Diabetes in young: Beyond type 1

Abstract

Although majority of diabetes in children is type1 diabetes, childhood type2 diabetes prevalence is rapidly increasing due to changing lifestyle. Most patients can be definitely grouped into either of the two but some present diagnostic difficulty due to overlapping and non specific clinical features and laboratory findings. MODY and several other diseases affecting the pancreas also result in childhood diabetes. Treatment of diabetes in children presents unique challenges and primary prevention is of prime importance.

Diabetes is the second most common chronic disorder in childhood, and in most populations was type 1 (absolute insulin deficiency) in about 90% or more cases. Obesity and type 2 diabetes (T2DM) in childhood were not common and often were secondary to diseases like Cushing syndrome. In the last two decades, the frequency of these inter-linked problems and the underlying insulin resistance (IR) has sky rocketed at an alarming rate across the world including India.[1] Young people experience progression of glucose intolerance as seen in adults with impaired glucose tolerance (pre-diabetes) preceding full-blown T2DM. It is worrying that initially seen mostly in older adolescents, T2DM and even pre-diabetes are now being encountered in ever-younger children.[2]

Ethnic and lab yield differences in antibody positivity (much lower in Indians as compared to Caucasians) have to be kept in mind, and the clinical profile should be kept in mind while interpreting these reports.

The typical clinical profile of T1DM is rapid onset of osmotic symptoms in a span of days to weeks, weight loss, and progression to ketosis / ketoacidosis. C-peptide levels are inappropriately low for the corresponding blood glucose levels. GAD and other autoantibodies may be positive, and other autoimmune disorders like hypothyroidism, vitiligo, or celiac disease may be present, or develop later. On the other hand, T2DM is marked by insidious onset (latent period of months to years before the patient becomes symptomatic), obesity, evidence of insulin resistance (acanthosis nigricans), and absence of autoimmunity. Hypertension and/or polycystic ovarian syndrome (PCOS) in girls and a strong family history of DM are often present. In most children, the distinction between these predominant two types is clear. However, in some adolescents, distinguishing T2DM from T1DM can be difficult at first encounter. T1DM may be detected before progression to ketoacidosis because of better awareness, the child may have been overweight to begin with, family history of DM may be present, Indian children are often antibody-negative even at diagnosis,[3] and there may be an apparent response to oral drugs as the honeymoon phase sets in. On the other hand, ketosis may be seen in T2DM, and C-peptide levels may be low initially because of glucotoxicity. However, with time, the clinical profile becomes clearer in many (but not in all) youth as the features of T2DM emerge: Obesity rather than overweight, features of metabolic syndrome like acanthosis nigricans, hypertension and/ or hypertriglyceridemia. C-peptide levels which are high or high-normal indicate preserved β-cells secretory function.

A small subset of the young may have other forms of diabetes. Maturity onset diabetes of the young (MODY), caused by monogenic defects in β cell function, and onset before 25 years of age, accounts for 0.2% - 5% of pediatric and adolescent diabetes. It is conspicuous by its indolent clinical course, three generation family history, and therapeutic response to sulfonylureas till later in clinical course.[4] Drug-induced DM is becoming a significant issue in pediatrics with the increasing use of corticosteroids, interferons, chemotherapy with L- asparaginase, thiazide diuretics, dilantin, and atypical anti-psychotics (in adolescents). The mechanism of causation may vary from absolute β-cell destruction (e.g. with intravenous pentamidine administration) to IR and superimposed β-cell dysfunction (e.g. with steroids.)[5] Systemic diseases involving the pancreas, diseases of the exocrine pancreas, syndromic conditions like Down, Turner, Kleinfelter, Prader Willi, Fredrich's Ataxia, DIDMOAD etc., insulin receptor defects, congenital infections, and endocrinopathies account for a small proportion of pediatric diabetes.[6]

Complications due to diabetes are linked with its duration, making youth with diabetes more prone to them, and at a younger age, which is often the most productive phase of their lives. Unlike in T1DM, complications in T2 DM may be present at or within 2 years of diagnosis as shown by TODAY and other studies.[7] Together, these result in significantly higher rates of micro and macrovascular morbidity and mortality.

Treatment of T2DM is a thorny issue. Significant lifestyle modifications are needed, but it is difficult to get patients and families to comply with them consistently for several years. The landmark TODAY study found that just under half the group had stable glycemic control with metformin monotherapy.[8] Addition of lifestyle intervention did not add much to reduction of HbA1c. The combination of rosiglitazone plus metformin was found to be superior, but given the serious adverse effects of the glitazones on the heart and the bladder cancer risk warning, this option is not a viable one. Serious adverse events were reported in a fifth of participants.[8] Other drugs may be needed in addition to metformin for glycemic control: Insulin, sulphonylureas, meglitinide, glucosidase inhibitors, and if FDA approval is received, DPP-4 inhibitors. When T2DM presents with ketosis, insulin required till the ketosis resolves. Screening for complications of DM must begin at onset in T2 DM and should be done annually. In addition to adequate glycemic control, associated co-morbidities like hypertension, dyslipidemia, and PCOS must be adequately treated.

