Type 2 diabetes in adolescents and young adults

Review

Type 2 diabetes in adolescents and young adults Nadia Lascar, James Brown, Helen Pattison, Anthony H Barnett, Clifford J Bailey, Srikanth Bellary

The prevalence of type 2 diabetes in adolescents and young adults is dramatically increasing. Similar to older-onset type 2 diabetes, the major predisposing risk factors are obesity, family history, and sedentary lifestyle. Onset of diabetes at a younger age (defined here as up to age 40 years) is associated with longer disease exposure and increased risk for chronic complications. Young-onset type 2 diabetes also affects more individuals of working age, accentuating the adverse societal effects of the disease. Furthermore, evidence is accumulating that young-onset type 2 diabetes has a more aggressive disease phenotype, leading to premature development of complications, with adverse effects on quality of life and unfavourable effects on long-term outcomes, raising the possibility of a future public health catastrophe. In this Review, we describe the epidemiology and existing knowledge regarding pathophysiology, risk factors, complications, and management of type 2 diabetes in adolescents and young adults.

www.thelancet.com/diabetes-endocrinology Vol 6 January 2018

Published Online August 25, 2017 http://dx.doi.org/10.1016/ S2213-8587(17)30186-9 School of Life and Health Sciences (N Lascar MD, Prof H Pattison PhD, Prof C J Bailey PhD) and Aston Research Centre for Healthy Ageing (ARCHA) (J Brown PhD, S Bellary MD), Aston University, Birmingham, UK; and Diabetes and Endocrine Centre, Heart of England NHS Foundation Trust, Birmingham, UK (Prof A H Barnett MD); and University of Birmingham, Birmingham, UK (Prof A H Barnett) Correspondence to: Dr Srikanth Bellary, Aston Research Centre for Healthy Ageing (ARCHA), Aston University, Birmingham B4 7ET, UK [email protected]

2003 2006 2013

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Type 2 diabetes is increasingly diagnosed in children, adolescents, and young adults. Prevalence estimates suggest a 31% increase in type 2 diabetes among people aged 10–19 years in the USA between 2001 and 2009, accounting for a prevalence of 0·48 per 1000 in this age group in 2009.5 Recent data from the SEARCH study (a multicentre, observational study in the USA involving 11 245 young people with type 1 diabetes [0–19 years] and 2846 with type 2 diabetes [10–19 years]),6 showed an annual increase of about 7% in the incidence of type 2 diabetes between 2002–03 and 2011–12 (from nine cases

80

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Epidemiology

per 100 000 to 12·5 cases per 100 000) among people aged 10–19 years in the USA, with substantial relative increases in all ethnic minority groups compared with non-Hispanic white people. In a nationwide screening programme7 for diabetes in Taiwan among children and adolescents (aged 6–18 years), with data from 1992–99, the incidence of newly diagnosed type 2 diabetes was 6·5 per 100 000 individuals, compared with 1·5 per 100 000 for type 1 diabetes. With respect to older age groups, the International Diabetes Federation8 estimated that roughly 23 million young adults aged 20–39 years had type 2 diabetes worldwide in the year 2000 (13% of 177 million total adults with type 2 diabetes). By 2013, this estimate had increased to 63 million (16% of 382 million total adults with type 2 diabetes),9–11 the biggest increases being in Africa, south-east Asia, and Western Pacific regions (figure 1). In a study of the age-specific incidence of type 2 diabetes in the UK (a retrospective cohort study of patients with newly diagnosed type 2 diabetes between 1990 and 2010), the investigators reported a substantial increase in the proportion of people aged 40 years or younger at diagnosis

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The global prevalence of diabetes in adults is about 8% (more than 90% of whom have type 2 diabetes), which is projected to increase to more than 10% by 2040.1 Although the increasing prevalence of diabetes among older adults is well recognised, the rising number of young people with type 2 diabetes is a more recent development and is of particular concern. Earlier onset of diabetes leads to longer lifetime exposure to hyperglycaemia and con­ sequently greater propensity for long-term complications. Additionally, the course of type 2 diabetes in young people could be more rapid and disruptive than in patients who develop the disease later in life, leading to early morbidity and poor quality of life.2 Moreover, when type 2 diabetes develops in adolescents and young adults, the adverse societal effects could be greater because of the presence of a chronic disease throughout patients’ working life. In this Review, we have defined type 2 diabetes in young people as onset of type 2 diabetes (American Diabetes Association [ADA]3 and WHO criteria4) in adolescents and young adults aged up to 40 years, excluding secondary diabetes (ie, drug-induced, chemical-induced, exocrine pancreatic insufficiency, and genetic defects), maturity-onset diabetes of the young, gestational diabetes, and rare forms of diabetes. We examine evidence in support of the hypothesis that type 2 diabetes in young people is a distinct pathological entity characterised by a more aggressive phenotype than when the disease occurs in later life.

Cases (millions)

Introduction

Lancet Diabetes Endocrinol 2018; 6: 69–80

Figure 1: Worldwide prevalence of type 2 diabetes in young people (aged <40 years), 2003–13 Data are from the International Diabetes Federation (IDF) atlas 2003,9 2006,10 and 2013.11

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between 1991 and 2010 (figure 2).12 The standardised incidence ratio (per 100 000 population) of newly diagnosed cases of type 2 diabetes at age 40 years or younger increased from 217 in 1996–2000 to 598 in 2006–10. Increasing numbers of children, adolescents, and young adults with type 2 diabetes have been reported across most regions of the world. In the UK,13 a higher prevalence was reported in 2007 in people of south Asian, African, and African-Caribbean origin compared with white European populations. Individuals born in the USA in the year 2000 have an estimated risk for diabetes by age 40 years of about 2·5% for men and 5% for women. These estimates are doubled for people who are Hispanic or Black, further suggesting that certain ethnic groups are disproportionately affected.14 However, evidence of apparent ethnic differences based on regional variations in prevalence (table 1) is limited because the diagnostic criteria used and methods of data collection are not always consistent.15–17

Pathophysiology

Decline in β-cell function The mechanisms leading to development of type 2 diabetes in young people are similar to those in older patients; however, the speed of onset, severity, and interplay of reduced insulin sensitivity and defective insulin secretion might be different in patients who develop the disease at a younger age.18 In adolescents with type 2 diabetes, as in later onset type 2 diabetes, the initial deterioration in β-cell function is characterised by loss of first-phase nutrientstimulated insulin secretion.6 However, some evidence suggests the second phase of nutrient-induced insulin secretion might be compromised earlier in the pathogenic process in younger individuals with type 2 diabetes.18,19 In a case-control study of African-American and white people in the USA, adolescents who are obese and have had type 2 diabetes for about 1·5 years have about a 75% reduction in first-phase insulin secretion and a 50% reduction in second-phase insulin secretion compared with 1800 1600

Male Female 891

Incidence per 100 000

1400 1200 1000 800

462

600

200 0

650

311

400 126 113 1991–95

371 244 2001–05 1996–2000 Time period

2006–10

Figure 2: Age-specific incidence of newly diagnosed type 2 diabetes in the UK, per 100 000 Data are for male and female individuals aged younger than 40 years at diagnosis. Adapted from Holden and colleagues,12 with permission.

