL AT 3 :00 a.m
– Give long acting at 11:00 p.m so peak comes
later
– Reduce dose of night time insulin
I

N Somogyi Phenomenon
S

U 20

I
10
N

I
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
N

E Cause:
C Counter regulatory hormones response to
hypoglycemia at med-night.
T
Increase in hepatic glucose production.
I
Insulin resistance because of the Counter
O
regulatory hormones.
N
 Dawn phenomenon
• Growth hormone surge at dawn raises insulin
requirement.
• Night time insulin taken early, fades out before
dawn.
• Fasting hyperglycemia

Solution
• Give long acting true basal insulin
• May need to increase dose of night time insulin
I

N Dawn Phenomenon
S

U 20

I
10
N

I
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
N

N
 High Insulin doses/
Resistance
Consider occult infections (UTI, abscess,
sinus, etc)
Consider other inflammatory conditions
(periodontal disease, etc)
200-300+ units total daily dose
Obesity
 Pearls for practice

 Bring fasting sugar to normal before trying to control post

prandial / random blood sugar.
 Control any underlying infection/stressful condition
vigorously.
 Keep meal timings regular with 6 hrs between the three
meals.

The quantity and quality of diet should be same at same

timings.

 Ensure proper storage of insulin.

 Sites of injection
• Arms 
• Legs 
• Buttocks 

• Abdomen 

Preferred site of injection is the abdominal wall due

to Easy access
Ample subcutaneous tissue
Absorption is not affected by exercise.
 A. Hypoglycemia
Definition: Glycemia < 3.8 mmol
Patients may experience hypoglycemia at
different glycemic levels

59
 Symptoms of Hypoglycemia
Mild Moderate to Severe
< 3.3 mmol/L < 2.8 mmol/L
Neurovegetative symptoms Symptoms of glucopenia
Sweating Confusion
Trembling Visual disturbances
Palpitations Weakness
Anxiety Speech disorder
Tingling Behavioural disorder
Pallor Drowsiness
Hunger Coma
Convulsions