management of type 2 diabetes focus on insulin therapy

Management of Type 2
Diabetes: Focus on Insulin
Therapy

International Diabetes Center


Presentation Overview
• Insulin secretion
– Beta-cell decompensation
• Insulin
– Types of Insulin (Basal and Bolus)
– Action times
– Insulin Analogs
• Insulin Regimens
– Rationale for selecting certain types of insulin
regimens
– Adjusting Insulin
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% of
Normal Function

Glucose (mg/dL)

Metformin
Thiazolidinediones
Medical
Nutrition
350

300
250
200
150
100
50

250
200
150
100
50
0

Secretagogue
Post Meal Glucose
Fasting Glucose

(11.1 mmol/L)
(7.0 mmol/L)

Most individuals with type 2
diabetes will eventually
require insulin therapy
Insulin Resistance
Insulin Level
At risk for Diabetes

-10

-5

Beta cell dysfunction

0

5

10

15

20

25

30

Years of Diabetes

Adapted from: UKPDS 33: Lancet 1998; 352, 837-853 DeFronzo RA. Diabetes. 37:667, 1988.
Saltiel J. Diabetes. 45:1661-1669, 1996. Robertson RP. Diabetes. 43:1085, 1994.
Tokuyama Y. Diabetes 44:1447, 1995. Polonsky KS. N Engl J Med 1996;334:777.

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Insulin Use in Type 2 Diabetes
• Insulin utilized to overcome both relative insulin
deficiency and insulin resistance

• Purpose of insulin regimen is to mimic normal insulin
secretion patterns
• Approximately 40-50% of patients will require insulin
for glycemic control
• Start dose conservatively and adjust dose based on
patterns of BG
– High dose insulin (>1.0 U/kg) often required to
overcome insulin resistance
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Insulin Processing
PC2 Endopeptidase

A-chain

C-peptide

Proinsulin
B-chain

Mature
Insulin

S

PC3 Endopeptidase

S

1

21
S
S

1

S
S

+

C-peptide

30

Insulin supplied in vial or cartridge
DiMarchi et al., Peptides-Chemistry and Biology 1992:26-28.
Howey et al., Diabetes 1994;43:396-402.

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Overcoming Insulin Resistance
Insulin
Glucose
G
G G
G GG

G G
G G
G

G

Nucleus

G

Insulin
Receptor
Glucose
Transporter
(GLUT4)

Insulin Sensitive Cell
(Muscle or Fat)

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Normal Insulin Secretion
Serum insulin (mU/L)

Meal

Meal

Meal

50
40

Bolus insulin needs

30
20
10

Basal Insulin Needs

0
0

2

4

6

8

10

12

14

16

18

20

22

24

Time (Hours)
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Insulins
Types

Examples

Bolus (Meal) Insulin
Rapid-acting
Short-acting

Insulin lispro, Insulin aspart
Regular

Basal (Background) Insulin
Intermediate-acting
Long-acting

NPH, Lente
Glargine

Pre-Mixed Insulin
NPH/Regular
NPL/Lispro
NPA/Aspart

70/30, 50/50
Mix 75/25
Mix 70/30

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Bolus/Pre-meal Insulin
Type of Insulin
Rapid-acting

Onset

Peak

Monitor effect at:

5-15 mins

1-2 hrs

2 hrs

30-45 mins

2-3 hrs

4 hrs

(Lispro, Aspart)

Regular

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Advantages of Rapid Acting
Insulin Analogs
• Modification of human insulin
– Increased rate of subcutaneous absorption
(more physiological)
• Reduced rates of hypoglycemia
• Convenience - increased flexibility
– Taken with meal (onset of action ~ 10 minutes)
– Reduced risk of exercise-induced hypoglycemia
– Limits need for snacks
– Can be used to cover snacks
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Basis of Insulin Selection
Short-Acting Vs. Rapid-Acting
Regular insulin best for
patients who:

1. Generally consume
between meal snacks
2. Eat inconsistently
throughout the day
(“grazers”)
3. Who delay start of meal
after insulin injection

Rapid Acting insulin best
for patients who:
1. Desire increased
flexibility or who vary
CHO intake
2. Don’t desire consistent
snack
3. Have either routine or
sporadic exercise
4. Desire injection
immediately pre-meal
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S

S

1

Insulin Lispro

21

A-chain
S

S
S

S

B28 B29
LYS PRO

1

30

B-chain
S

S
21

1

Insulin Aspart

A-chain
S
1

B-chain

S

S
S
B28
ASP

30

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Free Insulin (pmol/L)

Lispro vs. Aspart Insulin Levels
After 10 Unit Subcutaneous
Injection
in Type 1 Diabetes

350
300

Lispro insulin

250

Aspart insulin

200
150
100
50
0

7

8

1
Time (Hours) 0
9

11

1
2

1
3

Hedman C et al. Diabetes Care. 2001;24:1120-1121 (abstract #465)
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Basal Insulin
Insulin

Onset

Peak

Monitor effect at:

NPH/Lente

2-4 hrs

4-8 hrs

8 - 10 hrs

2 hrs

No peak

12-24 hrs

Glargine

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Glargine

S

S

1
S
S
1

S
S

• Less soluble than regular
insulin at physiologic pH
Gly
• Once daily PM injection
• Constant concentration
profile over 24-hours (No
peak activity)
Arg Arg • No pre-mixing

