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Type 2 diabetes mellitus: incidence, management and prognosis
DIABETES MELLITUS
Type 2 diabetes mellitus: incidence, management and prognosis
due to autoimmune destruction of insulin producing beta cells in the pancreas. Affected children will die unless insulin therapy is instituted. In contrast, most adults with diabetes have type 2, characterised by a relative insulin secretory defect, and target tissue resistance to the effects of insulin. There has been a dramatic rise in the prevalence of type 2 diabetes in adult populations since about the 1950s, and this has been related to the increased prevalence of obesity. It is likely that type 2 diabetes in children is now emerging for the same reasons. In the UK, type 2 diabetes in children began to appear in the late 1990s, particularly in ethnic minority children. These were of Pakistani, Middle East or African-Caribbean origin; 12e16 years of age; and characterised by severe insulin resistance as assessed by hyperinsulinaemia. A British Paediatric Surveillance Unit (BPSU) case finding survey in 2005 identified an incidence of 0.53 new cases per 100,000 per year. This compares to an incidence of 28 cases per 100,000 per year for children aged 0e14 years with type 1 diabetes in 2013. Although over 50% of affected children were of White UK origin, the likelihood of a newly diagnosed child having type 2 diabetes was 14 times higher for a child of AfricanCaribbean or South Asian origin. The National Paediatric Diabetes Audit for 2013/14 identified about 500 children and young people with type 2 diabetes, compared to over 26,000 with type 1 diabetes. A second BPSU survey was undertaken in 2015/16 and is likely to show a significant rise in incidence.
Timothy Barrett
Abstract Type 2 diabetes mellitus in childhood emerged in the UK in about 2000, and now affects about 500 children or 2% of all childhood diabetes in the UK. It is an aggressive disease in children, with rapidly progressive pancreatic beta cell decline and early development of complications. It characteristically presents in an obese child, around the time of puberty, with osmotic symptoms or as a coincidental finding. A small proportion may present with metabolic decompensation and diabetic ketoacidosis. Acanthosis nigricans is a common feature. There is a significant female preponderance, with children from ethnic minorities disproportionately represented, and usually a history of type 2 diabetes mellitus in first degree relatives. In contrast to type 1 diabetes, children with type 2 may develop complications within 1e2 years of diagnosis. The differential diagnosis includes type 1 diabetes, usually distinguished by the presence of GAD65 autoantibodies; diabetes secondary to monogenic causes, transplant and immunosuppression. Management includes confirming the diagnosis of diabetes according to World Health Organisation criteria; screening for both microvascular complications and complications of metabolic syndrome; and initiating lifestyle, dietary and exercise advice to decrease calorie intake and increase energy expenditure. Children with osmotic symptoms or HbA1c greater than 69 mmol/ mol (8.5%) should be commenced on insulin therapy then weaned off over 1e3 months. Metformin should also be instituted from diagnosis provided there is no ketoacidosis, and the dose increased to the maximum tolerated. Insulin is currently the only second line treatment licensed for use in the UK. A pragmatic approach is to offer once a day long acting insulin; and add in mealtime short acting insulin if insufficient response. The glycated haemoglobin target for optimal glycaemic control is less than 53 mmol/mol (7.0%). Future treatments under investigation for paediatric use drugs targeting the insulin resistance, the beta cell failure, and glucose availability. It is likely that these clinical trials will generate an evidence base for better treatments in future.
Pathology and course of the disease Type 2 diabetes (T2DM) in children and young people is clearly different to type 1 diabetes, and the underlying pathology is similar to that in adults with type 2 diabetes; that is, insulin resistance and beta cell failure. However, we now know that childhood type 2 diabetes has unique features, including more rapid progression of pancreatic beta cell failure, poorer response to treatments, earlier onset of complications, and more rapid progression of complications. There may also exist subgroups of children who have different rates of progression of the disease. T2DM is also frequently associated with other features of the insulin resistance or metabolic syndrome. These include obesity, dyslipidaemia, hypertension, albuminuria, ovarian hyperandrogenism, non-alcoholic fatty liver disease (NAFLD), and obstructive sleep apnoea. There is also a component of systemic inflammation as estimated by elevated C-reactive protein, inflammatory cytokines and white blood cell counts. The natural history in childhood starts with fasting hyperinsulinaemia, exacerbated by obesity. This is followed by postprandial hyperglycaemia, when the pancreatic beta cells are unable to maintain high enough circulating insulin levels to respond to a glucose load (impaired glucose tolerance on an oral glucose tolerance test). Due to a combination of lipid and glucose toxicity on beta cells, increasing tissue insulin resistance and hepatic glucose output, fasting hyperglycaemia follows. Early on in the natural history there is loss of the first phase insulin response. There is second phase hyperinsulinaemia in response to an oral glucose tolerance test, but a progressive loss such that many affected adults eventually become insulin dependent. Insulin resistance means an impaired response to the physiological actions of insulin on carbohydrate, lipid and protein metabolism and on endothelial function.
Keywords diabetes; youth
Introduction, definition and epidemiology Diabetes mellitus is the name given to a wide spectrum group of disorders characterised by raised plasma glucose. In paediatric practice, type 1 diabetes accounts for about 96% of all affected children, and is characterised by an absolute insulin deficiency
Timothy Barrett PhD MB BS FRCP FRCPCH FHEA DCH is Professor of Paediatrics at the School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, UK. Conflict of interest: none declared.
PAEDIATRICS AND CHILD HEALTH --:-
1
Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Barrett T, Type 2 diabetes mellitus: incidence, management and prognosis, Paediatrics and Child Health (2016), http://dx.doi.org/10.1016/j.paed.2016.12.006
DIABETES MELLITUS
The principal tissues affected by insulin resistance are liver, muscle and fat. In the liver this impaired insulin related inhibition of hepatic gluconeogenesis results in increased hepatic glucose output, exacerbating hyperglycaemia. In muscle, reduced transport of carbohydrates into muscle combined with lipid deposition in muscle cells leads to impaired exercise ability and lowered threshold for tiredness with exercise. In fat tissue, there is impaired insulin-mediated inhibition of hormonedependent lipase, with breakdown of lipids to free fatty acids and glycerol, contributing to the dyslipidaemia. The Treatment Options for type 2 diabetes in Adolescents and Youth (TODAY) was a landmark clinical trial that compared the effects of metformin, metformin plus rosiglitazone, and lifestyle interventions on the glucose control of 677 young people with type 2 diabetes. There was a rapid loss of glycaemic control in many of the participants, even though they only had a short (less than one year) duration of diabetes. The rate of loss of glycaemic control even on 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 present at diagnosis: 14% of participants had blood pressure at or above the 95th percentile, 13% had microalbuminuria, 80% had low HDL-cholesterol level, and 10% had raised 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 renal and neurological complications appeared within 5 years of diagnosis; and major complications such as dialysis, blindness or amputation, appear from 10 years after diagnosis.
