Type 1 and Type 2 Diabetesin Children and Youth:

What’s New and What’s TrueFrancine Ratner Kaufman, MD, FAAPDistinguished Professor Emerita of Pediatrics and Communications, The Keck School of Medicine of the University of Southern CaliforniaCenter for Diabetes and Endocrinology, Childrens Hospital Los AngelesChief Medical Officer of Medtronic DiabetesLos Angeles, CA

Prepared for your next patient.

I am the Chief Medical Officer for Medtronic Diabetes.

Disclaimer

Disclaimers continued

• Statements and opinions expressed are those of the authors and not necessarily those of the American Academy of Pediatrics.

• Mead Johnson sponsors programs such as this to give healthcare professionals access to scientific and educational information provided by experts. The presenter has complete and independent control over the planning and content of the presentation, and is not receiving any compensation from Mead Johnson for this presentation. The presenter’s comments and opinions are not necessarily those of Mead Johnson. In the event that the presentation contains statements about uses of drugs that are not within the drugs' approved indications, Mead Johnson does not promote the use of any drug for indications outside the FDA-approved product label.

Outline of Presentation1. Presentation, Diagnostic Criteria, Screening

2. Rates, Causes – Genes/Environment

3. Treatment

4. Co-morbidities and Complications

5. Prevention

11 8/12-Year-Old Female PatientsType 2 Diabetes (T2)• Chief complaint: Urinates 2 to 3 times

at night times 2 months– A1C 8.2% at outside clinic

• Weight 78 kg, BMI >95th percentile for age/gender – Reported 30 lb weight gain last

year, recent loss• BP 128/83• Menses at age 10 years – irregular• Prenatal – excessive maternal weight

gain, ? diabetes, • Family history

– Mother from Arizona, AI/HA, + for obesity

– Father is non-Hispanic White, hypertension

Type 1 Diabetes (T1)• Chief complaint: Urinates 2 to 3 times

at night times 2 weeks– A1C 8.2% at outside clinic

• Weight 63 kg, body mass index (BMI) >85th percentile for age/gender– Reported 15 lb weight gain last

year, recent loss • Blood pressure (BP) 92/65• Menses at 10 years – irregular• Prenatal – excessive maternal weight

gain, no diabetes• Family history

– Mother from Arizona, HA, + for obesity

– Father non-Hispanic White, hypertension

• Presentation– T1 rapid onset, severe hyperglycemia, acidosis, diabetic

ketoacidosis (DKA)• Results of TrialNet show T1 can be indolent

– T2 indolent, mild hyperglycemia, rare acidosis, no DKA• AA high rate of mild DKA, higher glucose/A1C, symptomatic at

presentation• Diagnostic criteria is the same for T1 and T2

– Symptoms of diabetes plus casual glucose ≥200 mg/dL – Fasting plasma glucose ≥126 mg/dL – 2-hour postload glucose ≥200 mg/dL during oral glucose tolerance

test (OGTT) • ?A1C >6.5%

– Used in adults but not established in children

Presentation, Diagnostic Criteria, Screening

Presentation, Diagnostic Criteria, Screening • Evidence of insulin

resistance, hypertension, dyslipidemia, NASH

• Presentation during or after puberty

• T2 in first-degree relative• Acanthosis nigricans,

sleep apnea, polycystic ovary syndrome (PCOS), candidiasis

• Evidence of insulin deficiency – hyperglycemia and acidosis, DKA mistaken for flu

• Hardest diagnosis in infants/toddlers

• No other family member• Other autoimmune

diseases

Zeitler P. Approach to the obese adolescent with new-onset diabetes. J Clin Endocrinol Metab. 2010;95(12):5163–5170

Screening for T1

• In the context of research trials– TrialNet, Immune

Tolerance Network,TEDDY, etc.

• Screen with antibodies,? genes

• Reason– Prevention studies

• Oral insulin, omegas, vitamin D, anti-CD3

– Natural history study

Immune Tolerance Network

The reason to screen and intervene early in T1D:

• Common, serious in terms of morbidity and mortality

• Latency period without symptoms

• Screening test with sensitivity and specificity

• Intervention early is more effective, preservesC-peptide

American Diabetic Association. Type 2 diabetes in children and adolescents. Diabetes Care. 2000;23(3):381–389

Criteria*: Overweight (BMI 85th percentile for age and sex, weight for height 85th percentile, or weight 120% of ideal for height)

PLUS: any 2 of the following risk factors:· Family history of diabetes mellitus (DM) 2 in first- or second-degree relative· Race/ethnicity · Signs of insulin resistance

Age of Initiation: Age 10 or at onset of puberty Frequency: Every 2 years in the context of health visit Test: Fasting plasma glucose preferred

* Clinical judgment should be used.