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individuals who were obese but did not have diabetes.20 Such a decrease in second-phase insulin secretion would take more than a decade to emerge in most patients with type 2 diabetes presenting in middle or later life.21,22 Emerging evidence suggests that loss of β-cell function is accelerated in young-onset type 2 diabetes. A 20–35% annual decline in β-cell function in adolescents aged 10–19 years with type 2 diabetes has been reported in the TODAY study,23 compared with the roughly 7% decline in older individuals with type 2 diabetes.23 These findings are consistent with data from a small but detailed glucose clamp study (six obese adolescents with type 2 diabetes; mean age 14·4 years)24 in this age group. Separate observational studies25,26 in adolescents of different ethnic groups have similarly confirmed the early deterioration of β-cell function in young people with diabetes. This decline in β-cell function was closely associated with the severity of insulin resistance in African-American adolescents, but less so in white and south-Asian adolescents. Thus, accelerated decline of β-cell function seems to make an important contribution to the development of type 2 diabetes in early life. The reasons for this rapid failure of both phases of nutrient-stimulated insulin secretion are unclear, but the evidence suggests that type 2 diabetes might have a more aggressive course with faster loss of β-cell function with young onset than with later onset.

Obesity-induced mechanisms The prevalence of obesity among children, adolescents, and young adults with type 2 diabetes is much greater than in older adults with type 2 diabetes (eg, >80% vs 56%26) and analyses of large databases27 have confirmed a strong inverse association between BMI and age at diagnosis of type 2 diabetes. When type 2 diabetes presents in later life, the severity of insulin resistance is often greater among individuals with a history of protracted and severe obesity, particularly with excess visceral adiposity.28 By contrast, an association between the degree of obesity and the extent of insulin resistance has not been a consistent finding in studies of adolescents with type 2 diabetes, and available data are insufficient to determine the involvement of visceral adiposity in this age group.19 However, insulin resistance is directly associated with an increased proportion of fat in muscle and liver in all age groups,6 and young people with type 2 diabetes can have much higher amounts of liver fat (up to 3 times) compared with BMI-matched individuals without diabetes and compared with patients who have developed type 2 diabetes in middle and later life.24,29 Compared with adolescents who are not obese, adolescents who are obese are reported to have chronically increased levels of circulating free fatty acids, which reduce insulin sensitivity and might contribute to increased reactive oxygen species and impaired insulin secretion.30 Chronic low-grade inflammation contributes to development of insulin resistance in www.thelancet.com/diabetes-endocrinology Vol 6 January 2018

Review

Type 1 diabetes

Young-onset type 2 diabetes

Type 2 diabetes

Sex

No difference

Female preponderance

Slight male preponderance

Ethnic origin

Common in white people, but all ethnic All ethnic groups affected, but Hispanics, groups affected African-Americans, native Americans, and south Asians disproportionately more affected

All ethnic groups affected, but Hispanics, African-Americans, native Americans, and south Asians disproportionately more affected

Usual clinical features

Often underweight, sometimes mildly Usually overweight, obese, or severely obese; obese; features of insulin resistance less metabolic syndrome; insulin resistance; dyslipidaemia; hypertension; polycystic ovary likely syndrome

Usually overweight, obese or, severely obese; metabolic syndrome; insulin resistance; dyslipidaemia; hypertension; polycystic ovary syndrome

Autoimmunity

Present

Absent

Absent or rare

Presentation

Often acute onset; ketoacidosis

Slow, asymptomatic; rarely ketoacidosis

Slow, asymptomatic

Family history

Family association might not be present

Very strong

Strong

Role of insulin in management

Insulin

Rapid progression to insulin (>50% by 2–5 years Gradual progression to insulin (usually after diagnosis) >5 years after diagnosis)

Table 1: Differences in clinical characteristics between type 1 diabetes, young-onset type 2 diabetes, and type 2 diabetes

type 2 diabetes, typically involving excess production of adipokines (tumour necrosis factor-α, interleukin 1β, and high-sensitivity C-reactive protein).30,31 Increased circulating concentrations of these pro-inflammatory markers have been reported in adolescents with type 2 diabetes in a cross-sectional study of 74 predominately Caucasian adolescents with type 2 diabetes aged 12–18 years and in 74 BMI-matched, age-matched, and sexmatched controls.31 Although obesity is clearly a prominent risk factor for type 2 diabetes in young people, studies focussed on insulin resistance, lipid metabolism, and inflammation lend support to the suggestion that development of diabetic hyperglycaemia in people aged 40 years and younger seems to be more strongly dependent on β-cell failure than in people who develop type 2 diabetes in later life.

Key drivers for the development of type 2 diabetes in young people Early life determinants

Changes in the intrauterine environment can affect the development of obesity and type 2 diabetes in adolescents and young adults. Maternal undernutrition and over-nutrition are associated with an increased risk of obesity and type 2 diabetes during adolescence and early adulthood, developing earlier than in those without such early life exposures.32,33 This association could depend in part on the extent and timing of catch-up growth in underweight offspring and the extent of excess adiposity in those with over-nutrition sustained beyond the first year of life.34 In a large prospective study of 27 899 participants born at full term between 1959 and 1965,35 rapid weight gain during the first 4 months of life was associated with an increased risk of overweight at age 7 years. The association between post-natal undernutrition and risk of type 2 diabetes in later life has also been shown in the Dutch famine study.36 Additionally, analysis of data from the SEARCH for diabetes in Youth study including 2342 individuals with type 1 and 331 individuals with type 2 diabetes indicated that type 2 www.thelancet.com/diabetes-endocrinology Vol 6 January 2018

diabetes with onset before age 20 years emerged 1–2 years earlier in offspring exposed to hyperglycaemia in utero.33 These observations have been attributed in part to epigenetic influences of the intrauterine and early postnatal environment on metabolic programming, but the molecular mechanisms remain speculative.37

Diet and obesity According to data from the Global Burden of Disease Study 2013,38 the global pandemic of overweight and obesity now affects 37% of men, 38% of women, 24% of boys, and 23% of girls (adults ≥20 years, children <20 years). Although the causes of obesity in children and adolescents are complex, obesity is clearly an important driver for the increasing prevalence of type 2 diabetes in young people and changes in lifestyle account for much of the increased prevalence of obesity and type 2 diabetes.39 Increasing consumption of energydense foods and sugar-rich drinks, and reduced physical activity, are the main contributors to obesity among young people.40 Regular consumption of sweetened beverages increases energy consumption by about 10%, while increased portion sizes, access to fast foods, and widespread and targeted advertising of unhealthy foods leads to increased adiposity in children, adolescents, and young adults.41,42 The widespread use of corn-derived fructose syrup as a sweetening agent in carbonated soft drinks has substantial effects on the development of adiposity, insulin resistance, hyperglycaemia, and other cardiometabolic risk factors in young people.43,44 Indeed, in the SEARCH study,45 few differences in macronutrient or fibre intake were identified between young people (aged 15–22 years) with type 1 diabetes versus those with type 2 diabetes, but those with type 2 diabetes consumed twice the amount of sweetened beverages.