Diagnosis of diabetes Diabetes is diagnosed when: C
OR: C
The post challenge plasma glucose is equal to or greater than 11.1 mmol/L (200 mg/dL). This must be undertaken as described by The World Health Organisation, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.
OR: C
Symptoms of thirst, polyuria, tiredness and weight loss and a random plasma glucose equal to or greater than 11.1 mmol/L (200 mg/dL). This can be performed at any time of the day regardless of the time of the last meal.
OR: C
HbA1c greater than 6.5% using a DCCT aligned assay.
There is no need to undertake an oral glucose tolerance test if diabetes can be diagnosed using fasting or random criteria. Impaired fasting glycaemia and impaired glucose tolerance are intermediate stages in the pathogenesis of disordered carbohydrate metabolism, but are NOT diabetes mellitus. Box 1
Diagnosis including history and investigation Diabetes is diagnosed according to World Health Organisation criteria (see box 1). Currently this requires a fasting or random capillary or venous glucose estimation; or measurement of glycated haemoglobin. The classic features of type 2 diabetes in childhood include a presentation with symptoms during the second decade of life, with a mean age of diagnosis around 13 years. This corresponds roughly with the peak of the growth spurt and associated physiological insulin resistance. More girls are affected than boys in a ratio of about 2:1, and this may be related to gender differences in body fat mass. Type 2 diabetes affects children of all ethnic origins, but in the UK it disproportionately affects those of nonEuropean descent, for instance children of South Asian origin (Pakistan, India, Bangladesh, Sri Lanka), or African-Caribbean children. Type 2 diabetes disproportionately affects families with lower socio-economic status. In about 85% there is a strong family history of type 2 diabetes or cardiovascular disease, often in a parent, sibling or grandparents. It is not unusual for children to be identified co-incidentally, apparently asymptomatic when screened either in primary care or on a glucose meter belonging to another family member with diabetes. However a minority present with metabolic decompensation and diabetic ketoacidosis. A further group may present with severe hyperosmolar non-ketotic dehydration, which has a high risk for fatality. Finally, type 2 diabetes is a non-autoimmune disease and not HLA-associated. The main differential diagnoses for type 2 diabetes are shown in Box 2. It cannot be stressed strongly enough
PAEDIATRICS AND CHILD HEALTH --:-
A fasting plasma glucose is equal to or greater than 7.0 mmol/L (126 mg/dL)
Differential diagnosis of Type 2 diabetes in children C
C
C
C
Type 1 diabetes. This is associated with diabetes autoantibodies in about 85% of affected children, and children have an absolute insulin requirement. Apparent type 2 diabetes with coexistent autoimmunity. About 10% of children with an apparent diagnosis of type 2 diabetes are found to have antibodies to Glutamate Decarboxylase (GAD65), islet cells (ICA), or insulin (IAA). Pancreatic beta cell function is significantly less in antibody positive children, and there is more rapid development of insulin dependence. It is likely that these children have type 1 diabetes with obesity. Flatbush diabetes. This is seen in some children of AfricanCaribbean origin, with a strong family history, sometimes autosomal dominant, and with a female preponderance, no HLA association and diabetes autoantibody negative. These children may present with ketoacidosis or ketosis and require insulin initially; but can be weaned off insulin while maintaining relatively good glycaemic control. Monogenic diabetes (formerly Maturity Onset Diabetes of the Young). This usually presents in families with autosomal dominant history; affects no more than 1% of children with diabetes; is not associated with obesity beyond the prevalence in the background population; and is not associated with insulin resistance.
Box 2
2
Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Barrett T, Type 2 diabetes mellitus: incidence, management and prognosis, Paediatrics and Child Health (2016), http://dx.doi.org/10.1016/j.paed.2016.12.006
DIABETES MELLITUS
that if there is any doubt about the diagnosis of type 2 diabetes, then it is much safer to commence insulin treatment and revise the diagnosis later. Certain events in early life may be associated with development of the insulin resistance syndrome and type 2 diabetes and can be enquired about in the history. Children born small for gestational age are at increased risk for insulin resistance related to decreased intrauterine growth; these children are also at increased risk for premature adrenarche. It is also important to ask in the history about other features relating to the metabolic syndrome. For girls, ask if menarche has occurred and at what age. Ask if periods are regular, are they painful or heavy, and does the girl suffer from excessive body hair. Secondly, consider the risk for obstructive sleep apnoea and ask if there is any night time snoring or day time sleepiness? Thirdly consider depression; many affected children have low self-esteem, feel bad about their body shape and have low motivation levels; this is underdiagnosed. Other health problems related to obesity include orthopaedic problems such as slipped upper 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 centile for age and sex. There is often acanthosis nigricans, a pigmented velvety thickening affecting skin flexures such as the neck, axillae and groins; this is a manifestation of insulin resistance. Blood pressure is often raised (systolic or diastolic blood pressures above 95th centile for age and height).
so increasing cardiovascular risk for these children. Albuminuria (either micro- or macro-) is present at the time of diagnosis in a significant proportion of teenagers with type 2 diabetes mellitus, and prevalence increases with duration of diabetes. Baseline digital retinal photographs should be undertaken as soon as practically possible after diagnosis as part of the national retinopathy screening programme.
