2. Classification and Diagnosis of Diabetes

Diagnosis, Classification, and Lifestyle Treatment of Diabetes

Diabetes mellitus is a group of metabolic diseases characterised by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The abnormalities in carbohydrate, fat, and protein metabolism that are found in diabetes are due to deficient action of insulin on target tissues. If ketones are present in blood or urine, treatment is urgent, because ketoacidosis can evolve rapidly.

Type 2 diabetes mellitus (T2DM) in children and adolescents is becoming an increasingly important public health concern throughout the world (1–17). Because of the relatively recent recognition of the problem in this age group, many children with new onset T2DM may be misclassified as having T1DM. Conversely, as the population becomes heavier, overweight adolescents with autoimmune diabetes may be misdiagnosed as having T2DM. T2DM is often associated with risk factors for cardiovascular disease that may already be present at the time of diagnosis, making normalization of blood glucose levels and diagnosis and treatment of hypertension and dyslipidemia important (18). T2DM occurs when insulin secretion is inadequate to meet the increased demand posed by insulin resistance (19). Thus, T2DM is commonly associated with other features of the insulin resistance syndrome [hyperlipidemia, hypertension, acanthosis nigricans, ovarian hyperandrogenism, non-alcoholic fatty liver disease (NAFLD)] (20). Insulin secretion depends on disease status and duration, and can vary from delayed but markedly elevated in response to a glucose challenge, to absolutely diminished (19). Adults with symptoms have 50% reduction at the time of diagnosis, and may become insulin dependent within a few years (21). T2DM occurs: in youth most often during the second decade of life, with a mean age of diagnosis of ∼13.5 years. This coincides with the peak of physiologic pubertal insulin resistance, which may lead to onset of overt diabetes in previously compensated adolescents. in all races, but at a much greater prevalence in those of non-white European descent, e.g. those of black African descent, native North American, Hispanic (especially Mexican)-American, Asian, South Asian (Indian Peninsula), and Native Pacific islanders. The SEARCH for Diabetes in Youth population-based study found the proportion of physician diagnosed T2DM among 10–19-year-olds to vary greatly by ethnicity in the US: 6% for non-Hispanic whites, 22% for Hispanics, 33% for blacks, 40% for Asians/Pacific Islanders, and 76% for Native Americans (8). In Hong Kong > 90% of young onset diabetes is T2DM (10), in Taiwan 50% (11) and nearly 60% in Japan (Ogawa et al. personal communication). in > 75% of cases in youth in the USA there is a first or second-degree relative with T2DM. in youth in the USA and Europe with body mass index (BMI) above 85th percentile for age and sex. In Japan, however, ∼30% of T2DM are not obese (17), in Asian Indian urban children, half of those with T2DM had normal weight (< 120% ideal for height) (12), and half of Taiwanese children with T2DM were not obese (11). in some asymptomatic individuals in high-risk populations during medical, school, or sports examinations (22,23). in the presence of ketosis/ketoacidosis, one third or more of newly diagnosed patients (24). This presentation is responsible for misclassification of T2DM patients as T1DM. occasionally with severe dehydration (hyperosmolar hyperglycemic coma, hypokalemia) at presentation, which can be fatal (24,25) with a sex ratio (male:female) that varies from 1: 4–1:6 in native North Americans to 1:1 in Asians and Libyan Arabs without associated HLA specificities. without associated islet cell autoimmunity (see autoimmunity T2DM). The pathophysiology of autoimmune 'T2DM' is unclear. It most likely represents autoimmune T1DM in overweight or obese individuals with underlying insulin resistance. It has been postulated that obesity and insulin resistance may promote an inflammatory response to antigen exposure caused by apoptosis of beta cells (26). Youth and adults in US and Europe who are clinically diagnosed with T2DM are found to have T1DM-associated auto-antibodies in 15–40% of cases, including many who are not receiving insulin one year after diagnosis (27–30). Antibody positive young adult individuals with the T2DM phenotype are significantly less overweight and younger than antibody negative patients (21, 27). Hemoglobin (HbA1c) concentrations are significantly higher in young adults with T2DM who are antibody positive compared with those who are antibody negative (27). ß-cell function is significantly less in antibody positive individuals, the most dramatic difference being reported in younger adult patients (25–34 years), resulting in more rapid development of insulin dependence, usually by 3 years duration (27, 30). The presence of islet cell antibodies (ICA) and glutamic acid decarboxylase antibodies in adults with clinically typical T2DM has been referred to as latent autoimmune diabetes of adults (27, 31). Neither the autoimmunity nor the diabetes is latent, however (26). Atypical diabetes mellitus (ADM) occurs throughout childhood, but rarely begins past age 40. It has only been described in young people of African descent. There is a strong family history in multiple generations with an autosomal dominant pattern of inheritance, but an abnormal sex ratio (M : F = 1 : 3). ADM is not associated with HLA specificities and islet autoimmunity does not occur. Ketosis or ketoacidosis is typical at onset. Insulin secretion is present but diminished and without long-term deterioration of function. Interestingly, insulin is often not required for survival after treatment of acute metabolic deterioration, although diabetes control may be poor and ketoacidosis may recur without insulin, e.g. with illness or pregnancy. ADM is not associated with obesity beyond that in the general population and it is not associated with insulin resistance. Monogenic diabetes (formerly referred to as maturity onset diabetes of the young or MODY) For more in depth information see the ISPAD Clinical Consensus Guidelines for Monogenic Diabetes (34). Identified in families with