Diagnostic Criteria and Classification of Diabetes

  • Rebekah GospinEmail author
  • Joel Zonszein
Living reference work entry

Later version available View entry history


Diabetes, a group of complex metabolic disorders, remains a major health problem in the twenty-first century. The unabated increasing rate of type 2 diabetes (T2DM) and obesity appears to be plateauing in the U.S.A. The incidence of the less common type 1 diabetes (T1DM) has also increased at a slower pace. Diabetes in children and adolescents, however, has accelerated and evolved into a heterogeneous condition that is more closely related to T2DM. The landscape of diabetes has changed dramatically in the past few decades. The knowledge gained from many large clinical trials and new drug development has led to a better understanding of the pathophysiology and treatment of each of the disease states. Diabetes remains characterized by elevated glycemic markers and distinctive complications. Better diagnosis and earlier treatment has resulted in fewer complications, but major challenges remain as the target guidelines are unmet in approximately half of the U.S. adult population, particularly among younger individuals in more susceptible ethnic and racial groups.

In this chapter we review the classification and diagnosis of the major types of diabetes. A well-established set of criteria is continuously revised to reflect current knowledge of the disease. Screening high-risk individuals has allowed for earlier diagnosis and patient-centered interventions to prevent complications. Fewer people now live with undiagnosed disease. While glycemic markers remain the gold standard for treatment and diagnosis, that advances in genetics and metabolomics will soon be used to better define and manage these conditions.

Due to the higher prevalence of obesity and diabetes in the young, diabetes in pregnancy is now found not only in those with established T1DM but also in those with T2DM. An increasing rate of women are diagnosed with diabetes during their pregnancy. Updated recommendations provide better methods and criteria for screening and diagnosis. We hope that this chapter helps to elucidate current and well-established criteria to screen high-risk individuals, allowing for both an earlier diagnosis as well as better patient-centered interventions to prevent future complications of this disease.


Type 1 Diabetes Mellitus Type 2 Diabetes Mellitus Obesity Prediabetes Gestational Diabetes Mellitus 

Diabetes mellitus is a group of diverse and complex metabolic disorders, characterized by elevated glycemic markers and distinctive complications. Type 1 (T1DM) and the more common type 2 diabetes (T2DM) are different diseases in pathogenesis and treatment. In both, defects in insulin secretion, insulin action, or both result in hyperglycemia which is the paramount feature used for diagnosis and treatment goals. Untreated hyperglycemia along with other cardiovascular risk factors can result in cardiovascular disease (CVD) manifested as myocardial infarction or stroke, events that are the most common cause of premature death in individuals with diabetes [1]. In parallel to CVD or large vessel disease, small vessel disease takes place that is correlated to the degree and duration of hyperglycemia. Individuals with microvasculopathy or small vessel disease can manifest ophthalmopathy with potential loss of vision, nephropathy leading to renal failure, peripheral neuropathy that together with vasculopathy increases the risk for foot ulcers and amputations. In addition, other complications such as erectile dysfunction, loss of hearing, and dementia are found to be more common and manifest earlier in individuals with diabetes. Complications are a major public health problem as they increase the use of health resources, health care cost, and cause loss of productivity [2].

The landscape of diabetes has changed during the past decades as can be appreciated in other chapters of this book. We have a much better understanding of the different disease processes called “diabetes mellitus.” There is ample literature, and numerous clinical trials pertaining not only to the management of hyperglycemia but also to the treatment of hypertension, dyslipidemia, antiplatelet therapy and revascularization [3]. Better outcomes between 1990–2010 have been found in the U.S.A. for rates of myocardial infarction, stroke, leg amputation, and death from hyperglycemic crisis, [4] but major challenges remain as these improvements were achieved with only fewer than half of U.S. adults meeting the recommended guidelines [5]. Thus, there is an opportunity to further improve outcomes, and lessen the magnitude of the public health burden caused by diabetes mellitus.

In the past, the classification was based on clinical findings such as age of onset, so-called juvenile or adult-onset diabetes, or treatment modalities, such as insulin-dependent versus non-insulin-dependent diabetes. Since 1979 the National Diabetes Data Group (NDDG) in conjunction with World Health Organization (WHO) revised and published new and unified criteria for the classification and diagnosis of diabetes mellitus [6]. As more information was accrued on the pathogenesis and etiology of diabetes, the NDDG criteria were modified by the International Expert Committee under the sponsorship of the American Diabetes Association. The vast majority of cases of diabetes fall into two broad etiopathogenetic categories. Type 1 diabetes (T1DM), written with a Latin numeral and avoiding the old terms of type I (Roman numeral) diabetes, juvenile diabetes, or insulin-dependent diabetes, is caused by deficiency of insulin secretion. The second and more prevalent category is type 2 diabetes (T2DM), also written with a Latin numeral, and no longer called type II diabetes, adult diabetes, or non-insulin-dependent diabetes (NIDDM). This disease is complex and characterized by a combination of resistance to insulin action and an inadequate compensatory insulin secretory response. In T2DM an asymptomatic or silent period of hyperglycemia often causes vascular and organ disease even before diabetes is diagnosed, thus the need for better screening, diagnosing, and treatment early in the disease process.


