Recent Advances in Pediatrics (Special Volume 13): Pediatric Endocrinology Suraj Gupte
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Type 2 Diabetes Mellitus in Children and Adolescents 1

John Punnose
 
INTRODUCTION
In the past, type 2 diabetes mellitus (DM-2) was generally regarded as a disease of adults and was referred to as “maturity-onset diabetes”. Diabetes mellitus (DM) in children and adolescents was almost always considered to be Type 1 diabetes (DM-1) of autoimmune etiology and accordingly all these patients were maintained on insulin therapy. However, since the 1970s, there have been case reports of DM-2 in the pediatric population of several ethnic minorities in North America.1 Over the past two decades, there is growing evidence to suggest an emerging DM-2 epidemic among children and adolescents of several countries.2 In some countries among the newly diagnosed DM in children, the DM-2 is more prevalent than DM-1.3 The epidemiological risk factors and the diagnostic criteria for this newly emerging public health problem have been clarified.4
Pediatricians should be aware of the changing pattern of DM among children. With the proper identification of DM-2, many of these children can avoid insulin injections and can be managed with oral anti-hyperglycaemic drugs.
 
EPIDEMIOLOGY
The epidemiology of DM-2 in children in North America has been extensively analysed by several population and clinic-based studies.4 DM-2 constitutes between 8 percent and 45 percent of recently diagnosed cases of diabetes among children and adolescents in the United States.4,5 Also, 94 percent of children and adolescents with DM-2 belong to minority communities ie. Pima Indians in Arizona, First Nations in Mannitoba, African Americans, Mexican Americans, Asian Americans, Hispanic children. By 1990s, DM-2 was reported among North American white children also.5 It is disturbing to observe that the incidence of DM-2 among children is on the rise. In 15-19 year old Pima Indians in Arizona, 2between the periods of 1967-1976 and 1987-1996, the prevalence of DM-2, ascertained by population screening, rose from 24 to 34 per 1000 boys (58% increase) and from 27 to 53 per 1000 girls (96% increase).6 In a pediatric referral centre in Cincinati, Ohio, among 10-19 year old African American and white children, a 10 fold rise in incidence of newly diagnosed DM-2 was observed from 1982 and 1994.7
In the 1990s, several reports of DM-2 among children emerged from other countries including Japan,3 Hong Kong,8 Bangladesh,9 Libya,10 Australia11 and New Zealand.12 In the same period, we observed emergence of DM-2 among the Arab children residing in the United Arab Emirates.13 Similar observation was made by Ehtisham et al, among United Kingdom children of Asian or Arab ethnic origin.14 In a recent hospital based survey from Chennai, Ramachandran et al showed clinical, biochemical and immunological evidence of DM-2 in 18 children below 15 years of age.15 The above reports strongly suggest that an ongoing ‘global epidemic’ of DM-2 is occurring among children. It seems that in populations with high prevalence of DM-2 among adults, there is spillover of the disease to childhood and adolescence.
 
