Insulin Resistance in Children Kellie Bryant. Introduction Type 2 diabetes once considered a disease of adults has increased dramatically since 1980 in.

Insulin Resistance in Children

Kellie Bryant

Introduction Type 2 diabetes once considered a

disease of adults has increased dramatically since 1980 in children.

One third of all children less than 18 years of age diagnosed with diabetes have type 2.

The incidence of type 2 diabetes have paralleled the prevalence of obesity.

Type 2 diabetes in children is most commonly diagnosed at puberty.

One of the major characteristics of type 2 diabetes is insulin resistance which is considered the hallmark of type 2 dm.

Physiologic Effects of Insulin Insulin is a hormone produced in the beta

cells of the pancreas. Insulin is formed from proinsulin When the pancreas is stimulated by

elevated blood glucose proinsulin is broken a part leaving insulin and C-peptide.

Both are secreted and enter the blood stream in equimolar amounts.

Normal insulin—0.5-0.7 units/kg of body weight per day.

Insulin’s Effects on Body Tissues Stimulates entry of amino acids into cells—

enhances protein synthesis Enhances fat storage and prevents the

mobilization of fat for energy Stimulates the entry of glucose into cells to use

as an energy source Promotes the storage of glucose as glycogen in

muscle and liver cells Inhibits production of glucose from liver or

muscle glycogen Inhibits the formation of glucose from non-

carbohydrates

Since insulin and C-peptide are jointly secreted, either can be used to monitor endogenous insulin production.

Normal values for fasting serum insulin and C-peptide are 0-30 µIU/ml

Characteristics of Insulin Resistance Metabolic state characterized by fasting

and or postprandial hyperinsulinemia Reduced hepatic and skeletal muscle

insulin sensitivity is compensated for by increased pancreatic insulin secretion to maintain normal blood glucose, which overtime contributes to the development of postprandial hypergycemia.

Therefore, insulin resistance is most familiarly associated with type 2 diabetes and seen in two prediabetic states—impaired fasting glucose and impaired glucose tolerance (most recently referred to as pre-diabetes.

Insulin resistance is also associated with hypertension, dyslipidemia and coronary heart disease.

It is speculated that hyperinsulinemia contributes to large vessel atheroschlerosis whether or not glucose intolerance exists.

Researchers believe that insulin resistance is caused by abnormalities within cells called post-binding abnormalities.

Many individuals with insulin resistance are deficient in a glucose transporter called a GLUT-4.

GLUT-4 is regulated by the amount of insulin present in the body.

Insulin Resistance and Thrifty Phenotype Hypothesis Hypothesis—poor nutrition in fetal

and infant life is believed to impair the normal development and function of beta cells as well as insulin-responsive tissues primarily in the skeletal muscle causing the development of insulin resistance

Maternal diabetes, high and low birth weights and the later development of diabetes has been reported in Pima Indians.

This suggests that high birth weight influences the development of insulin resistance as much as fetal underdevelopment

Predictors or Insulin Resistance--Adults BMI of 25 or higher Waist circumference >40 inches in men and

35 inches in women Triglyceride >150 HDL-C <40 Blood pressure >130/85 Fasting blood glucose >110 Although these are adult references many

practitioners use these values along with other predictors as possible clinical signs of insulin resistance

According to Hansen, Fulop and Hunter studies for children should include Fasting blood glucose Fasting insulin Lipoproteins Cortisol Free T4 TSH (thyroid stimulating hormone Serum acetone HbA1c Urinalysis of glycosuria and ketonuria

Karotype and specialized genetic studies may be necessary if unusual phenotypic features are present to suggest chromosomal syndrome that may be associated with insulin resistance

Radiograph of the left hand and wrist may be indicated to assess bone age since insulin resistance in children is associated with advanced skeletal maturation.

Acanthosis nigricans Result of hyperinsulinemia

(consequence of insulin resistance Caused from the binding of insulin

to insulin-like growth factor receptors on keratinocytes and fibroblasts which results in hyperplasia of the skin

Causes light brown to black velvety rough areas typically at the base of the neck and skin folds

May be seen over joints including elbow, knees and knuckles or on the face and palms

60-90% of children who develop diabetes have acanthosis nigricans

It is helpful clinical sign because it is truly a manifestation of insulin resistance

Insulin Resistance Syndrome Characterized by hyperinsulinemia and

one or more of the following HTN Hypertriglyceridemia Hypercholesterolemia Decreased HDL, Increased LDL Obesity Menstrual disturbances Hirsutism

Insulin Resistance Seen as early as 2 years of age in

children with with appropriate genes, and environmental influences (ethnicity, obesity, decreased activity