Diabetes, and in particular T2DM, remains a major health problem in the twenty-first century, with increasing rates of obesity a closely linked calamity. The number of individuals affected continues to increase and T2DM is being diagnosed in a younger population. Worldwide the prevalence is also increasing [7] as populations are shifting from rural to more urban ecosystems where there is easier accessibility to high caloric food that is accompanied by less exercise and societal stressors. The projections done at the end of last century have already been surpassed [8]. It was expected that the number of Americans with diagnosed diabetes would increase 165 %, from 11 million in 2000 (prevalence of 4.0 %) to 29 million in 2050 (prevalence of 7.2 %), attributing 37 % to changes in demographic composition, 27 % to population growth, and 36 % to increased prevalence rates. The latest data from the American Diabetes Association (ADA) in 2015 showed that diabetes is already affecting 29.1 million Americans (9.3 % of the population) [9]. While the incidence has doubled in the last two decades, since 2008 it has slowed down or plateaued, but less so in minority populations. The increased rate of this disease is multifactorial owing to aging, improved survival rates, growth of at-risk minority populations, increased obesity, and sedentary lifestyle. In addition the number of individuals having undiagnosed diabetes has also decreased, attributed in part to easier diagnostic tests such as the inclusion of glycated hemoglobin A1c test, also called HbA1c, or A1c [10].

Obesity in U.S. adults, defined as a body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 30 or greater, changed little between 1960 and 1980 (from 13 % in 1960 to 15 % in 1980) but doubled from 15 % to 31 % between 1980 and 2000 [11]. While the trend has decelerated, the prevalence of obesity remains high, affecting approximately 35 % of the adult population [12]. The rate of obesity among U.S. adults also appears to be leveling off, decreasing between 2008 and 2012 [10]. Using data from the National Health and Nutrition Examination Survey (NHANES) the prevalence of total, diagnosed, and undiagnosed diabetes in U.S. adults in 2011–2012, using A1c, FPG, or 2-h plasma glucose, was 14.3 % for “total diabetes,” 9.1 % for “diagnosed diabetes,” and 5.2 % for “undiagnosed diabetes” [13]. The prevalence of total diabetes remains higher in older age-groups, and compared with non-Hispanic whites with a prevalence of 11.3 %, it is more common in non-Hispanic blacks 21.8 %, Hispanics 22.6 %, and non-Hispanic Asians 20.6 %. In the same study, the percentage of people with diabetes who were undiagnosed decreased from 40.3 % in 1988–1994 to 31.0 % in 2011–2012 in the total U.S. population, but this improvement lagged in certain subgroups including the younger population aged 20–44 years (40 % in 1988 and 40 % in 2012), the non-Hispanic Asian (50.9 %), Hispanic (49.0 %), non-Hispanic black (36.8 %), with fewer undiagnosed cases in the non-Hispanic white (32.3 %) population. This is encouraging as better and earlier diagnosis should prompt initiation of treatment for glycemia as well as other CVD risk factors and provide health benefits [14]. The disparity rates of diabetes and undiagnosed diabetes in ethnic/racial minority populations and the young may reflect less access to health care as well as other social determinants of health. In addition, the Asian American population, while less obese using BMI standards, have a greater cardiometabolic risk and therefore the recent recommendation to consider diabetes testing for all Asian American individuals with a BMI of 23 or greater [15].

Also alarming is the rate of prediabetes . The most recent data from 2009–2012, based on fasting glucose or A1c levels, showed that 37 % of U.S. adults aged 20 years or older and 51 % of those aged 65 years or older had prediabetes. Applying this percentage to the entire U.S. population in 2012 yields an estimated 86 million Americans aged 20 years or older with prediabetes. On the basis of fasting glucose or A1c levels, and after adjusting for population age differences, the percentage of U.S. adults aged 20 years or older with prediabetes in 2009–2012 was similar for non-Hispanic Whites (35 %), non-Hispanic Blacks (39 %), and Hispanics (38 %).

The less common T1DM has also slowly increased in incidence and accounts for approximately 5 % of the U.S. diabetes population [16]. Diabetes diagnosed in children and adolescents was almost entirely considered to be T1DM. It is now viewed as a complex disorder with heterogeneity in its pathogenesis, clinical presentation, and clinical outcome. The occurrence of T2DM in youth, particularly in the overweight minority youth, has been clearly documented. In the SEARCH for Diabetes in Youth Study that began in 2000 with an overarching objective to describe childhood diabetes amongst the five major race and ethnic groups in the U.S.A., an increased incidence of diabetes in youth has been found [17]. A significant increase in the incidence of T1DM among non-Hispanic White youth occurred from 2002 through 2009 with an annual increase of 2.72 % per year, but even more important is the prevalence of prediabetes and T2DM becoming increasingly more common in obese children and adolescents [17]. Until the last decade, T2DM accounted for less than 3 % of all cases of new-onset diabetes in adolescents; it has now increased to 45 % [18]. The progression to T2DM in obese children is faster than in adults and it is also associated with several metabolic and CVD complications. The diagnosis of T2DM in the youth now accounts for 20–50 % disproportionately affecting minority race/ethnic groups. This is significant because it is the working force in our country and as they enter adulthood with several years of disease duration and possible chronic complications it may result in decreased productivity and increased healthcare spending, impacting the country as a whole. Also, the high prevalence of diabetes in a reproductive age-group may potentially increase the incidence of diabetes in the next generations [19]. Nonetheless, the silver lining is that with better screening tests, earlier diagnosis, and appropriate treatment, reductions in complications and mortality is already taking place [4].


It is impossible in this chapter to review in depth the many types of diabetes. The majority of individuals can be assigned a specific type, but this is not always intuitive, and not all individuals necessarily fit into one single category. This has been further complicated by the evolution of T2DM, a disease that has been transformed into a “more aggressive disorder,” affecting a younger population, with more lipotoxicity and insulin resistance. The concept that T2DM is a disease found in adults and T1DM only in children is no longer accurate, as both diseases occur in both cohorts. Similarly patients with T2DM may develop diabetic ketoacidosis (DKA), an acute complication that used to be found mainly in T1DM. Nonetheless, obtaining a careful history will define the majority and the proper diagnosis can be supported by biomedical markers, or even genetic studies (in monogenetic diseases) that can help establish an accurate diagnosis, which will ultimately be vital for proper management.

Diabetes can be classified into the following general categories:
  1. 1.

