This document discusses prediabetes in children. It begins by defining prediabetes according to the ADA and WHO. It then discusses the prevalence of prediabetes in children, which ranges from 13.1-16.1% according to various studies. Risk factors for prediabetes in children include obesity, family history of diabetes, puberty, male sex, younger age, and certain ethnic origins. The pathophysiology and progression from prediabetes to diabetes is also reviewed. Treatment focuses on lifestyle changes and weight management, though some studies showed metformin may help in the short term. Screening and treatment guidelines are provided.

1. PREDIABETES IN
CHILDREN
PG STUDENT – DR ANCHLESH TEKAM
PG GUIDE – DR THAKRE MADAM

2. CONTENTS
• DEFINITIONS
• PREVALENCE OF PREDIABETES IN CHILDREN
• PATHOPHYSIOLOGY
• IDENTIFIED RISK FACTORS
• PROGRESSION FROM PREDIABETES TO DIABETES
• TREATMENT
• SUMMARY
• REFERENCES

3. DEFINITIONS
• Prediabetes is defined by plasma glucose levels that
are elevated above the normal range, but below the
threshold for diabetes.
• Early diagnosis of prediabetes identifies persons at risk
and prevents progression to type 2 diabetes mellitus
(T2DM) and cardiovascular disease.

4. ADA definition of prediabetes.
• Patients are at increased risk for diabetes if they have ANYONE of
the following 3 states:
1.Impaired fasting glucose (IFG) 100-125 mg/dl
2.Impaired glucose tolerance (IGT) A plasma glucose level obtained 2
hours after a 75-g oral glucose challenge > 140 mg/dl but < 200
mg/dl
3.Hemoglobin A1c level of 5.7%-6.4%

5. ADA definition of prediabetes.

6. WHO definition of prediabetes
• Patients are at increased risk for diabetes if they have 1 or both
of the 2 following states:
1. IFG: a fasting plasma glucose level of 110-125 mg/dl
2. IGT: a plasma glucose level obtained 2 hours after a 75-g oral
glucose challenge > 140 mg/dl but < 200 mg/dl.
• Neither definition of prediabetes includes other risk factors for
diabetes, such as family history of diabetes, obesity, or
parameters of the metabolic syndrome.

7. Prevalence of Prediabetes in the Pediatric Population
1 Prevalence using IFG and IGT.
• In 2005-2006,the prevalence of IFG and IGT were determined
among adolescents in the United States aged 12-19 years, using the
ADA criteria.
• The prevalence were found to be:
• • IFG only: 13.1%
• • IGT only: 3.4%
• • Anyone IFG and IGT: 16.1%.
• Li C, Ford ES, Zhao G, Mokdad AH. Prevalence of pre-diabetes and its association with clustering of cardio metabolic risk
factors and hyperinsulinemia among U.S. adolescents: National Health and Nutrition Examination Survey 2005-2006. Diabetes
Care. 2009;32:342-347.

8. Prevalence of prediabetes on the basis of IFG alone
• Previous studies in adolescents have shown that the prevalence of
IFG (>100 mg/dl) in this age group has increased markedly in recent
decades.
• In 1988-1994, the prevalence of IFG was 1.76%,increasing to 7.0%
in 1999-2000 and to 23% in 2007-2008.
• Fagot-Campagna A, Saaddine JB, Flegal KM, Beckles GL; Third National Health and Nutrition
Examination Survey. Diabetes, impaired fasting glucose, and elevated HbA1c in U.S. adolescents: the
Third National Health and Nutrition Examination Survey. Diabetes Care. 2001;24:834-837.

9. Prevalence of prediabetes on the basis of A1c alone
• In a multiethnic cohort study conducted between 2005 and 2010,
1156 obese children and adolescents (40% boys) underwent an oral
glucose tolerance test (OGTT) and A1c measurement.
• In 21% of these patients, A1c levels were 5.7%-6.4%.
• Among children classified as being at increased risk for diabetes on
the basis of their A1c values, only 47% were categorized as being at
increased risk on the basis of their OGTT results.
• Moreover, 27% of children with A1c levels below 5.7% were
diagnosed with prediabetes on the basis of OGTT results.
• Nowicka P, Santoro N, Liu H, et al. Utility of hemoglobin A(1c) for diagnosing prediabetes and diabetes in obese children
and adolescents. Diabetes Care. 2011;34:1306-1311.