Management A useful review was published by The International Society for Paediatric and Adolescent Diabetes, from which this article has been informed. The main emphasis of management is on lifestyle modification. The overall management goals are to achieve weight loss; and to achieve an increase in exercise capacity. The risk of microvascular and macrovascular complications in adults increases with both the duration of diabetes and lack of glycaemic control, and this has now also been shown in childhood onset diabetes so it is vital to achieve and sustain metabolic control through normalisation of glycaemia; and control of comorbidities including hypertension, dyslipidaemia, nephropathy, and non-alcoholic fatty liver disease. Reducing the rate of complications may require tighter glucose control in childhood onset type 2 diabetes than in childhood type 1 diabetes. Education around lifestyle modification involves not just the child but also his/her family. The whole family may need education to understand the principles of treatment for type 2 diabetes and the critical importance of lifestyle changes if chronic complications are to be prevented. The whole family should be encouraged to change their diet consistent with healthy eating recommendations, including individualised counselling for weight reduction, reduced total and saturated fat intake, and increased fibre intake. The key areas that have been found important in children include elimination of sugar-containing soft drinks and juice; taking meals on schedule and in one place, with no other activity (e.g. TV), and ideally as a family group; portion control by reducing portion sizes; and limiting high fat, high calorie density food in the home. Exercise management means developing individual exercise programs that are enjoyable, affordable for the family, and participated in by at least one other family member. Families should be encouraged to develop an achievable daily exercise program, including reducing sedentary time. Opportunities may include using stairs instead of elevators; walking part of the way to school; using an exercise machine at home, or exercise DVDs; and walking with a family member after school. The UK guidelines of at least one hour a day of exercise that makes one out of breath are not usually achievable for children with Type 2 diabetes, at least initially. Any exercise is beneficial, and promoting achievable targets with a gradual build-up, may avoid disillusionment. Self monitoring of capillary blood glucose is very important in childhood to detect hyperglycaemia and its response to interventions. This should be undertaken regularly, and include a combination of fasting and post prandial (about 1.5 hours after meals) glucose checks. Once glycaemic goals have been met, the frequency of monitoring may be reduced to 2e3 fasting and 2e3 post prandial capillary checks per week. Testing should be undertaken more frequently during intercurrent illness. Clearly,
Investigations A capillary or laboratory plasma or venous glucose is necessary to make the diagnosis of diabetes mellitus. It is also helpful to have a baseline HbA1c, to provide an estimation of the duration of hyperglycaemia before diagnosis. In addition to routine measurements of height, weight and blood pressure, other investigations at the point of diagnosis should include an assessment for ketone production; urea and electrolytes for assessment of osmolarity and dehydration; assessment for infection (urinary tract, respiratory tract, skin); autoantibodies for type 1 diabetes; 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. Raised liver enzymes more than twice the upper limit of normal are suggestive of Non Alcoholic Fatty Liver Disease (NAFLD). Hepatic steatosis is present in 25e45% of adolescents with type 2 diabetes mellitus, and is part of the spectrum of NAFLD. NAFLD is the commonest cause of cirrhosis in children in the UK. After the acute phase, as soon as any metabolic decompensation is corrected, other baseline assessments should include a blood sample for lipids and cholesterol; early morning urine for albumin creatinine ratio; and retinopathy screen. Hypertriglyceridemia and decreased high-density lipoprotein cholesterol are characteristics of dyslipidaemia associated with type 2 diabetes. Other findings include raised very-low density lipoprotein (VLDL), elevated LDL-c, elevated lipoprotein a, and increased small dense LDL particles. Decreased lipoprotein lipase activity, increased lipoprotein glycation and increased lipoprotein oxidation mean that the lipoproteins are more atherogenic,
PAEDIATRICS AND CHILD HEALTH --:-
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Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Barrett T, Type 2 diabetes mellitus: incidence, management and prognosis, Paediatrics and Child Health (2016), http://dx.doi.org/10.1016/j.paed.2016.12.006
DIABETES MELLITUS
children on insulin therapy should be undertaking more frequent testing. Glycated haemoglobin should be assessed every 3 months if on insulin treatment. The aims of pharmacological therapy are to decrease insulin resistance (e.g. metformin), increase insulin secretion (e.g. sulphonylureas), slow post prandial glucose absorption (acarbose, not recommended in children), or finally to increase glucose entry 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, without risk for hypoglycaemia. It is standard UK practice to start therapy with metformin from diagnosis, alongside diet, exercise and lifestyle modification. Metformin belongs to a class of drugs called biguanides, and acts on insulin receptors in fat, muscle and liver. It reduces hepatic glucose production by decreasing gluconeogenesis; increases insulin-stimulated glucose uptake; may have some effect on reducing appetite; and can reduce HbA1c by 1e2%. A recent large randomised controlled trial comparing 3 treatment regimes found that monotherapy with metformin alone was associated with durable glycaemic control in about half of children and adolescents with type 2 diabetes. It can however have intestinal side effects including transient abdominal pain, diarrhoea and nausea. The usual starting dose is 500 mg once a day, increasing over 6e8 weeks to the maximum tolerated dose, or 2 g/day, in 2 divided doses. However there is a liquid preparation available (250 mg/5 ml), which allow a slower titration of dose; or alternatively, an extended release preparation. There is also the advantage that for girls with the complication of polycystic ovarian syndrome, metformin may normalise ovulatory abnormalities. This may, of course, increase the risk of pregnancy and girls need to be counselled about this. If there is inadequate glycaemic control on metformin, then it is currently standard UK practice to add in insulin. Despite hyperinsulinaemia and insulin resistance, relatively small doses of a long acting insulin analogue preparation may be effective without mealtime boluses. If despite long acting insulin therapy, glycaemic control is still suboptimal, then rapid or short acting insulin should be added for post-prandial hyperglycaemia. The side-effects of insulin are hypoglycaemia and weight gain; so clearly this is not an ideal agent. Sadly the best randomised controlled trial to date compared regimes which included rosiglitazone, a thiazolidinedione which is restricted for use in Europe due to a possible association with cardiovascular events in older people with type 2 diabetes. We desperately need an evidence base for alternative second line agents for glycaemic control in type 2 diabetes. The issues around challenges in undertaking clinical trials in this age-group are covered extensively in a recent consensus document. All other agents are not currently approved for use in children and young people under 18 years of age. These agents include sulphonylureas and meglitinide/repaglinide, which act by increasing insulin secretion. The major adverse effect is hypoglycaemia, which may 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 oedema. Alpha glucosidase inhibitors such as acarbose reduce the absorption of carbohydrates in the small intestine, and cause flatulence which limits compliance.