    Type 1 diabetes (T1DM), a disease caused by β-cell failure and severe or absolute insulin deficiency

  2. 2.

    Type 2 diabetes (T2DM), a complex multisystem disease with carbohydrate and lipid metabolic derangements, characterized by vascular inflammation, and premature mortality, all characterized by elevated glycemic markers caused by a secretory defect of insulin on the background of insulin resistance

  3. 3.

    Others, diabetes due to other causes such as monogenic diabetes syndromes, diseases of the pancreas, drug- or chemical-induced diabetes, secondary to hormonal disorders

  4. 4.

    Gestational diabetes mellitus (GDM), diabetes diagnosed during pregnancy

Following is a short discussion related to classification shown in Table 1. We discuss changes that have occurred in the most common types of diabetes, and only annotate the less common types. For additional information, see the American Diabetes Association (ADA) position statement “Diagnosis and Classification of Diabetes Mellitus” [3].
Table 1


1. Type 1 diabetes (T1DM)

 Immune-Mediated Diabetes

 Latent autoimmune diabetes in adults (LADA)

 Idiopathic Diabetes

2. Type 2 diabetes (T2DM)

3. Others

 Neonatal diabetes and maturity-onset diabetes of the young [MODY])

 Diseases of the exocrine pancreas (such as cystic fibrosis)

 Hormonal, drug, chemical-induced diabetes

 New-Onset Diabetes Mellitus After Transplantation (NODAT)


4. Gestational Diabetes (GDM)

Type 1 Diabetes

Immune-Mediated Diabetes. This form of diabetes accounts for approximately 5 % of those with diabetes and results from a cellular-mediated autoimmune destruction of the β-cells of the pancreas. Markers of the immune destruction of the β-cell include islet cell autoantibodies, autoantibodies to insulin, autoantibodies to glutamic acid dehydrogenase (GAD65), and autoantibodies to the tyrosine phosphatases IA-2 and IA-2b. One or more of these autoantibodies are usually present in close to 90 % of individuals when initially detected. In addition there is a strong HLA association, with linkage to the DQA and DQB genes, and it is influenced by the DRB genes. These HLA-DR/DQ alleles can be either predisposing to or protective against the development of diabetes. Immune-mediated diabetes commonly occurs in childhood and adolescence, but it can occur at any age, even in the eighth and ninth decades of life. Autoimmune destruction of β-cells has multiple genetic predispositions and is related to environmental trigger factors that are still poorly understood. These patients are also prone to other autoimmune disorders such as autoimmune thyroid disease, Addison’s disease, vitiligo, autoimmune hepatitis, myasthenia gravis, celiac sprue, and pernicious anemia. In immune-mediated diabetes the rate of β-cell destruction is variable. It is rapid typically in infants and children, and often slow in adults. When acute or rapid β-cell destruction occurs, development of ketoacidosis may be the first manifestation. Others, particularly in adults, may have a more insidious process that can rapidly change to severe hyperglycemia and/or ketoacidosis in the presence of stressors such as infection [20].

Latent autoimmune diabetes in adults (LADA). In the typical presentation of LADA, β-cell function is impaired but remains present for many years and therefore ketoacidosis is rare and the presentation is similar to the garden variety T2DM. This type of diabetes is coined with the term latent autoimmune diabetes of the adult (LADA). Among patients with phenotypic characteristics of T2DM, LADA can occur as often as 25 % in individuals below the age of 35 years, and as often as 10 % in those older than 35 years [21]. Prospective studies have shown that β-cell failure develops within 5 years in the majority but may take up to 12 years in some. The prevalence and clinical characterization is important as many are erroneously diagnosed with T2DM. Individuals with LADA eventually need insulin replacement therapy and are at risk for ketoacidosis, thus proper and early diagnosis is crucial for initiation of insulin therapy [22].

Idiopathic Diabetes. Idiopathic diabetes is a disease for which the exact cause is unknown, as the name implies. It resembles immune-mediated T1DM in that individuals have permanent insulinopenia and are prone to ketoacidosis. The distinction is that these individuals have negative immune markers for β-cell autoimmunity and are not HLA associated. Only a minority of patients fall into this category and are most often of African, Caribbean, or Asian ancestry. Individuals with this form of diabetes have been described to suffer from episodic ketoacidosis and exhibit varying degrees of insulin deficiency between episodes. They may present with severe β-cell dysfunction and DKA, reflecting an absolute requirement for insulin replacement therapy, however the need for insulin is not permanent, suggesting a recovery of endogenous insulin secretion and function after acute episodes [23].

Type 2 Diabetes

This is the most common type of diabetes and accounts for close to 95 % of all cases. T2DM is a true conglomeration of many metabolic disorders. It frequently remains undiagnosed for many years as hyperglycemia develops gradually and it is mild and asymptomatic. It is often associated with other CVD risk factors such as obesity, dyslipidemia, and hypertension and often the diagnosis is established at the time of a CVD event. Collectively, these disorders that are now classified as T2DM have a strong genetic predisposition, their risk increases with age, but during the past decades they have affected a younger population. The disease may be “unmasked” by conditions that exacerbate insulin resistance such as pregnancy or administration of corticosteroids. The pathophysiological components are intricate but defects in β-cell function with impaired insulin secretion remain the hallmark. In addition to β-cell dysfunction many other metabolic abnormalities take place simultaneously and involve glucagon-producing α-cell dysfunction, as well as abnormalities in adipocytes, hepatic, gastrointestinal, renal, and central nervous system [24].

In T2DM the pancreatic α-cells secrete inappropriately high amounts of glucagon, resulting in endogenous glucose production in spite of hyperglycemia and hyperinsulinemia, the two main factors typically responsible for decreasing endogenous glucose production. This inappropriate hyperglucagonemia is in part responsible not only for the fasting hyperglycemia but is also a major contributor to prandial hyperglycemia found in T2DM.