Screening for T2American Diabetes Association (ADA) / American Academy of

Pediatrics (AAP) Consensus Statement, 2000

Screening for T2

Measurement6th GradeN = 6367

8th GradeN = 1740

BMI (kg/m2) Mean (SD) 22.4 (5.7) 24.3 (5.9)

BMI percentile (adjusted for age and gender)

<8585–94

≥95

50.5%19.8%29.7%

51.0%19.8%29.2%

Fasting glucose (mg/dL)

Mean (SD)<100

100–109110–125

≥126

93.4 (6.7)84.0%14.7%1.2%

0.1%*

98.2 (8.5)59.5%34.3%5.8%

0.4%**

Fasting insulin (µU/mL) ≥30 6.2% 36.2%

Results of the HEALTHY Study and Pilot – Diabetes Not Found

Baranowski T, Cooper DM, Harrel J, et al. Presence of diabetes in a U.S. eighth-grade cohort. Diabetes Care. 2006;29(2):212–217; HEALTHY Study Group; Kaufman FR, Hirst K, Linder B, et al. Risk factors for type 2 diabetes in a sixth-grade multiracial cohort: the HEATHLY study. Diabetes Care. 2009;32(5):953–955

*n=6 of which only 1 confirmed on follow-up testing**n=7

Causes: Genes and the Environment• 3–5% increase in T1 consistently• T2 from <2–25% of new onset diabetes

SEARCH for Diabetes in Youth Study Group; Liese AD, D’Agostino RB Jr, Hamman RF, et al. The burden of diabetes mellitus among US youth: prevalence estimate from the SEARCH for Diabetes in Youth Study. Pediatrics. 2006;118(4):1510–1518

Causes: Obesity as a Risk Factor

• Type 2 – 100% African American– 95% non-Hispanic – 91% Hispanic

• Type 1 – 44% BMI >85th percentile – 30% BMI >95th percentile– Greater than the general population rates

Search Data

BMI >85th Percentile at Diagnosis

SEARCH for Diabetes in Youth Study Group; Liese AD, D’Agostino RB Jr, Hamman RF, et al. The burden of diabetes mellitus among US youth: prevalence estimate from the SEARCH for Diabetes in Youth Study. Pediatrics. 2006;118(4):1510–1518

ENVIRONMENTAL

TRIGGERS

TIME

Causes T1B

ETA

CELL M

ASS

GENETICS BETA CELL INJURY DIABETES

“PRE” DIABETE

S

NEWLY DIAGNOSED DIABETES

HUMORAL AUTOANTIBODIES

CELLULAR (T CELL) AUTOIMMUNITY

LOSS OF INSULIN

GLUCOSE STARTS TO INCREASE

(ICA, IAA, GAD65A, ICA512A)

Honeymoon

Causes T1: Genes and Antibodies• 4 antibodies: glutamic acid decarboxylase (GADA), islet

tyrosine phosphatase (IA2), zinc transporter 8 A (ZnT8A), insulin autoantibodies (IAA)– >90% newly diagnosed +Abs; 3.5–4% of unaffected first-degree

relatives • 40–50% of genetic predisposition on short arm of

chromosome 6, Class II HLA region of the major histocompatibility complex (MHC) – Whites HLA-DR3 or HLA-DR4, Blacks HLA-DR7, Japanese HLA-DR9

• ~11 other loci, insulin gene chromosome 11 (INS-VNTR), T-cell activation and regulation genes (CTLA-4), protein tyrosine phosphatase N22 (PTPN22), genes in interleukin pathway (IL-2R) – HLA, CTLA-4, and PTPN22 are associated with other autoimmune

diseases

Causes T1 Number of Antibodies

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

7270

11384

61598966

41465852

30334035

22191919

782

10 1

Number at Risk

Su

rviv

al D

istr

ibu

tion

Fu

ncti

on

P-value <0.001(Log Rank Test)

