► Introduction, definition and epidemiology
Diabetes mellitus is the name given to a group of broad-spectrum disorders characterized by elevated plasma glucose. In practical pediatrics, type 1 diabetes accounts for around 96% of all affected children and is characterized by absolute insulin deficiency due to autoimmune destruction of insulin-producing beta cells in the pancreas.
Affected children will die unless insulin therapy is instituted. In contrast, the majority of adults with diabetes have type 2, characterized by a relative defect in insulin secretion, and resistance of target tissues to the effects of insulin. There has been a dramatic increase in the prevalence of type 2 diabetes in adult populations since the 1950s, and this has been linked to the increasing prevalence of obesity.
Type 2 diabetes in children is likely emerging for the same reasons. In the United Kingdom, type 2 diabetes in children began to appear in the late 1990s, particularly in ethnic minority children. These were from Pakistan, the Middle East or Africa-Caribbean; from 12 to 16 years of age; and characterized by severe insulin resistance as assessed by hyperinsulinemia.
A survey by the British Pediatric Surveillance Unit (UVPB) in 2005 detected an incidence of 0.53 new cases per 100,000 inhabitants per year. This compares with an incidence of 28 cases per 100,000 inhabitants per year for children aged 0 to 14 years with type 1 diabetes in 2013.
Although more than 50% of affected children were of white UK origin, the likelihood of having a child with newly diagnosed type 2 diabetes was 14 times higher for a child of Caribbean African or South Asian origin. The National Pediatric Diabetes Audit for 2013/14 identified around 500 children and young people with type 2 diabetes, compared to more than 26,000 with type 1 diabetes. A second UVPB survey was carried out in 2015/16 and is likely to show a significant increase in incidence.
► Pathology and evolution of the disease
Type 2 diabetes (T2DM) in children and young people is clearly different from type 1 diabetes, and the underlying pathology is similar to that of adults with type 2 diabetes; i.e. insulin resistance and beta cell failure . However, it is now known that type 2 diabetes has unique characteristics, including more rapid progression of pancreatic beta-cell insufficiency, decreased response to treatments, earlier onset, and more rapid progression of complications.
There may also be subgroups of children who have different rates of disease progression. T2DM is also frequently associated with other features of insulin resistance or metabolic syndrome. These include obesity, dyslipidemia, hypertension, albuminuria, ovarian hyperandrogenism, nonalcoholic fatty liver disease (NAFLD), and obstructive sleep apnea. There is also a component of systemic inflammation estimated by C-reactive protein, inflammatory cytokines, and elevated white blood cell counts.
The natural history in childhood begins with fasting hyperinsulinemia, exacerbated by obesity.
This is followed by postprandial hyperglycemia , when pancreatic beta cells are unable to maintain circulating insulin levels in response to a glucose load (impaired glucose tolerance in a glucose tolerance test). Due to a combination of lipid and glucose toxicity in beta cells, increasing tissue insulin resistance and hepatic glucose production, fasting hyperglycemia occurs.
In early natural history there is a loss of the first phase of the insulin response. There is a second phase of hyperinsulinemia in response to an oral glucose tolerance test, but such a progressive loss leads many affected adults to eventually become insulin dependent. Insulin resistance means an altered response to the physiological actions of insulin on carbohydrate, lipid, and protein metabolism and on endothelial function.
The main tissues affected by insulin resistance are the liver, muscle and fat.
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Treatment Options for Type 2 Diabetes in Adolescents and Young People (TODAY) was a landmark clinical study that compared the effects of metformin, metformin plus rosiglitazone, and lifestyle interventions on glucose control in 677 young people. with type 2 diabetes. There was a rapid loss of glycemic control in many of the participants, even though they only had a short duration of diabetes (less than 1 year).
The rate of loss of glycemic control - even with therapy - was significantly faster than published rates in adults. In the same study, many of the participants had evidence of microvascular complications and risk factors for macrovascular complications at the time of diagnosis:
- 14% of participants had blood pressure equal to or greater than the 95th percentile
- 13% had microalbuminuria
- 80% had low HDL cholesterol
- 10% had increased triglycerides
These complications appear to progress faster in children than in adults: a study in First Nation Canadians with childhood type 2 diabetes showed that neurological complications appeared within 5 years of diagnosis; and that important complications such as dialysis, blindness or amputation appear 10 years after diagnosis.
► Diagnosis including history and investigation
Diabetes is diagnosed according to the World Health Organization (See Box 1). Currently this requires fasting or random capillary or venous glucose testing; or a measure of glycosylated hemoglobin.
The classic features of type 2 diabetes in childhood include presentation with symptoms during the second decade of life, with a mean age of diagnosis of around 13 years. This roughly corresponds to peak growth and the associated physiological insulin resistance . Girls are affected more than boys in a ratio of approximately 2:1, and this may be related to gender differences in body fat mass.