Adipocytes play a crucial role in patients with central obesity and T2DM as they become ineffective in storing energy, instead triglycerides accumulate as ectopic fat in vital organs such as the liver (fatty liver or hepatic steatosis). Increased free fatty acid flux and ectopic lipid accumulation play an important role in the pathogenesis of insulin resistance, promote hepatic lipogenesis, and atherogenic dyslipidemia. Together with the abnormal adipocytes, the high number of macrophages “sprinkled” in visceral adiposity produce adipokines and cytokines that exacerbate insulin resistance and contribute to vascular inflammation. These are some of the important components responsible for premature CVD morbidity and mortality, sometimes even before hyperglycemia develops or T2DM is diagnosed.

The gastrointestinal tract contributes to the disease process by abnormal secretion of incretin hormones such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), two peptides that account for 90 % of the incretin effect and are responsible for maintaining glucose homeostasis, especially during the fed state.

The kidneys are important glucose regulators and have a central role in T2DM as they dramatically increase the amount of filtered glucose, an adaptive mechanism that probably developed during periods of food deprivation to ensure sufficient energy. Patients with diabetes have a “maladaptation” with increased expression and activity of the SGLT2 transporter, which reabsorbs glucose and further exacerbates hyperglycemia by as much as 20 % in poorly controlled diabetes.

Finally, the central nervous system (CNS), the “main glucose regulator,” is also critical in obesity and diabetes. An adaptation to years of fuel deprivation may have resulted in CNS maladaptation (known as the Thrifty Gene Hypothesis) causing obesity and T2DM. The elevated levels of insulin and leptin are not providing adequate feedback as these individuals are resistant to these two nutrient hormones in addition to other brain nutrient sensing pathways, and therefore lack proper feedback regulation. Furthermore, other major defects in fuel regulation exist that include abnormal neuropeptide Y (NPY), ghrelin, as well as other orectic and anorectic peptides. The result is expressed phenotypically as obesity, insulin resistance, dyslipidemia, and T2DM. In summary, hyperglycemia is just a marker of a very intricate metabolic derangement with multiple pathophysiological disturbances that involve different organs and endocrine and neurological pathways. With this insight, it is not surprising that in T2DM the use of monotherapy alone is rarely enough to reach or maintain glycemic goals, and combination therapy is often necessary.

Other Specific Types

Monogenic Diabetes. Some rare forms of diabetes result from mutations in a single gene and are called monogenic. They account for about 1–5 % of all cases of diabetes in young people. In most cases the gene mutation is inherited; in the remaining cases the gene mutation develops spontaneously. Most of these mutations reduce the body’s ability to produce insulin. When hyperglycemia is first detected in childhood it may be erroneously diagnosed as T1DM, and when diagnosed in adulthood it is often erroneously diagnosed as T2DM [25]. Since some monogenic forms of diabetes can be treated with oral diabetes medications a correct diagnosis is important for proper treatment as it can lead to better glucose control. Genetic testing can diagnose most forms of monogenic diabetes and testing of other family members may also be indicated to determine whether they are at risk for diabetes. The two main forms of monogenic diabetes are neonatal diabetes mellitus (NDM) and a more common form called maturity-onset diabetes of the young (MODY).

Maturity-Onset Diabetes of the Young (MODY) Monogenic defects in β-cell function are inherited in an autosomal dominant pattern resulting in impaired insulin secretion but minimal or no defects in insulin action. Since the onset of hyperglycemia occurs at an early age, they are referred to as maturity-onset diabetes of the young (MODY). Six genetic loci on different chromosomes have been identified with the most common form associated with mutations on chromosome 12 in a hepatic transcription factor referred to as hepatocyte nuclear factor (HNF)-1α [26]. A second form is associated with mutations in the glucokinase gene (that serves as a glucose sensor) on chromosome 7p. The defective glucokinase molecule converts less glucose to glucose-6-phosphate and therefore stimulates less insulin secretion by the β-cell. This defect results in increased plasma levels of glucose. The less common forms result from mutations in other transcription factors, including HNF-4α, HNF-lβ, insulin promoter factor (IPF)-1, and NeuroD1. Since hyperglycemia is not completely deregulated in these diseases, there are fewer observed complications and in fact individuals with MODY due to mutations in the GCK gene generally require no treatment at all. Mutations in HNF1A or HNF4A commonly respond well to sulfonylureas which is the treatment of choice [27].

Neonatal Diabetes (NDM). Neonatal diabetes is a term used for diabetes diagnosed within the first 6 months of life and can be either transient or permanent [28]. The most common is a transient form of the disease with a genetic defect on ZAC/HYAMI imprinting. The permanent form of the disease has a defect in the gene encoding the Kir6.2 subunit of the β-cell KATP channel [29]. Recognition of this disorder is important as it can be successfully treated with sulfonylureas [30].

Other Types of Diabetes

  • Genetic defects in the mitochondrial genome, which is inherited purely from the mother, can be associated with diabetes [31]. Point mutations in mitochondrial DNA are associated with diabetes and deafness. This is an identical mutation to that found in the MELAS syndrome which presents with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like syndrome but without diabetes, suggesting different phenotypic expressions of a single genetic lesion.

  • Autosomal dominant abnormalities in conversion of proinsulin to insulin can result in glucose intolerance and mild hyperglycemia [32]. Other forms of monogenic diabetes have been identified with an autosomal inheritance defect that causes mutations in the insulin molecule leading to impaired receptor binding and causing minimally impaired or normal glucose metabolism.

  • Leprechaunism and the Rabson-Mendenhall syndrome are two pediatric syndromes that have mutations in the insulin receptor gene with subsequent alterations in insulin receptor function and extreme insulin resistance [33]. The former has characteristic facial features and is usually fatal in infancy, while the latter is associated with abnormalities of teeth and nails and pineal gland hyperplasia.