0 1 2 3 4 5 6 7

STRATA: 1 Ab (ICA Only) 2 Abs3 Abs 4 Abs

Years Followed

Causes T2: THE HEALTHY MIDDLE SCHOOL STUDY

Distribution of Glycemic Risk Factors by BMI Percentile<85

(N=3221)85–94

(N=1255)95

(N=1882)

Fasting glucose (mg/dL) 92.8 (6.7) 93.3 (6.8) 94.5 (6.6)

Fasting glucose ≥100 13.5% 15.5% 20.8%

p <.0001§

Fasting insulin (μU/mL) 8.4 (5.2) 12.8 (7.5) 22.1 (15.8)

Fasting insulin ≥30 0.8% 3.0% 19.6%

p <.0001§

6th Grade Students—Predominately Minority

Baranowski T, Cooper DM, Harrel J, et al. Presence of diabetes in a U.S. eighth-grade cohort. Diabetes Care. 2006;29(2):212–217; HEALTHY Study Group; Kaufman FR, Hirst K, Linder B, et al. Risk factors for type 2 diabetes in a sixth-grade multiracial cohort: the HEATHLY study. Diabetes Care. 2009;32(5):953–955

Weiss R, Taksali SE, Tamborlane WV, et al. Predictors of changes in glucose tolerance status in obese youth. Diabetes Care. 2005;28(4):902–909

• 117 obese children and adolescents

• NGT• N=84

• IGT• N=33

• NGT• N=76

(90.5%)

• IGT• N=8 (9.5%)

• NGT• N=15

(45.5%)

• IGT• N=10

(30.3%)

• T2DM• N = 8

(24.2%)

Mean follow-up of 20.4 + 10.3 months

Baseline and outcome glucose tolerance classification T2DM, type 2 diabetes

Causes T2

IGT to NGT IGT to T2D

BMI 33 versus 44

BMI z-score 2.27 versus 2.76

Weight Δ kg 6.1 versus 27

BMI Δ 1.06 versus 6.8

Causes T2Comparison of Subjects with Impaired Glucose Tolerance (IGT) Who Developed

Type 2 Diabetes and Who Reverted to Normal Glucose Tolerance (NGT)

Weiss R, Taksali SE, Tamborlane WV, et al. Predictors of changes in glucose tolerance status in obese youth. Diabetes Care. 2005;28(4):902–909

Dabalea D, Hanson RL, Bennett PH, et al. Increasing prevalence of Type II diabetes in American Indian children. Diabetologia. 1998;41(8):904–910

Diabetes in pregnancy can lead to a cycle of diabetes affecting future generations.

Causes T2: Gestational Diabetes as a Driver of T2

Causes T2: Progression from Pre-diabetes to Diabetes Pre-diabetes A1C 5.8–<6.4%

15% IFG, FPG >100 mg/dL25% IGT in obese,

2h OGTT PG >140 mg/dL

DiabetesA1C >6.4%

FPG >126 mg/dL, RPG >200 mg/dL3,700/ year (TIDM 16,000)

6% W, 67% AI1/3 AA, HA, API

Metabolic Syndrome Risk Factors

31.3% BMI>85th percentile

16.9% obese

Insulin sensitivity 75%Impaired glucose toleranceBeta-cell 50%

Insulin sensitivity 50%DiabetesBeta-cell 75%

Gunger N, Bacha F, Saad R, et al. Youth type 2 diabetes: insulin resistance, beta-cell failure, or both? Diabetes Care. 2005;28(3):638–644; Arslanian SA, Lewy VD, Danadian K. Glucose intolerance in obese adolescents with polycystic ovary syndrome: roles of insulin resistance and beta-cell dysfunction and risk of cardiovascular disease. J Clin Endocrinol Metab. 2001;86(1):66–71; and Bacha F, Saad R, Gungor N, et al. Adiponectin in youth: relationship to visceral adiposity, insulin sensitivity, and beta-cell function. Diabetes Care. 2004;27(2):547–552

• Family History • Environmental Factors • Genetic Susceptibility• Beginning in Utero• Maternal Obesity• Breast Feeding

Obesity Insulin sensitivity 75% Normal glucose tolerance Beta-cell function 2Xs

11 8/12-Year-Old Female Patients• Obtain the following work up:

– Random plasma glucose 247 mg/dL, repeat A1C 8.5%

– CO2 20 meq/L, venous pH 7.38, LDL 178 mg/dL, triglycerides 215 mg/dL

• ANTIBODIES ALL NEGATIVE• Treatment: In- or out-patient?