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Incretin mimetics show more promise and many trials are underway to assess benefit for children. Glucagon-like peptide-1 receptor agonists (GLP-1) 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 they 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. They can however be given orally. Bariatric surgery may in future be considered for adolescents with obesity-related complications, including type 2 diabetes. Gastric bypass has significant complications including malabsorption of essential vitamins and minerals. However gastric banding appears to have lower morbidity and mortality; and has been associated with a 70% remission rate in adults (Box 3).
Follow-up Annual review for children with type 2 diabetes should include a reassessment for co-morbidities to include degree of obesity, non-alcoholic liver disease, dyslipidaemia, hypertension, menstrual irregularities, obstructive sleep apnoea, mood and affect. Investigations should include blood pressure at each visit (average of 3 measurements using appropriate sized cuff); height, weight and BMI at each visit; lifestyle, diet and exercise assessment; and annual review investigations to include
Treatment of Type 2 diabetes C
C
C
C
C
If presentation with osmotic symptoms; and/or HbA1c 75 mmol/ mol (9%); and/or diabetic ketoacidosis: start insulin treatment with lifestyle, diet and exercise measures; and metformin if not ketoacidotic. Try to wean off insulin and titrate up metformin to maximum tolerated dose (maximum 2 g/day) over 3 months. If asymptomatic presentation or mildly symptomatic only, without ketoacidosis, start lifestyle, diet and exercise advice and metformin and titrate up metformin to maximum tolerated dose (maximum 2 g/day). Review 3 monthly with a target HbA1c 47.5 mmol/mol (6.5%); if target not being met, add in long acting insulin analogue; if this does not achieve target, add in short acting insulin as mealtime boluses. Hypertension or microalbuminuria. Confirmed hypertension (BP greater than 95th centile for age, gender and height), or microalbuminuria on 2 out of 3 occasions, should be treated with an ACE inhibitor, or, if not tolerated, an angiotensin receptor blocker. Side effects can include cough, hyperkalaemia. Dyslipidaemia. The goal is to achieve an LDL-C less than 2.6 mmol/L. The intervention to lower LDL-C is dietary intervention to decrease total and saturated fat intake. If LDL-C remains raised after 3e6 months of optimising diet, then treatment with statin should be considered.
Box 3
4
Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Barrett T, Type 2 diabetes mellitus: incidence, management and prognosis, Paediatrics and Child Health (2016), http://dx.doi.org/10.1016/j.paed.2016.12.006
DIABETES MELLITUS
liver function tests, random lipids and cholesterol as a screen; early morning urine for albumin creatinine ratio; retinopathy screening.
Kelsey MM, Geffner ME, Guandalini C, et al. Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) Study Group. Presentation and effectiveness of early treatment of type 2 diabetes in youth: lessons from the TODAY study. Pediatr Diabetes 2016; 17: 212e21. Klingensmith G, Pyle L, Arslanian S, et al. for the TODAY Study Group. The presence of GAD and IA2 antibodies in youth with a type 2 diabetes phenotype. Diabetes Care 2010; 33: 1970e5. Lee-Jones K, Arslanian S, Peterokova V, Park J, Tomlinson M. Effect of metformin in paediatric patients with type 2 diabetes: a randomized controlled trial. Diabetes Care 2002; 25: 89e94. Morales A, Rosenbloom A. Death caused by hyperglycaemic hyperosmolar state at the onset of type 2 diabetes. J Pediatr 2004; 144: 270e3. Nadeau K, Anderson B, Berg E, et al. Youth-onset type 2 diabetes consensus report: current status, challenges, and priorities. Diabetes Care 2016; 39: 1635e42. National Paediatric Diabetes Audit Report 2013-14. Part 1: Care Processes and Outcomes. Royal College of Paediatrics and Child Health, 2015. NHS Choices. Physical activity guidelines for children and young people. http://www.nhs.uk/Livewell/fitness/Pages/physicalactivity-guidelines-for-young-people.aspx. OECD. Incidence estimates of type-1 diabetes, children aged 0e14 years, 2013. In: Health at a Glance:Europe 2014. Paris: OECD Publishing, 2014. http://dx.doi.org/10.1787/health_glance_eur-2014-graph36-en. Public Health England. Sugar Reduction the evidence for action. Public Health Engl October 2015; 1e48. https://www.gov.uk/ government/.../Sugar_reduction_The_evidence_for_action.pdf. UKPDS Group. Intensive glucose control with sulphonylureas of insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837e53. Zeitler P, Fu J, Tandon N, et al. Type 2 diabetes in the child and adolescent. Pediatr Diabetes 2014; 15(suppl 20): 26e46. Zeitler P, Hirst K, Pyle L, et al. TODAY Study Group. A clinical trial to maintain glycemic control in youth with type 2 diabetes. N Engl J Med 2012; 366: 2247e56.
Prevention In the UK we have not seen the rapid rise of childhood type 2 diabetes that we expected 10 years ago. However, the large numbers of children with obesity and impaired glucose tolerance suggests that we still have the potential for greater numbers of children developing type 2 diabetes. Prevention of childhood onset type 2 diabetes requires prevention of obesity, particularly in at risk groups such as children from ethnic minorities. Primary prevention of type 2 diabetes involves reversing eating and sedentary behaviour trends in homes, schools and communities that lead to excess calorie intake and decreased energy expenditure. The recent Public Health England report suggesting reduction in sugar intake is an important document which needs to be implemented in full. A FURTHER READING Banerji M. Diabetes in African Americans: unique pathophysiologic features. Curr Diab Rep 2004; 4: 219e23. Copeland KC, Zeitler P, Geffner M, et al. TODAY Study Group. Characteristics of adolescents and youth with recent-onset type 2 diabetes: the TODAY cohort at baseline. J Clin Endocrinol Metab 2011; 96: 159e67. Dart AB, Martens PJ, Rigatto C, Brownell MD, Dean HJ, Sellers EA. Earlier onset of complications in youth with type 2 diabetes. Diabetes Care 2014; 37: 436e43. Dixon J, O’Brien P, Playfair J, et al. Adjustable gastric banding and conventional therapy for type 2 diabetes. JAMA 2008; 299: 316e23. Ehtisham S, Barrett T, Shaw N. Type 2 diabetes mellitus in children e an emerging problem. Diabet Med 2000; 17: 867e71. Haines L, Wan K, Lynn R, Barrett T, Shield J. Rising incidence of type 2 diabetes in children in the United Kingdom. Diabetes Care 2007; 30: 1097e101.