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Glucose
Utilization Rate

(mg/kg/min)

Glargine: Activity Profile
(Hourly Mean Values)

6

5

Insulin Glargine

4

NPH insulin

3
2
1
0
0

10
20
Time (h) after subcutaneous
injection

Lepore et al. Diabetes 1999;48(suppl 1):A97. Abst 416; Study 1015

30
=End of observation
period

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Relative Insulin Effect

Insulin Time Action Curves
Rapid (Lispro, Aspart)
Short (Regular)
Intermediate (NPH)

Long (Glargine)

0

2

4

6

8

10

12

14

16

18

20

Time (Hours)

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Insulin Regimens
• Combination Oral Agent-Insulin
– Single bedtime injection Glargine or NPH

• Physiologic Insulin Stage 4
– Basal/Bolus Regimen
– 4 or more injections/day

• Conventional (Mixed) Insulin Stages 2 and 3

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Type 2 Master DecisionPath
Entry Criteria

Therapies
Insulin Deficiency:
Symptomatic, Lean

Fasting <<200 mg/dL (11.1 mmol/L)
Fasting 200 mg/dL (11.1 mmol/L)
Casual <<250 mg/dL (13.9 mmol/L)
Casual 250 mg/dL (13.9 mmol/L)
HbA1c
<8%
HbA1c

<8%

Lowers HbA1c

Insulin Resistance:
HTN, Dyslipidemia,
Obesity

Medical Nutrition Stage
Medical Nutrition Stage
Oral Agent Stage
Oral Agent Stage

Fasting 200–300 mg/dL
Fasting 200–300 mg/dL
(11.1 ––16.7 mmol/L)
(11.1 16.7 mmol/L)
Casual 250–350 mg/dL
Casual 250–350 mg/dL
(13.9 ––19.4 mmol/L)
(13.9 19.4 mmol/L)
HbA1c
8-11%
HbA1c
8-11%

Insulin Deficiency
Secretagogues

Fasting >>300 mg/dL (16.7 mmol/L)

Fasting 300 mg/dL (16.7 mmol/L)
Casual >>350 mg/dL (19.4 mmol/L)
Casual 350 mg/dL (19.4 mmol/L)
HbA1c
>>11%
HbA1c
11%

~2%

Combination Oral Agent Stage
Combination Oral Agent Stage
Secretagogue

Note: Each stage requires a preset BG target: and a timeline to
reach that goal

Insulin Resistance
Sensitizers

~1%

+

Sensitizer

Combination Oral Agent/Insulin Stage
Combination Oral Agent/Insulin Stage

~2-4%

Oral Agent + Insulin

Physiologic Insulin Stage 4
Basal/Bolus Insulin
RA - RA - RA - G

> 4%

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Selecting an Insulin Regimen
Consider Combination Oral Agent Insulin or
Insulin Stages 2 or 3 if:
–
–
–
–

Consistent in schedule/routine
Exhibiting barriers to insulin initiation
Overwhelmed with insulin initiation
Opposed to multiple insulin injections

– Unable/unwilling to take a noon injection

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Selecting an Insulin Regimen
Consider Physiologic Insulin Stage 4 if:
–
–
–
–
–
–

Desires more schedule flexibility (travel)
Desire to improve glycemic control
Works rotating shifts
Varies food intake in time/amount (skips meals)
Willing to test post-meal BG
No barriers to more intensive regimen

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Transition from Oral Agent Therapy to
Oral Agent plus Insulin
• Oral Agent and Basal Insulin
– No kidney or liver disease
– HbA1c <11%
– Fasting BG > 126 mg/dL (7.0 mmol/L)
– Post prandial BG < 160 mg/dL (8.9
mmol/L)
– Patient resistance to multiple injections
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Combination Oral Agent and
Combination Oral Agent and
Insulin Stage
Insulin Stage
OA – 0 – (OA) – G or N
OA – 0 – (OA) – G or N

•
•
•
•
•
•

Maintain oral agent(s)
– Sulfonylurea, Metformin or Thiazolidinedione
Start Bedtime Glargine (or NPH)
– 0.1 U/kg Total Daily Insulin Dose
Target fasting blood glucose < 120 mg/dL (6.7 mmol/L)
Increase by 1-4 U based on patterns of blood glucose
Max. dose is 0.4 U/kg at bedtime
Start pre-meal/bolus insulin based on PPG patterns >160 mg/dL
(8.9 mmol/L)

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Secretagogue + Insulin

Secretagogue

Pancreas
• Increased and
supplemental insulin
secretion

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Combination Sulfonylurea (S) and
Combination Sulfonylurea (S) and
Glargine (G) Insulin Stage
Glargine (G) Insulin Stage
S–0–0–G
S–0–0–G

Serum insulin (mU/L)

Sulfonylurea stimulated
insulin secretion

50

Glargine
(0.1 U/kg)

Glimepiride
( 4 mg)

40
30
20

Glargine

10
0
0

2

4

6

8

10

12

14

16

18

20

22

24

Time of Day
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