10. Prevalence of Prediabetes in Children/Adolescents in the U.S.

11. Pathophysiology of Prediabetes
• Development of diabetes from normal glucose tolerance is a
continuous process.
• The first stage is characterized by insulin resistance
accompanied by a compensatory increase in insulin secretion;
this stage can last several years.
• Patients with both IFG and IGT have insulin resistance, but the
site of their predominant insulin resistance differs.
• Those with IFG have predominantly hepatic insulin resistance,
whereas those with IGT have predominantly muscle insulin
resistance.

12. Pathophysiology of Prediabetes
• In the second stage, beta-cells fail to compensate for increased
insulin resistance and hyperglycemia develops, progressing
from prediabetes to overt diabetes as beta-cell failure worsens.
• This progressive loss of beta-cell secretion probably has a
combination of genetic, environmental, and biochemical
determinants.
• The early presentation of prediabetes and T2DM in children
raises the possibility of an accelerated pathophysiologic
process in the young.

13. Pathophysiology of Prediabetes
Poor nutrition/lifestyle
Insulin Resistance
Impaired glucose tolerance
Chronic inflammation
Prediabetes
Diabetes
Complications

14. Identified Risk Factors for Prediabetes
1. OBESITY
• The prevalence of prediabetes varies among different studies of
obese children.
• IGT was detected in 25% of obese children aged 4-10 years and 21%
of obese adolescents aged 11-18 years.
• Sinha R, Fisch G, Teague B, et al. Prevalence of impaired glucose tolerance among children
and adolescents with marked obesity. N Engl J Med. 2002;346:802-810

15. Identified Risk Factors for Prediabetes
1. OBESITY
• In a study of 736 overweight and obese children in Italy, 7.66% had
IFG and only 3.18% had IGT.
• When compared with normal-weight adolescents, obese adolescents
had a
2.6- fold higher rate of prediabetes
• Cambuli VM, Incani M, Pilia S, et al. Oral glucose tolerance test in Italian overweight/obese children and
adolescents results in a very high prevalence of impaired fasting glycaemia, but not of diabetes. Diabetes
Metab Res Rev. 2009;25:528-534.

16. Identified Risk Factors for Prediabetes
2. Family history of diabetes.
• Family history is a strong risk factor.
• Among children and adolescents aged 7-15 years from Mexico, IFG
(according to ADA criteria) was identified in 88% of those with a family
history, compared with 1.9% of those without.
• Furthermore, the presence of family history in a first-degree relative
was associated with IFG, even in the absence of obesity.
• Rodriguez-Moran M, Guerrero-Romero F, Aradillas-Garcia C, et al. Obesity and family history
of diabetes as risk factors of impaired fasting glucose: implications for the early detection of
prediabetes. Pediatr Diabetes. 2010;11:331-336.

17. Identified Risk Factors for Prediabetes
2. Family history of diabetes.
• Similarly, among obese children from Germany, a history of parental
diabetes was associated with a 9.5-fold increased risk for
prediabetes.
3. Puberty.
• Among 437 overweight children and adolescents, puberty (Tanner
stage 2 or higher) was associated with a 5.5-fold increased risk
compared with the pre-pubertal period.
• Reinehr T, Wabitsch M, Kleber M, de Sousa G, Denzer C, Toschke AM. Parental diabetes,
pubertal stage, and extreme obesity are the main risk factors for prediabetes in children and
adolescents: a simple risk score to identify children at risk for prediabetes. Pediatr Diabetes.