– Do you start insulin?– Metformin alone is first-line therapy

when glucose level is <250 mg/dL and patient is non-ketotic

– All patients and families receive diabetes and lifestyle education.

• Obtain the following workup:– Random plasma glucose,

247 mg/dL, repeat A1C 8.5%– CO2 16 meq/L, venous pH 7.32,

LDL 165 mg/dL, triglycerides200 mg/dL

• ANTIBODIES GADA+• Treatment: In- or out-patient?• What kind of insulin treatment?

– Intensive?• All patients and families receive

diabetes and lifestyle education.

New onset of diabetesBMI >85th percentile

Pancreaticautoantibodies

Type 1

Insulinrequirement

Consider MODY; if not obese,

NHW

Likely Type 2

Monitor course

Type 2

C-peptide normal/elevated• Type 2 ?adherence• Severe resistance/deficiency

Positive

Negative

No

Yes

Zeitler P. Approach to the obese adolescent with new-onset diabetes.J Clin Endocrinol Metab. 2010;95(12):5163–5170

Treatment: Determining Diabetes Type in Youth with BMI >85th Percentile

Treatment: Diabetes is Hard to Manage

Age Pre-Meal BG HS/Night BG A1c

Toddler (0–5 years) 100–180 110–200 ≥7.5 & ≤8.5%

90–180 School-age(6–11 years) <8%

Adolescent(12–19 years) 90–130 90–150 <7.5%

Type 2 80–130 90–150 <7.0%

Silverstein J, Klingensmith G, Copeland K, et al. Care of children and adolescents with type 1 diabetes: a statement of the American Diabetes Association. Diabetes Care. 2005;28(1):186–212

Early and Persistent Glucose Control is Important.

Treatment

• Glucose monitoring – Self-monitoring glucose, continuous

glucose monitoring, understanding glucose targets, A1C quarterly

• Medications – Insulin therapy: Multiple injections, pens,

pumps, changing dosages prn• Medical nutrition therapy

– Balancing food: Managing carbs, weight • Psychosocial support• Assess, treat co-morbidities, complications

– BP, cholesterol, thyroid, celiac, eye exams, microalbuminuria, disordered eating

• Visits to health care team– Routine pediatric care, flu shots, hepatitis

B immunization, transition planning– Sick day management

• Glucose monitoring – Self-monitoring glucose, understanding

glucose targets, A1C quarterly • Medications

– Glucose lowering agents Metformin, insulin therapy Others not approved

• Medical nutrition therapy– Weight reduction, lifestyle counseling

• Psychosocial support• Assess, treat co-morbidities, complications

– BP, cholesterol, disordered eating, PCOS, NASH, microalbuminuria, eye exams

• Visits to health care team– Routine pediatric care, flu shots, hepatitis

B immunization, transition planning– Sick day management

Silverstein J, Klingensmith G, Copeland K, et al. Care of children and adolescents with type 1 diabetes: a statement of the American Diabetes Association. Diabetes Care. 2005;28(1):186–212

Early and Persistent Glucose Control is Important.

Treatment: DCCT Results, EDIC Results and Rate of Severe Hypoglycemia

0

0.1

0.2

0.3

0.4

0.5

0 1 2 3 4 5 6 7

Years in EDIC

1

3

5

7

9

11

13

15

6 7 8 9 10 11 12

Retinop

Neph

Neurop

DCCT Results

EDIC Results

Reduction in Severe Hypoglycemia

52 studies show that CSII is significantly more effective in lowering A1C compared to MDI and conventional insulin therapy.