PAEDIATRICS AND CHILD HEALTH --:-
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Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Barrett T, Type 2 diabetes mellitus: incidence, management and prognosis, Paediatrics and Child Health (2016), http://dx.doi.org/10.1016/j.paed.2016.12.006
Type 2 diabetes mellitus: incidence, management and prognosis
due to autoimmune destruction of insulin producing beta cells in the pancreas. Affected children will die unless insulin therapy is instituted. In contrast, most adults with diabetes have type 2, characterised by a relative insulin secretory defect, and target tissue resistance to the effects of insulin. There has been a dramatic rise in the prevalence of type 2 diabetes in adult populations since about the 1950s, and this has been related to the increased prevalence of obesity. It is likely that type 2 diabetes in children is now emerging for the same reasons. In the UK, type 2 diabetes in children began to appear in the late 1990s, particularly in ethnic minority children. These were of Pakistani, Middle East or African-Caribbean origin; 12e16 years of age; and characterised by severe insulin resistance as assessed by hyperinsulinaemia. A British Paediatric Surveillance Unit (BPSU) case finding survey in 2005 identified an incidence of 0.53 new cases per 100,000 per year. This compares to an incidence of 28 cases per 100,000 per year for children aged 0e14 years with type 1 diabetes in 2013. Although over 50% of affected children were of White UK origin, the likelihood of a newly diagnosed child having type 2 diabetes was 14 times higher for a child of AfricanCaribbean or South Asian origin. The National Paediatric Diabetes Audit for 2013/14 identified about 500 children and young people with type 2 diabetes, compared to over 26,000 with type 1 diabetes. A second BPSU survey was undertaken in 2015/16 and is likely to show a significant rise in incidence.
Timothy Barrett
Abstract Type 2 diabetes mellitus in childhood emerged in the UK in about 2000, and now affects about 500 children or 2% of all childhood diabetes in the UK. It is an aggressive disease in children, with rapidly progressive pancreatic beta cell decline and early development of complications. It characteristically presents in an obese child, around the time of puberty, with osmotic symptoms or as a coincidental finding. A small proportion may present with metabolic decompensation and diabetic ketoacidosis. Acanthosis nigricans is a common feature. There is a significant female preponderance, with children from ethnic minorities disproportionately represented, and usually a history of type 2 diabetes mellitus in first degree relatives. In contrast to type 1 diabetes, children with type 2 may develop complications within 1e2 years of diagnosis. The differential diagnosis includes type 1 diabetes, usually distinguished by the presence of GAD65 autoantibodies; diabetes secondary to monogenic causes, transplant and immunosuppression. Management includes confirming the diagnosis of diabetes according to World Health Organisation criteria; screening for both microvascular complications and complications of metabolic syndrome; and initiating lifestyle, dietary and exercise advice to decrease calorie intake and increase energy expenditure. Children with osmotic symptoms or HbA1c greater than 69 mmol/ mol (8.5%) should be commenced on insulin therapy then weaned off over 1e3 months. Metformin should also be instituted from diagnosis provided there is no ketoacidosis, and the dose increased to the maximum tolerated. Insulin is currently the only second line treatment licensed for use in the UK. A pragmatic approach is to offer once a day long acting insulin; and add in mealtime short acting insulin if insufficient response. The glycated haemoglobin target for optimal glycaemic control is less than 53 mmol/mol (7.0%). Future treatments under investigation for paediatric use drugs targeting the insulin resistance, the beta cell failure, and glucose availability. It is likely that these clinical trials will generate an evidence base for better treatments in future.
Pathology and course of the disease Type 2 diabetes (T2DM) in children and young people is clearly different to type 1 diabetes, and the underlying pathology is similar to that in adults with type 2 diabetes; that is, insulin resistance and beta cell failure. However, we now know that childhood type 2 diabetes has unique features, including more rapid progression of pancreatic beta cell failure, poorer response to treatments, earlier onset of complications, and more rapid progression of complications. There may also exist subgroups of children who have different rates of progression of the disease. T2DM is also frequently associated with other features of the insulin resistance or metabolic syndrome. These include obesity, dyslipidaemia, hypertension, albuminuria, ovarian hyperandrogenism, non-alcoholic fatty liver disease (NAFLD), and obstructive sleep apnoea. There is also a component of systemic inflammation as estimated by elevated C-reactive protein, inflammatory cytokines and white blood cell counts. The natural history in childhood starts with fasting hyperinsulinaemia, exacerbated by obesity. This is followed by postprandial hyperglycaemia, when the pancreatic beta cells are unable to maintain high enough circulating insulin levels to respond to a glucose load (impaired glucose tolerance on an oral glucose tolerance test). Due to a combination of lipid and glucose toxicity on beta cells, increasing tissue insulin resistance and hepatic glucose output, fasting hyperglycaemia follows. Early on in the natural history there is loss of the first phase insulin response. There is second phase hyperinsulinaemia in response to an oral glucose tolerance test, but a progressive loss such that many affected adults eventually become insulin dependent. Insulin resistance means an impaired response to the physiological actions of insulin on carbohydrate, lipid and protein metabolism and on endothelial function.
Keywords diabetes; youth
Introduction, definition and epidemiology Diabetes mellitus is the name given to a wide spectrum group of disorders characterised by raised plasma glucose. In paediatric practice, type 1 diabetes accounts for about 96% of all affected children, and is characterised by an absolute insulin deficiency
Timothy Barrett PhD MB BS FRCP FRCPCH FHEA DCH is Professor of Paediatrics at the School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, UK. Conflict of interest: none declared.