Physical activity Physical inactivity is associated with an increased risk of obesity. However, because of methodological deficiencies and the scarcity of reliable baseline data, quantification of 71

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the secular changes in leisure time activity in adolescents and young adults is difficult.46 Nevertheless, evidence suggests that increased use of cars and mass transit, leading to less walking, and the widespread popularity of leisure-time pursuits that require little physical activity, such as television and video games, contribute to sedentary behaviours among young people.46,47 Physical activity declines further in adolescents compared with younger children and only a small proportion meet recommended levels. For example, data from surveys48–51 in Europe and North America have indicated that indicated that only 20% of adolescents aged 13–15 years participated in 60 min of moderate or vigorous activity per day, with girls being less active than boys. Physical inactivity among young people is associated with increased risk of metabolic syndrome, insulin resistance, and type 2 diabetes.52,53 The Bogulusa Heart Study,52 a cross-sectional cohort study in 1420 young adults aged 20–38 years of young adults, reported an inverse association between leisuretime physical activity and risk factors for insulin resistance. Similarly, the CARDIA study,53 a multicentre population-based longitudinal cohort study in 5115 participants aged 18–30 years, physical inactivity was strongly associated with risk of type 2 diabetes, hypertension, and metabolic syndrome. Although aerobic exercise can delay or prevent the development of type 2 diabetes in older adults, the expected metabolic benefits derived from aerobic activity are comparatively less in young people with type 2 diabetes.54 Thus, although insufficient physical activity makes an important contribution to the pathogenesis of type 2 diabetes in young people, the potential for increased physical activity as a treatment strategy needs further research.

Socioeconomic factors Socioeconomic deprivation within affluent societies is a risk factor for obesity and type 2 diabetes, especially among inner city populations. For young individuals at least, this association might be attributable more to consumption of energy-dense convenience foods and sedentary habits than to an absolute lack of availability or affordability of healthier options, often reflecting educational factors and local practices.55–57 The effects of deprivation are magnified by the pre­ disposition to type 2 diabetes in some ethnic migrant communities.58 However, it is difficult to dissect the contributions of genetic determinants, environmental influences, and cultural constraints, especially for pre-adult and early adult development of type 2 diabetes.55–57 Socioeconomic interventions can relieve absolute deprivation, but do not necessarily alter individual lifestyle choices. Thus, re-housing or changing facilities within neighbourhoods can bring about modest reductions in the incidence of obesity and type 2 diabetes, but the complex interactions of multiple diabetogenic factors continue to mask appreciation of the contribution of individual 72

determinants of risk.59,60 Indeed, obesity is also common among members of affluent societies who are not deprived, and this observation cannot be accounted for by ethnicity or culture, thereby implicating individual lifestyle and behavioural choices as risk factors with the greatest effect on the pathogenesis of type 2 diabetes in young people.61,62

Family history A family history of type 2 diabetes is inversely associated with age of onset of type 2 diabetes.63 In a 2004 study63 of 5193 participants from different ethnic backgrounds, including Anglo-Celtic, Indian, Australian Aboriginal, and Pacific Islander, age of onset of diabetes reduced by 1·7 years for every 10% increase in family members affected by diabetes. Similar associations have been reported in Korean,9 Chinese,64 and Indian populations.65 In a genetic study in the UK, patients with type 2 diabetes who were diagnosed at younger than 55 years had a stronger and different genetic predisposition than did patients diagnosed at older ages.66 In a large Scottish population-based cohort study,67 genetic risk of type 2 diabetes conferred by 61 gene variants was associated with a younger age at diagnosis and younger age at initiation of insulin treatment. Although parental diabetes has a strong association with early-onset type 2 diabetes in offspring, disentangling of genetic and socially acquired factors is not simple. For example, increased risk of type 2 diabetes among young people in Afro-Caribbean and south-Asian communities is strongly affected by cultural factors, especially among women; attempts to analyse this effect through studies68–70 of migrant individuals have shown a tendency of migrant populations to adopt a mix of cultures that still precludes dissection of specific risk factors. Studies71–74 in Mexican and Asian populations have identified several mutations associated with type 2 diabetes in young people. The high prevalence of type 2 diabetes in the parents of young people diagnosed with type 2 diabetes could reflect a stronger genetic predisposition, even when monogenic diabetes is excluded. This hypothesis suggests that efforts to define genes that cause type 2 diabetes by linkage might be more powerful if focused on young adults with diabetes, raising the question of whether type 2 diabetes in older populations has a relatively smaller genetic contribution and a stronger environmental contribution.66

Female sex and polycystic ovarian syndrome Young-onset type 2 diabetes is more common in women and girls than in men and boys, irrespective of ethnic origin. In the SEARCH study of US children and adolescents (aged 10–19 years),6 incidence of type 2 diabetes in female individuals was nearly twice that of male individuals.6 Female sex has been associated with early-onset type 2 diabetes (<30 years) in Bangladesh75 and Jamaica,76 which has been attributed to the increase in overweight and obesity in girls and young women in these countries. www.thelancet.com/diabetes-endocrinology Vol 6 January 2018

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The risk of type 2 diabetes is substantially raised in young women diagnosed with polycystic ovary syndrome,77 and is possibly associated with insulin resistance in polycystic ovary syndrome.78,79 In the Australian Longitudinal Study on Women’s Health,77 in women aged 28–33 years and of similar BMI, the prevalence of type 2 diabetes was 5·1% in women with polycystic ovary syndrome and 0·3% in women without. In studies in the USA and Asia of women aged 20–35 years, the incidence of type 2 diabetes in women with polycystic ovary syndrome was three-times higher than in the general population.79

Non-alcoholic fatty liver disease Non-alcoholic fatty liver disease (NAFLD) seems to be a stronger risk factor for young-onset type 2 diabetes than for type 2 diabetes that develops in middle or later life. NAFLD is twice as common in adolescents than in older patients with type 2 diabetes, and is commonly associated with insulin resistance in adolescents and young adults with type 2 diabetes.80,81 In an Indian study,82 the prevalence of NAFLD in 924 patients with type 2 diabetes aged 25–40 years was 55% versus 58% in those aged 41–50 years, 55% in those aged 51–60 years, and 62% in those aged 61–70 years; however, liver enzyme concentrations were higher in patients aged 25–40 years than in patients with type 2 diabetes older than 40 years. In a cross-sectional study83 across 12 centres in the USA of 675 participants (44 with type 2 diabetes and 158 with pre-diabetes; mean age 12·6 years), the prevalence of non-alcoholic steato hepatitis (NASH) was higher in those with type 2 diabetes (43%) compared with those with pre-diabetes (34%) and normal glucose tolerance (22%). The extent to which excess ectopic fat and particularly NAFLD are driving insulin resistance in young people with type 2 diabetes remains unclear, but alcohol does not seem to be an important cause of fatty liver in this age group.