Most common in puberty secondary to increased growth hormone secretion

Higher rate among African Americans, Hispanics and American Indians

Seen across all racial boundaries with increased obesity

Both parents obese the child has 66% chance of developing obesity

50% chance if one parent is obese Hyperinsulinemia contributes to

development of obesity and obesity exacerbates insulin resistance Insulin stimulates the appetite due to

its anabolic mechanisms

Obesity and high body fat mass decrease insulin sensitivity in skeletal muscle and liver

Children usually begin to develop body fat mass in preschool years

Obesity is the most significant risk factor for developing insulin resistance

Obesity In the last 30 years the % of young

people who are overweight has doubled

10-15% of children 6-17 years are overweight

40% of obese 7 year olds and 70% of obese adolescents become obese adults

Physical activity On a steady decline Many children live in single parent

or dual working households—more latchkey kids

Television Many children begin watching TV as

early as 6 months and are regular viewers by age 2.

American children watch TV for an average of 4 hours a day—2400 hours in one year

More time spent watching TV, computer and video games and less time in physical activity

Fast Food On any given ay 7% of the American

population eats fast food. Today’s children have grown up in the era

of “enhanced portion size” Typical fast food mal is high in calories, fat

and sugar Even though families may choose to eat

from home many rely on pre-processed “fast food” equivalents purchased at the grocery store because of lack of time to prepare a meal from scratch

Treatment Alteration in lifestyle including

modifications of Eating habits Increased physical activity Prevention—curb the incidence of

childhood obesity

Educational efforts targeted at the eating habits of both parents and children

Requires significant family involvement

May benefit from multidisciplinary approach from: primary care physician, RD or CDE, school personnel, psychologist

MNT remains the mainstay in treatment Regimen used most often by pediatric

diabetes dietitians is a variation of CHO counting

Reductions in calories and recommendations of 50% CHO, 20% protein and 30% fat

Fixed amount of CHO at each meal and snack

Physical activity increases the body’s sensitivity to insulin during activity and up to one day after activity

Studies show that regular aerobic exercise can reduce the risk of developing diabetes by 1/3 to ½

Encourage daily with a sustained heart rate of 80% of maximum for 20-30 minutes

Children should be encouraged to participate in activities they can perform easily and frequently

Helpful if physical activity is “family centered”

Pharmacalogical Agents Under exploration in the treatment

of insulin resistance Thiazolidionediones (TZD’s)

directly address insulin resistance They enhance glucose transport

into target cells (especially muscle and adipose tissue)

TZD’s activate the peroxisome-proliferator receptor-gamma which stimulates a genetic transcription factor that enhances production of GLUT-4

Many individuals with insulin resistance are deficient in GLUT-4

Biguanides (Metformin) inhibit glucose release from the liver by blocking gluconeogenesis and glycogenolysis

Biguanides associated with weight loss

There are no specific guidelines for using pharmacological agents in the treatment of insulin resistance

Specifically none of these medications have been sanctioned by the FDA to use in children

Given the prominence of insulin resistance and pathophysiology it is logical to theorize that reduction of insulin resistance before the development of diabetes may at least delay its occurrence

Recommendations Canadian Pediatric Society position

statement for all health care professionals to promote healthy active living for all family members

Highlights of recommendations Inquire about eating habits and physical

activity at all health care visits Promote consumption of fiber rich foods

instead of high fat high sugar foods Encourage to spend 30 minutes every

day in physical activity Counsel families to reduce sedentary

lifestyles—limit exposure to TV, video or computer games

Encourage parents to be positive role models and incorporate physical activities all family members can do together

Advise parents to enroll their children in age and developmentally appropriate recreational activities

Advocate Initiatives to serve healthy foods and

eliminate the sale of high CHO soft drinks and high fat/sugar snacks in schools

Policies to reduce the sale of over-sized fast foods

Initiatives that provide children with quality daily physical education classes and use of school facilities after school

Community sport and recreation programs

Construction of safe recreation facilities, parks and playgrounds

Physical education throughout all age groups in all schools

Allocation of funding for research in the prevention of childhood obesity

Oklahoma State Department of Health-Chronic Disease Service-Recommendations All overweight children with 2 other risk

factors tested for diabetes at the onset of puberty (random bs or 8h fasting bs)

If tests negative but remains high risk, test annually thereafter with aggressive lifestyle modifications

Treat HTN, dyslipidemia, etc aggressively and evaluate yearly

Families should be counseled on eating habits that maintain normal body wt and 30 minutes of daily physical activity as a family lifestyle

Conclusion Certain genes predispose certain

people to develop insulin resistance, but other factors—inactivity, wt gain trigger insulin resistance

Treatment is change in lifestyle Treatment must include the family

and a team effort with healthcare professionals