Certain ethnic races like South Asians, African Americans, and Hispanics are genetically more susceptible to obesity and IR. Rapid changes in the environment i.e. increased availability of calories, decreased time, and decreased need for and safe access to physical activity have worsened the situation. Much data has accumulated on the adverse pre-and post-natal environmental factors contributing to disease risk in later life (Barker's hypothesis; developmental origin of adult disease). Epigenetic models demonstrate the transmission of these risk factors across generations.[9] Thus, babies born to mothers who gain excessive weight, those who gain insufficient weight or those who consume insufficient protein during pregnancy, are more likely to develop diabetes later in life. Babies born small for gestational age (SGA), common in India, are more prone to IR, especially if they are given energy dense feeds and experience rapid catch-up growth.[10]

Primary prevention is of paramount importance, given the grave natural progression of the disease. At the level of the first contact health care giver, it should involve identifying at-risk situations. Obese women should be encouraged to lose weight before pregnancy and to avoid excessive weight gain during pregnancy. Maternal nutrition should be improved, including adequate protein and micronutrients, while avoiding too much fat. Adequate glycemic control should be achieved in gestational diabetes (GDM) with appropriate therapeutic regimens. When both parents are obese, or when the baby is SGA or LGA, they should be cautioned about over-feeding or lack of activity should begin at birth and continue through childhood. Annual growth charting and BP screening should be done. Families of children gaining weight rapidly need counseling about the need for a balanced diet and daily exercise.[11] Screening for diabetes (fasting and 2-hour post-glucose blood glucose) should be done for children with predisposing conditions[9] e.g. Turner or Cushing syndrome) and all overweight (BMI ≥ 85^th percentile) Indian children ≥ 10 years of age with any one of the following risk factors: Family history of T2DM in first/ second degree relative, acanthosis nigricans, hypertension, polycystic ovaries, or dyslipidemia, SGA at birth or maternal history of GDM. If normal, the asymptomatic screening should be continued every 3 yearly.[10]

It is important for obstetricians, pediatricians, and the primary health care givers to be sensitized to prevent obesity and its sinister consequences like diabetes. The medical and financial burden of T2DM is far greater in children, while as a developing country, our ability to shoulder this burden is limited. This huge challenge needs urgent attention, not just by health personnel, but at all levels of the society.[12] Consumption of “unhealthy commodities” (soft drinks and processed foods that are high in salt, fat, and sugar, as well as tobacco and alcohol) is increasing very rapidly in low- and middle-income countries (LMICs), while it is plateauing or declining in high-income countries (HICs).[13] Strong political will to implement policy changes for health benefits and public education is necessary if a major impact is to be made.

Schools must be mandated to * ensure an hour of exercise daily by each child, * monitor growth annually, and * avoid availability of junk food on their premises. Schools and other institutions can also be encouraged to * provide their playing fields after work hours to neighboring children. City governments must urgently ensure * proper roads and side paths so that walking and cycling are safe and * some open spaces where children can play. States can enforce * differential pricing for food commodities, e.g. full-fat milk is priced high to subsidize low fat milk; and * packaged calorie dense or high sugar foods (chips, sweetened drinks) taxed to subsidize foods high in protein like lentils, milk, and eggs. Given the increasing rates of inflation seen in high protein foods in India in the last 2 years,[14] such measures may be crucial in ensuring that healthy foods are accessible to low-income families while discouraging consumption of junk foods. * Professional societies like Endocrine Society of India, Indian Academy of Pediatrics, Indian Medical Association, and others can pressurize governments to take steps in this direction. * Public awareness advertisements increasing the glamor quotient of healthy foods can be released by governmental bodies and NGOs to partly counter the high pressure advertising done by manufacturers of junk foods. As with cigarettes, * junk food packaging could carry suitable health warnings. Some foods may be * considered for outright banning, as has been done with gutkha (oral tobacco) recently in India. Similarly, in September 2012, the New York City Board of Health banned sales of sodas and other sugary drinks in packs more than 16 oz at restaurants and other eateries.[15] Other initiatives planned in the United States include taxing sugary drinks or prohibiting the sale of sugary drinks and low-nutrition snacks in municipal buildings or schools.

In conclusion, the incidence of childhood T2DM is increasing rapidly amongst our adolescents and young adults, and along with its co-morbidities and complications, it can pose enormous health hazards and financial burden to our youth. It is of paramount importance to make its diagnosis (cf. T1DM) and ensure timely and appropriate management with lifestyle intervention, metformin, and other drugs. However, the ultimate goal must be prevention. For this, urgent action is needed at the individual, institutional, and societal levels.