Medical Management of Type 1 Diabetes, 8th Edition

Diagnosis and Classification/Pathogenesis

Highlights

Diagnosis and Classification

Criteria for Diagnosis

Distinguishing Type 1 Diabetes from Other Forms

Conclusion

Clinical Presentation of Type 1 Diabetes

Clinical Onset of Diabetes Symptoms and Metabolic Decompensation

Remission or Honeymoon Phase

Pathogenesis

Pathophysiology of the Clinical Onset of Type 1 Diabetes

Stages in the Development of Type 1 Diabetes

Genetics of Type 1 Diabetes

Conclusion

Highlights:

Diagnosis and Classification/Pathogenesis

DIAGNOSIS AND CLASSIFICATION

Diabetes encompasses a wide clinical spectrum, but in general can be divided into four categories:

Type 1 diabetes (due to autoimmune ß-cell destruction, usually leading to absolute insulin deficiency)

Type 2 diabetes (due to a progressive loss of adequate ß-cell insulin secretion frequently on the background of insulin resistance)

Gestational diabetes mellitus (diabetes diagnosed in the second or third trimester of pregnancy that was not clearly overt diabetes prior to gestation)

Specific types of diabetes due to other causes, e.g., monogenic diabetes syndromes (such as neonatal diabetes and maturity-onset diabetes of the young), diseases of the exocrine pancreas (such as cystic fibrosis and pancreatitis), and drug-or chemical-induced diabetes (such as with glucocorticoid use, in the treatment of HIV/AIDS, or after organ transplantation)

The criteria for diagnosing diabetes include:

fasting plasma glucose concentration ≥126 mg/dL (7.0 mmol/L),

2-h glucose after a 75-g oral glucose tolerance test (OGTT) ≥200 mg/dL (11.1 mmol/L),

hemoglobin A1c (A1C) ≥6.5%, or

random plasma glucose level ≥200 mg/dL (11.1 mmol/L) in the presence of classic signs and/or symptoms of diabetes (polyuria, polydipsia, unexplained weight loss, hyperglycemic crisis).

Unless there is a clear clinical diagnosis (meeting final criterion above), a second test is required to confirm the diagnosis of diabetes.

Type 1 diabetes often presents with symptoms or DKA. However, studies that follow relatives of those with type 1 diabetes, or birth cohorts with genetic risk markers, have been able to detect type 1 diabetes at an earlier stage, such as through an OGTT.

Type 1 diabetes accounts for 5–10% of all cases of diabetes in the developed world. The term juvenile-onset diabetes is a misnomer, as type 1 diabetes can develop at any age. Some estimates are that more than half of cases have onset after age 18 years.

Type 1 diabetes and type 2 diabetes are heterogeneous diseases in which clinical presentation and disease progression may vary considerably.

Classification is important for determining therapy, but some individuals cannot be clearly classified as having type 1 or type 2 diabetes at the time of diagnosis.

The traditional paradigms of type 2 diabetes occurring only in adults and type 1 diabetes only in children are no longer accurate, as both diseases occur in both cohorts.

Overweight and obesity have historically been associated with type 2 diabetes, but the rise in rates of obesity in children and adults has confounded older paradigms that incident type 1 diabetes is associated with normal or low body weight.

Occasionally, people with type 2 diabetes may present with diabetic ketoacidosis (DKA), but later require no or only intermittent insulin treatment. Commonly referred to as ketosis-prone diabetes mellitus, this occurs mainly in Black individuals with obesity and a strong family history of diabetes, negative autoimmune markers, and lack of genetic association with human leukocyte antigen (HLA) markers.

The routinely available laboratory tests that help differentiate between the type 1 and type 2 diabetes are serum C-peptide and autoantibodies to islet cell components; however, even these tests can be problematic.

Almost all people with long-standing type 1 diabetes will have C-peptide values below the lower limit of normal, but at diagnosis C-peptide may be in the normal range while there is still a viable ß-cell mass.

Approximately 15% of people with clinical type 1 diabetes do not have autoantibodies at the time of diagnosis; conversely, 6–10% of those with clinical type 2 diabetes do have autoantibodies.

Absent availability of measurement of autoantibodies or C-peptide, clinicians should base treatment on clinical characteristics and the ability to follow the person closely. Insulin should be the default treatment in most unclear cases.

Difficulties in distinguishing diabetes type may occur in all age groups at onset, but the true diagnosis usually becomes more obvious over time.

Several forms of diabetes are associated with monogenetic defects in ß-cell function. These include neonatal diabetes and what was formerly referred to as maturity-onset diabetes of the young (MODY).