Type 2 diabetes affects children of all ethnicities, but in the UK it disproportionately affects those of non-European descent, for example children of South Asian origin (Pakistan, India, Bangladesh, Sri Lanka) or Africa Caribbean. Type 2 diabetes disproportionately affects families with lower socioeconomic status.
In 85% there is a strong family history of type 2 diabetes or cardiovascular disease, often in a parent, sibling or grandparents.
It is not uncommon for children to be identified coincidentally, apparently asymptomatic, in a primary care center or when measuring glucose in another family member with diabetes. However, a minority presents with metabolic decompensation and diabetic ketoacidosis .
Another group may present with severe non-ketotic hyperosmolar dehydration , which has a high risk of mortality.
Finally, type 2 diabetes is a non-autoimmune and non-HLA associated disease. The main differential diagnoses of type 2 diabetes are shown in box 2. It cannot be stressed strongly enough if there is any doubt about the diagnosis of type 2 diabetes, then it is much safer to start treatment with insulin and then review the diagnosis.
Certain early life events may be associated with the development of insulin resistance syndrome and type 2 diabetes and may be asked in the history. Children born small for gestational age are at increased risk of insulin resistance due to decreased intrauterine growth; These children also have an increased risk of premature adrenarche. It is also important to ask the history about other features related to metabolic syndrome.
In girls, ask if they had menarche and at what age. Ask if their periods are regular, painful or heavy, and if they have excessive body hair.
Second, consider the risk of obstructive sleep apnea and ask if you snore at night or are drowsy during the day.
Thirdly consider depression ; Many affected children have low self-esteem, feel bad about their bodies and have low levels of motivation; this is underdiagnosed.
Other health problems related to obesity include problems such as slippery femoral epiphysis; pancreatitis, cholecystitis, and idiopathic intracranial hypertension.
On examination, almost all affected children are overweight or obese , with a body mass index above the 85th percentile for age and sex.
There is often acanthosis nigricans , a velvety pigmented skin that affects the inflections of the skin such as the neck, armpits and groin: this is a manifestation of insulin resistance.
Blood pressure is often elevated (systolic or diastolic blood pressure above the 95th percentile for age and height).
► Investigations
Hepatic steatosis is present in 25-45% of adolescents with type 2 diabetes mellitus.
Capillary, plasma or venous glucose is necessary to make the diagnosis of diabetes mellitus. It is also useful to have a baseline HbA1c, to provide an estimate of the duration of hyperglycemia before diagnosis. In addition to routine measurements of height, weight, and blood pressure, other investigations should be included at the time of diagnosis such as an assessment of ketone production; urea and electrolytes to assess osmolarity and dehydration; infection evaluation (urinary tract, respiratory tract, skin); type 1 diabetes autoantibodies; and baseline liver function.
The presence of type 1 diabetes autoantibodies suggests the diagnosis of type 1 diabetes, and an earlier need for insulin therapy.
Liver enzymes increased to more than twice the upper limit of normal are suggestive of nonalcoholic fatty liver disease (NAFLD). Hepatic steatosis is present in 25-45% of adolescents with type 2 diabetes mellitus, and is part of the NAFLD spectrum. NAFLD is the most common cause of cirrhosis in children in the UK.
After the acute phase, as soon as any metabolic decompensation is corrected, other baseline evaluations such as a blood sample for lipids and cholesterol should be included; first morning urine for albumin creatinine ratio; and screening for retinopathy. Hypertriglyceridemia and decreased HDL cholesterol are hallmarks of dyslipidemia associated with type 2 diabetes. Other findings include increased very low-density lipoprotein (VLDL), elevated LDL-c, elevated lipoprotein a, and increased small dense particles of LDL.
Decreased lipoprotein lipase activity, increased lipoprotein glycosylation, and increased lipoprotein oxidation mean that lipoproteins are more atherogenic , increasing cardiovascular risk for these children.
Albuminuria (either micro or macro) is present at diagnosis in a significant proportion of adolescents with type 2 diabetes mellitus, and the prevalence increases with the duration of diabetes .
Baseline digital retinal photographs should be performed as soon as practically possible after diagnosis as part of the national retinopathy screening program.
► Management
A useful review was published by the International Society for Pediatric and Adolescent Diabetes, from which this article is reported. The main emphasis of management is lifestyle modification. The overall management goals are to achieve weight loss; and achieve an increase in exercise capacity.
The risk of microvascular and macrovascular complications in adults increases with the duration of diabetes and with lack of glycemic control, and this has also been shown in diabetes in childhood, so it is vital to achieve and maintain metabolic control through normalization of glycemia; and control of comorbidities including hypertension, dyslipidemia, nephropathy, and non-alcoholic fatty liver disease. Reducing the rate of complications may require tighter glucose control in childhood type 2 diabetes than in childhood type 1 diabetes.