18. Identified Risk Factors for Prediabetes
4. Sex.
• The prevalence of prediabetes is 2.4-fold higher in boys.
5. Age.
• Adolescents aged 12-15 years have been reported to have a
significantly higher rate of prediabetes than those aged 16-19 years.
• This may be related to the peak of pubertal insulin resistance that
occurs during early adolescence.
• Li C, Ford ES, Zhao G, Mokdad AH. Prevalence of pre-diabetes and its association with clustering of cardio
metabolic risk factors and hyperinsulinemia among U.S. adolescents: National Health and Nutrition
Examination Survey 2005-2006. Diabetes Care. 2009;32:342-347.

19. Identified Risk Factors for Prediabetes
6. Cardio metabolic risk factors.
• Adolescents with 2 or more cardio metabolic risk factors
(hypertension, dyslipidemia, and hypertriglyceridemia) have a 2.7-fold
higher rate of prediabetes than those with no cardio metabolic risk
factors.
7. Ethnic origin.
• Data from the National Health and Nutrition Examination Survey
among US adolescents revealed that non-Hispanic black youth have
demonstrated lower rates of prediabetes than non-Hispanic white
youth (prevalence ratio, 0.6; 95% confidence interval, 0.4-0.9).
• Li C, Ford ES, Zhao G, Mokdad AH. Prevalence of pre-diabetes and its association with clustering of
cardio metabolic risk factors and hyperinsulinemia among U.S. adolescents: National Health and
Nutrition Examination Survey 2005-2006. Diabetes Care. 2009;32:342-347.

20. Progression From Prediabetes to Diabetes
• Annually, 5%-10% of adults with prediabetes progress to overt
diabetes.
• Unlike adults, children and adolescents with prediabetes can convert
back to normoglycemia.
• In a study of 117 obese children and adolescents OGTT tests were
performed at baseline and after approximately 2 years.

21. Progression From Prediabetes to Diabetes
• Out of 33 children with IGT at baseline, 15 (45.5%) reverted to normal
glucose tolerance, 10 (30.3%) continued to have IGT, and 8 (24.2%)
developed T2DM.
• Severe obesity, weight gain, IGT, and black race emerged as the best
predictors of developing T2DM,
• whereas baseline fasting glucose, insulin level, and C-peptide level
were not predictive.
• Weiss R, Taksali SE, Tamborlane WV, Burgert TS, Savoye M, Caprio S. Predictors of changes in glucose
tolerance status in obese youth. Diabetes Care. 2005;28:902-909.

22. Progression From Prediabetes to Diabetes
• In another study, 128 overweight/obese Hispanic children with a
family history of T2DM were evaluated annually for 4 years with an
OGTT; the ADA criteria for prediabetes were used.
• Tremendous variability was seen in the individual patterns of change
in glucose status from year to year.
• Only 13% of participants had persistent prediabetes, whereas 47%
had intermittent prediabetes, with no clear pattern over time.
• Goran MI, Lane C, Toledo-Corral C, Weigensberg MJ. Persistence of prediabetes in overweight and obese
Hispanic children: association with progressive insulin resistance, poor beta-cell function, and increasing
visceral fat. Diabetes. 2008;57:3007-3012.

23. Progression From Prediabetes to Diabetes
• A high rate of reversion from IGT to normal glucose tolerance was
demonstrated in 128 obese white European youth diagnosed with IGT
in 2003-2006.
• After a mean of 3.9 years of follow-up, 75% of these children
converted to normal glucose metabolism, 16% continued to have IGT,
2% developed T2DM, and 7% were lost to follow-up.
• Kleber M, deSousa G, Papcke S, Wabitsch M, Reinehr T. Impaired glucose tolerance in obese white children
and adolescents: three to five year follow-up in untreated patients. Exp Clin Endocrinol Diabetes.
2011;119:172-176.

24. Is Prediabetes a Disease?
• Prediabetes is a recognized risk factor for both T2DM and
cardiovascular disease.
• However, it also can be considered a disease per se.
• Among adults, prediabetes is associated with retinopathy, a 2-fold
increased incidence of microalbuminuria, and neuropathy.
• No data describing the impact of prediabetes on morbidity in children
are yet available.