  • Abnormalities of insulin action stemming from mutations in the insulin receptor range from hyperinsulinemia and modest hyperglycemia to severe diabetes. In the past, this syndrome was termed type A insulin resistance, it has characteristic phenotypic manifestations such as acanthosis nigricans, virilization, and/or cystic ovaries [34]. In addition to alterations in the structure and function of the insulin receptor patients with insulin-resistant lipoatrophic diabetes may have abnormalities that reside in the postreceptor signaling transduction pathways [35].

  • Many other genetic syndromes can be accompanied by an increased incidence of diabetes. These include the chromosomal disorders such as Down syndrome, Klinefelter syndrome, and Turner syndrome. Wolfram syndrome is an autosomal recessive disorder characterized by insulin-deficient diabetes, with other manifestations that include diabetes insipidus, hypogonadism, optic atrophy, and neural deafness [31].

Genetics and Metabolomics. Readily available commercial genetic testing now enables a more accurate diagnosis of the monogenic forms of diabetes, leading to proper treatment regimens, as well as screening and diagnosing other family members. Unfortunately both T1DM and T2DM are polygenetic diseases and therefore genetic identifications are difficult in the great majority of individuals with diabetes. The regions identified by genome-wide association studies (GWAS) have contributed little to determining causation of the disease, [36] but have contributed to our understanding of the role that genes may play in differentiating types of diabetes and its pathophysiological mechanisms. By using GWAS one can differentiate genetic code across a population, as one or more variations in the code are found more often in those with a given trait. Even small genetic variations – called single nucleotide polymorphisms (SNPs) – can have a major impact on a trait by swapping just one of the 3.2 billion “letters” that make up the human genome [37].

The genetic risk for developing T2DM appears to have a close interaction with the ecosystem, and since no changes in the human genome are expected to have taken place in the short period of time that the epidemic developed, other pathways are probably involved [38]. Epigenetic changes caused by the environment are a likely explanation for the rapid transformation in T2DM whereby it is affecting a younger population and is associated with more insulin resistance and abnormalities in lipid metabolism [39]. In T1DM, fewer genetic associations have been linked to development of the disease, and the majority are related to autoimmunity [40].

Metabolomics, the scientific study of chemical processes involving metabolites, can be used as a tool since T2DM impacts multiple metabolic pathways. Statistical chemoinformatics and metabolic physiology can contribute to a better understanding of the disease in each individual [41]. Recent research revealed that T2DM progression is marked by incomplete β-oxidation, altered amino acids, blood bile acids, and choline containing phospholipids. Identification of these markers provides an opportunity for therapeutic interventions. The use of metabolomics is slowly being implemented to better understand and treat T2DM, as well as its associated cardiometabolic disease risk [42]. Characterization of metabolic changes is key to early detection, treatment, and understanding molecular mechanisms of diabetes.

With progress in genetics and metabolomics we now have better and newer insights into the pathophysiology of diabetes as well as disease prediction. Small-molecule metabolites have an important role in biological systems and represent attractive candidates to our understanding of T2DM phenotypes. Rather than continuing to rely on glucose biomarkers for diagnosis and clinical characteristics to identify the type of diabetes, we must transition to an era where genetics and metabolomics will demystify the mechanisms of T2DM and eventually be used for better screening, diagnostics, and specific treatment.

Diseases of the Exocrine Pancreas. Pancreatic disease and/or extensive injuries to the pancreas can cause or be associated with diabetes [26]. Pancreatic adenocarcinoma is related to diabetes even when a small portion of the pancreas is involved. Other disorders such as cystic fibrosis and hemochromatosis can cause impaired β-cell function, particularly when severe [43]. Often it is difficult to assess in each individual if diabetes is caused only by the severity of pancreatic injury or disease, or by clinical, radiological, and pathological features that distinguish it from other forms of chronic pancreatitis. It affects young adults who present with abdominal pain due to pancreatic calculi, and progressive exocrine pancreatic failure resulting in malabsorption, cachexia, and diabetes. The exact etiology is unknown, but this disorder is associated with poverty and malnutrition. Diabetes develops up to a decade after the first symptoms. Microvascular complications may develop and macrovascular complications are less common. In spite of poor nutrition and lack of obesity, these individuals are insulin resistant, and may present with very high blood glucose levels, but diabetic ketoacidosis is rare [44]. It is important to recognize this disorder in industrialized countries as well, in view of the more recent global migration.

Endocrine-Related Diabetes. Endocrine-related diabetes can be found in individuals with diseases due to excessive hormone secretion such as acromegaly (growth hormone), Cushing’s (cortisol), glucagonoma (glucagon), or pheochromocytoma (epinephrine). These hormones antagonize insulin action and cause an increase in insulin requirements. Diabetes will develop in at-risk individuals with preexisting defects in insulin secretion. The rare somatostatinomas can cause hyperglycemia, mainly by inhibiting insulin secretion. In endocrine disorders the focus should be on identifying and treating the underlying disease which will alleviate the severity of hyperglycemia [3].

Uncommon Forms Associated with Immune-Mediated Disorders. Uncommon forms of immune-mediated disorders are conditions likely to cause or be associated with diabetes because of idiosyncratic autoimmune abnormalities. Antibodies have been described to affect circulating insulin and insulin receptor. Anti-insulin receptor antibodies are occasionally found in patients with systemic lupus erythematosus and other autoimmune diseases. In the past, this syndrome was termed type B insulin resistance syndrome where a highly specific autoantibody is produced against the cell surface insulin receptor blocking the normal binding of endogenous insulin and therefore causing diabetes [45]. Interestingly, similar antibodies also found in individuals with autoimmune disorders can act as insulin agonists after binding to the receptor and thereby cause hypoglycemia. In stiff-man syndrome, an autoimmune disorder of the central nervous system characterized by stiffness of the axial muscles with painful spasms, high GAD autoantibody titers are common and approximately one-third of individuals suffering from this condition can develop diabetes [46].