multigenerational diabetes; including asymptomatic individuals identified through testing of family members. Monogenic diabetes is not associated with obesity beyond that in the general population and it is not associated with insulin resistance The clinician is obliged to weigh the evidence in each individual patient to distinguish between T1DM and T2DM. The reasons for this conundrum are: with increasing obesity in childhood, as many as 15–25% of newly diagnosed T1DM (or monogenic diabetes) patients may be obese. the significant number of pediatric patients with T2DM demonstrating ketonuria or ketoacidosis at diagnosis (2). T2DM is common in the general adult population, with a random family history of ∼15% or greater in minority populations, reducing the specificity of a positive family history. positive family history for T2DM is increased for patients with T1DM as much as threefold over the non-diabetic population and T1DM is more frequent in relatives of patients with T2DM (35, 36). There is considerable overlap in insulin or C-peptide measurements between T1DM, T2DM and MODY at onset of diabetes and over the first year or so. This overlap is due to the recovery phase of autoimmune-mediated T1DM (the honeymoon) and degree of glucotoxicity/lipotoxicity impairing insulin secretion at the time of testing in both T1DM and T2DM. In addition the insulin resistance of obesity raises residual C-peptide levels in obese adolescents with T1DM. Such measurements are thus relatively valueless in the acute phase. [The role of C peptide may be more helpful in established diabetes as persistent elevation of C-peptide above the level of normal would be unusual in T1DM after 12–24 months.] The criteria and classification of diabetes are presented in greater detail in the ISPAD Clinical Practice Consensus Guidelines: Definition, Epidemiology, Diagnosis and Classification of Diabetes (37) Diagnostic criteria for diabetes are based on BG measurements and the presence or absence of symptoms (E) (38,39). Three ways to diagnose diabetes are possible and each, in the absence of unequivocal hyperglycemia, must be confirmed, on a subsequent day, by any one of the three methods given below. Diabetes is diagnosed when: A fasting plasma glucose (FPG) is ≥ 7.0 mmol/l (126 mg/dl) or The post challenge plasma glucose is > 11.1 mmol/l (200 mg.dl) performed as described by the World Health Organization (39), using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water. or Symptoms of diabetes and a casual plasma glucose ≥ 200 mg/dl (11.1 mmol/L). Casual is defined as any time of day without regard to time since last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss. Diabetes in children, including T2DM, usually presents with characteristic symptoms such as polyuria, polydipsia, blurring of vision, and weight loss, in association with glycosuria and, in some cases, ketonuria. In its most severe form, ketoacidosis or hyperglycemic hyperosmolar state may develop and lead to stupor, coma, and in absence of effective treatment, death. The diagnosis is usually confirmed quickly in symptomatic individuals by measurement of a marked elevation of the blood glucose level. In this situation, if ketones are present in the blood or urine, treatment is urgent. Waiting another day to confirm the hyperglycemia may be dangerous in allowing ketoacidosis or hyperosmolarity to evolve. In the absence of symptoms or presence of mild symptoms of diabetes, hyperglycemia detected incidentally or under conditions of acute infective, traumatic, circulatory, or other stress may be transitory and should not in itself be regarded as diagnostic of diabetes. The diagnosis of diabetes, in the absence of symptoms, should not be based on a single plasma glucose concentration. Diagnosis may require continued observation with fasting and/or 2-h postprandial BG levels and/or an oral glucose tolerance test (OGTT). An OGTT should not be performed if diabetes can be diagnosed using fasting, random, or postprandial criteria, as excessive hyperglycemia can result using a fasting OGTT in these circumstances. (E). If doubt remains, periodic re-testing should be undertaken until the diagnosis is established or refuted. There are individuals whose glucose levels do not meet the criteria for diabetes, but are too high to be considered normal. Impaired glucose tolerance (IGT) and impaired fasting glycaemia (IFG) are intermediate stages in the natural history of disordered carbohydrate metabolism between normal glucose homeostasis and diabetes (E). IFG and IGT are not interchangeable and represent different abnormalities of glucose regulation. IFG is a measure of disturbed carbohydrate metabolism in the basal state, while IGT is a dynamic measure of carbohydrate intolerance after a standardized glucose load. Patients with IFG and/or IGT are now referred to as having 'pre-diabetes', indicating the relatively high risk for development of diabetes in these patients (38). IFG and IGT may be associated with the metabolic syndrome (MS), which includes obesity (especially abdominal or visceral obesity), dyslipidemia of the high-triglyceride and/or low-high density lipoprotein type, and hypertension. Individuals who meet the criteria for IGT or IFG may be euglycemic in their daily lives as shown by normal or near-normal glycated hemoglobin levels, and those with IGT may manifest hyperglycemia only when challenged with an OGTT. FPG < 5.6 mmol/L (100 mg/dL)= normal fasting glucose. FPG 5.6–6.9 mmol/L (100–125 mg/dL)= IFG. FPG ≥ 7.0 mmol/L (126 mg/dL)= provisional diagnosis of diabetes (the diagnosis must be confirmed, as described above under 'Diagnostic criteria for type 2 diabetes'). The corresponding categories for IGT when the OGTT is used are as follows: 2-h postload glucose < 7.8 mmol/l (140 mg/dl)= normal glucose tolerance. 