type_1_diabetes_treatment_options_part_3.ppt

T1d

1. Type 1 Diabetes
Treatment Options
Stanley Schwartz Mark Stolar
Emeritus, Univ of Pa
Part 3

2. Postprandial Glucose Contribution
to A1C
% Contribution
A1C Range (%)
0
20
40
60
80
100
FPG (Fasting Plasma Glucose)
PPG (Postprandial Plasma Glucose)
>10.2
70%
30%
9.3-10.2
60%
40%
8.5-9.2
55%
45%
7.3-8.4
50%
50%
<7.3
30%
70%
Data from Monnier L, et al. Diabetes Care2003; 26:881-885

3. The Basal/Bolus Insulin Concept
•Basal insulin
–Suppresses glucose production between meals
and overnight
–Nearly constant levels
–~50% of daily needs
•Bolus insulin (mealtime or prandial)
–Limits hyperglycemia after meals
–Immediate rise and sharp peak at 1 hr
–~10% to 20% of daily requirement at each meal
•Ideally, for insulin replacement therapy, each component
should come from a different insulin with specific profile
Rosenstock J. Clin Cornerstone. 2001;4:50

4. 4:00 16:00 20:00 24:00 4:00
BreakfastLunch Dinner
8:0012:008:00
Time
Insulin Action
Rapid-Acting Insulin Analogs
Provide Ideal Prandial Insulin Profile
Fast Analog Therapy
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

5. 4:00 16:00 20:00 24:00 4:00
BreakfastLunch Dinner
8:0012:008:00
Time
Basal
Basal/Bolus Treatment Program With
Rapid-and Long-Acting Analogs
Insulin Action
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
Fast Analogs
Please see accompanying prescribing information

6. The Insulin Pump as Adjunctive Therapy
4:00 16:00 20:00 24:00 4:00
BreakfastLunch Dinner
8:00
Time
BolusBolusBolus
Basal Infusion
Insulin Action
12:008:00

7. β-Cell (Islet Cell) Classification Model-
Implications for Therapy:Targets for Adjunctive Therapies
Direct Effect on β-Cells
On #1-3of ‘Egregious Eleven’
1β-CELL Incretin
2
α-Cell Glucagon Incretin, Pramlintide
3↓INCRETIN EFFECT Incretin
4
Egregious Eleven Defect Intervention / Therapy

8. Disrupted Insulin and Glucagon Regulation: Central
Role in Diabetes Pathophysiology
•Hyperglucagonemia is a characteristic of T1DM and T2DM
•Data suggest a central role for glucagon dysregulation in diabetes pathophysiology
–Without paracrine intraislet insulin signals from juxtaposed β cells (image), α cells hypersecrete
glucagon (diagram)
–Hyperglucagonemia can account for abnormalities associated with lack of insulin (eg, increased
ketogenesis)
Cryer P. Endocrinology. 2012;153:1039-1048.
Unger R, et al. J Clin Invest. 2012;122:4-12.
Bosco D, et al. Diabetes. 2010;59:1202-1210.
Glucose, etc
GlucagonNo Insulin
α
cell
β
cell
  
α cells
β cells

9. Unger RH, et al. J Clin Invest. 2012;122(1):4-12.
Type 1 DM
Glucagon Is Central to Hyperglycemia in Type 1 Diabetes:
ie Exogenous Insulin Doesn’t Suppress Glucagon
Insufficient

10. GCG
(140 pg/mL)
Correcting Hyperglucagonemia May Improve Glucose
Variability: Evidence in Mice
•Leptin correction of hyperglucagonemia decreased glucose variability
•Decreased insulin dose prevented hypoglycemia
Unger RH, et al. J Clin Invest. 2012;122(1):4-
12.
GCG, glucagon
•NOD mice (T1DM model)
•Optimal insulin dose: 0.2 U
twice daily
•Suboptimal insulin dose: 0.02
U twice daily
•Leptin infusion to suppress
glucagon
700
600
500
400
200
100
02 68 18
Time, day
Glucose, mg/dL
0
300
161412104
GCG
(52 pg/mL)
GCG
(55 pg/mL)
Optimal insulin dose
Suboptimal insulin dose + leptin infusion

11. Addressing the alpha cell in type 1
Diabetes
•Glucagon dysregulation is a key contributor to
increased risk of hypoglycemia and hyperglycemia in
T1DM and T2DM
•Increased risk of hypoglycemia can be mitigated by
educating patients regarding signs, symptoms, and
treatment of hypoglycemia and can be treated with
exogenous glucagon
•Approaches to correct hyperglucagonemia may
improve glycemic control in patients with T1DM
•At present only pramlintideis approved to treat the
glucagon defect in Type 1 Diabetes

12. ●37-amino acid peptide
●Located almost entirely in -cells
●Cosecreted with insulin during meals
●Receptor characterized in CNS
Adapted from Koda JE, et al.Diabetes. 1995.
Amylin: Co-secreted With Insulin
and Deficient in Diabetes
Plasma insulin (pM)
Plasma amylin (pM)
30
25
20
15
10
5
7 am Midnight5 pmNoon
Time
600
400
200
0
MealMealMeal
Time after Sustacal meal (min)
0
5
10
15
20
-30 0 306090120150180
Without diabetes
(n=27)
Type 1(n=190)
Insulin-using
Type 2(n=27)
Plasma amylin (pM)
Meal
Insulin
Amylin
n=6 healthy
subjects

13. Glucoregulatory Actions of
Amylin
*
*
* In man
Glucagon
Secretion
Amylin
Glucose
Insulin
Satiety
Gastric Emptying
Digestion