Naomi Berrie Diabetes Center

Type 1 Diabetes Update2008

Robin Goland, MD

Type 1 diabetes is:

A manageable conditionA chronic conditionOften challenging

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Entirely compatible with a happy and healthy childhood and family life

Type 1 Diabetes Overview

Definitions

Epidemiology

PathophysiologyPathophysiology

Diagnosis

Prevention of Complications

Clinical Managementg

Experimental Treatment

Type 1 Diabetes: Historical Description

Two Main Types of Diabetes

What is type 1 diabetes?

Auto-immune destruction of insulin-producing cells of pancreas.

People with type 1 diabetes are healthy and we expect them to remain healthy throughout their livesto remain healthy throughout their lives.

Chronic diabetes complications- microvascular and C fmacrovascular damage. Complications only occur after many

years of uncontrolled high blood sugars.

Type 1 Diabetes Epidemiology

24 million people in US (7% population) have diabetesp p ( p p )

5-10% of total is type 1 diabetes

Staggering healthcare cost

Incidence increasing, particularly in young children

Type 1 Diabetes Epidemiology

1.9 per 1000 US school children

12-15 cases per 100,000

Male:female 1:1

Peak ages 5-7 and at puberty

Mostly Caucasians; African Americans at 20-30% less risk

Seasonal variation: peak in fall and winterSeasonal variation: peak in fall and winter

Wh d l d l t 1Why do people develop type 1 diabetes?

Combination of genetic and environmental causes

Children inherit diabetes-related genes from both their mother and father, even if no one in either family has diabetes.

There is also an environmental factor, not yet identified, such as a virus that tips over a genetically predisposed person into developing diabetes. Trigger often occurs years before diagnosis.

T 1 Di b t I id 100 000Type 1 Diabetes Incidence per 100,000 in Children < 14 years old

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Type 1 Diabetes Epidemiology

Prevalence in school-age children in US: 1.9 per 1000

Annual incidence: 12 to 15 cases per 100,000

Male: Female ratio: 1:1

Peak ages: 5 to 7 yearspuberty

Mostly Caucasians affected, African-Americans are at 20-30% less risk

Seasonal variation: peak in fall and winterSeasonal variation: peak in fall and winter

Genetic Risk in Type 1 Diabetes:Genetic Risk in Type 1 Diabetes: Common HLA Haplotypes

DQB1 DRB1

Hi h Ri k

QDQA1

DRB1DRA6p

High RiskDR3: DQB1*0201, DQA1*0501, DRB1*0301 DR4: DQA1*0301, DQB1*0302, DRB1*0401, ,ProtectiveDR2: DQB1*0602, DQA1*0102,, DRB1*1501

BDC

E id th t T 1 Di b t iEvidence that Type 1 Diabetes is Autoimmune

Autopsy studies documenting immune infiltration of islets

Preservation of beta cell function with immune intervention

Association with other autoimmune disease: thyroid disease, celiac, others

Progression of Type 1 Diabetes

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Clinical Presentation

Can occur at any age

Patients often lean and Caucasian although not always

Presentation often abrupt can present in DKA; positive urine ketonesPresentation often abrupt, can present in DKA; positive urine ketones

Not accompanied by metabolic syndrome

Positive antibodies against GAD, insulin, islet cells

Low or undetectable c-peptide and insulin level

Prevention of T1DM Complications

Acute: Hypoglycemia, DKA

Chronic: Microvascular

Chronic: Macrovascular and Neuropathic

Chronic: Psychosocial

Type 1 Diabetes: DCCT

Intensive therapy reduced R ti th b 76%Retinopathy by 76%Nephopathy by 57%Neuropathy by 60%

Adverse effects included hypoglycemia and weight gain

EDIC study progression ofEDIC study – progression of retinopathy after the DCCT

Goals of treatment in type 1 diabetes

Normal growth and development and a well-adjusted patient and family

Promotion of blood sugars near-normal most of the time -perfection not required to stay healthy

Reduction of high blood sugars

Reduction of low blood sugarsReduction of low blood sugars

Optimal self-management to match insulin with food and activity

What we Measure in Type 1 Diabetes

BLOOD SUGAR (glucose) by fingerstick. Affected by food, particularly b h d t d b l i icarbohydrate, and use by muscles in exercise.