Education around lifestyle modification is not only for the child, but also for his or her family . The entire family may need education to understand the principles of type 2 diabetes treatment and the critical importance of lifestyle changes to prevent chronic complications.
The entire family should be encouraged to change the consistency of the diet with healthy eating recommendations, including individualized counseling for weight reduction, reducing total and saturated fat intake, and increasing fiber intake. Key areas that have been found important in children include the elimination of sugary sodas and juices ; eat meals on time and in one place, without other activity (for example, TV), and ideally with the family group; portion control by reducing portion size; and limit high-fat, high-calorie-dense foods at home.
Exercise management involves developing individual exercise programs that are enjoyable, affordable for the family, and involve at least one other family member. Families should be encouraged to develop a daily exercise program, including reducing sedentary time.
Opportunities may include using stairs instead of elevators; walk part of the way to school; use a home exercise machine, or exercise DVDs; and walking with a family member after school. The UK guideline recommendations of at least one hour a day of exercise to exhaustion are usually not possible for children with type 2 diabetes, at least initially. Any exercise is beneficial, and promoting achievable goals with a gradual increase can avoid disappointment.
Self -monitoring of capillary blood glucose is very important in childhood to detect hyperglycemia and its response to interventions. This should be done regularly and include a combination of fasting and postprandial (approximately 1.5 hours after meals) glucose monitoring.
Once the objectives have been achieved, the frequency of monitoring can be reduced to 2-3 fasting controls and 2-3 post-prandial capillary controls per week. Checks should be performed more frequently during intercurrent illnesses. Clearly, children receiving insulin treatment should be monitored more frequently. Glycosylated hemoglobin should be evaluated every 3 months if you are on insulin treatment.
First-line therapy should always be metformin
The goals of drug therapy are to decrease insulin resistance (e.g., metformin), increase insulin secretion (e.g., sulfonylureas), slow postprandial glucose absorption (acarbose, not recommended in children), or finally increase the entry of glucose into cells (insulin).
First-line therapy should always be metformin , as there is a reasonable evidence base for its use, and a good safety profile, with no risk of hypoglycemia. It is standard practice in the UK to initiate metformin therapy upon diagnosis, along with diet, exercise and lifestyle modification.
Metformin belongs to a class of drugs called biguanides, and acts on insulin receptors in fat, muscle and liver . Reduces hepatic glucose production by decreasing gluconeogenesis; increases insulin-stimulated glucose uptake; may have some effect on reducing appetite; and can reduce HbA1c by 1-2%.
A recent large randomized controlled trial comparing 3 treatment regimens found that metformin monotherapy alone was associated with durable glycemic control in about half of children and adolescents with type 2 diabetes. However, it may have intestinal side effects including transient abdominal pain, diarrhea and nausea.
The usual starting dose is 500 mg once daily, increasing over 6-8 weeks to the maximum tolerated dose, or 2 g/day in 2 divided doses. However, a liquid preparation is available (250 mg/5 mL), which allows for slower dose titration; or alternatively, an extended release preparation. There is also the advantage that for girls with the complication of polycystic ovarian syndrome, metformin can normalize ovulatory abnormalities. This can, of course, increase the risk of pregnancy and girls need to be counseled on this point.
If there is inadequate glycemic control with metformin, then it is currently standard practice in the UK to add insulin . Despite hyperinsulinemia and insulin resistance, relatively small doses of a long-acting analog insulin preparation can be effective without meal boluses. If despite long-acting insulin therapy, glycemic control remains suboptimal, rapid or short-acting insulin should be added for postprandial hyperglycemia.
The side effects of insulin are hypoglycemia and weight gain; So clearly this is not an ideal agent . Unfortunately, the best randomized controlled trial to date compares regimens that included rosiglitazone, a thiazolidinedione that is restricted for use in Europe due to a possible association with cardiovascular events in older people with type 2 diabetes. Evidence of alternative treatment agents is desperately needed. second line for glycemic control in type 2 diabetes. Issues regarding the challenges of conducting clinical trials in this age group are fully developed in a recent consensus document.
All other agents are not currently approved for use in children and youth under 18 years of age. These agents include sulfonylureas and meglitinide/repaglinide, which act by increasing insulin secretion. The main adverse effect is hypoglycemia, which can be prolonged. Thiazolidinediones are also not recommended for use in children. They work by increasing insulin sensitivity in muscle, fat and liver. Side effects include weight gain and edema. Alpha glucosidase inhibitors such as acarbose reduce carbohydrate absorption in the intestine, and cause flatulence, which limits treatment adherence.
