1. Type 1 Diabetes in Adults
Andrej Janež, MD PhD
Dept. of Endocrinology Diabetes and Metabolic Diseases
University Medical Center Ljubljana

2. Prevalence of Diabetes in the United States
US Population: 275 Million in 2000
Undiagnosed diabetes 5.2 million
Diagnosed type 2 diabetes
12 million
Diagnosed type 1 diabetes ~1.0 million
Type 1 diabetes misdiagnosed as type 2 diabetes ~1.0 million
Centers for Disease Control. Available at: EURODIAB ACE Study Group. Lancet. 2000;355: ; Harris MI. In: National Diabetes Data Group. Diabetes in America. 2nd ed. Bethesda, Md: NIDDK; 1995:15-36; U.S. Census Bureau Statistical Abstract of the U.S.; 2001

3. Incidence of Type 1 Diabetes
Incidence increasing by 3.4% per year
50% of patients diagnosed before age 20 years
50% of patients diagnosed after age 20 years
Often mistaken for type 2 diabetes—may make up 10% to 30% of individuals diagnosed with type 2 diabetes
Oral agents ineffective; insulin therapy required
Autoimmune process slower and possibly different
Can usually be confirmed by beta cell antibodies
Loss of c-peptide
EURODIAB ACE Study Group. Lancet. 2000;355: ;
Naik RG, Palmer JP. Curr Opin Endocrinol Diabetes. 1997;4:

4. Making the Diagnosis of Type 1 Diabetes
Symptoms of diabetes Polyuria, polydipsia, polyphagia, diabetic
plus ketoacidosis (DKA)
Random plasma glucose 200 mg/dL*
Fasting plasma glucose (FPG) 126 mg/dL*
Oral glucose tolerance test (OGTT) with 2-hour value 200 mg/dL*
Loss of c-peptide c-peptide<0.8 ng/dL
Presence of islet autoantibodies GADA, ICA, IA-2A, IAA
*Requires confirmation by repeat testing
American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S5-S10

5. Natural History of “Pre”–Type 1 Diabetes
Putative
trigger
-Cell mass 100%
Cellular autoimmunity
Circulating autoantibodies (ICA, GAD65, ICA512A, IAA)
Loss of first-phase
insulin response (IVGTT)
Abnormal glucose tolerance (OGTT)
Clinical
onset
Genetic
predisposition
Insulitis -Cell injury
-Cell insufficiency
Diabetes
Time
Eisenbarth GS. N Engl J Med. 1986;314:

6. Rationale for Intensive Therapy of Type 1 Diabetes Glucose Control Is Critical

7. Risk of Progression of Microvascular Complications vs A1C DCCT
Relative risk 20
Retinopathy
Neuropathy 15
Microalbuminuria 10 5 1 5 6 7 8 9 10 11 12
A1C (%)
A1C=hemoglobin A1c
Skyler JS. Endocrinol Metab Clin North Am. 1996;25:

8. T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus.
Intensive Therapy for Diabetes: Reduction in Incidence of Complications
T1DM
DCCT
T2DM
Kumamoto
UKPDS
A1C
9%  7%
8%  7%
Retinopathy
63%
69%
17%–21%
Nephropathy
54%
70%
24%–33%
Neuropathy
60%
58% –
Cardiovascular disease
41%*
52*
16%*
Review Data
T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus.
*Not statistically significant due to small number of events.
†Showed statistical significance in subsequent epidemiologic analysis.
DCCT Research Group. N Engl J Med. 1993;329: ; Ohkubo Y, et al. Diabetes Res Clin Pract. 1995;28: ; UKPDS 33: Lancet. 1998;352: ; Stratton IM, et al. Brit Med J. 2000;321:

9. DCCT End of randomized treatment
Long-term Microvascular Risk Reduction in Type 1 Diabetes Combined DCCT-EDIC
Intensive
Conventional
A1C
12%
Retinopathy progression
(incidence)
10% 8% 6%
P<0.001
P<0.001
P=0.61
DCCT End of randomized treatment
EDIC Year 1
EDIC Year 7
No. Evaluated
Conventional
Intensive
DCCT/EDIC Research Group. JAMA. 2002;287:

10. Cost-Effectiveness of Intensive Therapy in Type 1 Diabetes DCCT Modeling Study
Years Free From Complication (Projected Average)
Conventional treatment
Intensive treatment
Proliferative retinopathy
39.1
53.9
Blindness
49.1
56.8
Microalbuminuria
34.5
43.7
End-stage renal disease (ESRD)
55.6
61.3
Neuropathy
42.3
53.2
Amputation
DCCT Research Group. JAMA. 1996;276:

11. Principles of Intensive Therapy of Type 1 Diabetes Targets

12. Current Targets for Glycemic Control
ADA
ACE LA
IDF
A1C (%)
Normal: 4%–6%
<7.0
6.5
<6.5
Fasting/Preprandial (mg/dL)
(plasma equivalent)
90-130
<110
110
<100
Postprandial (mg/dL)
(2-hour)
<180*
<140
140
<135
*Peak
American Diabetes Association. Diabetes Care. 2004,27:S15-S35.
The American Association of Clinical Endocrinologists. Endocr Pract. 2002; 8(suppl. 1):40-82.
Chacra AR, et al. Diabetes Obes Metab. 2005;7:
IDF (Europe) European Diabetes Policy Group. Diabet Med. 1999;16:

13. Principles of Intensive Therapy of Type 1 Diabetes Insulin Options

14. Action Profiles of Insulins
Aspart, glulisine, lispro 4–5 hours
Regular 6–8 hours
Plasma
insulin
levels
NPH 12–16 hours
Detemir ~14 hours
Ultralente 18–20 hours
Glargine ~24 hours 1 2 5 3 4 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Hours
Burge MR, Schade DS. Endocrinol Metab Clin North Am. 1997;26: ; Barlocco D. Curr Opin Invest Drugs. 2003;4: ; Danne T et al. Diabetes Care. 2003;26:

15. Normal Daily Plasma Insulin Profile Nondiabetic Obese Individuals
U/mL
100 B L D 80 60 40 20
0600
0800
1200
1800
2400
0600
Time of day
B=breakfast; L=lunch; D=dinner
Polonsky KS et al. N Engl J Med. 1988;318:

16. Basal/Bolus Treatment Program with Rapid-acting and Basal Analogs
Breakfast
Lunch
Dinner
Rapid
Rapid
Rapid
Plasma insulin
Basal
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time

17. Physiologic Multiple Injection Regimens The Basal-Bolus Insulin Concept
Basal insulin
Controls glucose production between meals and overnight
Near-constant levels
Usually ~50% of daily needs
Bolus insulin (mealtime or prandial)
Limits hyperglycemia after meals
Immediate rise and sharp peak at 1 hour postmeal
10% to 20% of total daily insulin requirement at each meal
For ideal insulin replacement therapy, each component should come from a different insulin with a specific profile or via an insulin pump (with one insulin)

18. Basal-bolus Therapy:
More frequent decision making, testing, and insulin dosing
Allows for variable food consumption based on hunger level
Ability to skip meal or snack if desired (bedtime)
Reduced variability of insulin absorption
Easy to adapt to acute changes in schedule (exercise, sleeping in on weekends)

19. Insulin Injection Devices
Insulin pens
Faster and easier than syringes
Improve patient attitude and adherence
Have accurate dosing mechanisms, but inadequate resuspension of NPH may be a problem

20. Mealtime Insulin and Severe Hypoglycemia Aspart vs Regular Insulin
Favors Regular Insulin
Favors Aspart
P Values NS
0.076
<0.050
<0.005
All severe hypoglycemia
Nocturnal event
Nocturnal, glucagon required
4–6 hours postmeal
Relative risk
Home PD et al. Diabet Med. 2000;17:

21. Bolus Bolus Bolus Basal Infusion
Variable Basal Rate Continuous Subcutaneous Insulin Infusion (CSII) 75
Breakfast
Lunch
Dinner 50
Plasma Insulin µU/ml)
Bolus
Bolus
Bolus 25
Basal Infusion
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time

22. Insulin Pumps Continuous Subcutaneous Insulin Infusion (CSII)
For motivated patients
Expensive
External, programmable pump connected to an indwelling subcutaneous catheter
Only rapid-acting insulin
Programmable basal rates
Bolus dose without extra injection
New pumps with dose calculator function
Bolus history
Requires support system of qualified providers

23. CSII vs Multiple Injections of Insulin Meta-analyses
Injection Therapy Better
Pump Therapy Better
Blood glucose concentration
Glycated hemoglobin
A1C
Insulin dose
Mean difference
Pickup et al. 12 RCTs
Weissberg-Benchell et al. 11 RCTs
RCT=randomized controlled trial
Pickup J et al. BMJ. 2002;324:1-6;
Weissberg-Benchell J et al. Diabetes Care. 2003;26:

24. Retinopathy Progression
Balancing Risk of Severe Hypoglycemia Against the Risk of Complications DCCT
Severe Hypoglycemia
Retinopathy Progression
100 patient-years
100 patient-years
120 16 14
100 12 80 10 60 8 6 40 4 20 2
5.0
5.5
6.0
6.5
7.0
7.5
8.0
8.5
9.0
9.5
10.0
10.5
5.0
5.5
6.0
6.5
7.0
7.5
8.0
8.5
9.0
9.5
10.0
10.5
A1C (%)
A1C (%)
DCCT Research Group. N Engl J Med. 1993;329:

25. Hypoglycemia Risk Factors
Patient Factors
Hypoglycemia unawareness
History of previous hypoglycemia
Defective glucose counterregulation
Long duration of diabetes
Erratic insulin absorption
Age less than 5 to 7 years
Behavioral Factors
Dietary inconsistency
Prolonged fasting
Missed meal or snack
Strenuous exercise
Medical Factors
Drug side effects (-blockers)
Dosing errors
Unpredictable insulin kinetics
Inappropriate insulin distribution

26. Weight Gain Insulin therapy reverses catabolic effects of diabetes
Glycosuria reduced
Normal fuel-storage mechanisms restored
Risk of hypoglycemia often causes patients to increase caloric intake and avoid exercise
Risk of weight gain decreases with more physiologic insulin administration
Flexible insulin dosing to meet dietary and exercise needs

27. Future Glucose Monitors
Guardian™ CGMS
External Closed-Loop
Minimally invasive continuous glucose monitors
Implanted glucose sensors
Implanted insulin pumps
“Closed-loop” systems
Freestyle Navigator™
Implanted Closed-Loop

28. Can Type 1 Diabetes Be “Cured?” Islet Cell Transplantation
7 Type 1 Patients, Aged 29 to 54 Years, With History of Severe Hypoglycemia and Metabolic Instability
Mean
A1C (%)
Mean C-peptide (ng/mL) *
5.7
8.4% * *
2.5
5.7%
0.48
Baseline
6 months after transplant
Baseline
Fasting
90 min postmeal
6 months after transplant
*P<0.001 vs baseline
Shapiro AMJ et al. N Engl J Med. 2000;343:

29. Opportunities for Intervention in Type 1 Diabetes
TrialNet
Multiple antibody positive
Genetically at risk
Loss of first-phase insulin response
-Cell mass
Newly diagnosed diabetes
Genetic
predisposition
Insulitis -Cell injury
-Cell insufficiency
Diabetes
Time