25. Is Prediabetes a Disease?
• Moreover, given the overlap between the metabolic syndrome and
prediabetes.
• It is hard to distinguish between the contribution of hyperglycemia
and the effect of other metabolic abnormalities.
• Finally, with the high rate of reversion to normal glucose tolerance,
the implication of the diagnosis of prediabetes in young adolescents
is unclear.

26. Treatment of Prediabetes
• The expert panel of the ADA focusing on prediabetes
acknowledged the strong association between diabetes
and obesity.
• They suggested that the first priority is maintenance of a healthy
weight and prevention of obesity.
• Several studies have demonstrated the success of interventions to
prevent obesity in children and adolescents.

27. Drug Intervention
• Adoption of a healthy lifestyle is beneficial to everyone.
• But, the question of drug therapy in children is much more
complicated.
• Several short-term studies (about 6 months in duration) in normo-
glycemic adolescents at risk for diabetes have shown that compared
with placebo, treatment with metformin results in a progressive
decline in fasting blood glucose.
• Srinivasan S, Ambler GR, Baur LA, et al. Randomized, controlled trial of metformin for obesity and insulin resistance in
children and adolescents: improvement in body composition and fasting insulin. J Clin Endocrinol Metab. 2006;91:2074-
2080. Abstract

28. Drug Intervention
• In a meta-analysis of 4 randomized controlled trials in participants younger
than 19 years who were treated with metformin for at least 2 months.
• A statistically significant mean reduction in fasting insulin and BMI was
seen with metformin (with and without lifestyle intervention) compared with
placebo.
• Metformin treatment of 15 obese adolescents with the polycystic ovary
syndrome and IGT was found to be beneficial; after 3 months, 8 patients
had normal glucose tolerance.
• Quinn SM, Baur LA, Garnett SP, Cowell CT. Treatment of clinical insulin resistance in children: a systematic review. Obes
Rev. 2010;11:722-730. Abstract
• Arslanian SA, Lewy V, Danadian K, Saad R. Metformin therapy in obese adolescents with polycystic ovary
syndrome and impaired glucose tolerance: amelioration of exaggerated adrenal response to adrenocorticotropin
with reduction of insulinemia/insulin resistance. J Clin Endocrinol Metab. 2002;87:1555-1559. Abstract

29. Prediabetes Process for Diagnosing
•S Screen
•A Assess and Advise
•F Follow-up
•E Evaluate progress

30. Screening Children for Prediabetes and Diabetes
• overweight and have 2 of any of the following risk factors
• Family history of type 2 diabetes in first- or second-degree
relative
• High-risk race/ethnicity
• Signs of insulin resistance or conditions associated with
insulin resistance
• Maternal history of diabetes of GDM during child’s gestation

31. Risk of Prediabetes in Adolescent Offspring of Mothers with GDM
Obese adolescents with normal glucose tolerant (NGT) (N=255)
No Exposure to GDM(n=210; 82.3%) Exposure to GDM (n=45; 17.7%)
Approx 5.75 times increase in risk; p < .001
Holder T, Giannini C, Samtoro N, et al. A low disposition index in adolescent offspring of mothers with
gestational diabetes: a risk marker for the development of impaired glucose tolerance in youth.

32. Screening Children for Prediabetes and Diabetes
• Begin screening at age 10 years or onset of puberty
• Screen every 3 years
• A1C test is recommended for diagnosis in children

33. Assessing Patients With Prediabetes
• What does the patient already know
• Determine what a patient already understands —or
misunderstands — at the start of discussions
• What is of concern/importance to the patient
• e.g., for women contemplating pregnancy, uncontrolled glucose
levels have been associated with birth defects
• Tailor information desired level of information
• Improves comprehension
• Limits emotional distress

34. Assessing Patients With Prediabetes
• Evaluate the predisposing risk factors
• Involve them in developing a management strategy, especially
changes in lifestyle
• Weight loss
• Increase activity
• Healthy eating
• Refer to HIGHER CENTRES for further evaluation if needed.

35. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: The
Evidence Report. NIH Publication # 98-4083, September 1998, National Institutes of Health.
American Diabetes Association. Diabetes Care. 2014;37(suppl 1):S14-S80.
Advice = Lifestyle Modification Facilitating Weight Loss
● Initial target: 1-2 pound/week weight loss
● Long-range goal: 7% loss of body weight
● Increase physical activity to ≥150 min/week
● Individualized medical nutrition therapy
● Provided by a registered dietitian

36. NIH Publication # 98-4083, September 1998, National Institutes of Health.
American Diabetes Association. Diabetes Care. 2014;37(suppl 1):S14-S80.
Advice = Lifestyle Modification Facilitating Weight Loss
• Reduce caloric intake
• Reduce dietary fat
• Limit intake of sugar-sweetened beverages
• Dietary fiber intake of 14 grams/1000 kcal
• Whole grains are 50% of grain intake
• 5-7 servings of fruits and vegetables a day

37. Advice = Achieving Healthy Eating Habits Plate Method
Non-starchy
vegetables
●Spinach
●Carrots
●Lettuce
●Greens
●Cabbage
●Green beans
●Broccoli
●Cauliflower
●Tomatoes
Grains and starchy foods
●Whole grain breads, whole
wheat or rye, Whole grain,
High-fiber
Protein
●Chicken or turkey,
●Fish
●Tofu
●eggs,
American Diabetes Association. Create your plate. Available at: http://www.diabetes.org/food-and-
fitness/food/planning-meals/create-your-plate/

38. Lifestyle Modification Physical Activity
Adults with prediabetes
Exercise program should include:
●≥150 minutes/week of moderate-intensity aerobic activity
●Spread over 3 or more days every week
●No more than 2 consecutive days without exercise
●Resistance training ≥2 times/week (If possible)
●Consider age and previous level of physical activity
Children with prediabetes, diabetes
Exercise program should include:
≥60 minutes of physical activity/day

39. Benefits of Physical Activity
• Increased insulin sensitivity
• Improved lipid levels
• Lower blood pressure
• Weight control
• Improved blood glucose control
• Reduced risk of CVD
• Prevent/delay type 2 diabetes
American Diabetes Association. Diabetes Care. 2014:37:S14-80.

40. EFFECTIVENESS OF DIABETES PREVENTION PROGRAM
PARAMETERS INTENSIVE LIFESTYLE METFORMIN
DELAY ONSET OF TYPE 2 DIABETES 11.1 YEARS 3.4 YEARS
REDUCED INCIDENCE OF TPYE 2
DIABETES
20% 8%
INCREASED LIFE EXPECTANCY 0.5 YEARS 0.2 YEARS
COST PER QALY $1124 $31286
Herman WH, et al for the Diabetes Prevention Program Research Group.Ann Intern Med. 2005:142:323-332

41. Overview of Trials in Prediabetes Lifestyle Modification Intervention
Study N Intervention Treatment
Risk
Reduction
Da Qing1,2 IGT 577 Lifestyle
6 years
20 years
34% - 69%
Finnish DPS3,4 IGT 523 Lifestyle
3+ years
7 years
58%
Diabetes Prevention
Program (DPP)5,6 IGT 3324 Lifestyle
3 years
10 years
58%
34%
1. Diabetes Care. 1997;20:537-544. 2. Lancet. 2008;371:1783-1789.
3. N Engl J Med. 2001;344:1343-1350. 4. Lancet. 2006;368:1673-1679.
5. N Engl J Med. 2002;346:393-403. 6. Lancet. 2009;374:1677-1686.

42. Overview of Trials in Prediabetes Pharmacologic Intervention
Study N Intervention Treatment
Risk
Reduction
Diabetes Prevention
Program (DPP)1,2 IGT 3324 Metformin
3 years
10 years
31%
18%
DREAM3 IGT 5269 Rosiglitazone 3 years 60%
STOP-NIDDM4,5 IGT 1429 Acarbose 3 years 21%
ACT NOW6 IFG ~600 Pioglitazone 3 years 81%
1. Diabetes Care. 2003;6:977–980. 2. Lancet. 2009;374:1677-1686.
3. Diabetes Care. 2011;34:1265-1269. 4. Lancet. 2002;359:2072-2077.
5. JAMA. 2003;290:486-494. 6. N Engl J Med. 2011;364:1104-1115.