PAEDIATRICS AND CHILD HEALTH --:-
1
Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Barrett T, Type 2 diabetes mellitus: incidence, management and prognosis, Paediatrics and Child Health (2016), http://dx.doi.org/10.1016/j.paed.2016.12.006
DIABETES MELLITUS
The principal tissues affected by insulin resistance are liver, muscle and fat. In the liver this impaired insulin related inhibition of hepatic gluconeogenesis results in increased hepatic glucose output, exacerbating hyperglycaemia. In muscle, reduced transport of carbohydrates into muscle combined with lipid deposition in muscle cells leads to impaired exercise ability and lowered threshold for tiredness with exercise. In fat tissue, there is impaired insulin-mediated inhibition of hormonedependent lipase, with breakdown of lipids to free fatty acids and glycerol, contributing to the dyslipidaemia. The Treatment Options for type 2 diabetes in Adolescents and Youth (TODAY) was a landmark clinical trial that compared the effects of metformin, metformin plus rosiglitazone, and lifestyle interventions on the glucose control of 677 young people with type 2 diabetes. There was a rapid loss of glycaemic control in many of the participants, even though they only had a short (less than one year) duration of diabetes. The rate of loss of glycaemic control even on 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 present at diagnosis: 14% of participants had blood pressure at or above the 95th percentile, 13% had microalbuminuria, 80% had low HDL-cholesterol level, and 10% had raised 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 renal and neurological complications appeared within 5 years of diagnosis; and major complications such as dialysis, blindness or amputation, appear from 10 years after diagnosis.
Diagnosis of diabetes Diabetes is diagnosed when: C
OR: C
The post challenge plasma glucose is equal to or greater than 11.1 mmol/L (200 mg/dL). This must be undertaken as described by The World Health Organisation, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.
OR: C
Symptoms of thirst, polyuria, tiredness and weight loss and a random plasma glucose equal to or greater than 11.1 mmol/L (200 mg/dL). This can be performed at any time of the day regardless of the time of the last meal.
OR: C
HbA1c greater than 6.5% using a DCCT aligned assay.
There is no need to undertake an oral glucose tolerance test if diabetes can be diagnosed using fasting or random criteria. Impaired fasting glycaemia and impaired glucose tolerance are intermediate stages in the pathogenesis of disordered carbohydrate metabolism, but are NOT diabetes mellitus. Box 1
Diagnosis including history and investigation Diabetes is diagnosed according to World Health Organisation criteria (see box 1). Currently this requires a fasting or random capillary or venous glucose estimation; or measurement of glycated haemoglobin. The classic features of type 2 diabetes in childhood include a presentation with symptoms during the second decade of life, with a mean age of diagnosis around 13 years. This corresponds roughly with the peak of the growth spurt and associated physiological insulin resistance. More girls are affected than boys in a ratio of about 2:1, and this may be related to gender differences in body fat mass. Type 2 diabetes affects children of all ethnic origins, but in the UK it disproportionately affects those of nonEuropean descent, for instance children of South Asian origin (Pakistan, India, Bangladesh, Sri Lanka), or African-Caribbean children. Type 2 diabetes disproportionately affects families with lower socio-economic status. In about 85% there is a strong family history of type 2 diabetes or cardiovascular disease, often in a parent, sibling or grandparents. It is not unusual for children to be identified co-incidentally, apparently asymptomatic when screened either in primary care or on a glucose meter belonging to another family member with diabetes. However a minority present with metabolic decompensation and diabetic ketoacidosis. A further group may present with severe hyperosmolar non-ketotic dehydration, which has a high risk for fatality. Finally, type 2 diabetes is a non-autoimmune disease and not HLA-associated. The main differential diagnoses for type 2 diabetes are shown in Box 2. It cannot be stressed strongly enough
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A fasting plasma glucose is equal to or greater than 7.0 mmol/L (126 mg/dL)
Differential diagnosis of Type 2 diabetes in children C
C
C
C
Type 1 diabetes. This is associated with diabetes autoantibodies in about 85% of affected children, and children have an absolute insulin requirement. Apparent type 2 diabetes with coexistent autoimmunity. About 10% of children with an apparent diagnosis of type 2 diabetes are found to have antibodies to Glutamate Decarboxylase (GAD65), islet cells (ICA), or insulin (IAA). Pancreatic beta cell function is significantly less in antibody positive children, and there is more rapid development of insulin dependence. It is likely that these children have type 1 diabetes with obesity. Flatbush diabetes. This is seen in some children of AfricanCaribbean origin, with a strong family history, sometimes autosomal dominant, and with a female preponderance, no HLA association and diabetes autoantibody negative. These children may present with ketoacidosis or ketosis and require insulin initially; but can be weaned off insulin while maintaining relatively good glycaemic control. Monogenic diabetes (formerly Maturity Onset Diabetes of the Young). This usually presents in families with autosomal dominant history; affects no more than 1% of children with diabetes; is not associated with obesity beyond the prevalence in the background population; and is not associated with insulin resistance.
Box 2
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DIABETES MELLITUS
that if there is any doubt about the diagnosis of type 2 diabetes, then it is much safer to commence insulin treatment and revise the diagnosis later. Certain events in early life may be associated with development of the insulin resistance syndrome and type 2 diabetes and can be enquired about in the history. Children born small for gestational age are at increased risk for insulin resistance related to decreased intrauterine growth; these children are also at increased risk for premature adrenarche. It is also important to ask in the history about other features relating to the metabolic syndrome. For girls, ask if menarche has occurred and at what age. Ask if periods are regular, are they painful or heavy, and does the girl suffer from excessive body hair. Secondly, consider the risk for obstructive sleep apnoea and ask if there is any night time snoring or day time sleepiness? Thirdly consider depression; many affected children have low self-esteem, feel bad about their body shape and have low motivation levels; this is underdiagnosed. Other health problems related to obesity include orthopaedic problems such as slipped upper 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 centile for age and sex. There is often acanthosis nigricans, a pigmented velvety thickening affecting skin flexures such as the neck, axillae and groins; this is a manifestation of insulin resistance. Blood pressure is often raised (systolic or diastolic blood pressures above 95th centile for age and height).
so increasing cardiovascular risk for these children. Albuminuria (either micro- or macro-) is present at the time of diagnosis in a significant proportion of teenagers with type 2 diabetes mellitus, and prevalence increases with duration of diabetes. Baseline digital retinal photographs should be undertaken as soon as practically possible after diagnosis as part of the national retinopathy screening programme.