Neonatal diabetes is a rare form of diabetes that occurs in the first 6 months of life. About 80% of cases have a monogenic cause. Low birth weight and developmental syndromes often co-exist with neonatal diabetes. Clinically, neonatal diabetes can either be transient or permanent.

Given the increased incidence of type 2 diabetes in youth, MODY now refers more specifically to monogenic diabetes inherited in an autosomal dominant pattern. People with MODY are commonly misdiagnosed as having type 1 or type 2 diabetes.

MODY is characterized by mild hyperglycemia at an early age (typically under age 25), an autosomal dominant pattern of inheritance, no evidence of autoimmunity, and no signs of insulin resistance barring co-existing obesity.

CLINICAL PRESENTATION OF TYPE 1 DIABETES

The presentation of type 1 diabetes covers a broad range, from mild, nonspecific symptoms or no symptoms to coma from severe DKA.

In children, the correct diagnosis is often delayed because the presenting symptoms are ascribed to another process.

In the U.S. approximately one-third of children with type 1 diabetes present in DKA. This is more common in younger children, those without private health insurance, African American children, and those with no family history of type 1 diabetes. There is some evidence that rates DKA at the time of presentation are increasing in children.

In adults, the presentation is often less acute, and may even be quite indolent, although an absolute requirement for insulin becomes evident with time.

When ongoing autoimmune destruction has reduced ß-cell mass by 80–90%, insulin secretory capacity becomes insufficient to normally regulate glucose metabolism.

Initially, only postprandial hyperglycemia occurs, but as insulin secretion is further compromised, progressive fasting hyperglycemia occurs.

When the plasma glucose concentration exceeds the renal threshold of ~180 mg/dL (10.0 mmol/L), glucosuria results in an osmotic diuresis, generating the classic symptoms of polyuria and a compensatory polydipsia.

If untreated, the symptoms usually progress to include weight loss, dehydration, ketonemia, and frank DKA.

After the correction of metabolic derangements at the time of diagnosis, endogenous insulin secretion may improve from the residual ß-cell population and exogenous insulin requirements may decrease dramatically.

During the remission or ‘honeymoon period,’ good metabolic control may be easily achieved with less intensive insulin therapy. The need for increasing exogenous insulin replacement is inevitable and should always be anticipated.

Preservation of C-peptide reserve is associated with less glycemic variability, lower A1C, and fewer chronic complications over time, but whether this is causal or just an association is still unclear.

PATHOGENESIS

Type 1 diabetes results from an interplay of genetic, immunological, and environmental factors leading to progressive autoimmune destruction of ß-cells.

Longitudinal studies of relatives of people with type 1 diabetes or of birth cohorts of children with high-risk HLA types have demonstrated that risk of development of type 1 diabetes can be quantified, and that the rate of progression to symptomatic disease can be predicted with reasonable accuracy. This has led to a consensus that type 1 diabetes can be divided into distinct stages, during which the progressive pathophysiology can be examined:

Stage 1: Presence of two or more type 1 diabetes-associated auto-antibodies, with fasting and stimulated glucose levels in the normal range;

Stage 2: Two or more autoantibodies with hyperglycemia below values diagnostic of diabetes (impaired fasting glucose and/or impaired glucose tolerance);

Stage 3: Hyperglycemia consistent with diabetes accompanied by typical symptoms and signs of hyperglycemia with or without ketosis.

Genetics play a key role in risk for type 1 diabetes. Family history of type 1 diabetes markedly increases risk in relatives, but 85–90% of people presenting with type 1 diabetes have no family history of the disease.

Predisposition is inherited as a heterogeneous polygenic trait with low penetrance. Alleles in the Class II HLA region on chromosome 6 account for 30–60% of genetic risk, with some alleles conferring risk and others associated with protection.

At least 60 non-HLA genes or loci are involved in genetic risk of type 1 diabetes.

Incomplete concordance for type 1 diabetes between identical twins suggests that epigenetic and/or environmental factors play a role in pathogenesis.

Numerous environmental influences have been examined, including viral infection, early life diet, infant gut microbiome, seasonality, and vitamin D pathway constituents. As yet, there is little direct evidence to link any specific factor(s) to triggering autoimmune destruction of the ß-cells in type 1 diabetes in humans.

Although autoantibodies are key markers for type 1 diabetes, the final common pathway for insulitis and destruction of ß-cells is cell-mediated immunity.

