Diabetes Mellitus
Classification of Diabetes Mellitus
David R. Weber, Nicholas Jospe
Diabetes mellitus (DM) is a common, chronic, metabolic disease characterized by hyperglycemia as a cardinal biochemical feature. The major forms of diabetes are differentiated by insulin deficiency vs insulin resistance: type 1 diabetes mellitus (T1DM ) results from deficiency of insulin secretion because of pancreatic β-cell damage; type 2 diabetes mellitus (T2DM) is a consequence of insulin resistance occurring at the level of skeletal muscle, liver, and adipose tissue, with various degrees of β-cell impairment. T1DM is the most common endocrine-metabolic disorder of childhood and adolescence, with important consequences for physical and emotional development. Individuals with T1DM confront serious lifestyle alterations, including an absolute daily requirement for exogenous insulin, the need to monitor their own glucose level, and the need to pay attention to dietary intake. Morbidity and mortality stem from a constant potential for acute metabolic derangements and from long-term complications. Potential acute complications include the development of hypoglycemia related to insulin excess or hyperglycemic ketoacidosis from insulin deficiency. Long-term complications typically manifest in adulthood and are related to the adverse effects of chronic hyperglycemia and associated metabolic abnormalities on tissues and organ systems. This can result in microvascular diseases such as retinopathy, nephropathy, and neuropathy, and macrovascular complications such as ischemic heart disease and arterial obstruction with gangrene of the extremities.
DM is not a single entity but rather a heterogeneous group of disorders in which there are distinct genetic patterns as well as other etiologic and pathophysiologic mechanisms that lead to impairment of glucose tolerance through deficient insulin production or action. The American Diabetes Association has proposed a diabetes classification system that includes 4 categories: type 1 diabetes, type 2 diabetes, other specific types, and gestational diabetes. An expanded list of diabetes etiologies is provided in Table 607.1 . The current criteria for the diagnosis of diabetes are provided in Table 607.2 . A thorough clinical history and physical exam are often sufficient to determine the etiology, however in some cases additional testing may be required.
Table 607.1
Etiologic Classifications of Diabetes Mellitus
Modified from Sperling MA, Tamborlane WV, Battelino T, et al: Diabetes mellitus. In Sperling MA, editor: Pediatric endocrinology , ed 4, Philadelphia, 2014, Elsevier, Box 19-1.
Table 607.2
| DYSGLYCEMIA | DIABETES MELLITUS |
|---|---|
| Impaired fasting glucose: | |
| Fasting (at least 8 hr) plasma glucose 100-125 mg/dL (5.6-7.0 mmol/L) |
Fasting (at least 8 hr) plasma glucose ≥ 126 mg/dL (7.0 mmol/L) Or |
| Impaired glucose tolerance: | |
| 2 hr plasma glucose during OGTT ≥ 140 mg/dL (7.8 mmol/L), but < 200 mg/dL (11.1 mmol/L) |
2 hr plasma glucose during OGTT ≥ 200 mg/dL (11.1 mmol/L) Or |
| Prediabetes: | |
| Hemoglobin A1c 5.7–6.4% (39-47 mmol/mol) |
Hemoglobin A1c ≥ 6.5% (48 mmol/mol) Or |
| Symptoms* of diabetes mellitus plus random or casual plasma glucose ≥ 200 mg/dL (11.1 mmol/L) † |
* Symptoms include polyuria, polydipsia, and unexplained weight loss with glucosuria and ketonuria.
† Results should be confirmed by repeat testing if in absence of unequivocal hyperglycemia.
OGTT, oral glucose tolerance test.