PATHOPHYSIOLOGICAL CONSIDERATIONS
DM-2 in adults is a complex, heterogenous disease with variable defects in insulin secretion and insulin action.16 The same heterogeneity in pathophysiology and clinical presentation is expected to occur in the pediatric form of the disease. As in adults, obesity is a major contributor to the development of DM-2 in children. The rising prevalence of DM-2 among Pima Indian children is closely linked with a parrellel rise in obesity prevalence.6 In a recent study of obese children and adolescents in United States, 25 percent of children in the age group 4 to10 yrs and 21 percent of the adolescents have impaired glucose tolerance.17 In overweight African American and white children, Nguyen et al demonstrated that body fat content (determined by dual energy X-ray absorptiometry) is a strong determinant of insulin resistance.18 In another study, visceral fat measured by MRI in Hispanic American children with high waist to hip ratio was independently and positively related to fasting insulin and was negatively related to insulin sensitivity.19 Physical inactivity and increased calorie and fat intake have been implicated as risk factors for childhood obesity. The ensuing obesity related insulin resistance plays a key role in the pathogenesis of childhood and adolescent onset Type 2 diabetes. The failure of hypersecretion of insulin by Beta cells to overcome this peripheral insulin resistance, results in relative insulin deficiency and diabetes.
The insulin resistance in DM-2 children may have other cutaneous or metabolic manifestations. Acanthosis nigricans (AN) characterized by 3hyperpigmentation and a velvety texture of skin in intertriginous areas, is regarded as a cutaneous marker of Insulin resistance. AN is observed in 60-95 percent of DM-2 children in various reports.20, 21 Polycystic ovarian syndrome, now regarded as an insulin resistant state, is noted in association with some adolescent DM-2 patients.22 These children with AN and/or polycystic ovary syndrome may have the full manifestations of Syndrome X (dysmetabolic syndrome) including glucose intolerance, increased very low density lipoprotein, increased triglycerides, decreased high density lipoprotein, hyperuricaemia and hypertension.23
A female preponderance of the DM-2 in children is stressed in several series.14,15 The mean age at diagnosis of DM-2 in children is between 12 and 14 years, corresponding with puberty. Hyperinsulinaemic euglycaemic clamp studies demonstrate that insulin mediated glucose disposal is 30 percent lower in pubertal children compared with prepubertal children and young adults.24 Increased growth hormone secretion is most likely responsible for the insulin resistance during puberty.
There is strong evidence to suggest that intrauterine exposure to diabetes per se conveys a high risk for the development of diabetes and obesity in offspring in excess of risk attributable to genetic factors alone.25, 26 In a case control study of native Canadian DM-2 children, maternal diabetes was found to be the strongest prenatal risk factor for the development of diabetes.27 The early onset of DM-2 in girls, possibly linked to intrauterine exposure to maternal hyperglycaemic environment, is likely to trigger a vicious cycle by further accelerating pubertal onset of the disease in their offspring. A link between low birth weight, smaller head circumference and thinness at birth and future development of DM-2 has been suggested.28,29 This ‘thrifty phenotype hypothesis’ suggests that poor nutrition in foetal and early infant life would lead to poor development and function of the Beta cells and insulin sensitive tissues (especially muscles). In this setting, the development of obesity in later life due to calorie surplus, will trigger the onset of type 2 diabetes.
There is a strong genetic and racial susceptibility for DM-2, which is later unmasked by several social, behavioural and environmental risk factors.30 Though several gene defects have been proposed, no common variant in any gene has been consistently associated with DM-2.31 The identification of the genetic defect(s) is difficult due to the marked genetic heterogeneity, variable disease expression and highly variable environmental factors involved in its pathogenesis. Probably, several functional or dysfunctional polymorphisms in a number of genes controlling insulin release, insulin resistance, energy balance are operational. Racial difference in insulin sensitivity are also evident in childhood. The metabolic differences between African Americans and white children 4are apparent in the Bogalusa Heart study.32 Among 1200 old adolescents (11 to 18 year olds), after correction for obesity, African Americans had higher insulin levels and lower glucose to insulin levels than whites, a pattern indicating reduced insulin sensitivity in black children. Similarly, in an analysis of 358 apparently healthy adults residing in the United Arab emirates, Pugh et al observed higher tendency for insulin resistance among South Asians and Peninsular Arab men compared to the Europeans.33
 
