Type 1 Diabetes

Treatment Options
Part 1

Stanley Schwartz Mark Stolar

Emeritus, Univ of Pa
 Type 1 Diabetes
• Diabetes mellitus type 1 (IDDM)

Hyperglycemia resulting from the autoimmune

destruction of the insulin-producing beta cells in
the pancreas-

insulin therapy is essential for survival= insulin

dependent unlike type 2 diabetes where insulin use
defines insulin treated not dependent
 Pathogenesis of Type 1 Diabetes

Immune Environmental
dysregulation triggers and
regulators

Loss of first-phase insulin

Interactions response
between
May be relapsing/remitting
genes
imparting Variable insulitis Glucose intolerance
susceptibility -cell sensitivity to
and resistance injury
-cell Mass

Overt diabetes
Pre-diabetes
Time

Adapted with permission from Atkinson MA, Eisenbarth GS. Lancet. 2001;358:221
 Type 1 Diabetes
• Insulin-deficient state
• Therapeutic goal: replace insulin
• Strategy: provide replacement insulin in
manner that mimics normal fasting/prandial
physiology
• This cannot always be done with current
insulin analogues
• Goal to reduce microvascular complications. Is
postprandial hyperglycemia more
pathogenic?
 DCCT Microvascular Complication
Event Rates and Risk Reductions

76%
Cumulative Incidence (%)

59%
39%

64%
54%

1 2
1 2 3

1. DCCT Research Group. Ophthalmology. 1995;102:647

2. DCCT Research Group. Kidney Int. 1995;47:1703
3. DCCT Research Group. Ann Intern Med. 1995;122:561
 The Downside to Intensive Insulin
Management
:1. Hypoglycemia
2. Weight gain
3. Glycemic, including daytime, variability
4. Doesn’t address non-insulin mediated
causes of hyperglycemia
in type 1 diabetes
 DCCT RESULTS
Severe Hypoglycemia
100
• Persistent three-fold increase in INT

80 • Increased risk of multiple episodes within

same patient (INT = 22%, CON = 4%)
Rate/100 Patient Years

60
Intensive • Number of prior episodes was strongest
40 predictor of future risk

20 • Current A1C not solely predictive of risk

Conventional
0
5 6 7 8 9 10 11 12 13 14

HbA1c (%) During Study

DCCT Research Group, Diabetes 1997;46:271-286

 Hypoglycemia Unawareness Is a
Dangerous Complication of T1DM
• Each episode of hypoglycemia reduces
counterregulatory response to low glucose
even after one episode
• Reduction in catecholamine response
decreases awareness/symptoms even after a
single episode
• Nocturnal hypoglycemia is most pathogenic
and unrecognized. Hypoglycemic awareness
decreases significantly in the elderly
 CV Consequences of Hypoglycemia

• Prolonged QT- intervals- Diabetologia 52:42,2009

– Can be of pronged duration IJCP Sup 129, 7/02

– Greater with higher catecholamine levels Europace 10,860

• Associated with Angina

ADA2010
Diabetes Care 26, 1485, 2003 / Ischemic EKG changes Porcellati,

• Associated with Arrhythmias

• Associated with Sudden Death Endocrine Practice 16,¾ 2010

• Increased Glycemic Variabilty-

Adverse ICU outcomes/Increased vascular inflammation Hirsch ADA2010
 The Downside to Intensive Insulin
Management
:1. Hypoglycemia
2. Weight gain
3.Glycemic, including daytime, variability
4. Doesn’t address non-insulin mediated
causes of hyperglycemia
in type 1 diabetes
 Consequences of Intensive Insulin
Therapy
Weight Gain

UKPDS (Type 2) Intensive DCCT (Type 1)

Conventional
10.0 30

25
7.5
20

15
5.0
10

Weight (kg)
2.5
Weight (kg)

0
0 -5
0 3 6 9 12 15 1 2 3 4
Time (y) Quartile of Weight Gain

Data from Purnell J, et al. JAMA 1998; 280:140-146

Data from UKPDS Group (UKPDS 33). Lancet 1998; 352:837-853
 Weight Gain
MEALTIME INSULIN THERAPY

10 +8.7 kg

6 +4.6 kg
Weight (kg)

0 BID Insulin Intensive BID Insulin

12

11

10

9
A1C (%)

8 -2.2%
ADA Goal
7

5 -2.6%
Yki-Jarvinen 1999 Henry 1993
4
 The Downside to Intensive Insulin
Management
:1. Hypoglycemia
2. Weight gain
3. Glycemic, including daytime, variability
4. Doesn’t address non-insulin mediated
causes of hyperglycemia
in type 1 diabetes