Toxins, medications, and viruses. Many drugs are known to impair insulin secretion and may precipitate or unmask diabetes in predisposed individuals who have underlying defects in insulin secretion. Certain toxins such as Vacor (a rat poison) and pentamidine can destroy pancreatic β-cells, and many other drugs can cause hyperglycemia by impairing insulin secretion or insulin action. In addition certain viruses have also been associated with α-cell destruction. This has been found in patients with congenital rubella, although most of these patients have HLA and immune markers characteristic of T1DM. In addition, coxsackievirus B, cytomegalovirus, adenovirus, and mumps have also been implicated in inducing the disease. Interferons, cytokines that “interfere” with viral replication and are used to activate immune cells (natural killer cells and macrophages) to increase host defenses, have been widely used during the past decade and individuals exposed to α-interferon have been reported to develop autoimmune thyroid disease, autoimmune T1DM, or both with generation of high titers of β-cell or thyroid antibody markers.

New-onset diabetes after transplantation (NODAT) is a serious and common metabolic complication after organ transplantation. It is defined as the onset of diabetes in previously nondiabetic individuals following organ transplantation, extending beyond the first month post transplantation [47]. During the past few years the occurrence has increased substantially with the highest incidence in the first 12 months following transplantation. Hyperglycemia in the first month post transplantation is referred to as transient hyperglycemia and may resolve; however, it is a predictor of NODAT [48]. Diagnosis of NODAT is based on the WHO/IDF glucose criteria, and the use of A1c alone is discouraged as it underestimates glycemia in chronic renal failure and is often complicated by the concomitant presence of anemia and iron deficiency [49].

Diagnostic Criteria

Categories of Increased Risk for Diabetes or Prediabetes

In 1997 and 2003, the Expert Committee on Diagnosis and Classification of Diabetes Mellitus recognized an intermediate group of individuals whose glucose levels do not meet criteria for diabetes, yet are higher than those considered normal [50]. These people were defined as having prediabetes. As shown in Table 2 the diagnosis can be established by impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). Individuals with IFG and/or IGT have a relatively high risk for the future development of diabetes, but should not be viewed as clinical entities in their own right but rather risk factors for diabetes. IFG and IGT are associated with other CVD risk factors such as abdominal or visceral obesity, dyslipidemia with high triglycerides and/or low HDL cholesterol, and hypertension.
Table 2

Diagnostic criteria for prediabetes and type 2 diabetes



Type 2 diabetes

Hemoglobin A1c (%)



Fasting glucose mg/dL



2-h glucose, mg/dL (after a 75 glucose challenge)



Classic symptoms + random glucose, mg/dL

Not applicable


In absence of unequivocal data, the test should be repeated for confirmation

Modified from “Standards of Medical Care in Diabetes -2015” [3]

The use of A1c levels, also a marker of CVD mortality, has helped to identify risk and determine when to initiate preventive interventions. As was the case with FPG and 2-h PG, defining a lower limit of an intermediate category of A1c is somewhat arbitrary, as the risk of diabetes with any measure or surrogate of glycemia is a continuum, extending well into the normal ranges. Prospective studies that used A1c to predict the progression to diabetes demonstrated a strong, continuous association between A1c and subsequent diabetes with an A1c of 6.0–6.5 % having a 5-year risk of developing T2DM of 25 % and 50 % and relative risk 20 times higher compared with an A1c of 5.0 % [51]. Other analyses suggest that an A1c of 5.7 % is associated with similar diabetes risk to the high-risk participants in the Diabetes Prevention Program (DPP) [52]. Hence, it is reasonable to consider an A1c range of 5.7–6.4 % as identifying individuals with high risk for future diabetes.

Asymptomatic High-Risk Individuals

Table 3 summarizes individuals that are at high risk to develop prediabetes and/or diabetes and should be tested early to establish the diagnosis and provide therapeutic interventions when necessary. Prediabetes or high risk for diabetes should not be viewed by itself as a clinical entity, rather the use of impaired glycemic control is a risk factor for both T2DM and CVD. In the rest of the chapter the term prediabetes will be used instead of “high risk for diabetes.” In T2DM, silent or asymptomatic disease is common and it is often of long duration before symptoms ensue. Diagnosis can be established by simple glycemic markers and effective interventions cannot only prevent progression of the disease – from prediabetes to diabetes – but also reduce complication risk. As shown in Table 3 individuals with high risk for diabetes are characterized by having other associated CVD risk factors such as visceral obesity, dyslipidemia (high triglycerides and/or low HDL cholesterol), and hypertension, and are more commonly found in minority ethnic/racial populations. Age remains a major risk factor and while in the past testing was recommended to begin at 45 years, with increased obesity and demographic changes it is now recommended in all adults, and particularly those with other additional risk factors. Individuals exposed to medications such as atypical antipsychotics, [53] antiretroviral agents, glucocorticoids, thiazide diuretics, beta blockers, and HMG-CoA reductase inhibitors (statins) should also be monitored and tested. Evaluation of patients at risk should always be patient centered and incorporate a global risk factor assessment for both diabetes and cardiovascular disease. Screening for and counseling about risk of diabetes should always be in the pragmatic context of cost, patient’s comorbidities, life expectancy, personal capacity to engage in lifestyle changes, early pharmacotherapy, and overall health goals.
Table 3

High risk individuals, criteria and risk factor for testing for prediabetes and diabetes

Symptomatic adults who are overweight or obese

BMI ≥ 25 Kg/m2 or BMI ≥ 23 Kg/m2 in Asian Americans


Two additional risk factors for diabetes

Children and adolescents ages 10–18 who are overweight and or obese:

BMI > 85th percentile for age and sex or

Weight for height >85th percentile or weight or

>120 % of ideal height


Two additional risk factors for diabetes

Risk Factors for Prediabetes and Diabetes

 All individuals more than 45 years old

 First degree relative with diabetes

 Member of an Ethic/Racial Minority Population

 Previous evidence of IGT or IFG


  With Previous Diagnosed of Gestational Diabetes

  Who delivered a baby weighting >9 lbs.

