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AFP June Clinical Sabin
AFP June Clinical Sabin
T
Background ype 2 diabetes mellitus (T2DM), and obesity. Furthermore, treatment
previously known as non-insulin options are limited by the lack of licenced
The incidence of type 2 diabetes mellitus dependent diabetes or adult- treatment modalities in the paediatric
(T2DM) in children and adolescents is onset diabetes, is a disorder arising from population, and adherence, psychosocial
increasing, mirroring the epidemic of insulin resistance and relative (rather than health and wellbeing are often poor.7
paediatric obesity. Early-onset T2DM is
absolute) insulin deficiency in the absence Early-onset T2DM is associated with
associated with poor long-term outcomes.
of autoimmune beta-cell destruction.1 It is significant long-term morbidity and
a polygenic disorder involving interactions mortality. Adolescents diagnosed with
Objectives
between genetic and environmental T2DM are predicted to lose 15 years from
In this article, we describe the growing risk factors that result in the underlying their remaining life expectancy when
problem of early-onset T2DM in Australia, pathophysiology of hepatic and muscle compared with their peers who do not
explore the difference between early- insulin resistance, and subsequent beta-cell have T2DM.8 Complications of diabetes
onset and adult-onset T2DM, and review failure.2 Most patients with this disorder are also common and present even earlier
the management of T2DM in children and are obese, and T2DM often remains than in adolescents with type 1 diabetes
adolescents. undiagnosed for many years while the mellitus (T1DM).9,10 A long-term study
patient progresses symptom-free through in Japan found that over a period of 20
Discussion the earlier stages of hyperglycaemia known years, 24% of the 1063 participants were
T2DM is difficult to differentiate from the as ‘pre-diabetes’. Pre-diabetes includes blind by a mean age of 32 years.11 Another
more common type 1 diabetes mellitus impaired fasting glucose (IFG; fasting study that followed 426 participants with
(T1DM) in the paediatric population. glucose between 5.6 and <7 mmol/L) and early-onset T2DM over a mean period of
Risk factors for T2DM include obesity, impaired glucose tolerance (IGT; two-hour 6.8 years found that 3% required renal
ethnicity and family history, and glucose levels between 7.8 and <11.1 dialysis by 35 years of age.12 Acquiring
adolescence is a predisposing time mmol/L in the oral glucose tolerance test).1 T2DM and its comorbidities at a younger
for the development of T2DM due to T2DM in children and adolescents age not only affects an individual’s ability to
physiological insulin resistance. Early- appears to be a more aggressive disease fully participate in study and work, but also
onset T2DM is more associated with than late-onset T2DM. Progression increases morbidity and mortality during
shorter duration to insulin requirement, from IFG or IGT to T2DM in children and the years of peak earning and working
development of diabetic complications adolescents does not necessarily progress capacity.13–15 T2DM in children and youth is
and cardiovascular disease than adult- linearly with time, and is faster than in therefore a major health issue.
onset T2DM and T1DM. The main goals adults, generally occurring over 12–21
in management include normalising
months.3–5 T2DM and ‘pre-diabetes’ with Demographics
hyperglycaemia, facilitating lifestyle
dysregulated glucose or insulin metabolism The prevalence of T2DM in children and
modifications and managing diabetes-
is integrally related to obesity, and is adolescents has increased around the
related and obesity-related comorbidities.
increasingly being seen in youth attending world, in parallel with the increase in
specialist obesity services.6 the rate of obesity.16–18 In Australia, the
The management of paediatric T2DM incidence of T2DM in patients under the
is complex as it involves managing the age of 17 years was approximately two per
comorbidities associated with diabetes 100,000 person-years, with a 27% rise in
© The Royal Australian College of General Practitioners 2016 AFP VOL.45, NO.6, JUNE 2016 401
CLINICAL T2DM IN CHILDREN AND ADOLESCENTS
average annual adjusted overall incidence therefore that this physiological, puberty- Diagnosis of T2DM in children
between 1990 and 2002.19 associated insulin resistance coincides and adolescents
Early-onset T2DM most commonly with the peak age of early-onset T2DM The presentation of T2DM varies from
occurs during adolescence and rarely presentation, and that pre-pubertal T2DM asymptomatic hyperglycaemia in a well
beforehand. Plasma insulin levels rise is much less common.9,22 Among the 1.2 child, perhaps detected through incidental
steadily from pre-pubertal baseline, peaking million youth in the SEARCH for Diabetes testing, to ketoacidosis in up to 25% of
during puberty then returning to pre- study, there were no children aged 4 years patients. These individuals are also at risk
pubertal levels by the third decade of life.20 or younger with T2DM, and only 19 cases of hyperglycaemic hyperosmolar non-
Insulin sensitivity decreases by around of children aged 5–9 years with T2DM ketotic state, which is associated with a
30% during puberty.21 It is no coincidence between 2002 and 2003.23 high mortality rate.24,25 The diagnosis of
T2DM in youth requires the diagnosis of
diabetes followed by the classification of
Box 1. Diagnosis of diabetes defined by the International Society of Paediatric diabetes type.26 It is worth noting that the
and Adolescent Diabetes (ISPAD) and American Diabetes Association (ADA) prevalence of T1DM is approximately 10-
guidelines26,30 fold higher than the prevalence of T2DM in
The diagnosis of diabetes is made by the measurement of hyperglycaemia in the absence of any most paediatric populations. Therefore, a
acute physiological stress and the presence of symptoms of hyperglycaemia: diagnosis of T1DM should be made in the
• fasting plasma glucose of ≥7.0 mmol/L acute setting if there is any doubt regarding
• plasma glucose of ≥11.1 mmol/L post-oral glucose tolerance test, with 1.75 g/kg (max 75g) of diabetes subclassifications.