2-h postload glucose 7.8–11.1 mmol/l (140–199 mg/ dl)= IGT. 2-h postload glucose > 11.1 mmol/l (200 mg/dl)= provisional diagnosis of diabetes (the diagnosis must be confirmed with additional testing, as described above). After the diagnosis of diabetes is established, autoantibody testing should be considered when diagnosing and treating T2DM. Diabetes autoantibody testing should be considered in all pediatric patients with the clinical diagnosis of T2DM because of the high frequency of islet cell autoimmunity in otherwise "typical" T2DM. Antibodies will indicate an earlier need for insulin as well as the need to monitor for thyroid autoimmunity and to consider other autoimmune disorders associated with T1DM. (E) Diabetes autoantibody testing also should be considered in overweight/obese children > 13 years of age with a clinical picture of T1DM (weight loss, ketosis/ketoacidosis), some of whom may have T2DM (E) Insulin resistance is an impaired response to the physiologic effects of insulin, including effects on glucose, lipid, and protein metabolism, and on vascular endothelial function. Insulin resistance occurs in most tissues including liver, muscle, and fat tissue and is influenced by sex, age, race/ethnicity, stage of sexual maturation, and total adiposity. While visceral adiposity is important in insulin resistance in adults, the specific contribution of visceral adiposity to insulin resistance in the pediatric population remains uncertain. Several events in development may be associated with increased risk for the insulin resistance syndrome. These include premature adrenarche in girls (pubic hair appearing before the age of 8 years) and being born small for gestational age. Girls with a history of premature adrenarche are at increased risk for ovarian hyperandrogenism and PCOS and thus, insulin resistance (40). Children born small for gestational age are at increased risk for insulin resistance related to decreased intrauterine growth (41) and also at increased risk for premature adrenarche. Diabetes is only one manifestation of the insulin resistance syndrome or the MS (22, 42–50). Other associations include: Obesity: Obesity has deleterious associations with morbidity and cardiovascular risk independent of effects related to insulin resistance and diabetes (51–54). Nephropathy: Albuminuria (either micro- or macro- ) is present at the time of diagnosis in a substantial number of adolescents with T2DM and prevalence increases with duration of diabetes (24). Proteinuria and focal segmental glomerular sclerosis have also been reported in African-American adolescents with severe obesity, in the absence of diabetes (55). Hypertension; Hypertension is estimated to account for 35–75% of diabetes complications, both microvascular and macrovascular (56). Diabetes or impaired glucose tolerance doubles the risk of developing hypertension (57). In addition, there is a possible genetic predisposition to hypertension in T2DM related to the associated angiotensin converting enzyme genotype (58). Hypertension in T2DM is due to volume expansion and increased vascular resistance (59) related to reduced (NO)-mediated vasodilatation and increased activity of the renin-angiotensin system. Dyslipidemia: Hypertriglyceridemia and decreased high-density lipoprotein cholesterol are the hallmarks of T2DM dyslipidemia. Additional findings include elevated very low-density lipoprotein (VLDL), elevated LDL-c, elevated lipoprotein(a), and increased small dense LDL particles. Decreased lipoprotein lipase activity, increased lipoprotein glycation and increased lipoprotein oxidation render the lipoproteins more atherogenic. (60,61) Ovarian hyperandrogenism and premature adrenarche (62): PCOS is being increasingly recognized in adolescents as part of the insulin resistance syndrome. Adolescents with PCOS have ∼40% reduction in insulin-stimulated glucose disposal compared to body composition matched non-hyperandrogenic control subjects (59). Decreasing insulin resistance may improve ovarian function and increase fertility. NAFLD: Hepatic steatosis is present in 25–45% of adolescents with T2DM and more advanced forms of NAFLD, such as non-alcoholic steatohepatitis, are increasingly common and associated with progression to cirrhosis (24, 64). NAFLD now represents the most common cause of cirrhosis in children and the most common reason for liver transplantation in adults in the US. Systemic inflammation: elevated C-reactive protein, inflammatory cytokines and white blood cell counts in obese adolescents have been associated with increased risk for cardiovascular disease in adults (54). Additional health problems related to obesity include Obstructive sleep apnea (OSA) with associated pulmonary hypertension (65), orthopedic problems resulting in diminishing physical activity (66,67), pancreatitis, cholecystitis and pseudotumor cerebri. In adults, there is a strong association between level of hyperglycemia and increased risk of macrovascular disease. Hyperglycemia, dyslipidemia, and hypertension are contributors to the acceleration of atherosclerosis in T2DM, along with oxidative stress, glycation of vascular proteins, and abnormalities of platelet function and coagulation. Defective endothelium dependent vasodilatation is an additional factor accelerating atherosclerosis in T2DM. It is an early sign of increased risk for cardiovascular disease, and predictive of cardiovascular events (68) (B) and occurs in obese children relative to their level of obesity and degree of insulin resistance (69) (B). Co-morbidities characteristic of the insulin resistance syndrome are commonly seen at diagnosis or appear early in the course of T2DM and should be tested for sooner than in T1DM, where these disorders are complications of the diabetes rather than co-morbid conditions (70, 71) (B). A more complete discussion of testing for complications/co-morbidities is presented in the ISPAD Clinical Practice Guidelines for microvascular and macrovascular complications (72). Either micro- or macro-albuminuria, may be present at the time of diagnosis and albuminuria should be evaluated at diagnosis and annually thereafter (55, 72)(E). Likewise, hypertension may be present at, or prior to diagnosis of diabetes and each individual should be evaluated at every visit for hypertension. Dyslipidemia is more common in type 2 diabetes and in family members, (60,61) and should be screened for when metabolic stability is achieved. Evaluation for NAFLD should be done at diagnosis and annually thereafter (24)(E). Inquiries about puberty, menstrual irregularities and obstructive sleep apnea should be made