ß-cell antigens are presented by MHC complexes I and II on antigen-presenting cells (APCs) to autoreactive CD4 T-cells, which stimulate CD8 + T-cells to attack ß-cells.

In addition to direct cytotoxicity, the release of cytokines also stimulates macrophages and other immune cells to further damage ß-cells, potentially triggering a positive feedback loop with further release of ß-cell antigens.

Increasing knowledge of the pathophysiology of type 1 diabetes has led to multiple clinical trials of interventions to prevent clinical disease or to preserve C-peptide in individuals with new-onset disease. Although most results have been discouraging, a trial of the anti-CD3 antibody teplizumab showed significant preservation of C-peptide in children and adults in Stage 2 of type 1 diabetes.

Section 1 – Diagnosis and Classification/Pathogenesis

1B – DIAGNOSIS AND CLASSIFICATION

Diabetes is a chronic disorder that is 1) characterized by hyperglycemia; 2) associated with major abnormalities in carbohydrate, fat, and protein metabolism; and 3) accompanied by a propensity to develop relatively specific forms of renal, ocular, neurologic, and premature cardiovascular diseases. Diabetes encompasses a wide clinical spectrum, but in general can be divided into four categories,¹:

    1.  Type 1 diabetes (due to autoimmune ß-cell destruction, usually leading to absolute insulin deficiency)

    2.  Type 2 diabetes (due to a progressive loss of adequate ß-cell insulin secretion frequently on the background of insulin resistance)

    3.  Gestational diabetes mellitus (diabetes diagnosed in the second or third trimester of pregnancy that was not clearly overt diabetes prior to gestation)

    4.  Specific types of diabetes due to other causes, e.g., monogenic diabetes syndromes (such as neonatal diabetes and maturity-onset diabetes of the young), diseases of the exocrine pancreas (such as cystic fibrosis and pancreatitis), and drug- or chemical-induced diabetes (such as with gluco-corticoid use, in the treatment of HIV/AIDS, or after organ transplantation)

Although type 1 diabetes accounts for ~5–10% of all diagnosed cases of diabetes, its immediate risks and stringent acute treatment requirements demand rapid recognition, early diagnosis, and effective management. This chapter explores characteristics that differentiate type 1 diabetes from other forms of diabetes, discusses criteria for diagnosis, and illustrates various clinical presentations.

CRITERIA FOR DIAGNOSIS

The criteria for diagnosing diabetes, shown in Table 1b.1,¹ include : 1) fasting plasma glucose concentration ≥126 mg/dL (7.0 mmol/L), 2) 2-h glucose after a 75-g oral glucose tolerance test (OGTT) ≥200 mg/dL(11.1 mmol/L), 3) hemoglobin A1c (A1C) ≥6.5%, or 4) random plasma glucose level ≥200 mg/dL (11.1 mmol/L) in the presence of classic signs and/or symptoms of diabetes including polyuria, polydipsia, and unexplained weight loss, or hyperglycemic crisis. Unless there is a clear clinical diagnosis (meeting criterion number 4), a second test is required to confirm the diagnosis of diabetes.

The clinical signs and/or symptoms that accompany diabetes are due to persistent hyperglycemia and include polyuria, polydipsia, fatigue, polyphagia, weight loss, and blurred vision. If there is ketosis or ketoacidosis, then abdominal pain, vomiting, dehydration, and/or altered level of consciousness can occur. In the young child or infant, these signs or symptoms are frequently missed, or ascribed to other illnesses, until the child presents significantly ill with ketoacidosis.

An elevated A1C confirms the presence of significant preexisting hyperglycemia (barring the presence of a hemoglobin variant). Prediabetes (previously known as impaired glucose tolerance or impaired fasting glucose), as distinguished from diabetes, refers to abnormal plasma glucose values that do not meet the established criteria to diagnose diabetes. Screening for prediabetes is generally reserved for those with risk factors for type 2 diabetes; however, prediabetes may be seen prior to the onset of type 1 diabetes due to autoimmune destruction of the ß-cell mass.² This has been observed in the context of research protocols in which high-risk relatives undergo screening and close follow-up,³,⁴ or in birth cohorts screened for high-risk HLA types.⁵,⁶ As clinical type 1 diabetes is preceded by an asymptomatic phase that can be identified by serum islet autoantibodies, the possibility of broader screening of islet autoantiboidies as biomarkers of impending type 1 diabetes has been proposed. Additionally, stages of type 1, beginning before the point of traditional clinical diagnosis, have been defined.²