DIAGNOSIS
The diagnostic criteria for DM, recommended by American Diabetic Association’s (ADA) expert committee is applicable for children.34 The diagnosis is made in a symptomatic patient if a random plasma glucose is more than 200 mg/dl (11.1 mmol/l) or a fasting plasma glucose is more than 126 mg/dl (7 mmol/l). In an asymptomatic patient, the abnormality should be reconfirmed on another day. Oral Glucose tolerance test is only rarely used for clinical purposes. Following 1.75 g/kg body weight (maximum 75 g) oral glucose load, a 2hr plasma value more than 200 mg/dl (11.1 mmol/l) confirms the diagnosis of DM.
DM in childhood and adolescence can be the manifestation of a wide spectrum of systemic diseases. The ADA expert committee classified these disorders as ‘other specific types’.34 Many of these genetic syndromes (insulin resistant syndromes, chromosomal and neurological syndromes, Congenital rubella syndrome etc), endocrinopathies, pancreatic diseases, drug induced DM can be suspected clinically. Excluding the above mentioned rare types of diabetes, in a global context, the common types of DM which are likely to pose diagnostic problems in pediatric practice are
  • Type 1 diabetes (immune-mediated, rarely idiopathic)
  • Early onset Type 2 diabetes
  • Atypical diabetes mellitus
  • Maturity-onset diabetes of young (MODY)
Atypical diabetes mellitus (ADM) is seen exclusively in the African American population as an autosomal dominant condition. This disorder displays features of both DM-1 and DM-2 with fluctuating insulin dependence.35 MODY represents a group of six autosomal dominant disorders with specific monogenic defects in Beta cell function.36 MODY is rare and is reported mainly in Caucasian population. The available evidence suggest that ADM and MODY are confined to the above mentioned racial groups.
Therefore, for pediatricians in South Asia, the task is mainly to differentiate early onset DM-2 from DM-1. But the differentiation of 5DM-1 and DM-2 is not always easy because of overlap of several features. Children with DM-2 may be ketotic or even may exhibit diabetic ketoacidosis at presentation37 and some of these children may not be obese.15 DM-1 in children and adolescents usually present acutely with ketoacidosis, but rarely can have a slower onset.34 With the rising prevalence of childhood obesity in the background population, many children with DM-1 may be obese on presentation.13 These atypical presentations produce practical difficulties in ‘typing’ DM among children.
ADA proposed a scheme for identification of various types of diabetes in pediatric practice, in which the main parameters being
  • Body weight (presence of obesity)
  • Fasting C peptide/insulin
  • Presence of serum autoantibodies.
In this scheme, a diagnosis of DM-2 in children can be made, provided 2 of the following 3 parameters are present
  • Presence of obesity (BMI > 85% of age and sex)
  • Normal or High Fasting Insulin/C-peptide
  • Absence of Beta cell autoantibodies (islet cell, insulin, Glutamic acid dehydrogenase)65
But the practical difficulty is that facilities for fasting Insulin/C peptide or serum autoantibody estimations are not available to most of the pediatricians.
It is recommended that the classification of childhood and adolescent DM should be routinely made based on the clinical findings at presentation and its subsequent clinical course.4 In unusual circumstances that require a specific classification to be made, further investigations are carried out in consultation with a diabetologist.
Styne from University of California recommends that in American Asians (and in other ethnic groups with high prevalence of DM-2), an obese child who has acanthosis nigricans and a positive family history of DM-2 should be considered as a candidate for type 2 diabetes.38 If the glucose level is high but there is no ketosis, the diagnosis is even more likely, although, ketosis is possible in children and adolescents with DM-2. This scheme can be recommended for identifying most of DM-2 children in South Asia. Further investigations as mentioned above, are reserved for other atypical situations. If facilities for further investigations are not available, a properly supervised clinical follow up will help in exclusion of Type 1 diabetes. A state of insulin independency (no ketosis without insulin) one year after diagnosis makes the diagnosis of DM-1 unlikely, while an independency after 2 years excludes this possibility.39
6
 
SCREENING
As with DM-2 in adults, a substantial number of DM-2 children remain in an asymptomatic state and are detected incidentally.13, 14 This ‘silent’ nature of the disease raises the issue of population screening for the disease. Moreover, the beneficial effects of early diagnosis and proper glycaemic control in DM-2 is convincingly proved in the United Kingdom Prospective Diabetes Study.40 The ADA recommends screening for DM-2 in overweight children (defined as BMI > 85th percentile for age and sex or Weight > 120 percent of ideal (50th percentile) for height), provided they have any two of the following risk factors:
  • Positive family history of DM-2 in first and second degree relatives
  • Member of a certain race/ethnic group like American Asians
  • Having signs of insulin resistance or conditions associated with it – acanthosis nigricans, hypertension, dyslipidaemia, polycystic ovary disease.
The recent reports of emergence of DM-2 among children of several ethnic groups in Asia3,13,15 further raises the relevance of adopting the above screening strategy to this region.
The ADA recommends to screen the children at the age of 10 years or at the onset of puberty if puberty occurs at a younger age. If negative, the screening should be repeated at every two years. The estimation of Fasting plasma glucose is the preferred method because of its lower cost and greater convenience. Fasting is defined as no consumption of food or beverage other than water for at least 8 hours before testing.
 