at diagnosis and regularly thereafter (65)(E). Additional information is available in the ISPAD Clinical Practice Guidelines on complications. (72). Dyslipidemia, hypertension and albuminuria are more common in type 2 diabetes compared to type 1 diabetes and may be present at diagnosis and should be assessed after blood glucose control has been optimized. Confirmed hypertension (BP> 95% for age, gender and height) or albuminuria should be treated with an ACE inhibitor or, if not tolerated, an angiotensin receptor blocker (E). Combination therapy may be required if hypertension or albuminuria does not normalize on single agent treatment (E). Side effects are cough, hyperkalemia, headache and impotence (73). In addition, major congenital malformations have been reported with first trimester exposure to ACE inhibitors but not with other antihypertensive agents in non-diabetic women (74). Testing for dyslipidemia should be performed soon after diagnosis when BG control has been achieved and annually thereafter. (60,61) E Goal is LDL-C < 2.6 mmol (100 mg/dl) (68). If LDL-C is borderline (2.6-3.4 mmol;100–129 mg/ dl), or elevated (≥ 3.4 mmol; 130 mg/dl), repeat lipid profile should be performed in 6 months and dietary intervention to decrease total and saturated fat initiated. If LDL-C remains elevated after 3-6 months of attempting to optimize blood glucose control and diet, pharmacotherapy is warranted (72). Statin therapy has been shown to be safe and effective in children as in adults and should be the first pharmacologic intervention (72) although long term safety data are not available. Special attention should be paid to symptoms associated with muscles and connective tissues, as there is an increased risk of rhabdomyolysis The of T2DM in children and adolescents has required that with the of T1DM in children and adolescents the between the treatment of these T1DM is throughout the population to T2DM in North and Europe those with e.g. levels, less less well This has not been described for Asian T2DM. age. T1DM occurs throughout childhood, when is T2DM occurs in when family of families with a with T1DM have family with the disease, while 75% or more of families of the with T2DM have such The of these family to control weight and is with complications in the family and a of and in the treatment In most T1DM, beyond insulin and glucose is only for those individuals who are overweight and In all youth with T2DM, the is on and on glucose and effects of have the of T1DM and blood glucose insulin In in with an that dense increasingly and have to the of T2DM in children and its in of of including hypertension, dyslipidemia, and in the of complications may require more control in insulin T2DM than in T1DM, and attention to as by the Diabetes (21). also the ISPAD Clinical Practice Guidelines for diabetes and family for youth with type 2 diabetes is as important as it is in type 1 diabetes. and for T2DM will on and in insulin therapy and may not be required in T2DM will a greater on dietary and physical activity than is required for T1DM. should be given by with and of the and of youth with T2DM should be in a and age Because the of youth with T2DM are the ISPAD Guidelines for are to the of youth and families with T2DM The family will need to the of treatment of T2DM and to the of the required to T2DM should that the in the diagnosis type 1 type in a minority of patients can be and for the youth and The can be by the of blood glucose metabolism using therapy is to the metabolic of the specific of the of diabetes. is the of treatment of T2DM The family and should the of obesity and T2DM. must have an of the health and of the to an effective should be made in small and with the that these need to be The patient and family should be to monitor the and of and physical in any a and is for The and treatment for T2DM should include a and/or to a with and in of children with is should be to family and should be to all The family should be to dietary with including for weight reduced total and saturated fat increased and increased physical activity specific dietary are given in the ISPAD Guidelines for dietary should include: on and in of these and and for can result in substantial weight and is one of the most important for weight loss. and for the family and for the patient in an age including about dietary and activity related to and activity by of and using for that should be on in one with other activity as a family and should be in a or and not from a or of high density and in the the of and control of positive of or weight reduction in high and for and activity as for of and activity and for and should be for each patient and family that are to family and and should be to all A family or should be identified who is available to in physical activity with the may be to patients and family members. to with the dietary and is important to the of the should include: and an daily is to the of increased at reducing such as the and the time in related may be the most effective activity to be as a This should include daily to be more such as using of or to and to and and (E). for to and physical activity, including increases in daily (E). of blood glucose should be performed of should be and include a of fasting and postprandial glucose have been fasting a and daily post after the are while the within the (E). If the impaired glucose tolerance more frequent testing should be for of acute illness or when symptoms of or patients should more frequent testing and be in with their diabetes for (E). Patients on insulin or need to monitor for asymptomatic (E). should be at a year and if insulin is being used or metabolic control is should be continued in addition to pharmacologic therapy The of pharmacologic therapy is to decrease insulin resistance, increase insulin or to postprandial glucose The first used should be It has the over of reduction in without the risk of weight is decreased or remains and LDL-C and levels decrease during for type 2 diabetes in children and adolescents. of with over 3 months the need to a or insulin or in with a or a inhibitor Patients for should be on the effects of diabetes and oral agents on and oral agent should be used during pregnancy.