Adapted from the Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, Diabetes Care 20 (Suppl 1):S5, 1999; and American Diabetes Association. Standards in Medical Care of Diabetes-2017. Diabetes Care 40 (Suppl 1):S11–S24, 2017
Type 1 Diabetes Mellitus
Formerly called insulin-dependent diabetes mellitus (IDDM) or juvenile diabetes, T1DM is characterized by low or absent levels of endogenously produced insulin and by dependence on exogenous insulin to prevent development of ketoacidosis, an acute life-threatening complication of T1DM. The natural history includes 4 distinct stages: (1) preclinical β-cell autoimmunity with progressive defect of insulin secretion, (2) onset of clinical diabetes, (3) transient remission honeymoon period, and (4) established diabetes during which there may occur acute and/or chronic complications and decreased life expectancy. The onset occurs predominantly in childhood, with a median age of 7-15 yr, but it may present at any age. The incidence of T1DM has steadily increased in nearly all parts of the world (Fig. 607.1 ). T1DM is characterized by autoimmune destruction of pancreatic islet β-cells. Both genetic susceptibility and environmental factors contribute to the pathogenesis. Susceptibility to T1DM is genetically controlled by alleles of the major histocompatibility complex (MHC) class II genes expressing human leukocyte antigens (HLAs). Autoantibodies to β-cell antigens including islet cell cytoplasm (ICA), insulin autoantibody (IAA), glutamic acid decarboxylase (GADA), islet antigen 2 (IA-2A, formerly ICA512), and zinc transporter 8 (ZnT8A) are detected in serum from affected subjects. These can be detected months to years prior to clinical onset of T1DM. In some children and adolescents with apparent T1DM, the β-cell destruction is not immune mediated. This subtype of diabetes occurs in patients of African or Asian origin and is distinct from known causes of β-cell destruction such as drugs or chemicals, viruses, mitochondrial gene defects, pancreatectomy, and ionizing radiation. These individuals may have ketoacidosis, but they have extensive periods of remission with variable insulin deficiency, similar to patients with T2DM. Patients with T1DM require lifelong treatment with insulin.
Type 2 Diabetes Mellitus
Formerly known as adult-onset diabetes mellitus or non–insulin-dependent diabetes mellitus, T2DM develops as a result of insulin resistance and progressive non-autoimmune β-cell failure. While T2DM has long been the most prevalent form of diabetes in adults, the dramatic rise in childhood obesity over the past few decades has led to a markedly increased incidence of this disease in children and adolescents. Pediatric T2DM may account for up to 80% of the new cases of diabetes in high-risk populations such as obese adolescents of African or Hispanic population ancestry (see Chapter 60 ). It is now apparent that childhood onset T2DM differs from adult disease in that it is associated with a more rapid decline in β-cell function and the earlier development of T2DM-related complications.
The presentation of T2DM is typically more insidious than that with T1DM. In contrast to patients with T1DM who are usually ill at the time of diagnosis and whose presentation rarely spans more than a few weeks, children with T2DM often seek medical care because of excessive weight gain and fatigue as a result of insulin resistance and/or the incidental finding of glycosuria during routine physical examination. A history of polyuria and polydipsia is not always a cardinal clinical feature in these patients. Acanthosis nigricans (dark pigmentation of skin creases in the nape of the neck especially), a sign of insulin resistance, is present in the majority of patients with T2DM and is accompanied by a relative hyperinsulinemia at the time of the diagnosis. However, the serum insulin elevation is usually disproportionately lower than that of age-, weight-, and sex-matched nondiabetic children and adolescents, suggesting a state of insulin insufficiency. Healthy lifestyle interventions and treatment with metformin remain the cornerstones of T2DM treatment in children and adolescents; however, insulin therapy is often required to control hyperglycemia. There is a strong heritable component to T2DM, although the genetic basis remains poorly understood. Population-based studies have linked T2DM risk with polymorphisms in a large number of genes related to insulin secretion, insulin action, energy expenditure, and birthweight; however, the collective contribution of these variants to overall T2DM risk remains low at <20%.
Other Specific Types of Diabetes
Monogenic Diabetes
The term monogenic diabetes is used to refer to a heterogeneous group of single-gene disorders resulting in impaired insulin secretion. This category encompasses maturity-onset diabetes of the young (MODY) as well as transient or permanent neonatal diabetes (TND or PND ). Characteristics of monogenic diabetes can include age of onset prior to 6 mo (for TND or PND), development of hyperglycemia prior to age 25 yr of age, and strong family history of diabetes. Monogenic etiologies are estimated to comprise anywhere from 1% to 10% of all diabetes cases, with the uncertainty related to the clinical difficulty in differentiating these cases from T1DM and T2DM. Monogenic forms of diabetes may present with hyperglycemia, and consequent polyuria and polydipsia, or may be diagnosed simply by routine screening. Extra-pancreatic manifestations vary by genetic defect (see Table 607.19 ), and can include hepatic, renal, and CNS manifestations. Treatment is guided by genetic diagnosis and clinical course, with some forms being responsive to oral sulfonylureas and others requiring insulin replacement. Children diagnosed with diabetes prior to 6 mo of age should have genetic testing for TND/PND, and older individuals with diabetes not characteristic of T1DM or T2DM in the setting of a family history of diabetes should have MODY genetic testing. A comparison of the 4 types of diabetes is noted in Table 607.3 .