Management A useful review was published by The International Society for Paediatric and Adolescent Diabetes, from which this article has been informed. The main emphasis of management is on lifestyle modification. The overall management goals are to achieve weight loss; and to achieve an increase in exercise capacity. The risk of microvascular and macrovascular complications in adults increases with both the duration of diabetes and lack of glycaemic control, and this has now also been shown in childhood onset diabetes so it is vital to achieve and sustain metabolic control through normalisation of glycaemia; and control of comorbidities including hypertension, dyslipidaemia, nephropathy, and non-alcoholic fatty liver disease. Reducing the rate of complications may require tighter glucose control in childhood onset type 2 diabetes than in childhood type 1 diabetes. Education around lifestyle modification involves not just the child but also his/her family. The whole family may need education to understand the principles of treatment for type 2 diabetes and the critical importance of lifestyle changes if chronic complications are to be prevented. The whole family should be encouraged to change their diet consistent with healthy eating recommendations, including individualised counselling for weight reduction, reduced total and saturated fat intake, and increased fibre intake. The key areas that have been found important in children include elimination of sugar-containing soft drinks and juice; taking meals on schedule and in one place, with no other activity (e.g. TV), and ideally as a family group; portion control by reducing portion sizes; and limiting high fat, high calorie density food in the home. Exercise management means developing individual exercise programs that are enjoyable, affordable for the family, and participated in by at least one other family member. Families should be encouraged to develop an achievable daily exercise program, including reducing sedentary time. Opportunities may include using stairs instead of elevators; walking part of the way to school; using an exercise machine at home, or exercise DVDs; and walking with a family member after school. The UK guidelines of at least one hour a day of exercise that makes one out of breath are not usually achievable for children with Type 2 diabetes, at least initially. Any exercise is beneficial, and promoting achievable targets with a gradual build-up, may avoid disillusionment. Self monitoring of capillary blood glucose is very important in childhood to detect hyperglycaemia and its response to interventions. This should be undertaken regularly, and include a combination of fasting and post prandial (about 1.5 hours after meals) glucose checks. Once glycaemic goals have been met, the frequency of monitoring may be reduced to 2e3 fasting and 2e3 post prandial capillary checks per week. Testing should be undertaken more frequently during intercurrent illness. Clearly,
Investigations A capillary or laboratory plasma or venous glucose is necessary to make the diagnosis of diabetes mellitus. It is also helpful to have a baseline HbA1c, to provide an estimation of the duration of hyperglycaemia before diagnosis. In addition to routine measurements of height, weight and blood pressure, other investigations at the point of diagnosis should include an assessment for ketone production; urea and electrolytes for assessment of osmolarity and dehydration; assessment for infection (urinary tract, respiratory tract, skin); autoantibodies for type 1 diabetes; 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. Raised liver enzymes more than twice the upper limit of normal are suggestive of Non Alcoholic Fatty Liver Disease (NAFLD). Hepatic steatosis is present in 25e45% of adolescents with type 2 diabetes mellitus, and is part of the spectrum of NAFLD. NAFLD is the commonest cause of cirrhosis in children in the UK. After the acute phase, as soon as any metabolic decompensation is corrected, other baseline assessments should include a blood sample for lipids and cholesterol; early morning urine for albumin creatinine ratio; and retinopathy screen. Hypertriglyceridemia and decreased high-density lipoprotein cholesterol are characteristics of dyslipidaemia associated with type 2 diabetes. Other findings include raised very-low density lipoprotein (VLDL), elevated LDL-c, elevated lipoprotein a, and increased small dense LDL particles. Decreased lipoprotein lipase activity, increased lipoprotein glycation and increased lipoprotein oxidation mean that the lipoproteins are more atherogenic,
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DIABETES MELLITUS
children on insulin therapy should be undertaking more frequent testing. Glycated haemoglobin should be assessed every 3 months if on insulin treatment. The aims of pharmacological therapy are to decrease insulin resistance (e.g. metformin), increase insulin secretion (e.g. sulphonylureas), slow post prandial glucose absorption (acarbose, not recommended in children), or finally to increase glucose entry 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, without risk for hypoglycaemia. It is standard UK practice to start therapy with metformin from diagnosis, alongside diet, exercise and lifestyle modification. Metformin belongs to a class of drugs called biguanides, and acts on insulin receptors in fat, muscle and liver. It reduces hepatic glucose production by decreasing gluconeogenesis; increases insulin-stimulated glucose uptake; may have some effect on reducing appetite; and can reduce HbA1c by 1e2%. A recent large randomised controlled trial comparing 3 treatment regimes found that monotherapy with metformin alone was associated with durable glycaemic control in about half of children and adolescents with type 2 diabetes. It can however have intestinal side effects including transient abdominal pain, diarrhoea and nausea. The usual starting dose is 500 mg once a day, increasing over 6e8 weeks to the maximum tolerated dose, or 2 g/day, in 2 divided doses. However there is a liquid preparation available (250 mg/5 ml), which allow a slower titration of dose; or alternatively, an extended release preparation. There is also the advantage that for girls with the complication of polycystic ovarian syndrome, metformin may normalise ovulatory abnormalities. This may, of course, increase the risk of pregnancy and girls need to be counselled about this. If there is inadequate glycaemic control on metformin, then it is currently standard UK practice to add in insulin. Despite hyperinsulinaemia and insulin resistance, relatively small doses of a long acting insulin analogue preparation may be effective without mealtime boluses. If despite long acting insulin therapy, glycaemic control is still suboptimal, then rapid or short acting insulin should be added for post-prandial hyperglycaemia. The side-effects of insulin are hypoglycaemia and weight gain; so clearly this is not an ideal agent. Sadly the best randomised controlled trial to date compared regimes which included rosiglitazone, a thiazolidinedione which is restricted for use in Europe due to a possible association with cardiovascular events in older people with type 2 diabetes. We desperately need an evidence base for alternative second line agents for glycaemic control in type 2 diabetes. The issues around challenges in undertaking clinical trials in this age-group are covered extensively in a recent consensus document. All other agents are not currently approved for use in children and young people under 18 years of age. These agents include sulphonylureas and meglitinide/repaglinide, which act by increasing insulin secretion. The major adverse effect is hypoglycaemia, which may 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 oedema. Alpha glucosidase inhibitors such as acarbose reduce the absorption of carbohydrates in the small intestine, and cause flatulence which limits compliance.