New-onset diabetes after transplantation: 2003 International consensus guidelines. Proceedings of an international expert panel meeting. Barcelona, Spain, 19 February 2003.

New classification and diagnostic criteria for diabetes mellitus

Self-reported diabetes is a valid outcome in pragmatic clinical trials and observational studies

To study trends in body mass index (BMI) at diagnosis of diabetes in all young Swedish adults in the age range of 15-34 years registered in a nation-based registry. The BMI was assessed at diagnosis in diabetic patients 15-34 years of age at diagnosis, for a period of 17 years (1983-1999). Islet cell antibodies (ICA) were measured during three periods (1987-1988, 1992-1993 and 1998-1999). A nationwide study (Diabetes Incidence Study in Sweden). A total of 4727 type 1 and 1083 type 2 diabetic patients. Incidence-year specific BMI adjusted for age, gender and time of diagnosis (month). Body mass index at diagnosis increased significantly both in type 1 (21.4 +/- 3.6 to 22.5 +/- 4.0; P < 0.0001) and in type 2 (27.4 +/- 6.8 to 32.0 +/- 6.0; P < 0.0001) diabetic patients, also when adjusted for age, gender and month of diagnosis. A similar significant increase in BMI was found in type 1 diabetic patients and in type 2 diabetic patients in the periods 1987-1988, 1992-1993 and 1998-1999; years when ICA were assessed and considered in the classification of diabetes. Despite this increase in BMI, there was no increase in the incidence of diabetes in young-adult people in Sweden. Body mass index at diagnosis of diabetes in subjects 15-34 years of age has substantially increased during 1983-1999 in Sweden when adjusted for age, gender and month of diagnosis.

