1. Insulin Therapy
Melissa Meredith, M.D.
2005

2. History of Insulin 1921: Pancreatic extract lowers blood glucose
1922: Insulin extract first used in humans
1925: Crystalline insulin (Regular) developed
1950/51: NPH/lente insulins developed
1982: Human recombinant insulin developed
1997: First insulin analog (lispro)
2001: Introduction of glargine and aspart insulin analogs
2005 (pending FDA approval): Insulin glulisine and insulin detemir

3. Insulin therapy
Control of blood glucose is a balance between insulin therapy, diet and activities
The goal is to keep glucose as near normal as possible
The type of insulin regimen used depends on many factors, e.g. patient age, compliance, patient schedule, etc.

4. Mimicking Nature With Insulin Therapy
Physiologic Insulin Secretion
24-hr Profile 50
Insulin
(µU/mL) 25
Basal Insulin
Breakfast Lunch Dinner
150
Glucose
(mg/dL)
100 50
Basal Glucose 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 AM
Time of Day PM
Skyler JS. In: DeFronzo RA, ed. Current Therapy of Diabetes Mellitus. St. Louis: Mosby- Year Book; 1998: ; Galloway JA, Chance RE. Horm Metab Res. 1994;26:591

5. The Basal/Bolus Insulin Concept
Basal Insulin
Suppresses glucose production between meals and overnight
50% of daily needs
Bolus Insulin (Mealtime or Prandial)
Limits hyperglycemia after meals
Immediate rise and sharp peak at 1 hour
10% to 20% of total daily insulin requirement at each meal
Slide 6-20
MIMICKING NATURE WITH INSULIN THERAPY
The Basal/Bolus Insulin Concept
Insulin is capable of restoring glycemia to nearly normal in most patients with type 2 diabetes. The basal/bolus insulin concept attempts to mimic, with insulin therapy, the patterns that normally control glucose in persons without diabetes. Basal insulin suppresses glucose production so that the levels remain nearly constant between meals and overnight. Basal insulin meets about half of the patient’s daily need for insulin and may be sufficient when considerable endogenous insulin remains. Bolus insulin (10% to 20% of the total daily insulin requirement given at each meal) limits hyperglycemia after meals. This tends to smooth the peaks of glucose that occur in response to these meals. Frequent glucose monitoring aids in determining the candidates for basal or mealtime regimens. Ideally, each component of insulin replacement therapy should come from a different type of insulin with a specific profile to fit the patient’s needs. Practical methods to accomplish this basal/bolus strategy will be illustrated later in this module.
Edelman SV, Henry RR. Insulin therapy for normalizing glycosylated hemoglobin in type II diabetes: applications, benefits, and risks. Diabetes Reviews. 1995;3: ; Kelley DB, ed. Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:56-72.

6. Comparison of Human Insulins and Analogues
Insulin Onset of Duration of Preparations Action Peak Action
Lispro/Aspart 5-15 minutes 1-2 hours 4-6 hours
Human Regular minutes 2-4 hours 6-10 hours
Human NPH/Lente 1-2 hours 4-8 hours hours
Human Ultralente 2-4 hours Unpredictable hours
Glargine 1-2 hours Flat ~24 hours
Slide 6-22
INSULIN TACTICS
Comparison of Human Insulins and Analogues
Insulin has been used therapeutically for more than 70 years. In general, human insulin, synthesized by genetically altered microorganisms, has a more rapid onset of action and a shorter duration of action than previous preparations derived from animal pancreas. Regular human insulin has an onset of action ranging from about 30 to 60 minutes with peak concentrations achieved at between 2 and 4 hours. The “intermediate-acting” insulins, NPH and lente, have gradual onset and peak effects usually between 4 and 8 hours, and a total duration of 10 to 20 hours. Human ultralente insulin is somewhat longer-acting, but still usually falls short of a 24-hour effect. Short-acting insulin analogues (lispro and aspart) have very desirable action profiles at mealtimes because they have an onset of action ranging from 5 to 15 minutes; the peak of action occurs 1 hour after injection, and the insulin effect practically vanishes 4 hours after administration. Insulin glargine is a long- acting analogue insulin that has essentially no peak. Glargine is absorbed within 1 to 2 hours and has a plasma concentration about 50% lower than that observed with NPH, but twice the duration of action.
Bolli GB, Di Marchi RD, Park GD, Pramming S, Koivisto VA. Insulin analogues and their potential in the management of diabetes mellitus. Diabetologia. 1999;42: ; Kelley DB, ed. Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:56-72; Edelman SV, Henry RR. Insulin therapy for normalizing glycosylated hemoglobin in type II diabetes: applications, benefits, and risks. Diabetes Reviews. 1995;3: ; Skyler JS. Insulin therapy in type 2 diabetes mellitus. In: DeFronzo RA, ed. Current Therapy of Diabetes Mellitus. St Louis, Mo: Mosby-Year Book Inc; 1998: ; Riddle MC. Evening insulin strategy. Diabetes Care. 1990;13:
The time course of action of any insulin may vary in different individuals, or at different times in the same individual. Because of this variation, time periods indicated here should be considered general guidelines only.

