Porth's Essentials of Pathophysiology, 4e

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Diabetes Mellitus and the Metabolic Syndrome

C h a p t e r 3 3

TABLE 33-3 Normal and Increased Fasting Plasma Glucose (FPG), Oral GlucoseToleranceTest (OGTT), and Hemoglobin A 1c (A1C) for Categories of Increased Risk for Diabetes and Criteria for Diagnosis of Diabetes

Categories of Increased Risk for Diabetes* Impaired fasting glucose (IFG)100 mg/dL (5.6 mmol/L) to125 mg/dL (6.9 mmol/L) Impaired glucose tolerance (IGT)140 mg/dL (7.8 mmol/L) to199 mg/dL (11.0 mmol/L)

Criteria for Diagnosis of Diabetes † ≥ 126 mg/dL (7.0 mmol/L) or

Test

Normoglycemia

FPG ‡

<100 mg/dL(5.6 mmol/L)

≥ 200 mg/dL (11.1 mmol/L) or

2-h plasma glucose in 75-g OGTT

<140 mg/dL(7.8 mmol/L)

≥ 6.5% or

A1C §

3.9%–5.6%

5.7%–6.4%

Other

Classic symptoms of hyperglycemia or

hyperglycemic crisis and a plasma glucose ≥ 200 mg/dL (11.1 mmol/L)

* For all three tests, risk is continuous below the lower limit of the range and becomes disproportionately greater at higher ends of the range. † Diagnosis of diabetes can be based on criteria 1 (FP), 2 (OGTT), 3 (A1C), or 4 (Other). In the absence of unequivocal hyperglycemia, criteria for 1–3 should be confirmed by repeat testing. ‡ Fasting is defined as no caloric intake for at least 8 hours. § A1C should be performed using a method that is certified by the National Glycohemoglobin Standardization Program and standardized or traceable to the Diabetes Control and ComplicationsTrial reference assay. Developed from American Diabetes Association. Diagnosis and classification of diabetes mellitus—2010. Diabetes Care. 32(Suppl 1):S62–S69.

quite variable, being rapid in some individuals (mainly infants and children) and slow in others (mainly adults). Some individuals, particularly children and adoles- cents, may present with diabetic ketoacidosis (DKA) as the first manifestation of the disease (to be discussed). Others may have modest elevations in FPG that can rapidly change to severe hyperglycemia and DKA in the presence of stress and infection. Still others, particularly adults, may retain sufficient beta cell function to delay onset of clinical diabetes for many years. The destruction of beta cells and absolute lack of insulin in people with type 1 diabetes mellitus mean that they are particularly prone to the development of DKA. One of the actions of insulin is the inhibition of lipolysis (i.e., fat breakdown) and release of free fatty acids (FFAs) from fat cells. In the absence of insulin, ketosis devel- ops when these fatty acids are released from fat cells and converted to ketones in the liver. Because of the loss of insulin response, all people with type 1A diabetes require exogenous insulin replacement to reverse the catabolic state, control blood glucose levels, and prevent ketosis. Type 1A Immune-Mediated Diabetes. Type 1A dia- betes, commonly referred to as type 1 diabetes , is char- acterized by immune-mediated destruction of beta cells. This type of diabetes, formerly called juvenile diabetes, occurs more commonly in children and adolescents. In fact, three quarters of all cases of type 1 diabetes occur in individual younger than 18 years of age. 11 Type 1A diabetes is an autoimmune disorder that is thought to result from a genetic predisposition

(i.e., diabetogenic genes); an environmental triggering event, such as an infection; and a T-lymphocyte–medi- ated hypersensitivity reaction against some beta cell antigens. Much evidence has focused on the inherited major histocompatibility complex (MHC) genes on chromosome 6 that encode human leukocyte antigen (HLA)-DQ and HLA-DR, especially DR-3 and DR-4. 3 In addition to the MHC susceptibility genes on chromo- some 6, an insulin gene regulating beta cell replication and function has been identified on chromosome 11. Type 1A diabetes–associated autoantibodies may exist for years before the onset of hyperglycemia. There are two main types of autoantibodies: insulin autoantibodies (IAAs) and islet cell autoantibodies, including antibodies directed at other islet autoantigens, including glutamic acid decarboxylase (GAD) and the protein tyrosine phos- phatase IA-2. 3,11 Testing for antibodies to GAD or IA-2 and for IAAs using sensitive assays can be used to iden- tify new cases of type 1 diabetes when diagnostic confu- sion between type 1 and type 2 diabetes occurs or there is future risk of type 1 diabetes (e.g., in siblings of a person with type 1). 1 These persons also have increased predis- position to other autoimmune disorders such as Graves disease, rheumatoid arthritis, and Addison disease. The fact that type 1 diabetes is thought to result from an interaction between genetic and environmental fac- tors led to research into methods directed at prevention and early control of the disease. These methods include the identification of genetically susceptible persons and early intervention in newly diagnosed persons with type 1 diabetes. After the diagnosis of type 1 diabetes,