Incretin mimetics are more promising and many trials are ongoing to evaluate the benefit in children. Glucagon-like peptide-1 (GLP-1) receptor agonists are secreted by L cells in the small intestine into the circulation in response to food. They act on pancreatic beta cells to increase insulin secretion. They also suppress glucagon secretion, prolong gastric emptying, and increase satiety.
They are rapidly degraded by dipeptidyl peptidase IV (DPP-IV). Side effects include nausea, vomiting, and dizziness, which may improve over time; and are administered by injection. DPP-IV inhibitors inhibit the enzyme that breaks down GLP-1, resulting in higher concentrations of GLP-1; However, unlike GLKP-1 agonists, they have no effect on gastric emptying, satiety or weight loss. However, they can be given orally.
Bariatric surgery may be considered in the future for adolescents with obesity-related complications, including type 2 diabetes. Gastric bypass has significant complications including malabsorption of essential vitamins and minerals. However, gastric bands appear to have lower morbidity and mortality; and is associated with a 70% remission rate in adults.
► Tracking
The annual review for children with type 2 diabetes should include a reassessment of comorbidities to include the degree of obesity, nonalcoholic liver disease, dyslipidemia, hypertension, menstrual irregularities, obstructive sleep apnea, mood, and the affection. Investigations should include blood pressure at each visit (average of 3 measurements using an appropriately sized cuff); height, weight and BMI at each visit; lifestyle, diet and exercise evaluation; and annual controls that include liver function tests, lipids and cholesterol as a screening; first morning urine for albumin creatinine ratio; retinopathy screening.
Prevention
In the UK the authors did not see the rapid rise in childhood type 2 diabetes that was expected 10 years ago. However, the large number of children with obesity and impaired glucose tolerance suggests that there is still the potential for a larger number of children who may develop type 2 diabetes. Prevention of childhood type 2 diabetes requires prevention of obesity, particularly in risk groups such as ethnic minority children.
Primary prevention of type 2 diabetes consists of reversing eating and sedentary behavior trends in homes, schools and communities, which leads to excess calorie intake and decreased energy expenditure. The recent Public Health England report suggests that reducing sugar intake is an important document that needs to be fully implemented.
⇒ Comment:
This report highlights that type 2 diabetes in childhood is an aggressive disease that leads to the early development of complications. It generally occurs in obese children close to puberty, with osmotic symptoms or as a finding during a routine check-up; a small proportion may present with diabetic ketoacidosis.
The predominant role of change in life habits is highlighted, not only for the child or adolescent but for the entire family. An adequate eating plan is necessary to reduce caloric intake and an increase in physical activity to increase energy expenditure. The first-line drug therapy is metformin, which must be adjusted in each case. Research into different therapeutic alternatives continues.
Table 1
Diagnosis of diabetes Diabetes is diagnosed when: • Fasting blood glucose is equal to or greater than 126 mg/dl. • Post-challenge blood glucose is equal to or greater than 200 mg/dl. This should be taken as defined by the World Health Organization, using a glucose load containing the equivalent of 75g of anhydrous glucose dissolved in water. • Symptoms of thirst, polyuria, fatigue and weight loss and a random blood glucose level equal to or greater than 200 mg/dl. This can be done at any time of the day regardless of the time of the last meal. • HbA1c greater than 6.5% using an aligned DCCT assay. An oral glucose tolerance test is not necessary if diabetes can be diagnosed using fasting or random criteria. Impaired fasting blood glucose and impaired glucose tolerance are intermediate states in the pathogenesis of carbohydrate metabolism disorder, but are NOT diabetes mellitus. |
Table 2
Differential diagnosis of type 2 diabetes in children • Type 1 diabetes. It is associated with diabetes antibodies in about 85% of affected children, and children have an absolute requirement for insulin. •Apparent type 2 diabetes with coexisting autoimmunity. Antibodies to glutamate decarboxylase (GAD65), islet cells (ICA), or insulin (IAA) are found in about 10% of children with an apparent diagnosis of type 2 diabetes. Pancreatic beta cell function is significantly lower in antibody-positive children, and there is a more rapid development of insulin dependence. These children are likely to have type 1 diabetes with obesity. •Flatbush diabetes. This type of diabetes can be seen in children of African-Caribbean origin, with a strong family history, sometimes autosomal dominant, and with female preponderance without association with the HLA and with negative antibodies for diabetes. These children may present with ketoacidosis or ketosis and require insulin initially; but they can be weaned from insulin as long as they maintain relatively good glycemic control. •Monogenic diabetes (formally Maturity Diabetes of the Young). It generally occurs in families with an autosomal dominant history; affects no more than 1% of children with diabetes; is not associated with obesity beyond population prevalence; and is not associated with insulin resistance. |