7. Insulin Action Profiles
140
Rapid acting (lispro, aspart)
120
100
Insulin Level (U/ml)
Short acting (Regular) 80
Intermediate (NPH, Lente) 60
Long acting (glargine) 40 20 2 4 6 8 10 12 14 16
Hours

8. Rapid-Acting Insulin Analogs Insulin Lispro and Insulin Aspart
Human Insulin
Insulin aspart
Aspartate at position B28 instead of proline
A-chain
Gly S 1 S 2
Insulin Aspart
Asp
Ala
Gln
Cys 5 20
Phe
Thr
Gln S
Ile
Insulin Lispro 1
Lys
Pro S
Lys 1
Pro 30 10 15 S
His S
Phe 25 5
B-chain
Gly
Insulin lispro
Positions of proline and lysine reversed at B28 and B29
His
Leu 20 10 15
Fast-acting analogs
Humalog® [package insert]. Indianapolis, IN: Eli Lilly and Company; 2002 NovoLog® [package insert]. Princeton, NJ: Novo Nordisk Pharmaceuticals, Inc;2002

10. Plasma Insulin (pmol/L) Plasma Insulin (pmol/L)
Short-acting Insulin Analogues: Lispro and Aspart Plasma Insulin Profiles
400
500
Aspart
Lispro
450
350
400
300
350
250
300
250
Plasma Insulin (pmol/L)
200
Plasma Insulin (pmol/L)
Regular
200
150
Human
150
100
Regular
100
Human
Slide 6-28
INSULIN TACTICS
Short-acting Insulin Analogues: Lispro and Aspart
Plasma Insulin Profiles
This figure shows two separate experiments displaying the plasma insulin profiles after injection of insulin lispro and insulin aspart in comparison to that of human regular insulin. The experiment with lispro, shown on the left, included 10 patients with type 1 diabetes, and the experiment with aspart shows findings from 18 healthy subjects. Both of these analogues have very rapid onset of action, which allows them to be taken immediately before meals. Both reach a peak about 1 hour after injection, with a decline in baseline levels in 4 hours, closely matching normal insulin patterns. The delayed and extended profile of human regular insulin is seen in both studies, with significant elevations above baseline persisting well beyond 4 hours after injection.
Heinemann L, Heise T, Wahl LC, et al. Prandial glycaemia after a carbohydrate-rich meal in type I diabetic patients: using the rapid acting insulin analogue [Lys(B28), Pro (B29)] human insulin. Diabet Med. 1996;13: ; Mudaliar SR, Strange P, Lindberg FA, et al. Insulin aspart (B28 asp-insulin): a fast-acting analog of human insulin. Diabetes Care. 1999;22: 50 50 30 60 90
120
150
180
210
240 50
100
150
200
250
300
Time (min)
Time (min)
Meal
SC injection
Meal
SC injection
Heinemann, et al. Diabet Med. 1996;13: ; Mudaliar, et al. Diabetes Care. 1999;22:

12. Comparison of bolus insulins
Regular insulin
Requires administration 20 to 40 minutes prior to meal
Mismatch with postprandial hyperglycemic peak
Potential for late postprandial and nocturnal hypoglycemia
Rapid-acting (lispro, aspart, glulisine)
Convenient administration at/after meal
Matches postprandial glycemic peak
Reduced late postprandial hypoglycemia
Frequent late postprandial hyperglycemia
Risk for early hyopglycemia
Slide 6-26
INSULIN TACTICS
Limitations of Human Regular Insulin
The preceding slides illustrate some of the limitations of human regular insulin. If it is given immediately prior to a meal, its onset of action is too slow to match the normal insulin peak and the blood glucose response to the meal is much greater than in a person without diabetes. To improve the relationship between the profile of action of regular insulin and the needs accompanying the meal, patients are routinely advised to administer their injection 20 to 40 minutes prior to the meal. This is inconvenient, is infrequently achieved, and poses the risk of premeal hypoglycemia if the meal is inadvertently delayed. Furthermore, the duration of action of regular insulin is much longer than the normal insulin peak following meals, typically at least 6 hours and up to 12 hours when large doses are injected. This persistence of high insulin levels leads to risk of hypoglycemia, which is often countered by between- meal snacks that foster weight gain in type 2 diabetes patients.

