Type 2 diabetes in children and youth Shokoufeh Bonakdaran, MD Assistant Professor of Endocrinology Mashhad University of Medical Sciences.

Type 2 diabetes in children and youth

Shokoufeh Bonakdaran, MD

Assistant Professor of Endocrinology

Mashhad University of Medical Sciences

There has been a rise in type 2 diabetes mellitus (T2DM) in children and adolescents, which may be related to global obesity trends , an actual rise in incidence and an increased diagnostic recognition that this condition can occur in children

The global burden of T2DM continues to rise as the worldwide

prevalence of adult diabetes is projected to increase from 246 to 380 million people by 2025.

T2DM currently accounts for 15% to 87% of newly diagnosed American youth compared with only 3% in the 1990s

Health burden

The decreasing age at onset of T2DM

has serious public health implications, as future generations are burdened with micro- and macrovascular complications at the peak of their productive years

Risk factors:

overweight or at risk for overweight Most pediatric patients are in the midst of puberty. 90% have at least one first- or second degree relative

with T2DM

- female predominance - more common among racial minorities, especially American Indians) and Asian/Pacific Islanders . genetic loci associated with higher risk for polygenic forms of

T2DM:transcription factor 7-like 2 gene (TCF7L2)

normal FPG in 91.5% combination of higher levels of

BMIz(standard deviation score for age and gender, HOMA-IR, and family history suggests the greatest risk for T2D and targets them for further evaluation and intensive preventative management.

clinical presentation of T2DM in youth can range from mild asymptomatic hyperglycemia to severe ketoacidosis

About one-third of T2DM patients are diagnosed by routine laboratory screening rather than as a result of specific complaints. Such accidental’ diagnosis is rare in T1DM

42% of African-American patients with T2DM presented with ketonuria and 25% with DKA

insulin resistance combined with the deleterious effect of chronic hyperglycemia on insulin secretion and action (glucose toxicity’) results in relative insulin deficiency

HHS

there are currently 29 reported cases of adolescents with HHS, of whom 26 were

African- Americans and 22 were males As in adults, HHS in adolescents is

associated with significant mortality (12 of these 29 cases, 41.4%

Accelerator Hypothesis

Obesity driven insulin resistance accelerates beta cell apoptosis through glucotoxicity and lipotoxicity

stressed beta cell metabolically and immunologicaly upregulated and more vulnerable to immune injury and apoptosis

obesity and weight gain are at the core of β-cell stress leading to both T1DM and T2DM and predicts earlier presentation of all diabetes types in individuals with increased weight gain

a 10% increment in relative weight was associated with a 50% to 60% increase in the risk of T1DM before age 3 years and a 20% to 40% increase from age 3 to 10 years

Autoimmunity?

a significant proportion of physician-diagnosed T2DM youth show evidence of pancreatic autoimmunity at screening

The presence of autoantibodies in adults with clinically suspected T2DM who have positive antibodies is associated with a high risk of eventually becoming insulin dependent, a condition termed latent autoimmune diabetes

children did not differ significantly from the children with T2DM and without autoantibodies with respect to age, gender, overweight status, lipids, blood pressure, C-peptide, glucose, and hemoglobin A1c (HbA1c) at manifestation as well as frequency of anti-thyroidal antibodies and insulin treatment during follow-up. Because starting insulin treatment in patients with T1DM is critical, the diagnosis of T2DM should be made with caution and only when beta-cell autoantibodies are negative.

In TODAY study

autoantibody positive patients: - Were less likely to have a first degree relative with diabetes- had lower BMI - lower systolic and diastolic blood pressure- higher HDL- Lower TG- higher HbA1C- Lower fasting C-peptide

- obese seropositive diabetic youth are closer to T1DM than their seronegative T2DM

TREATMENT

initial approach to the treatment of T2DM generally focuses on improvement in insulin

sensitivity, either through modification of

lifestyle habits or through pharmacologic intervention.

Patients who are not critically ill but

have signs of dehydration, ketosis, severe

hyperglycemia, or HbA1c >8.5% require treatment with insulin

Despite the goal of withdrawing insulin therapy after its initial introduction, only 28% of patients

were able to come off insulin, and of those, 60%required reinitiation of insulin because of poor control

PHARMAOCOTHERAPY

metformin is the only U.S. Food and Drug Administration (FDA)-approved oral treatment for youth with type 2 diabetes

Medication be titrated to a maximum dose of 2,000 mg/day, divided twice daily, based on effectiveness and tolerance of side effects

once glycemic control fails, additional agents, and typically insulin, are considered

bedtime long-acting analog (glargine or detemir) at a dose of 0.3–0.4 units/kg/day. thiazolidinediones (TZDs) and insulin secretagogues are

not FDA approved glinides(repaglinide and nateglinide, short-acting insulin

secretagogues) and glucosidase inhibitors (acarbose), are available for adults but are not approved in pediatrics

But!

Surveys show that ;50% of youth were treated with secretagogues in 2000 and 28% in 2008, and 9% were treated with TZDs in 2000

glucagon-like peptide (GLP)-1

GLP1 : data in pediatrics is almost nonexistent. administration of single 2.5- and 5-microg doses of

exenatide were associated with dose-dependent increases in plasma exenatide concentrations and improved postprandial glucose concentrations compared with placebo

there are no study outcomes of liraglutide in adolescents with type 2 diabetes.

Currently, there are no data on the use of dipeptidyl peptidase-4 inhibitors in pediatrics

COMORBIDITIES ANDCOMPLICATIONS

49% of young people with diabetes had systolic hypertension( eight times higher than in type 1 diabetes)

Microalbuminuria was more prevalent in youth with type 2 diabetes (22.2%) compared with youth with type 1 diabetes (9.2%) AND the rate of progression of microalbuminuria seems to be more rapid in adolescents with type 2 diabetes

Dyslipidemia, a major comorbidity of obesity, is present in high rates in youth with type 2 diabetes, ranging from 18 to 61% at diagnosis

management of hypertension

blood pressure tables must be used for diagnosis of hypertension.

Hypertension in pediatrics (blood pressure >95% for age, sex, and height, especially in conjunction with albuminuria) should be treated aggressively

If tolerated, an ACE inhibitor should be used; otherwise, an angiotensin receptor blocker should be used

hyperlipidemia

goal of LDL <100 mg/dL, triglycerides <150 mg/Dl, and HDL >35 mg/dL

Treatment strategies include maximizing

Non pharmacologic interventions for LDL

of 100–129 mg/dL, considering medication

on the basis of presence of other risk factors for LDL of 130–159 mg/dL, and initiating medication for LDL >160 mg/dL

Statin therapy has been shown to be safe and effective in youth and should be the first pharmacologic intervention

If triglycerides are >1,000 mg/dL, treatment with fibric acid should be considered to reduce the risk of pancreatitis