Download Diabetes-Update-2009.3

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
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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 = All
Creas= 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 a
glucose 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?
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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 Noninsulin 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, 2008
Author: Tom Graves
Photos: Jebb Harris
What a difference a pill makes...
Quiz
• Who was the first recipient of Injected
Insulin?
BETA CELL MASS
Natural History of Type 1 Diabetes
GENETIC
PREDISPOSITION
INSULITIS
BETA CELL INJURY
“PRE”DIABETES
DIABETES
TIME
Beta-Cell Destruction
Areas of Research
Natural History of Type 1 Diabetes
Prevention:Nutritional Intervention to Prevent (NIP)
Type 1 Diabetes
BETA CELL MASS
Prevention: Oral
Insulin Trial
TEDDY
Intervention
Studies –
MMF - Abate
T1DGC
GENETIC
PREDISPOSITION
INSULITIS
BETA CELL INJURY
“PRE”DIABETES
CLINICAL
ONSET
DIABETES
TIME
RESCUETransplant
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 Experience
Concerns
• 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 Diabetes
New and Old Insulins
X
X
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
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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
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www.t1diabetes.nih.gov
www.diabetestrialnet.gov
www.childrenwithdiabetes.com
www.jdrf.org
www.diabetes.org