Diego Ize Ludlow MD Mark A Sperling MD

Division of Endocrinology, Diabetes, and Metabolism, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, 3705 Fifth Avenue, 4A-400, Pittsburgh, PA 15213-2583, USA

Classification, the systematic grouping of disease entities by etiology or other categories, is useful because it guides the thinking of physicians, informs their actions, and provides value to their patients. A classical example is anemia, in which hemoglobin of approximately 6 g/dL or less is associated with typical symptoms, such as pallor, fatigue, and shortness of breath irrespective of the cause. Although initial treatment may include transfusion, subsequent management is guided by the cause: essential factors for hemoglobin synthesis (iron, vitamin B12, folic acid); correction of factors that promote excessive peripheral destruction of red blood cells (splenectomy, steroids for immune hemolysis, avoidance of drugs, such a sulfonamides in those with G6PD deficiency); and congenital or acquired defects in hemoglobin synthesis (hemoglobinopathy, bone marrow infiltration). Knowledge of the etiology of diabetes mellitus (DM) is not as advanced as that of anemia, but it has become increasingly apparent that the classification of DM as type 1, type 2, and "other" is inadequate. This article provides a rational conceptual framework for the classification of DM based on the rapidly evolving understanding of congenital or acquired defects in insulin secretion and congenital or acquired factors that affect insulin's ability to evoke its biologic effects (ie, insulin sensitivity or its mirror image, insulin resistance [IR]). DM results when the normal constant of the product of insulin concentration times the insulin action, a parabolic relationship (Fig. 1), is inadequate to prevent hyperglycemia and its clinical consequences of polyuria, polydipsia, and weight loss. When an increase in IR can be compensated by increased insulin secretion, DM does not result as long as this constant is maintained. By simul-

* Corresponding author.

E-mail address: [email protected] (M.A. Sperling).

0031-3955/05/$ - see front matter © 2005 Elsevier Inc. All rights reserved.

doi:10.1016/j.pcl.2005.07.001 pediatric.theclinics.com

Fig. 1. The hyperbolic relationship of insulin resistance and (-cell function. In a subject with normal (-cell reserve an increase in insulin resistance results in increased insulin release and normal glucose tolerance (black arrow). In an individual where the capacity to increase insulin release is compromised, increased insulin resistance with no (3-cell compensation results in progression from normal glucose tolerance to impaired glucose tolerance to diabetes (gray arrow). The product of insulin sensitivity (the reciprocal of insulin resistance) and acute insulin response (a measurement ( -cell function) has been called "disposition index.'' This index remains constant in an individual with normal (-cell compensation in response to changes in insulin resistance. IGT, impaired glucose tolerance; NGT, normal glucose tolerance; T2D, type 2 diabetes.

Fig. 1. The hyperbolic relationship of insulin resistance and (-cell function. In a subject with normal (-cell reserve an increase in insulin resistance results in increased insulin release and normal glucose tolerance (black arrow). In an individual where the capacity to increase insulin release is compromised, increased insulin resistance with no (3-cell compensation results in progression from normal glucose tolerance to impaired glucose tolerance to diabetes (gray arrow). The product of insulin sensitivity (the reciprocal of insulin resistance) and acute insulin response (a measurement ( -cell function) has been called "disposition index.'' This index remains constant in an individual with normal (-cell compensation in response to changes in insulin resistance. IGT, impaired glucose tolerance; NGT, normal glucose tolerance; T2D, type 2 diabetes.

taneously considering insulin secretion and insulin action in any given individual, it becomes possible to account for the natural history of DM in that subject: the reasons for its clinical appearance at that time, or its temporary resolution or exacerbation (eg, diabetic ketoacidosis in a patient with type 2 DM). Diabetes is the extreme phenotypical manifestation of the combination (-cell malfunction and IR. This syndrome can be the result of the severe failure of one of the components of the homeostatic system or of combinations of milder defects in each component (Fig. 2).

A clear clinical example of these relationships (see Figs. 1 and 2) is the classical presentation of type 2 diabetes. An obese individual with DM may return to normoglycemia through weight loss. The decrease in IR through weight loss allows the remaining (-cell function to achieve a new homeostatic balance, which could easily be lost with further increased IR (eg, by weight gain, pregnancy, illness), or by further impairment of the (-cell secretory function [1].

This concept is strongly supported by data obtained from knockout mice. The muscle insulin receptor knockout mice develop severe IR but compensatory hyperinsulinemia allows for regulation of the blood glucose in the normal range [2]. By contrast, (-cell defects with coexistent IR lead to diabetes, as is the case in the insulin receptor substrate-1/insulin receptor knockout [3]. Type 2 diabetes is most often a ''two-hit'' phenomenon, in which IR is accompanied by a (-cell defect preventing compensatory up-regulation of insulin secretion.

Fig. 2. The spectrum of (3-cell failure and insulin resistance syndromes. (3-cell failure can be genetic, as in MODY; acquired secondary to environment (drugs, virus, and so forth); or autoimmune. The combination of different degrees of these factors leads to the different manifestations of the (3-cell failure and insulin resistance diseases. AN, acanthosis nigricans; CFRD, cystic fibrosis-related diabetes; MODY, maturity-onset diabetes of the young; PCOS, polycystic ovary syndrome; T1a, type 1a diabetes mellitus (autoimmune); T1b, type 1b diabetes (idiopathic); T2DM, type 2 diabetes mellitus.

Fig. 2. The spectrum of (3-cell failure and insulin resistance syndromes. (3-cell failure can be genetic, as in MODY; acquired secondary to environment (drugs, virus, and so forth); or autoimmune. The combination of different degrees of these factors leads to the different manifestations of the (3-cell failure and insulin resistance diseases. AN, acanthosis nigricans; CFRD, cystic fibrosis-related diabetes; MODY, maturity-onset diabetes of the young; PCOS, polycystic ovary syndrome; T1a, type 1a diabetes mellitus (autoimmune); T1b, type 1b diabetes (idiopathic); T2DM, type 2 diabetes mellitus.

In the following paragraphs, insulin secretion and insulin action are considered separately and then examples of their interaction in clinically relevant situations are provided. A rational framework for the classification of DM is provided, which informs and guides the reader in later articles in this issue describing various forms of DM.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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