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Type 1 diabetes in children and youth is typically characterized by weight loss, polyuria, polydipsia, blurring of vision, very high plasma glucose concentrations, and ketonuria.
Another challenge among young people is the possibility of misdiagnosis of monogenic diabetes as type 1 and type 2.
The clinical characteristics of a child with monogenic diabetes compared to children and youth with type 1 and type 2 are shown in Table 1.5. In scenarios when monogenic diabetes is misdiagnosed as type 1 or 2, the aforementioned criteria should be considered as a whole rather than individually and are not absolute. Diabetes is characterized by hyperglycemia, and thus diagnostic tests focus on establishing elevated blood glucose levels [69]. In the absence of symptoms clearly attributable to diabetes, a diagnosis should not be based on a single measurement, but requires results within the diabetes range on two separate days.
The most notable change in diagnostic criteria in recent years is the recommendation by the ADA and WHO to use HbA1c for diagnosis of diabetes. HbA1c is a hemoglobin variant primarily composed of glycohemoglobin, which is formed by the nonenzymatic attachment of glucose to hemoglobin [70].
The major disadvantage of HbA1c is that there are a number of nonglycemic conditions that interfere with the assay. Cutpoints of HbA1c have been set using similar methods to those adopted for the setting of blood glucose criteria. Although support for the use of HbA1c for diagnosis of diabetes has increased over the years, several questions about its suitability remain.
A further concern about moving from glucose to HbA1c to diagnose diabetes is that we will observe a change in prevalence of diabetes, as an elevated HbA1c does not identify exactly the same individuals as does an elevated blood glucose. In general, the use of HbA1c for diagnosis of diabetes results in a lower prevalence of diabetes with the magnitude of the difference between blood glucose-based prevalence and HbA1c-based prevalence varying widely between populations [80]. Diagnosis of diabetes using HbA1c is now recommended by both the ADA and WHO as detailed in Table 1.6. National Diabetes Data Group: Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance.
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Rhen T, Cidlowski JA: Antiinflammatory action of glucocorticoids–new mechanisms for old drugs. Forrest JM, Menser MA, Burgess JA: High frequency of diabetes mellitus in young adults with congenital rubella. Pak C, Eun H-M, McArthur R, Yoon J: Association of cytomegalovirus infection with autoimmune type 1 diabetes. Solimena M, De Camilli P: Autoimmunity to glutamic acid decarboxylase (GAD) in Stiff-Man syndrome and insulin-dependent diabetes mellitus. Khan C, Baird K, Flier JS, Jarret D: Effects of autoantibodies to the insulin receptor on isolated adipocytes. Craig ME, Hattersley A, Donaghue KC: Definition, epidemiology and classification of diabetes in children and adolescents.
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The diagnosis is usually very clear with high random glucose values, and there is rarely a need to investigate with an oral glucose tolerance text (OGTT). Although type 1 diabetes remains the most common form of diabetes in youth of European background, type 2 diabetes is increasingly common, especially among adults at particularly high risk of type 2 diabetes.
These cases present a problem under the current classification as they present with an overlapping phenotype of both type 1 and type 2 diabetes and have been referred to as hybrid diabetes, double diabetes, or latent autoimmune diabetes in youth (LADY) [66].
As noted previously, monogenic diabetes results from the inheritance of mutation(s) in a single gene that regulates ?-cell function or less commonly in genes related to insulin resistance. Monogenic diabetes should be considered in a child initially diagnosed as type 1 who has been diagnosed at less than 6 months of age, has a family history of diabetes with a parent affected, evidence of endogenous insulin production outside the “honeymoon” phase of diabetes with detectable C-peptide, and the absence of pancreatic islet autoantibodies (measured at diagnosis) [67]. Firstly, HbA1c has far less day-to-day biological variation than fasting or 2-hour glucose [77].
The other important disadvantage is the need for a laboratory to use an IFCC aligned assay and be part of a standardization program, which may not be possible in developing countries.
For example, what should be the appropriate HbA1c ranges for pre-diabetes or intermediate glycemia?

It should, however, be noted that a similar discrepancy in individuals identified also applies to diagnosis by fasting glucose compared to diagnosis by 2-hour plasma glucose in the OGTT.
As discussed earlier, it is important to ensure that the HbA1c assay used meets stringent quality assurance test and is aligned with the IFCC standardization program. Type 2 diabetes in children is associated with milder symptoms and is often associated with obesity. With the increase in obesity over the last 20 years, there has been an increase in type 2 diabetes in children especially among ethnicities at high risk as well as an increase in the number of children with type 1 who are overweight. In such children, presentation of double diabetes is similar to LADA in adults.However, unlike LADA, little is known about the prevalence of double diabetes or the prevalence and significance of autoimmune markers in children.
For children, the oral glucose load is proportional to body weight at 1.75 g per kg body weight.
Secondly, HbA1c is stable for one week at room temperature after collection while glucose is susceptible to glycolysis despite the use of fluoride oxalate to preserve the sample. This latter cutpoint has been adopted by the ADA and WHO as an appropriate cutpoint for diabetes. It is also important to ensure that there are no clinical conditions that preclude its accurate measurement. In these cases, diagnosis is made using any one of OGTT, fasting plasma glucose, or HbA1c, with preference for HbA1c as there is no requirement to fast.
Type 2 diabetes may also be present in youth with ketosis or ketoacidosis, which serves only to compound the problem further.
In addition, whether autoimmune-positive youth with double diabetes progress more rapidly to insulin dependence than those with type 2 diabetes without is not known.
Recently, HbA1c has been added as an acceptable and reliable means of diagnosing diabetes (discussed later).
By the 1990s, supported by strong evidence from two studies, the Diabetes Control and Complications Trial [71] and the United Kingdom Prospective Diabetes Study [72], and the development of new high through put methods and improved coefficients of variation (CV), HbA1c had become the cornerstone marker in the monitoring of diabetes. While a practical delineation between these may be the use of insulin, it can no longer be assumed that those on insulin are type 1. In more recent years, a US national glycohemoglobin standardization program has been established and the International Federation of Clinical Chemistry (IFCC) has taken the lead to ensure that HbA1c assays are standardized. Finally, glucose levels are also susceptible to modification by short-term lifestyle intervention while HbA1c reflects glycemia over a period of 3 to 4 months. Other investigations which could provide insight include measurement of C-peptide, characteristic type 1 antibodies, for example anti-GAD antibodies, and the monitoring of endogenous insulin secretion over time [17].
It has been suggested that the current classification of diabetes should be revised to include this new phenotype [66].

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