GADA persistence and diabetes classification

Screening for Abnormalities of Carbohydrate Metabolism in Teens

Diabetes mellitus (DM), a prevalent metabolic disorder, poses significant diagnostic and therapeutic challenges, especially, in the early stage diagnosis of diabetes related complications. Accurate early stage diagnosis of diabetes and its complications is essential for preventing chronic health problems, improving treatment outcomes, and reducing healthcare costs by enabling timely medical interventions and personalized ailment management strategies. However, conventional diagnostic techniques often face challenges to offer the required sensitivity and accuracy that are essential for early stage detection and classification of diabetes and its complications. In this context, we developed an advanced diagnostic model that utilized gold nanoparticles (AuNPs) functionalized with 4-mercaptophenylboronic acid (AuNPs@4MPBA) to enable both specific and nonspecific SERS detection of diabetes biomarkers in serum samples. In this study, the artificial intelligence (AI)-assisted self-calibration method was smartly integrated within the SERS-based diagnostic system to enable efficient early stage detection of diabetes and its associated complications. This combined diagnostic approach, demonstrating high diagnostic accuracy required only minimal sample volumes for the implementation unlike conventional diagnostic methods. Essentially, a ResNet-LSTM multihead self-attention neural network, integrated with the self-calibrating SERS technique facilitated the precise classification as well as detection of diabetes and related complications. Unlike the conventional diagnostic methods with limited scope of tracking the postmedication complications, the present self-calibrating SERS-AI combined diagnostic method provided accurate reliable diagnosis of the diabetic patients even with the premedication history. Furthermore, the incorporation of cosine similarity and Pearson's correlation methods ascertained the generalization and improved accuracy of the diagnostic model, apart from limiting the scope of clinical misdiagnosis.

In 1980, the World Health Organisation (WHO) ended a long phase of confusion by providing international standards for diagnosis and classification of diabetes [1]. Before this, confusion existed with respect to the glucose threshold for diagnosis of diabetes and other categories of glucose intolerance as well as the glucose load used for the oral glucose tolerance test. As always, however, new scientific data and insight combined with health political issues have led to several revisions of the diagnostic criteria and classification of patients with diabetes as well as with other categories of glucose intolerance. The first revision was made in 1985 [2], the second in 1999 [3] and most recently the third revision came out in 2006 [4] based on a collaborative effort between WHO and the International Diabetes Federation (IDF). In addition to these global definitions, national agencies like the American Diabetes Association (ADA) [5,6] as well as international organizations such as the IDF [7] have provided definitions that are not fully in accordance with the WHO definitions of diabetes, glucose intolerance and the metabolic syndrome (Table 1). This lack of concordance has not only created confusion among researchers but also among clinicians. As a consequence of the use of different diagnostic criteria, studies and trials may no longer be directly comparable as “diabetes” “IGT” or “IFG” no longer represents the same population in different studies. Finally, the fact that leading personalities within the field of diabetes have identified themselves with some definitions and not with others as the “fathers and mothers” of the different definitions has split observers and users into groups of “believers” rather than into scientific orientation. This chapter focuses on the following questions related to definition and classification of diabetes:

ObjectiveC-peptide is a main outcome measure in treatment trials of diabetes. C-peptide also has a role in the classification of diabetes, which is often difficult in adults and this is also increasingly recognised in adolescents and elders.AimWe aimed to describe the levels of C-peptide in relation to age and body mass index (BMI) in a large population-based cohort of adults with newly diagnosed diabetes and compare the capabilities of C-peptide, age and BMI to discriminate between autoimmune and non-autoimmune diabetes.Subjects and methodsBlood samples from 1180 patients were analysed regarding islet cell antibody, glutamic acid decarboxylase antibody and fasting C-peptide (FCP). Receiver operating characteristics (ROC) curves were analysed to check the ability of age, BMI and C-peptide to discriminate between autoantibody-positive (Ab+) and -negative (Ab−) diabetes.ResultsMean FCP was 0.73±0.5 (range 0.13–1.80) nmol/l in the Ab+ and 1.42±0.9 (range 0.13–8.30) nmol/l in the Ab−. FCP was 0.02 nmol/l higher per year increase in age at diagnosis of diabetes. Mean BMI was 26.0±4.8 (range 18.0–39.0) kg/m2 in the Ab+ and 28.9±5.3 (range 15.5–62.6) kg/m2 in the Ab−. FCP increased with age also within each BMI group. The highest area under the curve (AUC) in the ROC analysis was found for C-peptide, followed by age and BMI (0.78, 0.68 and 0.66 respectively).ConclusionsAt diagnosis of diabetes, C-peptide was superior to age and BMI in discriminating between autoimmune and non-autoimmune diabetes. C-peptide increased significantly with BMI and age, latter also within each BMI group. Most of the adults had normal or high levels of C-peptide at presentation of diabetes among the autoimmune patients.

