Type 1 Diabetes Mellitus:Update on Diagnosis

and Management in Children and

Adolescents

Mark Daniels, MD

CHOC/PSF Pediatric Endocrinology

February 18, 2009

Topics of Discussion

• The Diagnosis of Diabetes Mellitus

• Typing Diabetes Mellitus

• Areas of Research

• Novel Technological Tools

• Novel Supplemental Therapies

• Departures from the Scene

Diabetes is out there!!!

• Approximately one in 300-400 children under the age of 18 has type 1 DM.

• ~1 million Americans have type 1 DM

• Over 30 million annual physician visits for DM related services

• Up to 5% of PICU admissions are for DKA

Where Does Insulin Come From?

Quiz

• What is the Latin Root for the word Pancreas?

Pan = AllCreas= Meat

Is it Diabetes?Criteria for the diagnosis of diabetes

1. Fasting Plasma Glucose >= 126 mg/dl

OR

2. Symptoms of hyperglycemia and a Casual Plasma Glucose >= 200 mg/dl (Casual is defined as any time of day regardless of last meal.)

OR

3. 2-hour plasma glucose >= 200 mg/dl during an OGTT. Test is done using aglucose load containing 75 g anhydrous glucose dissolved in water.*

*In the absence of unequivocal hyperglycemia, these criteria should be confirmed by repeat testing on a different day

Modified from Diabetes Care 32:S62-S67, 2009

Could it be “pre-diabetes

FASTING CRITERIA:

• FPG <100 mg/dl = normal fasting glucose;

• FPG 100–125 mg/dl = IFG (impaired fasting glucose);

OGTT CRITERIA:

• 2-hour postload glucose <140 mg/dl = normal glucose tolerance;

• 2-hour postload glucose 140–199 mg/dl = IGT (impaired glucose tolerance)

Modified from Diabetes Care 32:S62-S67, 2009

What Type Is It?

• “…for the clinician and patient, it is less important to label the particular type of diabetes than it is to understand the pathogenesis of the hyperglycemia and to treat it effectively.”

• Diabetes Care 32:S62-S67, 2009

Type 1? Type 2? Or Something Else?

• Type 1

• Type 2

• Genetic-Monogenic

• Mitochondrial

• Medication-induced

• Pancreatic Destruction/Disease– CF– Pancreatitis

Type 1 DM

• Previously known as Juvenile-Onset, or Insulin Dependent Diabetes Mellitus

• Rapid progression –weeks to months• Absolute need for insulin• Autoimmunity in 90% (GAD65, ICA, IAA)• May present in Diabetic Ketoacidosis• Obesity is NOT protective• Usually childhood, but ANY age

What causes Type 1 DM?

• It is likely an “Autoimmune” attack on the Beta cells of the pancreas– Both Genetic and Environmental factors– 50% concordance in twins– Up to 6% of sibs, and 5% of children of

people with DM will also develop diabetes– Environmental trigger---Virus?

Type 2 DM

• Previously known as Adult Onset and Non-insulin dependent DM

• Usually associated with Obesity

• Antibodies negative (usually)

• Insulin and C-Peptide may be inappropriately normal or elevated

• May be treatable with oral medications, or may require insulin therapy from outset

Screening for Type 2 DM• Test children 10 years and over who are overweight (BMI >85th

percentile for age and sex, weight for height >85th percentile, or weight >120% of ideal for height) and have any TWO of the following risk factors:

• Family history of type 2 diabetes in first- or second-degree relative

• Race/ethnicity of Native American, African American, Latino, Asian American, or Pacific Islander

• Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, polycystic ovary syndrome, or small-for-gestational-age birth weight)

• Maternal history of DM or Gestational DM during the child's gestation

• Testing can be repeated every 3 years. FPG is the preferred test

Other Types of Diabetes

• Genetic Diabetes– MODY

• 9 defined types presenting after 1 year of life and usually before age 25

• Antibody negative• Insulinopenia• May be treatable with oral medications

– Neonatal Diabetes (KCNJ11, IPF1, GCK)• Presents in first 6 months, often with DKA• May be Transient (18 months) or Permanent• May be treatable with oral medications

Not type 1, Not type 2

Baby Ethan

OC Register July 11, 2008Author: Tom GravesPhotos: Jebb Harris

What a difference a pill makes...

Quiz

• Who was the first recipient of Injected Insulin?

TIMETIME

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DIABETES

“PRE”-DIABETES

GENETICPREDISPOSITION

INSULITISBETA CELL INJURY

Natural History of Type 1 DiabetesNatural History of Type 1 Diabetes

Beta-Cell Destruction

Areas of Research

TIMETIME

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DIABETES

“PRE”-DIABETES

GENETICPREDISPOSITION

INSULITISBETA CELL INJURY

Prevention:Nutritional Intervention to Prevent (NIP) Type 1 Diabetes

CLINICALCLINICALONSETONSET

Intervention Studies – MMF - Abate

Natural History of Type 1 DiabetesNatural History of Type 1 Diabetes

Prevention: Oral Insulin Trial

RESCUE-

Transplant

TEDDY

T1DGC

TrialNet is an international network of Diabetes centers that is dedicated to

the study, prevention, and early treatment of type 1 diabetes.