anhydrous glucose dissolved in water Delayed treatment of T1DM in
• symptoms of diabetes, such as polyuria, polydipsia, nocturia, unexplained weight loss and a
youth increases the risk of diabetic
random plasma glucose of ≥11.1 mmol/L
ketoacidosis.27,28 Less common causes
• glycated haemaglobin (HbA1c) of >6.5%*
*The test should be performed in a laboratory using a method that certified by the National Glycohemoglobin
of diabetes, such as monogenic diabetes
Standardization Program (NGSP) and standardised to the Diabetes Control and Complications Trial (DCCT) due to hepatocyte nuclear factor 4
assay. A value of less than 6.5% does not exclude diabetes diagnosed using glucose tests.30,57 The role of alpha (HNF4A) and HNF1A mutations
HbA1c alone in diagnosing diabetes in children has not been established.
(previously known as mature-onset
402 AFP VOL.45, NO.6, JUNE 2016 © The Royal Australian College of General Practitioners 2016
T2DM IN CHILDREN AND ADOLESCENTS CLINICAL
© The Royal Australian College of General Practitioners 2016 AFP VOL.45, NO.6, JUNE 2016 403
CLINICAL T2DM IN CHILDREN AND ADOLESCENTS
may also promote weight loss.45 Long-term worth noting that while initiating insulin peptidase-4 (DPP-IV) inhibitors, although
metformin use is associated with a 1–2% injections will improve glycaemic control promising, require further investigation as
reduction in HbA1c.41 Insulin therapy is and heighten awareness of diabetes, early there are no long-term safety data and they
required for those with an HbA1c >9%, insulin therapy may also lead to poorer are not approved for use in those <18 years
severe hyperglycaemia (serum glucose compliance with treatment, leading to less of age.41,50
>15 mmol/L), or ketosis/ketoacidosis on patient contact and poorer diabetes control The overall goal of initial treatment is to
presentation (serum ketone ≥1.0 mmol/L in the long term.48 The decision for initiating achieve an HbA1c of <6.5%.41 Education for
and/or serum pH <7.3 ± bicarbonate insulin should therefore be made carefully, home blood glucose level (BGL) monitoring
<15 mmol/L).46 balancing the medical benefits with the is necessary to monitor fasting and
A variety of insulin regimens, such as adolescent and family dynamics. postprandial BGLs to achieve target BGL
basal insulin (0.25–0.5 units/kg starting dose) Other available oral antidiabetic agents (4–8 mmol/L) and HbA1c ranges (<6.5%).
or prandial insulin, are effective in achieving are either not approved for use in those A multidisciplinary approach involving
metabolic control.41 Although there are no aged younger than 18 years or are still under paediatric/adult endocrinologists, diabetes
data to date comparing different insulin investigation. Sulfonylureas are associated educators, dietitians, social workers and
regimens in adolescents, this needs to be with hypoglycaemia and a greater degree psychologists is required to achieve this, as
tailored to the patient’s requirements. Adult of weight gain (compared with metformin), well as lifestyle changes.
studies have shown that a basal glargine and may potentially accelerate the loss of
regimen is as effective as prandial lispro beta-cell function.49 Other medications, Management of comorbidities
insulin, with added benefits of simplicity such as thiazolidinediones, α-glucosidase Youth with newly diagnosed T2DM have a
and lower risk of hypoglycaemia.47 It is inhibitors, incretin-mimetics and dipeptidyl high prevalence of complications relating
Nephropathy Often present at diagnosis • Spot urine: 30–299 mg/g • If persistent (>2 samples), start ACE
14–22% in cross-sectional studies • 24-hour urine: 20–199 mcg/min inhibitor therapy even if BP normal
• Can be elevated due to smoking, • Aim to normalise microalbuminuria
exercise and menstruation • Treat hypertension
• Exclude orthostatic proteinuria and
renal causes
Depression Up to 14.7% and is more common Screen for symptoms of depression at Refer to mental health clinician
in girls diagnosis and periodically, especially in
those with poor glycaemic control and/or
frequent visits to emergency department
ACE, angiotensin-converting-enzyme inhibitor; BP, blood pressure; HDL, high-density lipoprotein; LDL, low-density lipoprotein; T2DM, type 2 diabetes mellitus
404 AFP VOL.45, NO.6, JUNE 2016 © The Royal Australian College of General Practitioners 2016
T2DM IN CHILDREN AND ADOLESCENTS CLINICAL
to diabetes and obesity at presentation.10 their care to maximise compliance and 14. Breton MC, Guenette L, Amiche MA,
Kayibanda JF, Gregoire JP, Moisan J. Burden of
Reports suggest the presence of optimise outcomes.
diabetes on the ability to work: A systematic
hypertension in 10–32% of patients, review. Diabetes Care 2013;36(3):740–49.
Authors
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Kung-Ting Kao MBChB, FRACP, Clinical Research of type 2 diabetes mellitus in children and
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non-alcoholic fatty liver disease in 22% at the Royal Children’s Hospital, Melbourne, VIC
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406 AFP VOL.45, NO.6, JUNE 2016 © The Royal Australian College of General Practitioners 2016