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Type 1 Diabetes in Adults
Andrej Janež, MD PhD
Dept. of Endocrinology Diabetes and
Metabolic Diseases
University Medical Center Ljubljana
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: http://www.cdc.gov/diabetes/pubs/estimates.htm;
EURODIAB ACE Study Group. Lancet. 2000;355:873-876; 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
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;355:873-876;
Naik RG, Palmer JP. Curr Opin Endocrinol Diabetes. 1997;4:308-315
Making the Diagnosis of Type 1 Diabetes
Symptoms of diabetes
plus
Polyuria, polydipsia,
polyphagia, diabetic
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
Natural History of “Pre”–Type 1
Diabetes
-Cell
mass 100%
Putative
trigger
Cellular autoimmunity
Circulating autoantibodies (ICA, GAD65, ICA512A, IAA)
Loss of first-phase
insulin response (IVGTT)
Abnormal glucose
tolerance (OGTT)
Genetic
predisposition
Insulitis
-Cell injury
Time
Eisenbarth GS. N Engl J Med. 1986;314:1360-1368
-Cell
insufficienc
y
Diabetes
Clinical
onset
Rationale for Intensive Therapy
of Type 1 Diabetes
Glucose Control Is Critical
Risk of Progression of Microvascular
Complications vs A1C
DCCT
Relative 20
risk
Retinopathy
Neuropathy
Microalbuminuria
15
10
5
0
1
5
6
7
8
9
A1C (%)
A1C=hemoglobin A1c
Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243-254
10
11
12
Intensive Therapy for Diabetes:
Reduction in Incidence of Complications
T1DM
DCCT
T2DM
Kumamoto
T2DM
UKPDS
9%  7%
9%  7%
8%  7%
Retinopathy
63%
69%
17%–21%
Nephropathy
54%
70%
24%–33%
Neuropathy
60%
58%
–
Cardiovascular
disease
41%*
52*
16%*
A1C
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;329:977-986; Ohkubo Y, et al. Diabetes Res Clin
Pract. 1995;28:103-117; UKPDS 33: Lancet. 1998;352: 837-853; Stratton IM, et al. Brit Med J.
2000;321:405-412.
Long-term Microvascular Risk Reduction
in Type 1 Diabetes
Combined DCCT-EDIC
Intensive
A1C 12
%
Conventional
Retinopathy
progression
(incidence)
0.5
0.4
10
%
0.3
8%
0.2
0.1
6%
P<0.00 P<0.00 P=0.61
1
1
DCCT
EDIC EDIC
End of
Year 1 Year 7
randomized
treatment
0
0
No. Evaluated
Conventional
Intensive
DCCT/EDIC Research Group. JAMA. 2002;287:2563-2569
1
169
191
2
3
4
5
Years in EDIC
203
222
220
197
581
596
158
170
6
7
192
218
200
180
Cost-Effectiveness of Intensive
Therapy in Type 1 Diabetes
DCCT Modeling Study
Proliferative retinopathy
Years Free From Complication
(Projected Average)
Conventional
Intensive
treatment
treatment
39.1
53.9
Blindness
49.1
56.8
Microalbuminuria
34.5
43.7
End-stage renal disease
(ESRD)
Neuropathy
55.6
61.3
42.3
53.2
Amputation
39.1
53.9
DCCT Research Group. JAMA. 1996;276:1409-1415
Principles of Intensive Therapy
of
Type 1 Diabetes
Targets
Current Targets for Glycemic Control
ADA
A1C (%)
ACE
LA
IDF
<7.0
6.5
90-130
<110
110
<100
<180*
<140
140
<135
<6.5
6.5
Normal: 4%–6%
Fasting/Preprandial (mg/dL)
(plasma equivalent)
Postprandial (mg/dL)
(2-hour)
*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;7:148-160.
IDF (Europe) European Diabetes Policy Group. Diabet Med. 1999;16:716-730.
Principles of Intensive Therapy
of
Type 1 Diabetes
Insulin Options
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
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
Hours
Burge MR, Schade DS. Endocrinol Metab Clin North Am. 1997;26:575-598; Barlocco D. Curr Opin Invest
Drugs. 2003;4:1240-1244; Danne T et al. Diabetes Care. 2003;26:3087-3092
Normal Daily Plasma Insulin Profile
Nondiabetic Obese Individuals
U/mL
100
B
L
D
1200
1800
80
60
40
20
0600
0800
Time of day
B=breakfast; L=lunch; D=dinner
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239
2400
0600
Basal/Bolus Treatment Program with Rapidacting and Basal Analogs
Plasma insulin
Breakfast
Lunch
Rapid
Dinner
Rapid
Rapid
Basal
4:00
8:00
12:00
16:00
Time
20:00
24:00
4:00
8:00
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)
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)
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
Mealtime Insulin and Severe Hypoglycemia
Aspart vs Regular Insulin
All severe hypoglycemia
Favors
Aspart
Favors
Regular
Insulin P Values
NS
Nocturnal event
0.076
Nocturnal, glucagon
required
<0.050
4–6 hours postmeal
<0.005
0.1
Home PD et al. Diabet Med. 2000;17:762-770
1
Relative risk
10
Variable Basal Rate Continuous Subcutaneous Insulin
Infusion (CSII)
75
Plasma Insulin µU/ml)
Breakfast
Lunch
Dinner
50
Bolus Bolus
Bolus
25
Basal Infusion
4:00
8:00
12:00
16:00
Time
20:00
24:00
4:00
8:00
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
CSII vs Multiple Injections of Insulin
Meta-analyses
Injection
Therapy
Better
Pump
Therapy
Better
Blood glucose
concentration
Glycated hemoglobin
A1C
Insulin dose
-2
-1
0
Mean difference
Pickup et al. 12 RCTs
RCT=randomized controlled trial
1 2
Weissberg-Benchell et al. 11
RCTs
Pickup J et al. BMJ. 2002;324:1-6;
Weissberg-Benchell J et al. Diabetes Care. 2003;26:1079-1087
Balancing Risk of Severe Hypoglycemia Against the Risk of
Complications
DCCT
Retinopathy Progression
Severe
Hypoglycemia
120
100
patien 100
tyears 80
100
16
patient-14
years
60
8
12
10
6
40
4
20
2
0
5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.510.010.5
0
5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.510.010.5
A1C (%)
DCCT Research Group. N Engl J Med. 1993;329:977-986
A1C (%)
Hypoglycemia
Risk Factors
Behavioral 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
• Dietary inconsistency
– Prolonged fasting
– Missed meal or snack
• Strenuous exercise
Medical Factors
•
•
•
•
Drug side effects (-blockers)
Dosing errors
Unpredictable insulin kinetics
Inappropriate insulin
distribution
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
Future Glucose Monitors
Guardian™ CGMS
Freestyle Navigator™
External Closed-Loop
• Minimally invasive
continuous glucose
monitors
• Implanted glucose
sensors
• Implanted insulin
pumps
• “Closed-loop”
systems
Implanted Closed-Loop
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 9
A1C
(%)
8
Mean
6
C-peptide
(ng/mL) 5
8.4
%
5
5.7
4
7
6
*
3
*
*
2
5.7
%
2.5
1
4
0.48
0
Baseline
6 months
after
transplant
*P<0.001 vs baseline
Shapiro AMJ et al. N Engl J Med. 2000;343:230-238
Baseline Fasting 90 min
postmeal
6 months
after
transplant
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
Time
-Cell
insufficienc
y
Diabete
s