13. Structure Insulin Glargine: 21A-Gly-30Ba-L-Arg-30Bb-L-Arg-insulin
A-CHAIN
Gly
SUBSTITUTION 1 5 10 15 20
Asn 1 5 10 15 20 25 30
B-CHAIN
EXTENSION
Arg
Insulin Glargine Structure
Insulin glargine (21A-Gly-30Ba-L-Arg-30Bb-L-Arg-human insulin) is an insulin analog produced by recombinant DNA technology. Insulin glargine has the same intrinsic activity as regular human insulin. Changes in amino acid content shift the isoelectric point, reducing the aqueous solubility of insulin glargine at physiological pH; and stabilizing the hexamer, delaying its dissociation into monomers. Consequently, insulin glargine has a delayed and prolonged absorption from the injection site following subcutaneous administration.
Insulin Glargine:
21A-Gly-30Ba-L-Arg-30Bb-L-Arg-insulin
Metabolites:
M1-21A-Gly-insulin
M2-21A-Gly-des-30B-Thr-insulin
pH=4; Clear solution; Do not mix

14. Insulin glargine clamp study: activity profile in T1DM30
(Hourly Mean Values)
Time (h) after sc Injection
=End of observation period 1 2 3 4 5 6
Glucose
Utilization Rate
(mg/kg/min)
Insulin Glargine
NPH insulin 20 10
PK/PD of Insulin Glargine Glycemic Clamp Study in T1DM
In contrast to NPH, insulin glargine had a peakless, long-lasting concentration/action profile closely mimicking a “square wave” shape. The investigators concluded that insulin glargine has more reproducible pharmacokinetics than NPH insulin.
Lepore et al. Diabetes 1999;48(suppl 1):A97. Abst 416; Study 1015
Lepore et al. Diabetes 1999;48(suppl 1):A97. Abst 416; Study 1015

15. Comparison of basal insulins
NPH/lente
Pronounced peaks
Less than 24-hour duration of action-requires BID dosing
Increased risk of hypoglycemia if meal delayed
Increased nocturnal hypoglycemia
Glargine
Usually once-a-day dosing
Flat peakless profile causes less hypoglycemia, esp. nocturnal
Risk of hypoglycemia when used as the only insulin
Slide 6-30
THE ROLE OF INSULIN IN TYPE 2 DIABETES
Limitations of Human NPH, Lente, and Ultralente
Clinical use of insulin lispro, a better mealtime insulin than human regular, has directed attention to the properties of extended-release human insulins that have been used to provide basal insulin replacement. Human NPH, lente, and ultralente insulin all have mean durations of action of less than 24 hours, precluding them from providing adequate basal insulin replacement for many patients. All three, but especially NPH and lente, have pronounced peaks of action. Ultralente is thought to have substantial day-to-day variation of action. These limitations cause variations of glucose levels and unpredictable hypoglycemia, which are the leading factors limiting glycemic control at the present time. Recurrent hypoglycemia with insulin therapy of type 2 diabetes may be one factor in weight gain.

16. Insulin regimens Split mixed (N/R BID) 2 injections/day
Inflexible- need to eat meals at consistent times with snacks to avoid hypoglycemia
MORE hypoglycemia with this regimen when control is “tight”
Does not allow for adjustments of insulin through the day

17. Twice-Daily Split-Mixed Regimen
Breakfast
Lunch
Dinner
Insulin Action
REG
NPH/ Lente
NPH/Lente
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342

18. Basal/Bolus Insulin Absorption Pattern With Rapid-Acting Insulin Analogs
Breakfast
Lunch
Dinner
Aspart Aspart Aspart or or or
Lispro Lispro Lispro
Insulin Action
NPH/Lente
NPH/Lente
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342

19. Intensive insulin regimens
Combine a basal insulin with injections of rapid-acting insulin before each meal
Typically 3-4 injections/day or insulin pump therapy
Requires more patient education and motivation

20. Basal/Bolus Treatment Program With Rapid- and Long-Acting Analogs
Breakfast
Lunch
Dinner
Aspart or Lispro
Insulin Action
Glargine
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted with permission from Leahy JL. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel Dekker Inc.; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342

21. Intensive Therapy of Diabetes
More flexible: timing and amount of meals
Allows patient to be in control, instead of insulin controlling lifestyle
Allows for frequent corrections/adjustments through the day
Requires multiple daily self-monitoring of BG to get best results
When used correctly will provide the best A1c with less hypoglycemia!