DISTINGUISHING TYPE 1 DIABETES FROM OTHER FORMS

Type 1 Diabetes

Although previously called juvenile-onset diabetes, type 1 diabetes can develop at any age,⁷ with some estimating that more than 50% of cases have onset after age 18 years.⁸ Because people with type 1 diabetes are insulinopenic, insulin therapy is essential to prevent rapid and severe dehydration, catabolism, ketoacidosis, and death. People diagnosed with symptoms are often lean and have experienced significant weight loss, polyuria, polydipsia, and fatigue before presentation. However, the secular trend of increasing obesity among adults and children can make differentiation of diabetes type at onset more difficult. At presentation, there is often significant elevation of A1C levels, providing evidence of weeks, if not months, of hyperglycemia. In addition, 85–90% have circulating autoantibodies directed against one or more islet cell components (islet cell autoantibodies—typically multiple autoantibodies, autoantibodies to insulin [IAA], GAD [also called GAD65 or GADA], tyrosine phosphatases IA-2A [ICA512] and IA-2B, and zinc transporter 8 [ZnT8]).²,⁹ C-peptide levels, which typically fall to undetectable levels over time, may be in the low normal range at diagnosis. Adults with more latent-onset type 1 diabetes may have normal C-peptide levels initially. Profound insulinopenia eventually occurs in most people.

Type 2 Diabetes

People with type 2 diabetes are less likely to develop ketoacidosis unless severely stressed physiologically, are generally but not always obese, may be asymptomatic or only mildly symptomatic, and usually have a family history of type 2 diabetes. Once referred to as adult-onset diabetes, type 2 diabetes generally presents after age 30, with incidence increasing through the seventh decade of age.¹⁰ However, due to increased rates of childhood obesity in recent decades, an increasing number of obese adolescents and young adults have been developing type 2 diabetes, especially among African Americans, American Indians/Native Alaskans, Hispanics, and Asian/ Pacific Islanders.¹¹ The discrimination between type 2 and type 1 diabetes is becoming increasingly difficult, as people with a type 2 phenotype may present in ketoacidosis but later become insulin-independent.¹² Conversely, increasing numbers of people with type 1 diabetes are overweight or obese at the time of presentation, and type 1 diabetes may have a relatively indolent onset in adults.

People with type 2 diabetes are not absolutely dependent on exogenous insulin for survival, although insulin therapy is often used to lower blood glucose levels, since there appears to be progressive ß-cell failure in type 2 diabetes as well. The development of type 2 diabetes in youth has significant public health consequences. The TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) Study demonstrated that type 2 diabetes may have a much more aggressive course in youth,¹³ with early and rapid deterioration of ß-cell function and faster progression to diabetes complications.¹⁴

Distinguishing among types of diabetes

Type 1 diabetes and type 2 diabetes are heterogeneous diseases in which clinical presentation and disease progression may vary considerably. Classification is important for determining therapy, but some individuals cannot be clearly classified as having type 1 or type 2 diabetes at the time of diagnosis. The traditional paradigms of type 2 diabetes occurring only in adults and type 1 diabetes only in children are no longer accurate, as both diseases occur in both cohorts. Occasionally, people with type 2 diabetes may present with diabetic ketoacidosis (DKA), but later require no or only intermittent insulin treatment. Commonly referred to as idiopathic type 1 diabetes or ketosis-prone diabetes mellitus, this occurs mainly in Black individuals with obesity and a strong family history of diabetes, negative autoimmune markers, and lack of genetic association with human leukocyte antigen (HLA) markers. At presentation, they have markedly impaired insulin secretion, but intensified diabetes management results in significant improvement in ß-cell function and eventual discontinuation of insulin therapy in many cases.

Children with type 1 diabetes typically present with the hallmark symptoms of polyuria/polydipsia and approximately one-third with DKA. The onset of type 1 diabetes is more variable in adults, with some presenting with classic symptoms or DKA and others having more indolent onset and months or even years of insulin independence, so called latent autoimmune diabetes of adults (LADA). Studies suggest that genes associated with type 1 and type 2 diabetes coexist in these people. It remains unclear whether LADA is 1) a late manifestation of type 1 diabetes, 2) an amalgamation of type 1 and type 2 diabetes, or 3) a completely separate and distinct form of diabetes.¹⁵

The routinely available laboratory tests that help differentiate between the type 1 and type 2 diabetes are serum C-peptide levels and measurements of autoantibodies to islet cell components; however, even these tests can be problematic. Although almost all people with long-standing type 1 diabetes will have C-peptide values below the lower limit of normal for that assay method, at diagnosis C-peptide may be in the normal range while there is still a viable ß-cell mass.²,⁹ Approximately 15% of people with clinical type 1 diabetes do not have autoantibodies at the time of diagnosis, so-called idiopathic type 1 diabetes.¹ Conversely, 6–10% of those with clinical type 2 diabetes do have autoantibodies. Absent availability of measurement of autoantibodies or C-peptide, clinicians should base treatment on clinical characteristics and the ability to follow the person closely. Insulin should be the default treatment in most unclear cases. Although difficulties in distinguishing diabetes type may occur in all age groups at onset, the true diagnosis usually becomes more obvious over time.