Bruttomesso D, Pianta A, Crazzolare D, et al. Continuous subcutaneous insulin infusion (CSII) in the Veneto region: efficacy, acceptability and quality of life. Diabet Med. 2002;19(8):628–634; Bell DSH, Ovalle F. Improved glycemic control with use of continuous subcutaneous insulin infusion compared with multiple insulin injection therapy. Endocr Pract. 2000;6(5):357–360; Rudolph JW, Hirsch IB. Assessment of therapy with continuous subcutaneous insulin infusion in an academic diabetes clinic. Endocr Pract. 2002;8(6):401–405; Chantelau E, Spraul M, Mühlhauser I, et al. Long-term safety, efficacy and side effects of continuous subcutaneous insulin infusion treatment for type 1 (insulin dependent) diabetes mellitus: a one centre experience. Diabetologia. 1989;32(7):421–426; Boland EA, Grey M, Oesterle A, et al. Continuous subscutaneous insulin infusion. A new way to lower risk of severe hypoglycemia, improve metabolic control, and enhance coping in adolescence with type 1 diabetes. Diabetes Care. 1999;22(11):1779–1784; Maniatis AK, Klingensmith GJ, Slover RH, et al. Continuous subcutaneous insulin infusion therapy for children and adolescents: an option for routine diabetes care. Pediatrics. 2001;107(2):351–356; Litton J, Rice A, Friedman N, et al. Insulin pump therapy in toddlers and preschool children with type 1 diabetes mellitus. J Pediatr. 2002;141(4):490–495; and Weissberg-Benchell J, Lomaglio JA, Seshadri R. Insulin pump therapy: a meta-analysis. Diabetes Care. 2003;26(4):1079–1087

Treatment T1: Insulin Pump Therapy Improves Control

(Insulin Pump)

Compared with MDI, insulin pumps are more effective at reducing A1C.

Treatment T1: CSII Reduces Incidents of Severe Hypoglycemia

Rudolph JW, Hirsch IB. Assessment of therapy with continuous subcutaneous insulin infusion in an academic diabetes clinic. Endocr Pract. 2002;8(6):401–405; Bode BW, Steed RD, Davidson PC. Reduction in severe hypoglycemia with long-term continuous subcutaneous insulin infusion in type 1 diabetes. Diabetes Care. 1996;19(4):324–327; and Boland EA, Grey M, Oesterle A, et al. Continuous subscutaneous insulin infusion. A new way to lower risk of severe hypoglycemia, improve metabolic control, and enhance coping in adolescence with type 1 diabetes. Diabetes Care. 1999;22(11):1779–1784

Severe hypoglycemic episodes MDI vs CSII

Treatment T1: Meta-analysis for Mean Difference in A1C between CSII and MDI

Pickup JC, Sutton AJ. Severe hypoglycaemia and glycaemic control in Type 1 diabetes: meta-analysis of multiple daily injections compared with continuous subcutaneous insulin infusion. Diabet Med. 2008;25(7):765–774

In 22 studies, severe hypoglycemia was reduced with CSII by a rate ratio of 2.89 for RCTs and 4.34 for before/after studies. The mean difference in A1C was 0.21% for RCTs and 0.72% for before/after studies, related to initial A1C (p<0.001).

Treatment T1: Continuous GlucoseMonitoring

Multiple RCTs have been performed

• Across the spectrum of glucose control

• Adults and children• Starting therapy MDI and CSII• All show relationship between

sensor use and decrease in A1C

Starting Therapyand A1C

Study Groups

Change in A1C

SAP vs Control

RealTrendN=132

MDI >8.0 SAP v CSII ~.5

EurythmicsN=83

MDI 8.2 SAP v MDI 1.23

OnsetN=154

New onset children

11.2SAP v CSII

.2OutcomeC-peptide

JDRFN=322

CSII or MDI7.6 and <7.0

CSII or MDI + CGM Adults .5

STAR 3N=495

MDI>7.4, <9.5 SAP v MDI Adults and

Children .6

Bergenstal RM, Tamborlane WV, Ahmana A, et al. Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes. New Eng J Med. 2010;363(4):311–320; Misso ML, Egberts KJ, Page M, et al. Continuous subcutaneous insulin infusion (CSII) versus multiple insulin injections for type 1 diabetes mellitus. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD005103; Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group; Beck RW, Buckingham B, Miller K, et al. Factors predictive of use and of benefit from continuous glucose monitoring in type 1 diabetes. Diabetes Care. 2009;32(11):1947–1953; and Raccah D, Sulmont V, Reznik Y, et al. Incremental value of continuous glucose monitoring when starting pump therapy in patients with controlled type 1 diabetes: the REALTrend study. Diabetes Care. 2009;32(12):2245–2250

