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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

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Type 1 diabetes in adults

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
Prevalence of Diabetesin 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: NationalDiabetes 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 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
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-peptidec-peptide<0.8 ng/dL

Presence of islet autoantibodiesGADA, 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
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 glucosetolerance (OGTT)

Clinical

onset

Genetic

predisposition

Insulitis-Cell injury

-Cell insufficiency

Diabetes

Time

Eisenbarth GS. N Engl J Med. 1986;314:1360-1368


Rationale for intensive therapy of type 1 diabetes glucose control is critical

Rationale for Intensive Therapyof Type 1 DiabetesGlucose Control Is Critical


Risk of progression of microvascular complications vs a1c d cct
Risk of Progression ofMicrovascular Complications vs A1C DCCT

Relative risk

20

Retinopathy

Neuropathy

15

Microalbuminuria

10

5

0

1

5

6

7

8

9

10

11

12

A1C (%)

A1C=hemoglobin A1c

Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243-254


Intensive therapy for diabetes reduction in incidence of complications
Intensive Therapy for Diabetes:Reduction in Incidence of Complications

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
Long-term Microvascular Risk Reduction in Type 1 DiabetesCombined DCCT-EDIC

Intensive

Conventional

Retinopathy progression

(incidence)

12%

A1C

10%

8%

6%

P<0.001

P<0.001

P=0.61

DCCTEnd of randomized treatment

EDICYear 1

EDICYear 7

No. Evaluated

Conventional 169 203 220 581 158 192 200

Intensive 191 222 197 596 170 218 180

DCCT/EDIC Research Group. JAMA. 2002;287:2563-2569


Cost effectiveness of intensive therapy in type 1 diabetes dcct modeling study
Cost-Effectiveness of IntensiveTherapy in Type 1 Diabetes DCCT Modeling Study

DCCT Research Group. JAMA. 1996;276:1409-1415


Principles of Intensive Therapy ofType 1 DiabetesTargets


Current targets for glycemic control
Current Targets for Glycemic Control

*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 ofType 1 DiabetesInsulin Options


Action profiles of insulins
Action Profiles of Insulins

2

3

4

5

6

7

8

9

12

13

14

15

16

17

18

19

20

21

22

23

24

0

1

10

11

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

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
Normal Daily Plasma Insulin ProfileNondiabetic Obese Individuals

U/mL

100

B

L

D

80

60

40

20

1200

2400

1800

0800

0600

0600

Time of day

B=breakfast; L=lunch; D=dinner

Polonsky KS et al. N Engl J Med. 1988;318:1231-1239


Basal bolus treatment program with rapid acting and basal analogs
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


Physiologic multiple injection regimens the basal bolus insulin concept
Physiologic Multiple Injection Regimens AnalogsThe 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
Basal-bolus Therapy: Analogs

  • 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 Analogs

Faster and easier than syringes

Improve patient attitude and adherence

Have accurate dosing mechanisms, but inadequate resuspension of NPH may be a problem

Insulin Injection Devices


Mealtime insulin and severe hypoglycemia aspart vs regular insulin
Mealtime Insulin and Severe Hypoglycemia AnalogsAspart vs Regular Insulin

Favors RegularInsulin

Favors Aspart

P Values

NS

0.076

<0.050

<0.005

All severe hypoglycemia

Nocturnal event

Nocturnal, glucagon required

4–6 hours postmeal

0.1 1 10

Relative risk

Home PD et al. Diabet Med. 2000;17:762-770


Variable Basal Rate Continuous Subcutaneous Insulin Infusion (CSII)

75

Breakfast

Lunch

Dinner

50

Bolus

Plasma Insulin µU/ml)

Bolus

Bolus

25

Basal Infusion

4:00

8:00

12:00

16:00

20:00

24:00

4:00

8:00

Time


Insulin pumps continuous subcutaneous insulin infusion csii
Insulin Pumps (CSII)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
CSII vs Multiple Injections of Insulin (CSII)Meta-analyses

Pickup et al. 12 RCTs

Weissberg-Benchell et al. 11 RCTs

InjectionTherapyBetter

PumpTherapyBetter

Blood glucose concentration

Glycated hemoglobin

A1C

Insulin dose

-2 -1 0 1 2

Mean difference

RCT=randomized controlled trial

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
Balancing Risk of Severe Hypoglycemia Against the Risk of ComplicationsDCCT

Retinopathy Progression

Severe Hypoglycemia

100 patient-years

120

100 patient-years

16

14

100

12

80

10

60

8

6

40

4

20

2

0

0

8.0

10.5

5.0

5.5

6.0

6.5

7.0

7.5

8.5

9.0

9.5

10.0

5.5

6.0

6.5

7.0

7.5

8.0

8.5

9.0

9.5

10.0

10.5

5.0

A1C (%)

A1C (%)

DCCT Research Group. N Engl J Med. 1993;329:977-986


Hypoglycemia risk factors
Hypoglycemia ComplicationsRisk Factors

  • Behavioral Factors

  • Dietary inconsistency

    • Prolonged fasting

    • Missed meal or snack

  • Strenuous exercise

  • 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

  • Medical Factors

  • Drug side effects (-blockers)

  • Dosing errors

  • Unpredictable insulin kinetics

  • Inappropriate insulin distribution


Weight gain
Weight Gain Complications

  • 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
Future Glucose Monitors Complications

Guardian™ CGMS

External Closed-Loop

  • Minimally invasive continuous glucose monitors

  • Implanted glucose sensors

  • Implanted insulin pumps

  • “Closed-loop” systems

Freestyle Navigator™

Implanted Closed-Loop


Can type 1 diabetes be cured islet cell transplantation
Can Type 1 Diabetes Be “Cured?” ComplicationsIslet Cell Transplantation

7 Type 1 Patients, Aged 29 to 54 Years, With History of Severe Hypoglycemia and Metabolic Instability

MeanC-peptide(ng/mL)

Mean

A1C (%)

*

5.7

8.4%

*

*

2.5

5.7%

0.48

Baseline

6 monthsafter transplant

Baseline

90 min postmeal

Fasting

6 monthsafter transplant

*P<0.001 vs baseline

Shapiro AMJ et al. N Engl J Med. 2000;343:230-238


Opportunities for Intervention in ComplicationsType 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


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