43. Follow up
• Shown to be important to success
• Provide annual screenings for the development of diabetes
• Every 12 months for those with prediabetes
• Every 3 years if screening is negative
• Continually screen for modifiable risk factors at each interaction
• Emphasize long-term goals of treatment
• Monitor weight loss progress

44. Follow up
• Provide ongoing counseling for lifestyle modification
• Consider pharmacologic therapy (e.g., metformin) if appropriate
 IGT, IFG and/or A1C of 5.7-6.49%
 Especially if BMI >35 kg/m2
 Age <60
 Women with prior gestational diabetes
• Provide referrals

45. Evaluation
• An integral part of clinical practice
• Patients who understand the disease are more likely to
 Acknowledge health problems
 Understand their treatment options
 Modify behaviors
 Adhere to medication schedules

46. Evaluation
Use a log to track different parameters:
Weight
Calorie intake
Hours of sleep
Exercise time
Daily fitness and strength training

47. SUMMARY
• Prediabetic states are prevalent among children and adolescents.
• The prevalence of IFG ranges from 13% to 40% and of IGT, from
2% to 5%, whereas approximately 20% have A1c levels of 5.7%-
6.4%.
• The prevalence of prediabetes is significantly higher
among obese pubertal children with a positive family history.
• Moreover, the prevalence of prediabetes has increased markedly
over recent decades.

48. SUMMARY
• In adults, prediabetes is associated with risk for cardiovascular
disease.
• Concerns have been raised about the potential effect of
prediabetes on morbidity in adolescents.
• High percentage of children and adolescents with prediabetes
will convert to normal glucose tolerance over time.
• Interventions in adolescents with prediabetes, lifestyle change
focusing on development of healthier dietary and activity habits is
the mainstay of treatment.

49. REFERENCES
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with clustering of cardiometabolic risk factors and hyperinsulinemia among U.S.
adolescents: National Health and Nutrition Examination Survey 2005-2006.
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• Fagot-Campagna A, Saaddine JB, Flegal KM, Beckles GL; Third National Health
and Nutrition Examination Survey. Diabetes, impaired fasting glucose, and elevated
HbA1c in U.S. adolescents: the Third National Health and Nutrition Examination
Survey. Diabetes Care. 2001;24:834-837.

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51. REFERENCES
• Cambuli VM, Incani M, Pilia S, et al. Oral glucose tolerance test in Italian
overweight/obese children and adolescents results in a very high prevalence of impaired
fasting glycaemia, but not of diabetes. Diabetes Metab Res Rev. 2009;25:528-534.
• Rodriguez-Moran M, Guerrero-Romero F, Aradillas-Garcia C, et al. Obesity and family
history of diabetes as risk factors of impaired fasting glucose: implications for the early
detection of prediabetes. Pediatr Diabetes. 2010;11:331-336.
• Reinehr T, Wabitsch M, Kleber M, de Sousa G, Denzer C, Toschke AM. Parental
diabetes, pubertal stage, and extreme obesity are the main risk factors for prediabetes in
children and adolescents: a simple risk score to identify children at risk for prediabetes.
Pediatr Diabetes. 2009;10:395-400.
• Weiss R, Taksali SE, Tamborlane WV, Burgert TS, Savoye M, Caprio S. Predictors of
changes in glucose tolerance status in obese youth. Diabetes Care. 2005;28:902-909.
• Goran MI, Lane C, Toledo-Corral C, Weigensberg MJ. Persistence of prediabetes in
overweight and obese Hispanic children: association with progressive insulin resistance,
poor beta-cell function, and increasing visceral fat. Diabetes. 2008;57:3007-3012.
• Kleber M, deSousa G, Papcke S, Wabitsch M, Reinehr T. Impaired glucose tolerance in
obese white children and adolescents: three to five year follow-up in untreated patients.
Exp Clin Endocrinol Diabetes. 2011;119:172-176.

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54. THANK
YOU