Treatment T1: Glycemic Control During Real-time CGMMeta-analysis of Randomized Controlled Trials Using Individual Patient Data

Pickup JC, Freeman SC, Sutton AJ. Glycemic control in type 1 diabetes during real time continuous glucose monitoring compared with self monitoring of blood glucose: meta analysis of randomized controlled trials using individual patient data. BMJ. 2011;343:d3805

Treatment T1: STAR 3 Study

7.3%7.5% 7.5% 7.5%

8.0%8.0%

8.1% 8.1%

Bergenstal RM, Tamborlane WV, Ahmana A, et al. Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes. New Eng J Med. 2010;363(4):311–320

Sensor Augmented Pump

A1C 8.3% n=244

Adults=166, Pediatrics=78

Multiple Injections

A1C 8.3% n=241

Adults=163, Pediatrics=78

A1C at 3, 6, 9, and 12 Months: All Patients

Treatment T1

7.5%

7.7%7.8%

7.9%8.3%8.4%

8.6%8.5%

A1C at 3, 6, 9, and 12 Months: Pediatrics 7–18 Years

Bergenstal RM, Tamborlane WV, Ahmana A, et al. Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes. New Eng J Med. 2010;363(4):311–320

-0.19

-0.64-0.79

-1.21-1.5

-1

-0.5

0

21-40% 41-60% 61-80% 81-100%Frequency of Sensor Use (% of Time)

Chan

ge in

A1C

at 1

Yea

r vs

Base

line

n=27 n=46 n=108 n=56

Treatment T1

The majority of patients used sensors >60% of the time.

SAP Groupn=247

MDI Groupn=248

PValue

Severe HypoglycemiaRate per 100 person-years

13.31 13.4 0.84

Diabetic Ketoacidosis Number of events(# pts)

3 (3) 2 (1) 0.38

Weight Change +2.4 kg +1.8 kg 0.19

Severe hypoglycemia rate low and at lower A1C, little DKA

A1C Reduction is Correlated with Increased Sensor Usebut Not an Increase in Hypoglycemia or DKA

Bergenstal RM, Tamborlane WV, Ahmana A, et al. Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes. New Eng J Med. 2010;363(4):311–320

Treatment T1

Sensor AugmentedInsulin Pump

Insulin Pump Therapy

Predictive LGS with restart when glucose returns

to normal

Present

Low Glucose Suspend

Past

Treat to targetClips off highs

Overnightclosed loop

Fully automated closed loop

Intermittent closed loop

Potential Future products

20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 540

40

80

120

160

200

240

280

Glu

cose (

mg/d

L)

SG #1 SG #2 SG (Control) MBG

20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54012345

eP

ID I

nfu

sio

n

Rate

(U

/h)

Time (h)

Night #2 (CL)Night #1 (CL) Day (OL)

The Evolution of a Fully-Automated Insulin Delivery System

Rosenbloom AL, Silverstein JH, Amemiya S. Type 2 diabetes in children and adolescents. Pediatric Diabetes. 2009;10(12):17–21

Treatment: T2 ISPAD Guidelines, 2009

• Randomized clinical trial with a pre-randomization run-in period– 704 patients at 15 clinical centers– 3 treatment regimens

• Metformin + Placebo • Metformin + Rosiglitazone• Metformin + Intensive Lifestyle Program• At treatment failure: Standardized approach to

insulin initiation

• Primary outcome: Time to failed glycemic control

• Inclusion criteria– Age 10–17 years– Duration of diabetes <2 years– BMI 85th percentile

Funded by National Institute of Diabetes and

Digestive and Kidney DiseasesNational Institutes of Health

Copeland KC, Zeitler P, Geffner M, et al. Characteristics of adolescents and youth with recent-onset type 2 diabetes: the TODAY cohort at baseline. J Clin Endocrinol Metab. 2011;96(1):159–167

Treatment T2

Medications at Presentation• No medication 11%• Insulin only 12%• Metformin only 49%• Metformin + insulin 25%• Other medication 4%