Clinical characteristics The clinical characteristics of type 2 diabetes in young people overlap substantially with those of type 1 diabetes, from which it needs to be differentiated, as well as with those of type 2 diabetes in older adults. The early loss of insulin secretory capacity in pre-adult and early adult presentations of type 2 diabetes is similar to the demise of β-cell function in type 1 diabetes, whereas the high prevalence of obesity seen in young people with type 2 diabetes is more in keeping with type 2 diabetes in older adults. Adolescents who develop type 2 diabetes also typically show similar clinical features of insulin resistance, dyslipidaemia, hypertension, and poly­ cystic ovary syndrome as are seen in later presentations, but the long-term consequences of early-onset comp­lications are only now becoming apparent.84,85 Despite shared clinical characteristics, young-onset type 2 diabetes can be differentiated from type 1 diabetes and from type 2 diabetes in older adults on the basis of www.thelancet.com/diabetes-endocrinology Vol 6 January 2018

certain phenotypic characteristics (table 1). Compared with individuals with type 1 diabetes, young people with type 2 diabetes do not have evidence of autoimmunity and typical symptoms of diabetes might be absent in a third of all patients;86 they are more likely to have hypertension and to be on statins and anti-hypertensives;87,88 and have a more adverse cardiovascular risk profile. The prevalence of microvascular complications with a shorter disease duration is also higher compared with patients with type 1 diabetes.89 Compared with later-onset type 2 diabetes, young-onset patients have a higher prevalence of family history of diabetes, are more likely to have diastolic hypertension, and tend to have worse glycaemic control than later-onset patients.26,27 Additionally, type 2 diabetes in young people is associated with a shorter time to initiation of insulin treatment compared with type 2 diabetes in older adults.90,91 Young people with type 2 diabetes develop adverse metabolic and cardiovascular risk profiles more rapidly and much sooner after diagnosis than do patients who develop type 2 diabetes in middle or later life.92 Although the features associated with these adverse risk profiles are not dissimilar, the greater intensity over a longer period will probably lead to a heightened risk of complications compared with patients who develop type 2 diabetes in later life.88 For example, the prevalence of obesity and metabolic syndrome (up to 70%) and of subdiabetic hyperglycaemia (impaired fasting glucose, impaired glucose tolerance, or both) is higher in young people with type 2 diabetes than in older people with these conditions.92,93 Early onset of type 2 diabetes in young adults has also been associated with a higher HbA1c compared with adults who develop diabetes at older ages in US,9 Asian,10 and UK94 populations. In a 2010 study95 of 995 Sri Lankan patients (aged 14–45 years, median age 38 years) with type 2 diabetes, apolipoprotein B (54% >1·2 g/L) and triglycerides (33% >1·5 mmol/L) were increased—consistent with increased cardiovascular risk. Similar results were reported in a UK study96 that compared the burden of atherogenic particles in patients with early onset type 2 diabetes (n=24) with late-onset type 2 diabetes (n=26). Moreover, in a separate UK study,97 apolipoprotein B concentrations remained significantly increased among patients with young-onset type 2 diabetes compared with older adults with type 2 diabetes despite adequate statin treatment.

Complications Earlier onset of type 2 diabetes is associated with a greater lifetime risk of diabetes-associated complications.98 Evidence from several cross-sectional studies99–102 has suggested that the burden of diabetes complications is greater for people with young-onset type 2 diabetes than for people with type 1 diabetes or later-onset type 2 diabetes. Based on a modelling study of a hypothetical cohort of adolescents and young adults in the USA,99 overall life expectancy among patients diagnosed with type 2 diabetes 73

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at 20–40 years is reduced by 14 years in men and 16 years in women compared with people without diabetes.

Microvascular complications Findings from several studies101–105 have shown a signif­ icantly higher prevalence of microvascular complications in people with young-onset type 2 diabetes compared with patients with type 1 diabetes or later onset type 2 diabetes. In the SEARCH study,100 the burden of microvascular complications (diabetic kidney disease, retinopathy, and peripheral neuropathy) was significantly increased among adolescents and young adults with type 2 diabetes (diagnosed before the age of 20 years) compared with individuals with type 1 diabetes. In a study comparing patients with type 1 diabetes with young-onset type 2 diabetes (ages 1–18 years; mean age of patients with type 1 diabetes 9 years, mean age of patients with type 2 diabetes 13·5 years), rates of microalbuminuria were significantly greater in patients with young-onset type 2 diabetes and these patients also had a faster progression to macroalbuminuria.102 Patients with youngonset type 2 diabetes also had a four-times increased risk of renal failure and relatively poor survival outcomes compared with patients of a similar age with type 1 diabetes for a similar duration.102 In a longitudinal observational multiethnic cohort study of 399 young people in the USA with type 1 and 2 diabetes diagnosed at age 20 years or younger, the prevalence of diabetic peripheral neuropathy assessed at 60 month follow-up was 3 times higher in those with type 2 diabetes (25·7%) compared with those with type 1 diabetes (8·2%).105 In a UK study,104 the prevalence of retinopathy (all stages) among young patients with type 2 diabetes (age of onset <40 years; n=464) was similar to the prevalence among patients with type 1 diabetes (n=842), despite a shorter duration of diabetes and similarly poor glycaemic control; the prevalence of retinopathy was higher in those with young-onset type 2 diabetes when corrected for diabetes duration. In a large (n=5983) retrospective study in Asia,100 the frequency of retinopathy, advanced eye disease, and photocoagulation was higher in patients with early-onset (before age of 30 years) versus late-onset type 2 diabetes. In a cross-sectional study of 2516 participants with type 2 diabetes (455 were younger than 40 years at diagnosis),103 10 years after diagnosis, the prevalence of retinopathy among patients with young-onset type 2 diabetes was significantly higher than in those with later-onset type 2 diabetes; hypertension and suboptimal glycaemic control were identified as predominant contributing risk factors.

Macrovascular complications Compared with individuals of similar age who do not have diabetes, people with young-onset type 2 diabetes have a substantially greater risk of macrovascular disease.90 In a large prospective study in the USA106 that compared young-onset versus late-onset type 2 diabetes in adults 74

(mean age at diagnosis 37·6 years vs 60 years), the risk of developing any macrovascular complication was twice as high in individuals with earlier onset disease. Furthermore, the risk of myocardial infarction was 14 times higher in patients with young-onset type 2 diabetes than in patients without diabetes, whereas the risk of myocardial infarction was much less (typically 2–4 times higher) in patients with type 2 diabetes presenting in middle and later life.106 In Hong Kong, where 20% of type 2 diabetes diagnosed since 1995 occurs in people aged 40 years or younger, a 7-year prospective study107 showed that when adjusted for age, patients with young-onset type 2 diabetes (n=2066) had 30–50% increased risk of cardiovascular disease and renal disease compared with patients with late-onset disease. At diagnosis, patients with young-onset type 2 diabetes had similar or worse metabolic risk profiles compared with late-onset disease, and the risks for cardiovascular and renal complications at any given age were greater in these patients, predominantly driven by longer disease duration.107 During the sixth decade of life, young-onset type 2 diabetes was associated with roughly double the risk of cardiovascular disease, chronic kidney disease, and all-cause mortality.107 Significant differences in surrogate markers of cardiovascular disease have been reported between individuals with type 1 diabetes, later onset type 2 diabetes, and young-onset type 2 diabetes.108–111 Compared with patients with type 1 diabetes or young individuals without diabetes, patients with young-onset type 2 diabetes (aged 14–30 years) show a greater frequency of increased carotid intimal-medial thickness.109,110 In an audit of an Australian hospital diabetes database,111 354 young adult patients with young-onset type 2 diabetes (onset between 15 and 30 years) had substantially increased macrovascular disease, including ischaemic heart disease and stroke, compared with 470 patients with type 1 diabetes. Although drawing of definitive conclusions is difficult from these observational studies, their results suggest that young-onset type 2 diabetes is associated with a much more frequent occurrence of adverse macrovascular and microvascular outcomes and a more rapidly progressing severity of complications than is seen in type 1 diabetes or later-onset type 2 diabetes.