22. Drawbacks of intensive insulin regimens
Requires frequent monitoring of glucose
Multiple daily injections of insulin
Requires intensive patient education/on-going support
Newer insulin analogues are more expensive

23. Other insulins and devices
Pre-mixed insulins
70/30 (N/R), 50/50 (N/R), 75/25 (N/Lispro) or 70/30 (N/Aspart)
All available in pens (except 50/50)
Best used in type 2 patients
NPH, Regular, Aspart, Lispro, and glargine are also available in pens

24. Insulin nomenclature- don’t be confused!
Humulin insulin is Lilly brand of human insulin- can be Regular, NPH, 70/30, or 50/50
Humalog is insulin lispro
Humalog mix is 75/25 (NPL/lispro)
Novolin is Novo-Nordisk brand of human insulin- Regular, NPH, or 70/30
Novolog is insulin aspart
NovoMix is 70/30 (NPA/aspart)
Lantus is insulin glargine
Apidra is insulin glulisine; and soon available will be insulin detemir (Levemir)

25. Insulin pumps Insulin pumps constantly infuse insulin subcutaneously
Program amount of insulin to infuse during basal hours and can deliver a bolus of insulin before a meal
Typically use aspart or lispro insulin in pumps, which makes the pumps very responsive
Considered the “gold standard” of treatment of type 1 diabetes

26. What exactly is an insulin pump?
First Insulin Pump (early 1970s)!!!

27. Insulin pumps
A small computerized device that delivers insulin continuously throughout the day.
Animas Disetronic Minimed
Show both pumps and various infusion sets.

28. Insulin pumps-benefits
The most physiological way to deliver insulin
The most flexible way to deliver insulin
Timing of meals
Exercise
Sick-days
Can attain excellent glucose control with less hypoglycemia

29. Insulin pumps-basal rate
Pumps now allow for up to 48 basal rates per day
Up to 3 basal “patterns”
Can program to match individual patient needs, e.g. strong dawn phenomenon
Have temporary basal rates- e.g. use for exercise

30. Insulin pumps- bolus 3 different types of bolus
Standard: bolus delivered immediately
Dual wave: can give certain percent immediately and rest over time (used for high carb, high fat meals)
Square wave: bolus delivered over a certain time, e.g. 3 hours: used for certain types of meals, gastroparesis

31. Insulin pump features
Program in carb ratio and insulin sensitivity factor
Enter blood glucose (or beam data from BD Logic meter) and carb amount and pump will automatically calculate bolus dose
Pump will calculate correction dose integrating data on glucose and insulin-on-board
Medtronic pumps can download to Website for analysis of data and data is available to provider who is linked to site

32. Insulin pumps-disadvantages
Cost ($5500 with $1-2000/yr. for supplies)
Skin problems
allergies/reactions to tape
infection at infusion site
Occasional pump malfunction
Lack of depot insulin- can rapidly develop DKA if infusion is disrupted

33. Which regimen to use? Depends on patient characteristics
daily schedule, timing of meals, exercise
patient willingness/ability to monitor, take multiple injections
Current pattern of high and low blood glucoses
What is goal of therapy?

34. Insulin and Glucose Patterns: Normal and Type 2 Diabetes
100
200
300
400
0600
1000
1800
1400
0200
2200
Time of Day B L D 20 40 60 80
120
mU/mL
mg/dL
B=breakfast; L=lunch; D=dinner
Adapted with permission from Polonsky KS et al. N Engl J Med. 1988;318:1231

35. Correcting Fasting Hyperglycemia…
Is Usually the First Task!!
300
Uncontrolled A1C ~9%
“Controlled” A1C <7%
200
PG (mg/dL)
A1C ~6%
100
Normal A1C 5%–6%
0800
1200
1800
0800
Time of Day
…then, Tackle Postprandial Hyperglycemia if A1C still >7%!
Adapted with permission from Cefalu WT. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel Dekker; 2002:1

36. Initiating Basal Insulin Therapy
Continue oral agent(s) at same dosage (eventually reduce)
Add single bedtime insulin dose (10 U)
Glargine insulin
NPH insulin
(70/30 before evening meal is also an option)
Adjust dose by fasting self-monitored BG with goal of
Titrate insulin dose weekly as needed:
Increase 2 U if FBG 121–140 mg/dL
Increase 4 U if FBG 141–160 mg/dL
Increase 6 U if FBG 161–180 mg/dL
Increase 8 U if FBG >180 mg/dL

37. Advancing Basal/Bolus Insulin
Indicated when FBG acceptable but
HbA1c >7%
and/or
SMBG before dinner >180 mg/dL
Insulin options
To bedtime NPH, add morning NPH and mealtime Regular or Lispro/aspart
To suppertime 70/30, add morning 70/30
To Glargine, add mealtime Regular or Lispro/aspart
Oral agent options
Usually stop sulfonylurea
Continue metformin for weight control?
Continue glitazone for glycemic stability?

38. Helpful hints to using insulin
Total insulin dose is based on weight (0.5 units/kg in DM 1 patients and 1 unit/kg in DM 2)
If adding one shot of insulin to oral meds, use 0.15 units/kg as starting dose
Base supplemental insulin dose on the “1700” rule (1700/total daily insulin= effect of 1 unit of insulin to lower blood glucose)
Use carbohydrate counting to estimate bolus dose
Patient education is essential- PLEASE refer patients to a diabetes educator!