Eating raises blood sugar. Stress and illness also raise blood sugar.

Skipping or delaying meals lower blood sugar. Exercise lowers blood sugar.

H l bi A1CHemoglobin A1C.

Normal insulin and glucose levels

Blood sugar problems can beBlood sugar problems can be fixed and prevented

How to recognize low blood sugar (hypoglycemia)

How to treat low blood sugar

How to prevent low blood sugar

How to recognize high blood sugar (hyperglycemia)

How to treat high blood sugar

How to prevent high blood sugar

R i i l bl dRecognizing low blood sugar

Sh ki P l i i S iShakiness Palpitations Sweating

Anxiety Dizziness Hungery gSevere untreated hypoglycemia can cause seizure or loss

Headache Fatigue Irritability

cause seizure or loss of consciousness

T f l bl dTreatment of low blood sugar1

Check blood sugar

2If <70-80 mg/dl, treat with 15 grams of carbohydrate

If using pump, suspend or disconnect

2

Check glucose again after 15 minutes

If glucose remains under 70 mg/dl

3

If glucose remains under 70 mg/dl, repeat treatment with 15 grams of carbohydrate

In unlikely case of low blood sugar 4

u e y case o o b ood sugaemergency (unconsciousness or seizure), use glucagon emergency kit.

Prevention of low blood sugar

Lows often occur because of mismatch between insulin and either food or exerciseinsulin and either food or exerciseAfter taking rapid-acting insulin, the meal should not be delayedExercise acts to lower blood sugar so reduce insulin or eat a snack with exerciseF t bl d h k d t t t tFrequent blood sugar checks and prompt treatment of low blood sugar will prevent serious lows

Recognizing high blood sugar

Frequent Urination Extreme Thirst

Blurred Vision Hunger Severe untreatedBlurred Vision Hunger Severe untreated hyperglycemia for many hours to days can cause dehydration and

Drowsiness Nausea

diabetic ketoacidosis

T f hi h bl dTreatment of high blood sugar

Check blood glucose

Check urine ketones if blood sugar > 300 mg/dl and advised by parent (ketones are breakdown

d t f f t th t l t i t t fproducts of fats that accumulate in states of insulin deficiency)

Gi i li (“ ti d ”) d i d bGive insulin (“correction dose”) as advised by parent

Give non sugary fluids as advised by parentGive non-sugary fluids, as advised by parent

Prevention of high blood sugar

High blood sugars often occur because of mismatch between insulin and food High blood sugar afterbetween insulin and food. High blood sugar after meals usually occurs because of inadequate pre-meal bolus insulin - increase for next timeHi h f i bl d bl d i h b fHigh fasting blood sugar or blood sugar right before a meal usually occurs because of inadequate long-acting or basal insulin - if this is a pattern, basal insulin can be increasedThe stress of illness raises blood sugar. Insulin doses often need to be temporarily increased indoses often need to be temporarily increased in times of illness.

Hemoglobin A1c is the gold standard measurement for assessment of diabetes management

Hemoglobin A1c specifically refers to the Amadori productOf the N terminal valine of each beta chain of HbA with glucoseOf the N-terminal valine of each beta chain of HbA with glucose

Glucose Schiff Base Amadori+

Hemoglobin A

Schiff Base(reversible)

AmadoriProduct

It is a reliable index of average blood glucose concentrations over the preceding 6 8 weeksthe preceding 6 – 8 weeks.