Other complications Complications such as impaired hearing and reduced fertility are frequently observed in patients with youngonset type 2 diabetes and these can substantially reduce quality of life.112–114 Risk of premature decline in cognitive function has been detected in patients with type 2 diabetes who present in middle and later life, and preliminary evidence115,116 suggests this decline could occur even earlier in patients with young-onset type 2 diabetes, with implications for health-care provision and social welfare. Many other morbidities associated with patients of all ages with type 2 diabetes, such as www.thelancet.com/diabetes-endocrinology Vol 6 January 2018

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psychological issues—especially depression—as well as reproductive issues and care pathways are beyond the scope of this Review.

Treatment Little evidence exists to inform optimal strategies for the management of young-onset type 2 diabetes and its rapidly developed complications: decisions are currently extrapolated from the evidence-based protocols that guide treatment of type 2 diabetes presenting in older adults. The American Academy of Pediatrics guideline2 and the ADA consensus report117 agree that the ideal goal of treatment for young people with type 2 diabetes is normalisation of glycaemic control to reduce the risk of acute and chronic complications. Lifestyle modifications are prioritised, and approved drug treatments can be considered when lifestyle alone is inadequate. The American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive type 2 diabetes management algorithm118 supports a general approach that balances age, life expectancy, and comorbidities, but there is no specific guidance according to age groups.

Lifestyle changes Although lifestyle modification is the most commonly used intervention in adolescents with type 2 diabetes, less than 20% achieve or maintain adequate glycaemic control with lifestyle intervention alone.118–121 Intervention studies involving diet alone to treat patients with youngonset type 2 diabetes have been limited. In a study120 of 20 obese children and adolescents (mean age 14·5 years) with type 2 diabetes, improvements in weight (BMI was reduced from 43·5 to 39·3 kg/m²), insulin sensitivity, Study type

Number of Ethnic origin participants

Wittmeier at al Retrospective (2012)119

80

89% first nations; 5% Caucasian; 6% other

Jones et al (2002)123

RCT

82

37% white; 30% black; 22% Hispanic; 5% Asian; 6% other

TODAY study RCT group (2012)126

699

Yeung et al (2014)127

Crosssectional

7481

53% non-Hispanic; 40% Hispanic; 8% other

South Asian and southeast Asian

and HbA1c concentration were seen after following a very low calorie diet (<800 kcal per day) for a 2 month period. These improvements were, however, not maintained after cessation of the diet. Aerobic activity, alone or in combination with diet, can reduce systolic blood pressure, reduce total cholesterol, raise HDL cholesterol, and improve endothelial function in overweight patients with young-onset type 2 diabetes.47 However, any potential benefits to the cardiovascular disease risk profile are lost within 3–6 months after cessation of exercise training, and do not confer protection against later cardiovascular events.47,121 Additionally, reviews49,121,122 of the limited number of studies done to date have not identified substantial or lasting benefits of doing aerobic exercise on glucose homoeostasis for patients who are obese with young-onset type 2 diabetes, unless accompanied by dietary intervention.

Pharmacological and surgical approaches Great uncertainty remains about the use of many novel drug treatments in individuals younger than 18 years, in whom concerns or absence of information about safety preclude or deter their use.117 This situation is compounded by difficulties in recruiting young people into clinical trials.117 Both metformin and glibenclamide can be used effectively, at least in the short-term, in children and adolescents with type 2 diabetes. Reductions in fasting plasma glucose (roughly 1·2 mmol/L) and HbA1c (>1%) have been reported with metformin monotherapy in children with type 2 diabetes aged 10–16 years.123 Substantial reductions in HbA1c were also shown in a study124 comparing metformin and glibenclamide as monotherapy and in combination: notably, the combination was no more effective than either of these drugs used alone.

Age range Diabetes (years) duration (years)

Intervention

<18

Lifestyle

<1

Follow-up Glycaemic outcomes (months) 12

54% achieved HbA1c <7%

8–16

··

Metformin versus placebo

4

Mean HbA1c was significantly lower in the metformin group compared with placebo (7·5% vs 8·6%)

10–17

<1

Metformin alone, metformin plus lifestyle, and metformin plus rosiglitazone

45

Metformin plus rosiglitazone significantly superior to metformin alone

<40 (mean 33)

10

Insulin treatment alone or in combination with oral glucose-lowering drugs

NA

Only 27% of participants achieved HbA1c <7%

Studies were included only if they were RCTs or observational studies with at least 50 participants. RCT=randomised controlled trial.

Table 2: Key studies showing the effectiveness of interventions to treat young-onset type 2 diabetes

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Sustainability of glycaemic control with metformin either alone or in combination with rosiglitazone or lifestyle was examined in the TODAY study125,126—a multiethnic cohort of 699 adolescents with type 2 diabetes diagnosed aged 10–17 years. Despite good treatment compliance, after a mean follow-up period of 3·86 years, 120 (52%) of 232 patients treated with metformin alone failed to achieve durable glycaemic control compared with 90 (39%) of 233 patients in the group who received metformin in combination with rosiglitazone and 109 (47%) of 234 patients who received metformin plus lifestyle. Metformin in combination with rosiglitazone was significantly superior to metformin alone. High HbA1c concentration and low insulin secretory capacity at baseline were independent predictors of risk for treatment failure (defined as HbA1c >8% for 6 months).125 The study also Panel 1: Challenges and strategies for prevention of type 2 diabetes in adolescents and young adults • Prevention trials have rarely specifically attempted to target young people, for whom different and more effective preventive strategies might be required • Understanding of effective strategies for prevention of young-onset type 2 diabetes is limited by considerable gaps in knowledge about the disease course and the relatively low number of young people with prediabetes compared with older adults141 • Current recommendations emphasise targeting individuals with high risk of young-onset type 2 diabetes such as ethnic groups with high susceptibility and those living in socioeconomically deprived areas117,141 • Education is considered to be the cornerstone of prevention; strong emphasis on healthy living within the school curriculum, concerted public health messaging, and use of social media channels have all been recommended117,139,140 • If prediabetes is identified, weight control by diet plus exercise is recommended in adolescents and young adults—the optimal approach for prevention of diabetes in this age group, however, continues to be debated117,122

Panel 2: Areas for further research into young-onset type 2 diabetes • Prospective cohort studies to define natural disease course and heterogeneity • Elucidation of individual risk factors and their role in pathogenesis, particularly in ethnic populations with high risk • Randomised controlled trials to assess the effectiveness and safety of existing therapies in young patients • Research into implementation of preventive measures in family and educational settings