  With Polycystic Ovarian Syndrome

 History of Cardiovascular Disease

 Cardiovascular Risk Factors (in addition to obesity)

  Hypertension ≥140/90 mmHg or therapy for hypertension

  Dyslipidemia-elevated fasting triglycerides ≥250 mg/dl 2.82 mmol/L

  Low High Density Lipoprotein HDL-cholesterol ≤35 mg/dl 0.90 mmol/L

All glycemic markers are appropriate

Diagnosis of Diabetes Mellitus

The diagnosis of diabetes is established solely by documentation of abnormal glycemic markers. As shown in Table 2 there are four criteria used to make a diagnosis of diabetes: elevated A1c test, fasting plasma glucose, plasma glucose 2-h after a 75 g oral glucose tolerance test (OGTT), or symptoms of diabetes with a random plasma glucose > 200 mg/dl. Advantages to using the A1c test include greater convenience as it can be done nonfasting at any time. Further, A1C reflects glycemic exposure over time with less variability than glucose determinations; it is less affected by acute illnesses, it has a greater preanalytical stability and has been standardized. Another reason to obtain an A1c determination is that it became the gold standard [52] for complications and represents a marker not only for microvascular complications but also for CVD and mortality [54]. These advantages must be balanced by the fact that the results may not have a good correlation to the average glucose in certain individuals, as it can be affected by alteration in red cell turnover and hemoglobinopathies. Other disadvantages are a greater cost and limited availability in certain regions of the developing world. Point-of-care assays, while convenient, are not as reliable since proficiency testing is not mandated for performing the test, and therefore POC assays are not recommended for diagnostic purposes. In addition to hemoglobinopathies and/or anemia, other factors such as age, race, or ethnicity also need to be taken into consideration when interpreting the A1c values [3].

Glucose tolerance tests are performed by providing either 75 or 100 g of glucose. This test, although more sensitive and specific than fasting glucose alone, is lengthy and cumbersome. Testing should be done in the morning after an overnight fast and at least 3 days of unrestricted diet, rich in carbohydrates. The subject should remain seated throughout the test and should not be permitted to smoke. Two or more values must be met or exceeded for a diagnosis. Glycemic values vary greatly, and the degree of hyperglycemia or glucose intolerance can improve or worsen according to changes in body weight, food intake, physical activity, stress, pregnancy, use of corticosteroids, or other medications. Performing OGTT is costly, needs to be done under controlled conditions, takes a long period of time, and more and more is used for research studies and less for clinical practice. While plasma glucose concentrations are distributed over a continuum, the threshold of a fasting plasma glucose (FPG) of 126 mg/dl has been used for diagnosis based on adverse outcomes related to microvascular complications. The concordance between the FPG and 2-h PG tests is imperfect as is the concordance between the A1c and either glucose-based test. NHANES data indicate that an A1c cut point of 6.5 % identifies one-third fewer cases of undiagnosed diabetes than a fasting glucose cut point of 126 mg/day. Compared with A1c and FPG cut points, the 2-h PG value diagnoses more people with diabetes. To establish the diagnosis, each value must be confirmed on a subsequent day by any one of the three criteria given. The FPG test criteria result in a lower prevalence of diabetes than OGTT (4.35 % vs. 6.34 %) in individuals without a medical history of diabetes. However, a widespread adoption of OGTT may have a large impact on the number of people diagnosed with diabetes. This is important since presently, a large population of adults with diabetes in the United States remains undiagnosed [55].

In the early stages, particularly in T2DM, the degree of hyperglycemia is sufficient to cause pathological changes, but it is not enough to cause clinical symptoms. Thus, a silent phase of the disease can exist for prolonged periods of time before it is diagnosed. Typically the disease progresses from prediabetes to overt T2DM. Undiagnosed T2DM is common in the United States. The Diabetes Prevention Program Research Group has shown the importance of early detection and lifestyle intervention to prevent future progression to overt diabetes [56]. In order to increase the cost-effectiveness of diagnosing otherwise healthy individuals, testing should be considered in high-risk populations. Measuring A1c is now the preferred screening test for clinical settings as it is easier and more acceptable to patients. Testing needs to be practical and cost effective and both OGTT and FPG are also suitable tests. With the availability of current tests, particularly A1c determinations, the diagnosis of both prediabetes and diabetes can be easily established; the emphasis however needs to be shifted in how the diagnosis is used for intervention and improving outcomes.

Diabetes in Pregnancy and Gestational Diabetes Mellitus (GDM)

Diabetes in pregnancy can be found in individuals with established T1DM or T2DM. Gestational diabetes mellitus (GDM) is diabetes diagnosed in the second or third trimester of pregnancy that is not clearly overt diabetes. The definition is independent of treatment use or whether or not it persists after pregnancy. Ideally evaluation should be performed before conception in all women, otherwise risk assessment for GDM should be undertaken at the first prenatal visit. It is likely that unrecognized prediabetes or T2DM may have antedated or begun concomitantly with pregnancy, a common finding particularly in minority populations.

The prevalence of GDM varies in direct proportion to the prevalence of T2DM, principally among different ethnic groups. Because of the ongoing epidemic of obesity and diabetes, more women of childbearing age may present with either diagnosed or undiagnosed T2DM in pregnancy [3]. It is therefore reasonable to test women with risk factors for T2DM at their initial prenatal visit, using standard diagnostic criteria. Different from previous recommendations, overt diabetes prior to conception or diabetes in the first trimester should now be classified as T2DM and not GDM, a diagnosis term that remains specific for those diagnosed in the second or third trimester of pregnancy.