Table 607.3
Key Features of Diabetes in Pediatric Patients
| TYPE 1 DIABETES | TYPE 2 DIABETES | MATURITY-ONSET DIABETES IN THE YOUNG | NEONATAL DIABETES | |
|---|---|---|---|---|
| Age at diagnosis | 6 mo-18 yr | Puberty; rarely younger than 10 yr | Younger than 25 yr | Younger than 6 mo |
| Causes and genetic factors | Autoimmune; genetic predisposition (HLA and other genes) | Obesity; genetic and ethnic predisposition | Autosomal dominant; HNF1A, HNF4A, GCK, HNF1B (rare) | KCNJ11, ABCC8, INS, and other genes |
| Associated features | Lean or weight loss at diagnosis; thyroid autoimmunity; celiac disease | Obesity; acanthosis nigricans; polycystic ovarian syndrome; hypertension; hyperlipidemia; fatty liver disease; family history | Lean or weight loss at diagnosis; GCK mutations are asymptomatic | Failure to thrive |
| Diabetic ketoacidosis at presentation | Yes; about 25% | Yes; 5–20% | No | Yes |
| Treatment | Insulin | Lifestyle modification; metformin; insulin | Sulfonylurea; no treatment for GCK mutations | Sulfonylurea for KCJN11 and ABCC8 mutations; insulin for other mutations |
From Cameron FJ, Wherrett DK: Care of diabetes in children and adolescents: controversies, changes, and consensus. Lancet 385:2096–2104, 2015, Table 1.
Other Etiologies of Diabetes
Examples include diabetes secondary to exocrine pancreatic diseases (cystic fibrosis), other endocrine diseases (Cushing syndrome), infection, and ingestion of certain drugs or poisons (the rodenticide Vacor). In organ transplantation survivors, there is a linkage between cyclosporine and tacrolimus and posttransplantation DM, ascribed to a number of mechanisms. Certain genetic syndromes, including those with abnormalities of the insulin receptor or the immune system are also included in this category.
Prediabetes
The term prediabetes is used to identify individuals with abnormalities in blood glucose homeostasis who are at increased risk for the development of diabetes (see Table 607.2 ). Prediabetes is defined by impaired fasting glucose (IFG, fasting glucose 100-125 mg/dL [5.6-6.9 mmol/L]), impaired glucose tolerance (IGT, 2 hr postprandial glucose 140-199 mg/dL (7.8-11 mmol/L), or hemoglobin A1c (HbA1c ) values of 5.7–6.4% (39-47 mmol/mol). A fasting glucose concentration of 99 mg/dL (5.5 mmol/L) is the upper limit of normal. This choice is near the level above which acute-phase insulin secretion is lost in response to intravenous administration of glucose and is associated with a progressively greater risk of the development of microvascular and macrovascular complications. Many individuals with IFG are euglycemic in their daily lives and may have normal or nearly normal HbA1c levels. Individuals with IFG often manifest hyperglycemia only when challenged with the oral glucose load used in the standardized oral glucose tolerance test.
Prediabetes is not a clinical entity but rather a risk factor for future diabetes and cardiovascular disease. This may be observed as an intermediate stage in any of the disease processes listed in Table 607.1 . Prediabetes is often associated with the insulin resistance syndrome (also known as metabolic syndrome ), which consists of insulin resistance, compensatory hyperinsulinemia to maintain glucose homeostasis, obesity (especially abdominal or visceral obesity), dyslipidemia of the high-triglyceride or low- or high-density lipoprotein type, or both, and hypertension. Insulin resistance is directly involved in the pathogenesis of T2DM.