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highlighted ethnic differences in response to treatment, with high failure rates among non-Hispanic black people (table 2). Rapid decline in β-cell function might largely explain the faster loss of glycaemic control and the earlier requirement for insulin therapy in patients with youngonset type 2 diabetes than in those with later-onset disease.23 Although some adolescents with type 2 diabetes can maintain glycaemic control for the first 2–3 years after diagnosis using lifestyle and metformin inter­ ventions,84 insulin is often preferred as the initial therapy and about a third of those receiving basal insulin are able to subsequently stop insulin as glycaemic control improves.84,88 About half of these patients require reinitiation of insulin within a few months because of poor control and some will require substantial insulin intensification.88 On the basis of the limited evidence available, the types of insulins selected and the monitoring methods seem to make little difference to the glycaemic control achieved or the complication status.127 Evidence to date has not established a reduction in adverse cardiovascular events with rigorous control of cardiovascular disease risk factors in adolescents with type 2 diabetes. Results from several studies127–131 have shown that typically less than a third of such patients achieve glycaemic or lipid targets and are less likely to be prescribed lipid-lowering treatments, renin-angiotensinsystem inhibitors, or anti-platelet drugs than are patients with type 2 diabetes who present later in life. Although many clinical trials for type 2 diabetes include individuals aged from 18 years, few young adults are usually recruited and few data specific to the effectiveness of treatments in the age range 18–40 years exist. Treatment approaches in this age group are therefore based on evidence from older patients with type 2 diabetes.118,132 Several oral and injectable glucose-lowering therapies are approved for type 2 diabetes and offer a wide choice in selecting appropriate therapeutic combinations. Many of these drugs, such as dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose co-transporter-2 inhibitors, have beneficial effects on bodyweight, insulin resistance, and β-cell preservation.132 Whether these drugs have favourable effects on the disease course in young people needs further investigation.132 Bariatric surgery has emerged as a viable treatment option in individuals with type 2 diabetes133,134 and evidence has shown that it is safe and effective in obese adolescents.135,136 Data for the effects of bariatric surgery in young people with type 2 diabetes are limited, but nevertheless encouraging, with significant improvements in weight and glycaemic indicators, as seen in older adults.135

Societal effects of type 2 diabetes in young people The frequency and severity of complications with youngonset type 2 diabetes might limit patients’ capacity to www.thelancet.com/diabetes-endocrinology Vol 6 January 2018

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work, and the economic and sociological consequences are therefore likely to be greater than for later-onset type 2 diabetes.136 Protracted depression requiring substantial ongoing psychological support is common with young-onset type 2 diabetes,137 and reduced quality of life due to visual impairment, frequency of health-care appointments, and lifestyle constraints are prominently cited by younger patients. Additionally, presence of type 2 diabetes during pregnancy can adversely affect maternal and fetal outcomes.138 Chronically disabling and life-threatening comor­ bidities such as early-onset end-stage renal disease, neuropathic pain, and cardiovascular conditions present enormous challenges for patient wellbeing and large potential costs for health-care provision. The continued increases in prevalence of obesity and type 2 diabetes in young adults also impinges on the lives of other family members, friends, work colleagues, and communities, and the prosperity of localities where prevalence is particularly high.136 Obesity and type 2 diabetes in young people have also been identified as particular threats to the capacity of health-care services across Europe and North America, including predictions that existing funding systems will not be able to accommodate the growing demands for the expensive long-term care that will be needed for management of disease complications.3,136,139 Effective strategies aimed at preventing young-onset type 2 diabetes are therefore needed to tackle this problem and the paucity of evidence in this area needs to be addressed urgently (panel 1).139–142

Summary and future research directions Although it is tempting to extrapolate the disease course of type 2 diabetes in young people as just an earlier and more rapid form of type 2 diabetes in older adults, distinctive differences are evident. The young-onset phenotype has a stronger family history, a greater association with obesity, early loss of both first and second phases of insulin secretion alongside often severe insulin resistance, early onset and rapid progression of microvascular and macrovascular complications, and poor sustainability of responsiveness to oral glucose-lowering therapies, frequently neces­sitating early introduction of insulin. Despite the many recognised genetic and environ­ mental components of young-onset type 2 diabetes, further elucidation of individual risk factors and their interactions is required to dissect the pathogenic process more closely and to better inform strategies for prevention and treatment (panel 2).117 The paucity of evidence on long-term treatment and outcomes for young-onset type 2 diabetes necessitates clinical investigations to test and refine the use of existing interventions. Exploration of more effective ways to implement preventive lifestyle measures in the family setting and to improve health education in the school curriculum will be particularly valuable to enable young people to make healthier lifestyle choices. The growing prevalence of type 2 diabetes in www.thelancet.com/diabetes-endocrinology Vol 6 January 2018

Search strategy and selection criteria We searched MEDLINE, PubMed, and Web of Science for articles published between Jan 1, 2000, and April 1, 2017. Search terms included “early-onset”, “young adults”, “youth”, “children”, and “adolescents”, in combination with the term “diabetes” and “type 2 diabetes”. To be considered relevant, studies had to be in human populations, published in English, and with a defined age-range (age of diagnosis younger than 40 years) for diagnosis of type 2 diabetes in young people. Case reports, editorials, and studies with important methodological limitations were excluded, as were studies of patients with type 1 diabetes, gestational diabetes, or maturity-onset diabetes of the young. Although type 2 diabetes in adolescents and young adults can be seen as a continuum, inevitably some distinct features occur within age groups that are affected by life events at different ages; to provide further clarity of such distinctions, in this Review, we have only highlighted studies that have included only adolescents or younger adults.

young people poses an extra devastating twist to the diabetes pandemic that requires strong public health messaging and investment from all stakeholders to mitigate a pending health-care disaster. Contributors NL, JB, and CJB did the literature search. NL and SB wrote the initial draft of the Review. JB, HP, CJB, and AHB critically revised and edited the Review. All authors approved the final submitted version. Declaration of interests AHB has received personal fees from Merck, Sharpe & Dohme, Novartis, Boehringer Ingelheim, Janssen, AstraZeneca, Novo Nordisk, Eli Lilly, and Sanofi-Aventis. CJB has received personal fees from AstraZeneca, Boehringer Ingelheim, Elcelyx, Lexicon, Poxel, Eli Lilly, Janssen, Merck, Sharpe & Dohme, Novo Nordisk, and Sanofi-Aventis. SB has received grants, personal fees, and support to attend educational meetings from Novo Nordisk; grants from The Binding Site; personal fees from AstraZeneca, Merck, Sharpe & Dohme, and Janssen; personal fees and support to attend educational meetings from Boehringer Ingelheim; personal fees and support to attend educational meetings from Eli Lilly; and personal fees and support to attend educational meetings from Sanofi-Aventis. NL, JB, and HP declare no competing interests. References 1 International Diabetes Federation. IDF Diabetes Atlas, 7th edn. Brussels: International Diabetes Federation, 2015. http://www. diabetesatlas.org (accessed April 1, 2017). 2 Copeland KC, Silverstein J, Moore KR, et al. Management of newly diagnosed type 2 diabetes mellitus (T2DM) in children and adolescents. Pediatrics 2013; 131: 364–82. 3 American Diabetes Association. Standards of medical care in diabetes—2016 abridged for primary care providers. Clin Diabetes 2016; 34: 3–21. 4 WHO. Definition and diagnosis of diabetes mellitus and intermediate hyperglycaemia: report of a WHO/IDF consultation. Geneva: World Health Organization, 2006. http://www.who.int/ diabetes/publications/Definition%20and%20diagnosis%20of %20 diabetes_new.pdf (accessed Jan 15, 2017). 5 Dabelea D, Mayer-Davis EJ, Saydah S, et al, for the SEARCH for Diabetes in Youth Study. Prevalence of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009. JAMA 2014; 311: 1778–86. 6 Mayer-Davis EJ, Lawrence JM, Dabelea D, et al, for the SEARCH for Diabetes in Youth Study. Incidence trends of type 1 and type 2 diabetes among youths, 2002–2012. N Engl J Med 2017; 376: 1419–29.