Gestational diabetes complicates $4 % of all pregnancies in the USA, but the true prevalence may range from 1 % to 14 % depending on the population studied [57]. Evaluation for GDM should be done early in pregnancy in women with risk factors shown in Table 4. If no diabetes is found at the initial screening, retesting should be repeated between 24 and 28 weeks of gestation.
Table 4

Recommendations for Gestational Diabetes Mellitus (GDM)

Test for T2DM in the first prenatal visit in those at risk

Test for GDM at 24–28 weeks of gestation in all

Woman with previous GDM are considered as having high risk for T2DM

  Need to be tested for T2DM at 6–12 weeks postpartum if negative, repeat every 3 years or earlier

  Consider providing lifestyle interventions and metformin therapy

Screening and diagnosing GDM One-Step Strategy

OGTT with 75 g at 24–28 weeks of pregnancy

Diagnosis when any plasma glucose values meet or exceed the following values:







1 h



2 h



Screening and diagnosing GDM Two-Step Strategy

50 g (random –non-fast) challenge at first gestational visit in high risk, or at 24–28 weeks

If 1 h post –challenge glucose ≥140 mg/dL (7.8 mmol/L) proceed to a OGTTa with 100-g of oral glucose

Diagnosis if at least two plasma glucose levels meet or exceed the following values:







1 h



2 h



3 h



aAmerican College of Obstetrics and Gynecology recommend a threshold of 135 mg/dl (7.5 mmol/L) in high risk individuals. Some recommend 130 mg/dL (7.2 mmol/L)

TDM Type 2 diabetes mellitus, OGTT Oral glucose tolerance test

All glycemic markers are appropriate

Early screening and diagnosis is crucial as proper monitoring and initiation of therapy reduces perinatal morbidity and mortality. There is consensus that overt diabetes, whether symptomatic or not, is associated with significant risk of adverse perinatal outcome [58]. The risk of adverse perinatal outcome associated with degrees of hyperglycemia appears to be less severe than the one found in overt T2DM. In general there are adverse outcomes associated with GDM, such as birth weight that is large for gestational age, excess fetal adiposity, and higher rate of cesarean section. However these are confounding characteristics that may be caused by obesity, more advanced maternal age, or other medical complications, rather than glucose intolerance. The relationship between high blood sugar levels and poor maternal and fetal outcomes was studied in normal (nongestational diabetes) pregnant women in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study [59]. In this study a direct correlation between fetal complications was found with a continuum between the degree of blood sugar levels and complications. Thus, hyperglycemia is an important marker of outcomes but controversy remains on the cost-effectiveness of diagnosis and the impact that treatment may have.

The most updated recommendations regarding testing for diabetes during pregnancy include screening high-risk patients for T2DM at the first prenatal visit. In those individuals not deemed to be high risk, screening should be done at 24–28 weeks gestation using either the one-step or two-step strategy. These methods and criteria for diagnosis are outlined in Table 4.

There are two approaches: a one-step and a two-step approach. Since 2011 Standards of Care, the ADA for the first time recommended that all pregnant women not known to have prior diabetes undergo a 75-g OGTT at 24–28 weeks of gestation, based on a recommendation of the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) [60]. In 2013 the NIH convened a panel of experts who recommended instead a two-step strategy [61], consisting of a 1-h 50-g glucose load test (nonfasting) followed by a screening plasma glucose measurement after 1 h. If the plasma glucose level measured 1 h after the load is 140 mg/dL, this should be followed by a diagnostic 3-h 100-g OGTT. When the diagnostic OGTT is employed, approximately 80 % of women with GDM are identified with a threshold value of 140 mg/dl. Ninety percent of women with GDM are identified when a cutoff of 130 mg/dl is used. The diagnosis of GDM is made with a 100-g OGTT using the criteria derived from the original work of O’Sullivan and Mahan, modified by Carpenter and Coustan as shown in Table 4. If found not to have GDM at the initial screening, women should be retested between 24 and 28 weeks of gestation, as is the recommendation for women of average risk. There are no available analyses to determine what strategy is best, the use of either method should be determined based on cost effectiveness and practicality.

Women with GDM need to be evaluated after delivery, as they may have antecedent diabetes diagnosed at the time of pregnancy. It is good medical practice to study the patient 6 weeks or more postpartum in order to classify them as normal, high risk for developing diabetes, or overt diabetes. Even with a negative postpartum test these patients need further monitoring as they remain at an increased risk of developing T2DM and cardiovascular disease.


Diabetes mellitus is a heterogeneous and complex metabolic disorder characterized by hyperglycemia and complications of premature cardiovascular disease and small vessel disease causing renal failure, eye disease, and neuropathy. The incidence of T1DM has slightly trended upward; on the other hand T2DM that is closely associated with obesity and insulin resistance has increased dramatically in prevalence and incidence globally and mainly in industrialized urban developed societies. This trend however appears to be slowing down. Diabetes affects a disproportionate number of minority populations and is associated with other cardiovascular risk factors. When not treated, it can result in premature cardiovascular morbidity and mortality. The classification and diagnosis criteria are continually revised to reflect current knowledge of the disease and the classification is now based on disease etiology. Screening and diagnosis has become easier, and less people live with undiagnosed disease. Both diagnosis and therapeutic management continue to be based on glycemic markers. There is great hope that with advances in genetics and metabolomics, better and more defined tests for diagnosis and management will be available. Currently, there is a well-established set of criteria to screen the high-risk population, allowing for an earlier diagnosis that should facilitate an earlier and more aggressive patient-centered intervention to prevent future complications.


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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Division of Endocrinology and Metabolism, Department of MedicineMontefiore Medical Center and Albert Einstein College of MedicineBronxUSA

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