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Naomi Berrie Diabetes Center

Type 1 Diabetes Update

2008

Robin Goland, MD

Type 1 diabetes is:

A manageable condition

A chronic condition

Often challenging

Entirely compatible with a happy

and healthy childhood and family

lif

Type 1 Diabetes Overview

Definitions

Epidemiology

Pathophysiology

Diagnosis

Prevention of Complications

Clinical Management

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 lives.

Chronic diabetes complications- microvascular and macrovascular damage. Complications only occur after many years of uncontrolled high blood sugars.

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Type 1 Diabetes Epidemiology

24 million people in US (7% population) have diabetes

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 winter

Why 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.

Type 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 years puberty

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

Seasonal variation: peak in fall and winter

Genetic Risk in Type 1 Diabetes: Common HLA Haplotypes

High Risk DR3: DQB1*0201, DQA1*0501, DRB1*0301 DR4: DQA1*0301, DQB1*0302, DRB1*0401

Protective DR2: DQB1*0602, DQA1*0102,, DRB1*1501

DQB1

DQA1

DRB1 DRA 6p

BDC

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Evidence 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 Progression to Type 1 Diabetes with Positive Antibodies

Clinical Presentation

Can occur at any age

Patients often lean and Caucasian although not always

Presentation 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

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Type 1 Diabetes: DCCT

Intensive therapy reduced

Retinopathy by 76%

Nephopathy by 57%

Neuropathy by 60%

Adverse effects included hypoglycemia and weight gain

EDIC 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 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 carbohydrate, 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.

Hemoglobin A1C.

Normal insulin and glucose levels Blood 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

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Recognizing low blood sugar

Shakiness Palpitations Sweating

Anxiety Dizziness Hunger

Headache Fatigue Irritability

Severe untreated

hypoglycemia can cause seizure or loss

of consciousness

Treatment of low blood sugar

Check blood sugar

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

If using pump, suspend or disconnect

Check glucose again after 15 minutes

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

In unlikely case of low blood sugar emergency (unconsciousness or seizure), use glucagon emergency kit.

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Prevention of low blood sugar

Lows often occur because of mismatch between insulin and either food or exercise

After taking rapid-acting insulin, the meal should not be delayed

Exercise acts to lower blood sugar so reduce insulin or eat a snack with exercise

Frequent blood sugar checks and prompt treatment of low blood sugar will prevent serious lows

Recognizing high blood sugar

Frequent Urination

Blurred Vision

Drowsiness

Hunger

Nausea

Extreme Thirst

Severe untreated

hyperglycemia for many hours to days

can cause dehydration and diabetic

ketoacidosis

Treatment of high blood sugar

Check blood glucose

Check urine ketones if blood sugar > 300 mg/dl and advised by parent (ketones are breakdown products of fats that accumulate in states of insulin deficiency)

Give insulin (“correction dose”) as advised by parent

Give 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 after meals usually occurs because of inadequate pre-meal bolus insulin - increase for next time

High 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 increased

The stress of illness raises blood sugar. Insulin doses often need to be temporarily increased in times of illness.

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

Hemoglobin A1c specifically refers to the Amadori product

Of the N-terminal valine of each beta chain of HbA with glucose

Glucose

+

Hemoglobin A

Schiff Base

(reversible)

Amadori

Product

It is a reliable index of average blood glucose concentrations over

the preceding 6 – 8 weeks.

Relationship of A1c to Blood Sugar

Cardiovascular

Disease

Diabetic

Retinopathy

Leading cause

of blindness

in working age

adults1

Diabetic

Nephropathy

Leading cause of

end-stage renal disease3

Stroke

2- to 4- fold increase in cardiovascularmortality and stroke2

Diabetic

Neuropathy

Leading cause of non-traumatic

lower extremity amputations4

Relationship of Diabetes Complications to Hemoglobin A1c

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Intensive

N (%)

Standard

N (%) HR (95% CI) P

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

Secondary

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

Nonfatal 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 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 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 time

Ongoing 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 support network) to be able to talk about their feelings about diabetes

Insulin 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

Insulin 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-novolog) 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 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.”

People with type 1 diabetes have an individualized insulin:carbohydrate ratio that helps guide how much insulin to take with each meal and snack.

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1 or 2 injections of NPH and regular insulin per day

Rigid rules for composition and timing of meals

Urine tests for glucose

Aggressive therapy unsafe and of unknown benefits

Hemoglobin A1c 11-12%

Inevitable eye and renal complications

Inevitable “noncompliance”

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

Evidence supporting glycemic control

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

Advances in Type 1 Diabetes Treatment

• 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, dieting

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

Basal-Bolus Insulin Treatment of Type 1 Diabetes 2008 Insulin Delivery Systems: Insulin Pens

Technologic AdvancesSmaller meters

Small blood sample (0.3 ul)

Short test time (<5 secs)

Self-contained strips

Alternate site testing

Improved Blood Sugar Monitoring

Switching to CSII results in:

Lower HbA1c

Less HypoglycemiaGreater Patient Satisfaction

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

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• Lispro/aspart insulin is given in a programmable “basal rate”every few minutes. Additional insulin is given in adjustable “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

Insulin Delivery in Pump Compared to Multiple Daily Injections

Early Insulin Pump

ANIMAS

COZMO

MINIMED

Continuous Subcutaneous Insulin Infusion(CSII

Closed-Loop Insulin Pump

• Implantable insulin pump coupled to glucose sensor

• Algorithm for insulin delivery based on glucose level

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

• Islet and Pancreas Transplant

• Closed loop system

• Stem Cell-based Therapy

Experimental Treatment of Type 1 Diabetes

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An intervention that can arrest the ongoing immune response

and induce tolerance

• Beta cell replacement with tolerance to the graft – 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 directly or the associated abnormalities.

Experimental Treatment of Type 1 Diabetes: The Challenge

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Anti-CD3 Preservation of Beta Cell Function Anti-CD20 Preservation of Beta Cell Function

Embryonic Stem Cell Research

Somatic Cell Nuclear

Transfer Creation of ALS

Neurons

Induced Pleuripotential

Stem Cells

Type 1 diabetes is:

A manageable condition

A chronic condition

Often challenging

Entirely compatible with a happy

and healthy childhood and family

lif