Mean ± SD or %

Age (years) 14.3 ± 2.0Race/Ethnicity

White 19.6% African American 37.4%

Hispanic 32.2% Native American 5.5%

Other/Unknown 5.3%

BMI (kg/m2)36.2 ± 7.9

25 - 71BMI Z-score +2.3 ± 0.5

Treatment T2: The TODAY Trial

Copeland KC, Zeitler P, Geffner M, et al. Characteristics of adolescents and youth with recent-onset type 2 diabetes: the TODAY cohort at baseline. J Clin Endocrinol Metab. 2011;96(1):159–167

A Clinical Trial to Maintain Glycemic Control in Youth with Type 2 Diabetes

TODAY Study Group; Zeitler P, Hirst K, Pyle L, et al. A clinical trial to maintain glycemic control in youth with type 2 diabetes. New Eng J Med. 2012:1–10

Treatment T2: The TODAY Trial Study Results

TODAY Study Group; Zeitler P, Hirst K, Pyle L, et al. A clinical trial to maintain glycemic control in youth with type 2 diabetes. New Eng J Med. 2012:1–10

TODAY Study Group; Zeitler P, Hirst K, Pyle L, et al. A clinical trial to maintain glycemic control in youth with type 2 diabetes. New Eng J Med. 2012:1–10

Treatment: Lifestyle Tips for Teens with Diabetes Series from National Diabetes Education Program

0

10

20

30

40

50

60

70

80

90

100

↑BP ↑TG ↓HDL ↑Waist MetS

%

Type1AType 2MetS: >2 cardiovascular disease (CVD) risk factors

Rodriguez BL, Fujimoto WY, Mayer-Davis EJ, et al. Prevalence of cardiovascular disease risk factors in U.S. children and adolescents with diabetes: the SEARCH for diabetes in youth study. Diabetes Care. 2006;29(8);1891–1896

• 68% American Indian37% Asian, 32% African American, 35% Hispanic,16% White (p<0.0001)

• At least 2 risk factors 92% of type 2 14% of type 1

(p<0.0001)

Co-morbidities and Complications: Cardiovascular Risk Factors—SEARCH Trial

Co-morbidities and Complications: Australia

Eppens MC, Craig ME, Cusumano J, et al. Prevalence of diabetes complications in adolescents with type 2 compared with type 1 diabetes. Diabetes Care. 2006;29(6):1300–1306

Complications T1: Catastrophe at Diagnosis—DKA • Severe metabolic disturbance

– Insulin deficiency, secondary counter-regulatory hormone elevation• North America and Europe statistics

– 30% of new cases, 20% of deaths from diabetes <20 years• 1/200 episodes result in cerebral edema

– 1/3 die, 1/3 permanently impaired, 1/3 recover• Costs: >2.5 billion dollars• Risk factors for cerebral edema

– Young age, poverty, no knowledge of signs and symptoms, lack of access to care– Lower pCO2 , higher BUN at DX, Rx with HCO3, smaller increase in Na

• Mechanism(s)– Osmotic cellular swelling versus vasogenic process

Glaser NS, Wooten-Gorges SL, Marcin JP, et al. Mechanism of cerebral edema in children with diabetic ketoacidosis. J Pediatr. 2004;145(2):164–171

Complications T2: Type 2 Diabetes is a Severe Disease• Hyperglycemic Hyperosmolar Non-Ketotic Syndrome—at onset—very high glucose

levels– 3.7% (7/190) in Philadelphia

Mortality 14.3%– Currently 28 reported other cases

Mortality 43%

• Pima Indians diagnosed at <20 years of age – 22% had microalbuminuria at diagnosis– Increased to 60% at 20–29 years of age

• Indigenous Canadians 23 years of age, 9 years duration – HbA1c 10.9%

67% poor glycemic control – 45% hypertension requiring treatment– 35% microalbuminuria (6% required dialysis) – 38% pregnancy loss – 9% mortality Fourtner SH, Weinzimer SA, Katz LEL. Hyperglycemic hyperosmolar non-ketotic syndrome in children with type 2 diabetes. Pediatr Diabetes. 2005;6(3):129–

135; Butler M, McKary RA, Popoff IJ, et al. Specific inhibition of PTEN expression reverses hyperglycemia in diabetic mice. Diabetes. 2002;51(4):1028–1034

Kaufman, Type 2 Youth

Complications and Co-Morbidities T2

TODAY Study Group; Zeitler P, Hirst K, Pyle L, et al. A clinical trial to maintain glycemic control in youth with type 2 diabetes. New Eng J Med. 2012:1–10

