Page 992 - Clinical Immunology_ Principles and Practice ( PDFDrive )

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Type 1 Diabetes

Leonard C. Harrison

Diabetes is not a single disease but a metabolic syndrome in be diagnosed clinically. However, in Caucasians, the diagnosis
which different mechanisms lead to deficiency of insulin and/ can be confirmed and in older individuals and less clear-cut cases
or impaired insulin action and persistent hyperglycemia. The may be clearly established by detecting circulating autoantibodies
American Diabetes Association classified diabetes into four cat- to islet antigens. These autoantibodies to insulin (IAAs), glutamic
egories based on etiology rather than age of onset (juvenile-onset acid decarboxylase 65 000 mol. wt. isoform (GADA), insulinoma-
versus adult-onset) or requirement for insulin therapy (insulin- like antigen-2 (IA-2A), and zinc transporter-8 (ZTA) are markers
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dependent versus noninsulin-dependent). The vast majority of of β-cell autoimmunity that appear many months to years before
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cases, approximately 10% and 90%, respectively, are attributed to symptoms and therefore denote high risk for clinical disease.
type 1 and type 2 diabetes. This chapter focuses mainly on type They are present in at least 90% of Caucasian children with
1 diabetes, which results from an absolute deficiency of insulin T1DA (compared with ≈1% of the background population)
secondary to the loss of pancreatic β cells. Type 1 diabetes is but in only ≈50% of Hispanic American and African American
classified as 1A (immune-mediated) or 1B (idiopathic), primarily children, an increasing number of whom have T2D and, in some
depending on the presence or absence, respectively, of pancreatic cases, T1DB. Negative results for islet autoantibodies in children
islet autoantibodies. However, as discussed below, type 1A diabetes with diabetes should also alert to the possibility of monogenic
(T1DA) and type 1B diabetes (T1DB) also differ in their natural maturity-onset diabetes of the young (MODY) and sulfonylurea
history and clinical features. receptor syndromes.
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Diabetes is diagnosed on the basis of the following criteria : The hallmark of T1DA is progression to absolute insulin
symptoms in association with a casual plasma glucose ≥200 mg/dL deficiency within several years after diagnosis. The connecting
(11.1 mmol/L) OR fasting plasma glucose ≥126 mg/dL (7.0 mmol/L) peptide in proinsulin (C-peptide) is secreted in an equimolar
OR 2-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) in an oral ratio to insulin and is used as a surrogate for insulin to evalu-
glucose tolerance test (OGTT; 75 g glucose in water). Without ate residual β-cell function in the face of exogenous insulin or
symptoms, the diagnosis of diabetes must rest on confirmation IAAs, or insulin antibodies induced by exogenous insulin. The
of a raised plasma glucose concentration. A further diagnostic plasma C-peptide in response to a mixed meal tolerance test is
criterion introduced by the World Health Organization (WHO) the gold standard. Although children with T1DA have lost most
in 2011, in particular for the diagnosis of type 2 diabetes, is a of their β-cell function at diagnosis, the measurement of plasma
confirmed blood glycated hemoglobin (HbA 1c ) ≥48 mmol/mol C-peptide is not a reliable way of distinguishing T1D, especially
(6.5%). Because HbA 1c is an integrated measure of glycemia over at diagnosis. Hyperglycemia impairs β-cell function, and when
many weeks, it is not suitable for diagnosing children or in the corrected by rehydration and insulin replacement, it may be
following circumstances: suspected type 1 diabetes; symptoms of followed by a “honeymoon phase” of partial recovery of β-cell
diabetes for <2 months; acute illness; medication that may increase function and a decreased requirement for exogenous insulin that
blood glucose (e.g., steroids, antipsychotics); and pregnancy. The may last many months. By several years after diagnosis, most
criteria for diagnosing gestational diabetes are stricter: fasting young children display little residual β-cell function; however,
plasma glucose ≥101 mg/dL (5.6 mmol/L) or 2-hour plasma in older children and adults, residual C-peptide secretion has
glucose in an OGTT ≥140 mg/dL (7.8 mmol/L). been observed for many years and is believed to be associated
The classic symptoms and signs of T1DA, because of high with better glycemic control.
concentrations of blood glucose, are polyuria, polydipsia, and Classically, T1DA was considered a disease of “juvenile onset”
unexplained weight loss; others include fatigue, increased hunger, in normal-weight individuals in contrast to type 2 diabetes with
impaired visual acuity as a result of changes in the refractive index onset in middle-aged, overweight individuals. However, this view
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of vitreous humor, tingling or numbness in the hands or feet requires reappraisal. First, 5–10% of adults who present with
resulting from sensory nerve changes, and vaginal irritation caused diabetes diagnosed initially as T2D and are typically overweight,
by Candida infection. If diabetes is undiagnosed or untreated, have evidence of low-grade islet autoimmunity manifest by the
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failure to metabolize glucose will result in the breakdown of fat, presence of GADAb, and occasionally IA-2Ab or ZTAb. If we
leading to ketonemia and ketoacidosis, which may be accompanied accept that they have a slowly progressive form of autoimmune
by nausea and hyperventilation before life-threatening ketoacidotic β-cell destruction, that was termed latent autoimmune diabetes
coma. In children presenting with the classic symptoms, T1D can in adults (LADA), their number doubles the prevalence of T1DA.

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