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55 Hulshof KF, Brussaard JH, Kruizinga AG, Telman J, Löwik MR. Socio-economic status, dietary intake and 10 y trends: the Dutch National Food Consumption Survey. Eur J Clin Nutr 2003; 57: 128–37. 56 Abouzeid M, Philpot B, Janus ED, Coates MJ, Dunbar JA. Type 2 diabetes prevalence varies by socio-economic status within and between migrant groups: analysis and implications for Australia. BMC Public Health 2013; 13: 252. 57 Giles-Corti B, Donovan RJ. Socioeconomic status differences in recreational physical activity levels and real and perceived access to a supportive physical environment. Prev Med 2002; 35: 601–11. 58 Delavari M, Sønderlund AL, Swinburn B, Mellor D, Renzaho A. Acculturation and obesity among migrant populations in high income countries—a systematic review. BMC Public Health 2013; 13: 458. 59 Spencer Bonilla G, Rodriguez-Gutierrez R, Montori VM. What we don’t talk about when we talk about preventing type 2 diabetes— addressing socioeconomic disadvantage. JAMA Internal Med 2016; 176: 1053–54. 60 Ludwig J, Sanbonmatsu L, Gennetian L, et al. Neighborhoods, obesity, and diabetes—a randomized social experiment. N Engl J Med 2011; 365: 1509–19. 61 Reinehr T. Type 2 diabetes mellitus in children and adolescents. World J Diabetes 2013; 4: 270–81. 62 Huang TTK, Goran MI. Prevention of type 2 diabetes in young people: a theoretical perspective. Pediatr Diabetes 2003: 4: 38–56. 63 Molyneaux L, Constantino M, Yue D. Strong family history predicts a younger age of onset for subjects diagnosed with type 2 diabetes. Diabetes Obes Metab 2004; 6: 187–94. 64 Ng MC, Lee SC, Ko GT, et al. Familial early-onset type 2 diabetes in Chinese patients: obesity and genetics have more significant roles than autoimmunity. Diabetes Care 2001; 24: 663–71. 65 Jali MV, Kambar S, Jali SM, Gowda S. Familial early onset of type-2 diabetes mellitus and its complications. N Am J Med Sci 2009; 1: 377–80. 66 Frayling TM, Wiltshire S, Hitman GA, et al. Young-onset type 2 diabetes families are the major contributors to genetic loci in the Diabetes UK Warren 2 genome scan and identify putative novel loci on chromosomes 8q21, 21q22, and 22q11. Diabetes 2003; 52: 1857–63. 67 Zhou K, Donnelly LA, Morris AD, et al. Clinical and genetic determinants of progression of type 2 diabetes: a DIRECT study. Diabetes Care 2014; 37: 718–24. 68 Krishnan S, Cozier YC, Rosenberg L, Palmer JR. Socioeconomic status and incidence of type 2 diabetes: results from the Black Women’s Health Study. Am J Epidemiol 2010; 171: 564–70. 69 Lee TC, Glynn RJ, Pena JM, et al. Socioeconomic status and incident type 2 diabetes mellitus: data from the Women’s Health Study. PLoS One 2011; 6: e27670. 70 Hasson RE, Adam TC, Pearson J, Davis JN, Spruijt-Metz D, Goran MI. Sociocultural and socioeconomic influences on type 2 diabetes risk in overweight/obese African-American and Latino-American children and adolescents. J Obes 2013; 2013: 512914. 71 Aguilar-Salinas CA, Reyes-Rodriguez E, Ordonez-Sanchez ML, et al. Early-onset type 2 diabetes: metabolic and genetic characterization in the Mexican population. J Clin Endocrinol Metab 2001; 86: 220–26. 72 Anuradha S, Radha V, Mohan V. Association of novel variants in the hepatocyte nuclear factor 4A gene with maturity onset diabetes of the young and early onset type 2 diabetes. Clin Genet 2011; 80: 541–49. 73 Gragnoli C, Menzinger Von Preussenthal G, Habener JF. Triple genetic variation in the HNF-4α gene is associated with early-onset type 2 diabetes mellitus in a Philippino family. Metabolism 2004; 53: 959–63. 74 Tanaka S, Kobayashi T, Tomura H, et al. A novel dominant-negative mutation of the hepatocyte nuclear factor-1α gene in Japanese early-onset type 2 diabetes. Horm Metab Res 2000; 32: 373–77. 75 Nizam S, Khalequzzaman M, Yatsuya H, et al. Incidence of young onset insulin-requiring diabetes mellitus among 18- to 30-year-olds in Dhaka, Bangladesh (1994–2003). Nagoya J Med Sci 2012; 74: 149–56. 76 Tulloch-Reid MK, Boyne MS, Smikle MF, et al. Clinical and laboratory features of youth onset type 2 diabetes in Jamaica. West Indian Med J 2010; 59: 131–38.