To assess changes in diabetes autoantibodies (DAs) over time in children and young adults with diabetes and determine whether observed changes were associated with demographic characteristics, clinical parameters and diabetes complications. Participants had DAs measured at baseline (10.3 ± 7.1 months after diabetes diagnosis) and at 12, 24months and ≥5 years after the baseline measurement. At the ≥5-year follow-up, the presence of diabetes complications was assessed. We examined the associations between change in number of positive DAs and changes in individual DA status with the participants' characteristics and clinical parameters over time. Out of 4179 participants, 62% had longitudinal DA data and 51% had complications and longitudinal DA data. In participants with ≥1 baseline positive DA (n=1699), 83.4% remained positive after 7.3 ± 2.3 years duration of diabetes. Decrease in number of positive DAs was associated with longer diabetes duration (p=0.003 for 1 baseline positive DA; p < 0.001 for 2 baseline positive DAs) and younger age at diagnosis (p < 0.001 for 2 baseline positive DAs). No associations were found between change in number of positive DAs in participants with ≥1 baseline positive DA (n=1391) and HbA1c, insulin dose, acute, or chronic complications after 7.7 ± 1.9 years duration of diabetes. DA status likely remains stable in the first 7 years after diabetes diagnosis. Younger age at diabetes diagnosis and longer duration were associated with less persistence of DAs. Measuring DAs after initial presentation may aid in diabetes classification but not likely in predicting the clinical course.