Relationship of A1c to Blood SugarRelationship of A1c to Blood Sugar

Diabetes: A Systemic DiseaseDiabetes: A Systemic Disease

Leading causeof blindness

2- to 4- fold increase in cardiovascularmortality

DiabeticRetinopathy

in working ageadults1 Stroke

mortality and stroke2

CardiovascularDisease

DiabeticNephropathy

Leading cause of 3end-stage renal disease3 Diabetic

NeuropathyLeading cause of non-traumatic

lower extremity amputations4lower extremity amputations

National Diabetes Information Clearinghouse. Diabetes StatisticsNational Diabetes Information Clearinghouse. Diabetes Statistics––Complications of Diabetes.Complications of Diabetes. (website)(website)http://www.niddk.nih.gov/health/diabetes/pubs/dmstats/dmstats.htm#comp. http://www.niddk.nih.gov/health/diabetes/pubs/dmstats/dmstats.htm#comp.

Relationship of Diabetes C li ti t H l bi A1Complications to Hemoglobin A1c

IntensiveN (%)

StandardN (%) HR (95% CI) PN (%) N (%) HR (95% CI) P

Primary 352 (6.86) 371 (7.23) 0.90 (0.78-1.04) 0.16

SecondarySecondary

Mortality 257 (5.01) 203 (3.96) 1.22 (1.01-1.46) 0.04

N f t l MI 186 (3 63) 235 (4 59) 0 76 (0 62 0 92) 0 004Nonfatal MI 186 (3.63) 235 (4.59) 0.76 (0.62-0.92) 0.004

Nonfatal Stroke 67 (1.31) 61 (1.19) 1.06 (0.75-1.50) 0.74

CVD D th 135 (2 63) 94 (1 83) 1 35 (1 04 1 76) 0 02CVD Death 135 (2.63) 94 (1.83) 1.35 (1.04-1.76) 0.02

CHF 152 (2.96) 124 (2.42) 1.18 (0.93-1.49) 0.17

In people with type 2 diabetes at high risk for CVD, with an A1C of 7 5% or more a therapeuticwith an A1C of 7.5% or more, a therapeutic strategy that targets an A1C <6% vs. 7.0-7.9% increases mortality over 3.5 years

There is no significant effect of the glycemic intervention on the primary outcome at this timeintervention on the primary outcome at this time

Ongoing follow-up and ongoing analyses (bothOngoing follow-up and ongoing analyses (both epidemiologic & within baseline subgroups) will add further insight and generate more hypotheses

Coping with diabetes

A diagnosis of type 1 diabetes is a big deal

Feelings of sadness, guilt, loneliness, and blame are common

It’s important for the patient and the whole family (and supportIt s important for the patient and the whole family (and support network) to be able to talk about their feelings about diabetes

I li t t t i t 1 di b tInsulin treatment in type 1 diabetes: Replacement treatment

Background or basal insulin given over 24 hours

Meal-related, or bolus, or prandial insulin is given to cover the carbohydrates in the food

I li b i b lti l i j ti bInsulin can be given by multiple injections or by pump

With injections, 1 shot is long-acting basal insulin, usually glargine (lantus) insulin. Additional shorts of rapid-acting insulin (lispro-humalog or aspart-insulin. Additional shorts of rapid acting insulin (lispro humalog or aspartnovolog) are given right before meals and snacks.

With the pump, only rapid acting insulin is used. Basal insulin is given in small increments all day long and bolus insulin is given through the pump’s catheterincrements all day long and bolus insulin is given through the pump s catheter right before meals and snacks.

Insulin Injections or Insulin Pump

Food in type 1 diabetes

There is NO such thing as a diabetic diet.

People with type 1 diabetes eat normally and “cover” the carbohydrates in food with insulin.

This is called “carbohydrate counting.”

P l ith t 1 di b t h i di id li dPeople with type 1 diabetes have an individualized insulin:carbohydrate ratio that helps guide how much insulin to take with each meal and snack.