Natural History

• Screen 100,000 relatives of people with type 1 Diabetes Mellitus with 2 goals:1 – Understand the blood markers (antibodies)

and risk factors that predict who will progress to Diabetes Mellitus, and

2 – Identify subjects who may be eligible for prevention/early intervention studies

NIP• Nearlyborns and

Newborns who have a family member with Type 1 Diabetes Mellitus are eligible

• Offered a common Dietary Supplement, DHA (an Omega-3 fatty acid) in hopes of “resetting” the immune system and preventing self-attack

Oral Insulin

• Previous Study (DPT-1) suggested that diabetes could be delayed or prevented in certain high risk individuals with an Insulin Pill

• This study will look at this group specifically.

• Insulin pill does not lower blood glucose, but may change immune system attack

Diabetes Vaccinations Under Investigation

• Diamyd– GAD 65 injection– Leads to tolerance/immunomodulation

• BCG (bacille Calmette-Guerin)– Induces Tumor Necrosis Factor (TNF)– TNF selectively destroys Autoreactive T-cells,

decreasing the autoimmune attack

Islet Transplants - Edmonton

Islet Transplants - Edmonton

• In its 2006 annual report, the Collaborative Islet Transplant Registry– 225 patients received islet transplants

between 1999 and 2005. – approx two-thirds of recipients achieved

“insulin independence”—defined as being able to stop insulin injections for at least 14 days. At 2-year follow-up, about one-third of recipients were still insulin free.

Islet Transplants – Side Effects

• Mouth sores• Stomach upset/Diarrhea. • Increased blood cholesterol levels,

hypertension, anemia, fatigue, decreased white blood cell counts, decreased kidney function, and increased susceptibility to bacterial and viral infections.

• Increased risk of tumors and cancer.

The Brazil Experience

• The researchers enrolled 15 patients aged 14 to 31 (mean 19.2) between November 2003 and July 2006. All patients had been diagnosed with type 1 diabetes mellitus within the prior six weeks.

• All patients were first given an immune ablative conditioning regimen (Cyclophosphamide and Antithymocyte globulin)

Results from Brazil

• At time of publication (2007), 13 of 14 patients were off insulin, at a mean of 16 months (range 1 -35 months)

• 1 patient went back on insulin at ~ 1 year.

The Brazil ExperienceConcerns

• Cyclophosphamide – toxic to gonads

• 1 patient had Bilateral pneumonia – resolved– Could there be worse side effects –worth it?

• Not placebo controlled– Good honeymoon?

• Final Results REMAIN TO BE SEEN

Quiz 3

• What is the Root meaning of Diabetes Mellitus?

Diabetes = Siphon

Mellitus = Honey-Like

Natural History of Type 1 DiabetesNatural History of Type 1 Diabetes

New and Old Insulins

XX

Quiz 4

• What is the Root meaning of the word Insulin?

From Insula or Island

Pumps

Features of Pumps

• Continuous insulin infusion at variable rates (Basal)

• On-board calculators for determining insulin bolus dose for correction of hyperglycemia and coverage of carbohydrate intake

• Integration with Glucose meter and/or Continuous Sensor

• Allows for flexibility compared to injections

Meters and Downloads

Sensors/CGMS

• Embedded in Pump– Medtronic

• Stand Alone– Medtronic Guardian RT– DexCom– FreeStyle Navigator

Glucose Trend DexCom

Caveats of Sensor Use

• It only works if you wear it!!!

• Overreacting is as dangerous as underreacting

• Data Fatigue is common

• It is NOT a replacement for testing

• Sleep deprivation is a problem

• We are seeing things we didn’t want to know about.

Quiz 6

• Exenatide (Byetta) was modeled after a digestive enzyme from what animal?

The Gila Monster

Pramlintide (Symlin)

• Amylin is a naturally occurring hormone substance made in the pancreas .

• It works in three areas:– Controls hunger/satiety in the brain– Slows the transit of food in the stomach– Decreases release of glucose from the liver

Pramlintide (Symlin)

Pramlintide

Quiz 5

• After Insulin was discovered by Banting and Best, for how much was the patent

sold?

$1

Complications and Monitoring

• Associated Autoimmunity– Annual TSH levels (consider Thyroid Ab’s)– Celiac Sprue Screen at Dx, then as needed– Addison’s Screening as needed

• Blood Pressure – each visit• Kidney Effects

– Urine Microalbumin for children over 10 and 5 years post-Dx, then annually.

• Ophthalmology– Dilated Exam at 5 years post-Dx, then annually

• Lipids – Initial screen, then every 5 years

Departures

• Exubera Inhaled Insulin

• Glucowatch

• Pork Insulin

• Lente and Ultralente Human Insulin

Summary

• The Diagnostic Criteria for Diabetes Mellitus and Pre-Diabetes

• Monogenic Diabetes

• New Research Areas and Advances

• Meter, Pump and Sensor Technologies

• Monitoring of Complications

• Novel Non-insulin supplemental medications to improve glycemic control

It’s All About the Kids

Courtesy PADRE

Resources for Practioners and Families

• www.t1diabetes.nih.gov

• www.diabetestrialnet.gov

• www.childrenwithdiabetes.com

• www.jdrf.org

• www.diabetes.org