Prevention or Interdiction of T1

• Anti-CD3• Mycophenolate Mofetil +/- Anti-CD25• Anti-CD20• Anti-thymocyte globulin• CTLA-4• GAD-Alum immunization• Intense metabolic control• Oral insulin• Supplemental vitamin D• Omega fatty acids• Hydrolyzed formula compared to cow's milk• Outside TrialNet and Immune Tolerance

Network– Alpha-1-antitrypsin, BCG, insulin peptide B:9-23,

heat shock protein DiaPep277

Some studies have shown an initial benefit in

C-peptide preservation.

Has tolerance been achieved or only

immuno-blockade?

Are multiple or sequential agents required?

What are the risks/benefits over

the long term?

TrialNet and Immune Tolerance Network

Social Norms Subculture

Sectors of Influence

Behavioral Settings

Individual Factors

Home

Communities

Health Care Access, Adherence

Schools and Child Care

Worksites

Age, Sex, SES, Race/Ethnicity

Culture

Psychosocial Factors - Stress

Genes,Gene-Environment

Interactions

Intrauterine Environment

Built EnvironmentGovernmentPublic HealthAgricultureEducation

MediaLand Use and

TransportationCommunitiesFoundations

IndustryFood

BeverageRetail

Leisure and RecreationEntertainment

Physical Activity

Food & Beverage

Intake

Energy BalanceEnergy Intake Energy Expenditure

ObesityInsulin Resistance/Deficiency

Type 2 Diabetes

5. Prevention Socio-ecological Model

• Intervention schools– Environmental changes, food

service, physical education– Behavior change—curriculum

based– Communications and

promotional campaign

49

• School unit of randomization• Primary outcome: Combined

prevalence of overweight plus obesity

• 42 schools – ≥50% minority and/or ≥50% with

free/reduced lunch– Comprehensive health screening,

results sent to parents

Diabetes Care 29:212–217, 2006

Prevention: The HEALTHY Study

• Reduction in percentage of overweight/obesity by 4% in both groups

• Prevalence of obesity declined more in intervention schools (p=0.05)

• Significant reduction in intervention schools (p=0.04)– BMI z-score – Prevalence of large waist circumference– Fasting insulin fell

• In the overweight/obese subgroup (n=2292), intervention schools had significantly greater decreases in prevalence of:– Obesity (p=0.04)– Large waist circumference (p=0.03)– Insulin (p=0.04)

HEALTHY Study Group; Foster GD, Linder B, Baranowski T, et al. A school-based intervention for diabetes risk reduction. New Eng J Med. 2010;363(5):443–453

Prevention: The HEALTHY Trial RESULTS

1. All foods and beverages served in schools meet Dietary Guidelines for Americans.

2. Increasing access to high-quality, affordable foods through new or improved grocery stores and healthier corner stores and bodegas.

3. Increasing the time, intensity, and duration of physical activity during the school day.

Prevention: RWJ F as in Fat

4. Increasing physical activity by improving the built environment in communities.

5. Using pricing strategies—both incentives and disincentives—to promote the purchase of healthier foods.

6. Reducing youths’ exposure to the marketing of unhealthy foods through regulation, policy, and effective industry self-regulation.

Conclusion

Gut

Food

Pancreas

Muscle

Glucose

Insulin

Type 1 diabetes• Genetic predisposition

and environmental triggers cause autoimmunity, +antibodies

• Rare in family members• Screening in research • Presentation rapid, severe,

but not always• Treatment with education,

support and intensive insulin, plus technology,risk of hypoglycemia, A1C main outcome measure

• Complications related to dysglycemia, occur in youth but rare, co-morbidities related to autoimmunity

• Prevention trials withmulti-agents/approaches

Type 2 diabetes • Genetic predisposition and

environmental trigger of obesity, insulin resistance and deficiency

• Common in first-, second-degree relatives

• Screening criteria but rare to find asymptomatic

• Presentation slow, mild, but not always, and maybe less than thought

• Treatment needs to be more aggressive than monotherapy to maintain glycemic control

• Complications common, early, co-morbidities related to insulin resistance

• Prevention addresses the environment to support healthy lifestyle adoption

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