MANAGEMENT
The goal of treatment in DM-2 is to normalize blood glucose values, HbA1c as well as to control other comorbid conditions such as hyperlipidemia and hypertension. Life style changes—behavioural modification, medical nutrition therapy and exercise, targeted at all these abnormalities form an essential component of therapy. But children and adolescents are particularly reluctant to make life style modifications. Moreover, there is a tendency for the patients and their parents to ignore the disease for long. This attitude arises from the fact that, uncontrolled state in DM-2, unlike in DM-1, is only mildly symptomatic or even asymptomatic. The children in general will not conceive the seriousness of the late complications of DM. In this context, there is a major role for proper diabetic education including training these children, in self monitoring of blood glucose. Medical nutrition therapy should be supervised by a dietician with adequate experience in nutritional management of children. The therapy should be individualized taking 7into consideration of the cultural and financial aspects of the family. These children should optimize the sedentary activities such as television viewing and computer use. Regular exercise plays a major role in weight management and in decreasing insulin resistance. It should be stressed that a DM-2 child is a member of a ‘Type 2 diabetic family’ in which the other members are also likely to have insulin resistance. Hence the life style changes should be targeted at the entire family.
The lifestyle modification alone can bring in proper metabolic control only in a minority of adults41 and children.42 Most of the DM-2 patients will eventually require some form of drug therapy. During the last decade, several new oral antihyperglycaemic drugs were introduced in the therapy of DM-2, the details of which are well summarized in two recent reviews.43, 44 It is reasonable to assume that the oral agents will be effective in children. The currently available oral antihyperglycaemic agents are as follows.
  • Sulphonylureas: Glibenclamide, glipizide, gliclazide, and glimepiride increases insulin secretion
  • Biguanides: Metformin decreases hepatic glucose output; increases insulin sensitivity
  • Meglitinide: Repaglinide and nateglinide increases insulin secretion for short period
  • Thiazolidenediones: Rosiglitazone and pioglitazone improve peripheral insulin sensitivity
  • Glucosidase inhibitors: Acarbose and miglitol lower posprandial blood glucose by slowing the absorption of complex carbohydrate
Of these, only metformin is presently approved by Food and Drug Administration of USA, for use in pediatric population. In a multicenter controlled clinical trial of the efficacy and safety of metformin in children with DM-2, improved glycaemic control was evident within 2 weeks of starting therapy.45 The drug also improved the serum lipid profile. But 25 percent of the children experienced abdominal cramping and diarrhea, which improved significantly with time. Metformin is contraindicated in hepatic or renal impairment, during radiological investigations with radiocontrast agents and in hypoxemic conditions. Additional benefits of metformin include reduction of weight and improvement of ovarian function in girls with polycystic ovary disease.
Sulphonylureas13–15,37 and acarbose14 are tried in a limited number of children with DM-2 and no major side effects are reported. In adolescents with irregular eating schedule, meglitinide may be an alternative to sulphonyureas. So far there are no reports of use of Thiazolidenediones in children. Till the safety profile of thiazolidenediones is established, its use in children cannot be recommended.
8As in adults, with progressive deterioration of beta cell function, many DM-2 children may require insulin. Insulin can be administered either in combination with other oral agents (as bed time insulin) or alone (twice a day or multidose regime). Those children presenting with severe glycemic symptoms or diabetic ketoacidosis should be managed initially with insulin. After metabolic stabilization, oral agents may be slowly introduced to the insulin regime. During the cross over period, monitoring for urine ketones is recommended to identify those DM-1 patients who have been misdiagnosed as having DM-2.
In conclusion, there is convincing evidence to suggest that the ongoing global epidemic of DM-2 in adults is spreading to children and adolescents. Over the years, the age of onset of DM-2 has been steadily decreasing and the disease can no longer be called ‘maturity onset’ diabetes. This progression seems to be the sequelae of rapid phase of moderni-zation with major life style changes resulting in childhood obesity and insulin resistance. Apart from producing glucose intolerance, insulin resistance induces a procoagulant state leading to precocious atherogenesis. Therefore, the major public health challenge is to design and implement strategies to prevent and treat the ongoing epidemic of childhood obesity. Our aim should be to delay the onset of insulin resistance syndrome in genetically predisposed individuals, to as late in life as possible.
 
SUMMARY AND CONCLUSION
Type 2 Diabetes Mellitus (DM-2) is emerging as a major public health problem among children and adolescents globally. The recent reports of identification of the disease in the pediatric population in many Asian countries, further support this view. There is evidence to link this ‘DM-2 epidemic’ among children, to the rising prevalence of childhood obesity, occurring as a sequelae of rapid urbanization. DM-2 results from the failure of the pancreatic Beta cells to hypersecrete insulin so as to overcome this obesity related insulin resistance. A pubertal onset and a female preponderance of DM-2 in children, have been observed. Many of these children have other stigmata of insulin resistance like acanthosis nigricans, hypertension, dyslipidaemia, polycystic ovary disease. The disease has a wide spectrum of presentations ranging from an asymptomatic state to an acute presentation with diabetic ketoacidosis. The distinction between Type 1 diabetes and Type 2 Diabetes in children is not always easy, as atypical forms of both types are increasingly being recognised. While in a research setting, the distinction can be made by estimating fasting Insulin or C peptide level and pancreatic islet cell antibodies, for routine clinical purposes, these tests are not freely 9available. In racial groups with high prevalence of DM-2 (as Asians), any obese diabetic child with acanthosis nigricans and a positive DM-2 family history, can be considered to have type 2 diabetes. As in adults, life style modification is an essential component of DM-2 management in children. Many of these children can be managed with oral anti hyper-glycaemic agents like Metformin and sulphonylureas, while the safety of the new oral agents like thiazolidenediones is not proved in pediatric practice. But the real public health challenge is to prevent the spread of DM-2 to our paediatric population by designing and implementing strategies to combat the ongoing epidemic of childhood obesity.
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