People with secondary and other types of diabetes have certain associated conditions or syndromes, such as endocrinopathies, diseases or surgery of the exocrine pancreas, use of medications such as glucocorticoids, or post-transplant diabetes.¹ Monogenic forms of diabetes are discussed more fully in the next section.

Women with gestational diabetes mellitus have onset or discovery of glucose intolerance during the second or third trimester of pregnancy, whereas women diagnosed with diabetes during the first trimester of pregnancy are classified as having preexisting undiagnosed diabetes (usually type 2).¹

Monogenic forms of diabetes

Several forms of diabetes are associated with monogenetic defects in ß-cell function. These include neonatal diabetes and what was formerly referred to as maturity-onset diabetes of the young (MODY). Given the increased incidence of type 2 diabetes in youth, MODY now refers more specifically to monogenic diabetes inherited in an autosomal dominant pattern. People with MODY are commonly misdiagnosed as having type 1 or type 2 diabetes.

Neonatal diabetes¹ is a rare form of diabetes that occurs in the first 6 months of life. About 80% of cases have a monogenic cause. Low birth weight and developmental syndromes often co-exist with neonatal diabetes. Clinically, neonatal diabetes can either be transient or permanent. Transient neonatal diabetes usually remits by a few months of age, but recurs in about 50% of cases, usually in adolescence or adulthood. Permanent neonatal diabetes most commonly results from mutations to one of the two subunits of the ATP-sensitive potassium channel of the ß-cell: 1) KCNJ11, which encodes Kir6.2 (inwardly rectifying potassium channel) or 2) ABCC8, which encodes SUR1 (the type 1 subunit of the sulfonylurea receptor, a member to the ATP-binding cassette transporter family). Correct diagnosis has important clinical implications, since neonatal diabetes due to potassium channel mutations can be treated with oral sulfonylureas. Mutations involving other genes including INS (encoding the preproinsulin molecule) can also lead to permanent neonatal diabetes. Table 1b.2¹ provides more detail about the genetics and clinical characteristics of neonatal diabetes syndromes.

MODY¹ is characterized by mild hyperglycemia at an early age (typically under age 25) with an autosomal dominant pattern of inheritance, no evidence of autoimmunity, and no signs of insulin resistance barring co-existing obesity. At least 13 MODY gene defects have been identified to date. The most common are in glucokinase (GCK-MODY), HNF1A (HNF1A-MODY) and HNF4A (HNF4A-MODY). Diagnosing the gene abnormality has important clinical implications. GCK-MODY's mild hyperglycemia is not associated with development of diabetes complications and does not require therapy, outside of pregnancy. HNF1A- and HNF4A-MODY respond well to sulfonylurea therapy. Diagnosis of MODY is important for other family members, and genetic testing of people with youth-onset diabetes has been shown to be cost-effective.¹⁶ Table 1b.2 provides more detail about the genetics and clinical characteristics of the most common forms of MODY.

Point mutations in mitochondrial DNA have been found to be associated with diabetes and deafness. In Wolfram Syndrome (referred to as DIDMOAD), diabetes and deafness are also associated with diabetes insipidus and optic atrophy. There are also unusual causes of diabetes that result from genetically determined abnormalities of insulin action. 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. The former has characteristic facial features and is usually fatal in infancy, whereas the latter is associated with abnormalities of teeth and nails and pineal gland hyperplasia.

CONCLUSION

People with type 1 diabetes are dependent on insulin for as long as they live. Any lean individual with typical signs and symptoms of hyperglycemia accompanied by weight loss should be assumed to have type 1 diabetes. A high index of suspicion is needed to diagnose diabetes in very young children. In older youth (particularly obese teens at risk for type 2 diabetes due to race or ethnicity) and in adults, distinguishing type 1 from type 2 diabetes may be difficult initially.

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1C – CLINICAL PRESENTATION OF TYPE 1 DIABETES

The presentation of type 1