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77 Joham AE, Ranasinha S, Zoungas S, Moran L, Teede HJ. Gestational diabetes and type 2 diabetes in reproductive-aged women with polycystic ovary syndrome. J Clin Endocrinol Metab 2014; 99: e447–52. 78 Traub ML. Assessing and treating insulin resistance in women with polycystic ovarian syndrome. World J Diabetes 2011; 2: 33–40. 79 Talbott EO, Zborowski JV, Rager JR, Kip KE, Xu X, Orchard TJ. Polycystic ovarian syndrome (PCOS): a significant contributor to the overall burden of type 2 diabetes in women. J Womens Health (Larchmt)2007; 16: 191–97. 80 Hecht L, Weiss R. Nonalcoholic fatty liver disease and type 2 diabetes in obese children. Curr Diab Rep 2014; 14: 448. 81 Bloomgarden ZT. Nonalcoholic fatty liver disease and insulin resistance in youth. Diabetes Care 2007; 30: 1663–69. 82 Kalra S, Vithalani M, Gulati G, et al. Study of prevalence of nonalcoholic fatty liver disease (NAFLD) in type 2 diabetes patients in India (SPRINT). J Assoc Physicians India 2013; 61: 448–53. 83 Newton KP, Hou J, Crimmins NA, et al, for the Nonalcoholic Steatohepatitis Clinical Research Network. Prevalence of prediabetes and type 2 diabetes in children with nonalcoholic fatty liver disease. JAMA Pediatr 2016; 170: e161971. 84 Klingensmith GJ, Connor CG, Ruedy KJ, et al, for the Pediatric Diabetes Consortium. Presentation of youth with type 2 diabetes in the Pediatric Diabetes Consortium. Pediatr Diabetes 2016; 17: 266–73. 85 Kelsey MM, Geffner ME, Guandalini C, et al, for the 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: 212–21. 86 Saydah SH, Imperatore G, Henkin L, et al. Trends and characteristics of self-reported case presentation of diabetes diagnosis among youth from 2002 to 2010: findings from the SEARCH for Diabetes in Youth Study. Diabetes Care 2015; 38: e84–85. 87 Eppens MC, Craig ME, Cusumano J, et al. Prevalence of diabetes complications in adolescents with type 2 compared with type 1 diabetes. Diabetes Care 2006; 29: 1300–06. 88 Pinhas-Hamiel O, Zeitler P. Acute and chronic complications of type 2 diabetes mellitus in children and adolescents. Lancet 2007; 369: 1823–31. 89 Copeland KC, Zeitler P, Geffner M, et al, for the 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: 159–67. 90 Song SH. Complication characteristics between young-onset type 2 versus type 1 diabetes in a UK population. BMJ Open Diabetes Res Care 2015; 3: e000044. 91 Mast R, Danielle Jansen AP, Walraven I, et al. Time to insulin initiation and long-term effects of initiating insulin in people with type 2 diabetes mellitus: the Hoorn Diabetes Care System Cohort Study. Eur J Endocrinol 2016; 174: 563–71. 92 Adam FMS, Diatri MC, Adam JMF, Seweng A, Tai ES. Prevalence of metabolic syndrome in young adults. Int J Sci Res 2015; 4: 2319–7064. 93 Song SH, Hardisty CA. Early onset type 2 diabetes mellitus: a harbinger for complications in later years—clinical observation from a secondary care cohort. Q JM 2009; 102: 799–806. 94 Gunathilake W, Song S, Sridharan S, Fernando DJ, Idris I. Cardiovascular and metabolic risk profiles in young and old patients with type 2 diabetes. Q JM 2010; 103: 881–84. 95 Katulanda GW, Katulanda P, Adler AI, et al. Apolipoproteins in diabetes dyslipidaemia in South Asians with young adult-onset diabetes: distribution, associations and patterns. Ann Clin Biochem 2010; 47: 29–34. 96 Song SH. Early-onset type 2 diabetes mellitus: a condition with elevated cardiovascular risk? Br J Diabetes Vasc Dis 2008; 8: 61–65. 97 Song SH, Gray TA. Early-onset type 2 diabetes: higher burden of atherogenic apolipoprotein particles during statin treatment. Q JM 2012; 105: 973–80. 98 Huo X, Gao L, Guo L, et al. Risk of non-fatal cardiovascular diseases in early-onset versus late-onset type 2 diabetes in China: a cross-sectional study. Lancet Diabetes Endocrinol 2016; 4: 115–24. 99 Rhodes ET, Prosser LA, Hoerger TJ, Lieu T, Ludwig DS, Laffel LM. Estimated morbidity and mortality in adolescents and young adults diagnosed with type 2 diabetes mellitus. Diabet Med 2012; 29: 453–63.

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100 Dabelea D, Stafford JM, Mayer-Davis EJ, et al, for the SEARCH for Diabetes in Youth Research Group. Association of type 1 diabetes vs type 2 diabetes diagnosed during childhood and adolescence with complications during teenage years and young adulthood. JAMA 2017; 317: 825–35. 101 Solis-Herrera C, Triplitt CL, Lynch JL. Nephropathy in youth and young adults with type 2 diabetes. Curr Diab Rep 2014; 14: 456. 102 Dart AB, Sellers EA, Martens PJ, Rigatto C, Brownell MD, Dean HJ. High burden of kidney disease in youth-onset type 2 diabetes. Diabetes Care 2012; 35: 1265–71. 103 Song SH, Gray TA. Early-onset type 2 diabetes: high risk for premature diabetic retinopathy. Diabetes Res Clin Pract 2011; 94: 207–11. 104 Song SH. Significant retinopathy in young-onset type 2 vs type 1 diabetes: a clinical observation. Int J Clin Pract 2016; 70: 853–60. 105 Jaiswal M, Lauer A, Martin CL, et al, for the SEARCH for Diabetes in Youth Study Group. Peripheral neuropathy in adolescents and young adults with type 1 and type 2 diabetes from the SEARCH for Diabetes in Youth follow-up cohort: a pilot study. Diabetes Care 2013; 36: 3903–08. 106 Hillier TA, Pedula KL. Complications in young adults with early-onset type 2 diabetes: losing the relative protection of youth. Diabetes Care 2003; 26: 2999–3005. 107 Chan JC, Lau ES, Luk AO, et al. Premature mortality and comorbidities in young-onset diabetes: a 7-year prospective analysis. Am J Med 2014; 127: 616–24. 108 Luk AOY, Lau ESH, So W-Y, et al. Prospective study on the incidences of cardiovascular-renal complications in Chinese patients with young-onset type 1 and type 2 diabetes. Diabetes Care 2014; 37: 149–57. 109 Gu W, Huang Y, Zhang Y, et al. Adolescents and young adults with newly diagnosed type 2 diabetes demonstrate greater carotid intima-media thickness than those with type 1 diabetes. Diabet Med 2014; 31: 84–91. 110 Shah AS, Dolan LM, Kimball TR, et al. Influence of duration of diabetes, glycemic control, and traditional cardiovascular risk factors on early atherosclerotic vascular changes in adolescents and young adults with type 2 diabetes mellitus. J Clin Endocrinol Metab 2009; 94: 3740–45. 111 Constantino MI, Molyneaux L, Limacher-Gisler F, et al. Long-term complications and mortality in young-onset diabetes: type 2 diabetes is more hazardous and lethal than type 1 diabetes. Diabetes Care 2013; 36: 3863–69. 112 Lerman-Garber I, Cuevas-Ramos D, Valdes S, et al. Sensorineural hearing loss—a common finding in early-onset type 2 diabetes mellitus. Endocr Pract 2012; 18: 549–57. 113 Ren J, Zhao P, Chen L, Xu A, Brown SN, Xiao X. Hearing loss in middle-aged subjects with type 2 diabetes mellitus. Arch Med Res 2009; 40: 18–23. 114 Bener A, Al-Ansari AA, Zirie M, Al-Hamaq AOAA. Is male fertility associated with type 2 diabetes mellitus? Int Urol Nephrol 2009; 41: 777. 115 Nolan JJ. Ageing brain abnormalities in young obese patients with type 2 diabetes: a cause for concern. Diabetologia 2010; 53: 2273–75. 116 Willette AA, Xu G, Johnson SC, et al. Insulin resistance, brain atrophy, and cognitive performance in late middle-aged adults. Diabetes Care 2013; 36: 443–49.
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