The “Bad Old Days of Type 1 Diabetes”Prior to 1980

1 or 2 injections of NPH and regular insulin per day

Rigid rules for composition and timing of meals

Urine tests for glucoseUrine tests for glucose

Aggressive therapy unsafe and of unknown benefits

H l bi A1 11 12%Hemoglobin A1c 11-12%

Inevitable eye and renal complications

Inevitable “noncompliance”

Advances in Type 1 Diabetes Treatment

Evidence supporting glycemic controlEvidence supporting glycemic control

Means for achieving glycemic control– Insulin analogues allowing basal/bolus therapy– Carbohydrate counting– Advances in monitoring – Insulin delivery systems– Integrated systems

Basal-Bolus Insulin Treatment of Type 1 Diabetes 2008

• Use of insulin:carb ratios to normalize postprandial meal glucose and allow flexibility in timing and content of meals

Use of corrective bolus to normalize glucose

Peakless insulin simpifies sick day management, skipping meals, dietingp y g , pp g , g

Diabetes education promoting self-care especially day-to-day insulin dose adjustment

Hemoglobin A1c 6.5-7.5%

Eye and renal complications rare

“Noncompliance” redefined

Insulin Delivery Systems: Insulin Pens

Insulin Pens– DisposableDisposable– No syringes and vials– Convenient– Small doses in 0.5 u increments

Improved Blood Sugar Monitoring

Technologic AdvancesSmaller metersSmall blood sample (0.3 ul) Short test time (<5 secs)Self-contained stripsAlternate site testingAlternate site testing

Non-Randomized Trials of CSII:Non Randomized Trials of CSII: Adolescents, Adults, Children

Switching to CSII results in:

Lower HbA1cL H l iLess HypoglycemiaGreater Patient Satisfaction

Insulin Delivery in Pump Compared toInsulin Delivery in Pump Compared to Multiple Daily Injections

• Lispro/aspart insulin is given in a programmable “basal rate”every few minutes. Additional insulin is given in adjustable “boluses” to cover meal related glucoseadjustable boluses to cover meal related glucose excursions.

Programmable basal rate offers advantage over injected basal insulin as it can be modified as necessary leading to enhanced lifestyle flexibility, especially helpful in managing dawn phenomenon and exercise.

CSII leads to more predictable insulin levels compared to MDI

Dual-wave and square wave bolus offers greater ability to match insulin to food

Early Insulin Pump

Continuous Subcutaneous Insulin Infusion(CSII

ANIMAS

MINIMED

ANIMAS

COZMO

Closed-Loop Insulin Pumpp p

• Implantable insulin pump coupled to glucoseImplantable insulin pump coupled to glucose sensor

Algorithm for ins lin deli er based on gl cose• Algorithm for insulin delivery based on glucose level

Experimental Treatment of Type 1 Diabetes

Immune Therapy: Rituximab, anti-CD3, CTLA4Ig, SYK inhibitor, GAD vaccine

• Islet and Pancreas Transplant

Closed loop system• Closed loop system

• Stem Cell-based Therapy

.

Experimental Treatment of Type 1 Diabetes: The Challenge

An intervention that can arrest the ongoing immune response and induce toleranceand induce tolerance

• Beta cell replacement with tolerance to the graft –h i l h i l i l l t?mechanical or even more physiological replacement?

• Is hypoglycemia preventable?

• Markers for individuals at risk for complications and interventions that will block the effects of hyperglycemia

.

interventions that will block the effects of hyperglycemia directly or the associated abnormalities.

Anti-CD3 Preservation of Beta Cell Function

ControlDrug treated

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Anti-CD20 Preservation of Beta Cell Function

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Embryonic Stem Cell Research

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Somatic Cell Nuclear Transfer Creation of ALS

NeuronsNeurons

Induced PleuripotentialStem Cells

Type 1 diabetes is:

A manageable conditionA chronic conditionOften challenging

QuickTime™ and adecompressordecompressor

are needed to see this picture.

Entirely compatible with a happy and healthy childhood and family life