Web Exclusives7 August 2018Annals for Educators - 7 August 2018FREEDarren B. Taichman, MD, PhDDarren B. Taichman, MD, PhDSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/AFED201808070 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Clinical Practice PointsMedication for Opioid Use Disorder After Nonfatal Opioid Overdose and Association With Mortality. A Cohort StudyPatients who survive an opioid overdose are at increased risk for subsequent nonfatal and fatal events. This study evaluated overdose survivors to determine whether use of medications for opioid use disorder (MOUDs) was associated with reduced mortality.Use this paper to:Ask your learners what steps are required immediately in the management of a patient with an opioid overdose. What interventions should be considered after management of acutely life-threatening issues?Ask your learners what options are available for patients with opioid use disorder. How do methadone, buprenorphine, and naltrexone work? How are they prescribed? Who may prescribe them, and what monitoring is required? How effective are they at reducing risk for subsequent overdose and/or death?How would your learners arrange for outpatient care of patients presenting with an opioid overdose? How often is this actually done at your center?Why do your learners think MOUDs are underused? What are the legal barriers to their use? Should these be changed? Review a recent ACP position paper to help frame your discussion. The editorialists believe that the persistent belief that MOUDs “substitute a new addiction for an old one” is part of the problem. What are reasonable concerns regarding MOUDs? Do the benefits outweigh the risks? Invite a specialist in substance abuse to join your discussion. Prognostic Implications of Single-Sample Confirmatory Testing for Undiagnosed Diabetes. A Prospective Cohort StudyCurrent clinical guidelines require repeated testing (“2-sample testing”) to confirm an elevated fasting glucose or hemoglobin A1c level and reduce the possibility of a false-positive diagnosis of diabetes mellitus. In this study, the authors examined the prognostic performance of a single-sample confirmatory definition of undiagnosed diabetes in identifying persons who subsequently developed diabetes or related complications.Use this paper to:Start a teaching session with a multiple-choice question. We've provided one below!Ask your learners how a diagnosis of diabetes is established. How do they do it? Do they confirm an abnormal glycemic test result on a separate sample? If not, why not?Should the results of this study alter how we diagnose diabetes? Why or why not? What are the study's limitations?What properties should we require of a diagnostic test?Given that diagnosing diabetes with tests performed on a single blood sample would be easier for patients and clinicians, why not take this approach now? Use the accompanying editorial to help frame your discussion. Storing and Disposing of Opioid Analgesics: What Does Our Medicine Tell Us?Medication diversion represents the largest source of misused opioid analgesics. Unused opioid analgesics are seldom safely stored or disposed of, creating a large supply for diversion. This brief research report assessed how often the package inserts of opioids contain information about the safe storage and disposal of the drug.Use this study to:Ask your learners if they know how patients should dispose of unused opioids. How should this be done?Do your learners ever talk about safe storage of opioids and what to do with the remaining supply after the drug is no longer needed for the reason it was prescribed? Have they ever discussed with their patients the potential for the drug's diversion and the role that might play in harming others?How would your learners counsel their patients? What specific advice would they provide?Beyond the GuidelinesWhat Should Be the Target Blood Pressure for This Older Patient With Hypertension? Grand Rounds Discussion From Beth Israel Deaconess Medical CenterThe optimum threshold above which to begin antihypertensive therapy as well as the optimum target blood pressure to achieve with medication are areas of controversy, especially in older adults. Two guidelines published in 2017 address this issue. In this Beyond the Guidelines, 2 experts debate application of these guidelines to the care of a 79-year-old man with hypertension.Use this feature to:Watch the short video of the patient's interview.Ask your learners what criteria should determine eligibility for antihypertensive treatment in persons aged 60 years or older. What should their target blood pressure be? Which antihypertensive agents are preferable?Watch the grand rounds presentation with your learners. Now how would they answer these questions?How would your learners discuss with a patient whether to initiate antihypertensive treatment?Be sure to answer the multiple-choice questions to earn CME/MOC credit for yourself!In the Clinic: Herpes ZosterPrimary care providers and hospitalists frequently encounter older or immunocompromised patients with herpes zoster accompanied by debilitating pain. Atypical presentations and zosteriform herpes simplex may present diagnostic challenges to clinicians. Are your learners prepared to prevent herpes zoster, diagnose it, and treat the complications?Use this feature to:Ask your learners who is at risk for herpes zoster.Who should be vaccinated against varicella zoster virus? How effective is the vaccine?Is laboratory testing required to diagnose herpes zoster? What is the differential diagnosis?When should an ophthalmologist or an otolaryngologist be consulted?How is herpes zoster treated? When is intravenous treatment needed?Use the multiple-choice questions to help introduce topics for discussion with your team, and log on to enter your answers to earn CME/MOC credit for yourself.Humanism and ProfessionalismOn Being a Doctor: A Beautiful DeathDr. Weatherly recalls her patient's grace when he was the only one who knew he was about to die.Use this essay to:Listen to an audio recording, read by Dr. Michael LaCombe. Ask what a “good death” is.What is our role in a patient's death? How would your learners have responded when this patient indicated with a smile that he would die that day?MKSAP 17 QuestionA 55-year-old man is evaluated following a screening for type 2 diabetes mellitus. He is asymptomatic. He has a history of hypertension and hyperlipidemia. There is no history of anemia, liver disease, or kidney disease. Medications are lisinopril and rosuvastatin.On physical examination, blood pressure is 123/76 mm Hg and pulse rate is 72/min. BMI is 28. The remainder of the examination is unremarkable.Laboratory studies:Hematocrit45.6%Creatinine1.0 mg/dL (88.4 µmol/L)Glucose, fasting128 mg/dL (7.1 mmol/L)Hemoglobin A1c5.6%Which of the following is the most appropriate diagnostic test to perform next?A. Fasting plasma glucoseB. Hemoglobin A1cC. Oral glucose tolerance testD. Random blood glucoseCorrect AnswerA. Fasting plasma glucoseEducational ObjectiveDiagnose type 2 diabetes mellitus.CritiqueA fasting plasma glucose measurement is the most appropriate diagnostic test for this patient. Diabetes mellitus can be diagnosed with an abnormal result of one screening test performed on two separate occasions. Although the hemoglobin A1c is normal in this patient, the fasting plasma glucose is abnormally elevated within the diagnostic range for diabetes mellitus. When discrepant results occur among different screening tests for diabetes, the American Diabetes Association recommends repeating the abnormal screening test. If the repeat fasting plasma glucose measurement is abnormal, the diagnosis of diabetes is confirmed. Screening for type 2 diabetes should begin in all asymptomatic patients at age 45 years. In adult patients with a BMI greater than or equal to 25, screening should occur at any age if one or more additional risk factors for diabetes is present.Use of the hemoglobin A1c as an initial screening test in this patient is appropriate as there is no evidence for anemia or kidney or liver disease that could decrease the reliability of the test. The value was normal and does not warrant a repeat measurement as the next diagnostic test to perform in this scenario.A 2-hour 75-g oral glucose tolerance test can be used as a screening tool for diagnosing diabetes. Since this test was not initially used for screening in this patient, it is most appropriate to repeat the abnormal screening test (fasting plasma glucose) that was already used for comparison.A random blood glucose measurement would be useful in this patient if he presented with classic hyperglycemic symptoms in the setting of a blood glucose level of 200 mg/dL (11.1 mmol/L) or above, as that would be diagnostic of diabetes. This patient is not symptomatic.Key PointWhen discrepant results occur among different screening tests for diabetes mellitus, the American Diabetes Association recommends repeating the abnormal screening test.BibliographyAmerican Diabetes Association. (2) Classification and diagnosis of diabetes. In: Standards of Medical Care in Diabetes-2015. Diabetes Care. 2015;38 Suppl 1:S8-16.Do you like reading Annals for Educators? Receive it direct to your inbox. Sign up for the Annals for Educators alert today. Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: From the Editors of Annals of Internal Medicine and Education Guest Editor, Gretchen Diemer, MD, FACP, Associate Dean of Graduate Medical Education and Affiliations, Thomas Jefferson University. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 7 August 2018Volume 169, Issue 3Page: ED3KeywordsBlood plasmaBlood pressureDiabetes mellitusDrugsGlucoseHemoglobinOpioidsRenal diseasesResearch laboratoriesType 2 diabetes ePublished: 7 August 2018 Issue Published: 7 August 2018 Copyright & PermissionsCopyright © 2018 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...

The Better Diabetes Diagnosis (BDD) study – A review of a nationwide prospective cohort study in Sweden