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Incretin mimetics show more promise and many trials are underway to assess benefit for children. Glucagon-like peptide-1 receptor agonists (GLP-1) 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 they 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. They can however be given orally. Bariatric surgery may in future be considered for adolescents with obesity-related complications, including type 2 diabetes. Gastric bypass has significant complications including malabsorption of essential vitamins and minerals. However gastric banding appears to have lower morbidity and mortality; and has been associated with a 70% remission rate in adults (Box 3).
Follow-up Annual review for children with type 2 diabetes should include a reassessment for co-morbidities to include degree of obesity, non-alcoholic liver disease, dyslipidaemia, hypertension, menstrual irregularities, obstructive sleep apnoea, mood and affect. Investigations should include blood pressure at each visit (average of 3 measurements using appropriate sized cuff); height, weight and BMI at each visit; lifestyle, diet and exercise assessment; and annual review investigations to include
Treatment of Type 2 diabetes C
C
C
C
C
If presentation with osmotic symptoms; and/or HbA1c 75 mmol/ mol (9%); and/or diabetic ketoacidosis: start insulin treatment with lifestyle, diet and exercise measures; and metformin if not ketoacidotic. Try to wean off insulin and titrate up metformin to maximum tolerated dose (maximum 2 g/day) over 3 months. If asymptomatic presentation or mildly symptomatic only, without ketoacidosis, start lifestyle, diet and exercise advice and metformin and titrate up metformin to maximum tolerated dose (maximum 2 g/day). Review 3 monthly with a target HbA1c 47.5 mmol/mol (6.5%); if target not being met, add in long acting insulin analogue; if this does not achieve target, add in short acting insulin as mealtime boluses. Hypertension or microalbuminuria. Confirmed hypertension (BP greater than 95th centile for age, gender and height), or microalbuminuria on 2 out of 3 occasions, should be treated with an ACE inhibitor, or, if not tolerated, an angiotensin receptor blocker. Side effects can include cough, hyperkalaemia. Dyslipidaemia. The goal is to achieve an LDL-C less than 2.6 mmol/L. The intervention to lower LDL-C is dietary intervention to decrease total and saturated fat intake. If LDL-C remains raised after 3e6 months of optimising diet, then treatment with statin should be considered.
Box 3
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DIABETES MELLITUS
liver function tests, random lipids and cholesterol as a screen; early morning urine for albumin creatinine ratio; retinopathy screening.
Kelsey MM, Geffner ME, Guandalini C, et al. Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) Study Group. Presentation and effectiveness of early treatment of type 2 diabetes in youth: lessons from the TODAY study. Pediatr Diabetes 2016; 17: 212e21. Klingensmith G, Pyle L, Arslanian S, et al. for the TODAY Study Group. The presence of GAD and IA2 antibodies in youth with a type 2 diabetes phenotype. Diabetes Care 2010; 33: 1970e5. Lee-Jones K, Arslanian S, Peterokova V, Park J, Tomlinson M. Effect of metformin in paediatric patients with type 2 diabetes: a randomized controlled trial. Diabetes Care 2002; 25: 89e94. Morales A, Rosenbloom A. Death caused by hyperglycaemic hyperosmolar state at the onset of type 2 diabetes. J Pediatr 2004; 144: 270e3. Nadeau K, Anderson B, Berg E, et al. Youth-onset type 2 diabetes consensus report: current status, challenges, and priorities. Diabetes Care 2016; 39: 1635e42. National Paediatric Diabetes Audit Report 2013-14. Part 1: Care Processes and Outcomes. Royal College of Paediatrics and Child Health, 2015. NHS Choices. Physical activity guidelines for children and young people. http://www.nhs.uk/Livewell/fitness/Pages/physicalactivity-guidelines-for-young-people.aspx. OECD. Incidence estimates of type-1 diabetes, children aged 0e14 years, 2013. In: Health at a Glance:Europe 2014. Paris: OECD Publishing, 2014. http://dx.doi.org/10.1787/health_glance_eur-2014-graph36-en. Public Health England. Sugar Reduction the evidence for action. Public Health Engl October 2015; 1e48. https://www.gov.uk/ government/.../Sugar_reduction_The_evidence_for_action.pdf. UKPDS Group. Intensive glucose control with sulphonylureas of insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837e53. Zeitler P, Fu J, Tandon N, et al. Type 2 diabetes in the child and adolescent. Pediatr Diabetes 2014; 15(suppl 20): 26e46. Zeitler P, Hirst K, Pyle L, et al. TODAY Study Group. A clinical trial to maintain glycemic control in youth with type 2 diabetes. N Engl J Med 2012; 366: 2247e56.
Prevention In the UK we have not seen the rapid rise of childhood type 2 diabetes that we expected 10 years ago. However, the large numbers of children with obesity and impaired glucose tolerance suggests that we still have the potential for greater numbers of children developing type 2 diabetes. Prevention of childhood onset type 2 diabetes requires prevention of obesity, particularly in at risk groups such as children from ethnic minorities. Primary prevention of type 2 diabetes involves reversing eating and sedentary behaviour trends in homes, schools and communities that lead to excess calorie intake and decreased energy expenditure. The recent Public Health England report suggesting reduction in sugar intake is an important document which needs to be implemented in full. A FURTHER READING Banerji M. Diabetes in African Americans: unique pathophysiologic features. Curr Diab Rep 2004; 4: 219e23. Copeland KC, Zeitler P, Geffner M, et al. TODAY Study Group. Characteristics of adolescents and youth with recent-onset type 2 diabetes: the TODAY cohort at baseline. J Clin Endocrinol Metab 2011; 96: 159e67. Dart AB, Martens PJ, Rigatto C, Brownell MD, Dean HJ, Sellers EA. Earlier onset of complications in youth with type 2 diabetes. Diabetes Care 2014; 37: 436e43. Dixon J, O’Brien P, Playfair J, et al. Adjustable gastric banding and conventional therapy for type 2 diabetes. JAMA 2008; 299: 316e23. Ehtisham S, Barrett T, Shaw N. Type 2 diabetes mellitus in children e an emerging problem. Diabet Med 2000; 17: 867e71. Haines L, Wan K, Lynn R, Barrett T, Shield J. Rising incidence of type 2 diabetes in children in the United Kingdom. Diabetes Care 2007; 30: 1097e101.
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