Pancreatic B-Cell Defects in Gestational Diabetes: Implications for the Pathogenesis and Prevention of Type 2 Diabetes

T. A. Buchanan
2001 Journal of Clinical Endocrinology and Metabolism  
Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia that results from tissue resistance to the glucoselowering effects of insulin and inadequate pancreatic B-cell compensation for that resistance (1). Longitudinal studies of people at risk for T2DM reveal that insulin resistance is often present years before the onset of hyperglycemia (2-4). Studies of the evolution of diabetes during a relatively short period (i.e. 5-7 yr) before the diagnosis in Mexican Americans and Pima
more » ... ans and Pima Indians have revealed that: 1) poor B-cell function and insulin resistance precede and predict the development of diabetes (4, 6); and 2) the progression from normal glucose tolerance to diabetes is attended by a decline in B-cell function and an increase in insulin resistance (6). These findings indicate that insulin resistance and B-cell dysfunction both occur in people who develop T2DM. They do not reveal whether declining B-cell function is an independent event that is simply coincident with insulin resistance in some members of the population or whether the two abnormalities are causally linked. Here, I will develop the theme that insulin resistance causes B-cell dysfunction in susceptible individuals, using information from women who are at increased risk for T2DM by virtue of a clinical diagnosis of gestational diabetes. Assessing B-cell function in vivo: the importance of insulin resistance B-cell function can be assessed by quantifying insulin responses to nutrients or by characterizing the composition of the peptide mix released by B-cells (e.g. proinsulin to insulin ratios) (7), or temporal patterns of insulin release (e.g. pulsatility; Refs. 8 and 9). Relatively little work has been done on the latter two areas in women with gestational diabetes mellitus (GDM). Some investigators have reported an increase in the ratio of proinsulin to insulin in the circulation of women with GDM (10). Others have failed to find such a difference (11). Here, the focus will be on B-cell function as assessed by quantitative insulin responses to nutrients. In 1981, Bergman et al. (12) proposed that there is a predictable relationship, in the shape of a rectangular hyperbola, between the quantity of insulin produced by B cells and the sensitivity of tissues to the glucose-lowering effects of that insulin. Kahn et al. (13) demonstrated that such a relationship is present across a wide range of insulin sensitivity in people with normal glucose tolerance. We found a hyperbolic relationship between insulin sensitivity and several measures of B-cell insulin release in women with impaired glucose tolerance (14). The amount of insulin released at a given level of insulin resistance is lower in people with abnormal compared with normal glucose tolerance (15). The general concept of hyperbolic relationships between insulin sensitivity and B-cell insulin release is depicted in the left panel of Fig. 1 . Each curved line (hyperbola) represents an isobar of B-cell compensation for ambient insulin resistance. Individuals whose sensitivity-secretion relationships lie on the same line have the same level of B-cell compensation. To the extent that insulin sensitivity and insulin release are the main determinants of glycemia, individuals on the same line will also have the same or very similar plasma glucose levels and glucose tolerance. People whose B-cell function worsens over time should move from a more favorable to a less favorable sensitivity-secretion relationship-movement down and to the left in Fig. 1 . Longitudinal studies in Pima Indians indicate that such movement (i.e. increasing insulin resistance with decreasing B-cell function; Ref. 6) does occur over the course of years during progression from normal glucose tolerance to T2DM. The right panel of Fig. 1 demonstrates the pitfalls that may be encountered when comparing quantitative aspects of Bcell function between individuals or groups with different levels of insulin sensitivity. Two groups that differ in their degree of insulin resistance should also differ in quantitative B-cell responses to glucose or other nutrients. If they fail to do so, as is true for the groups depicted in the right panel of Fig. 1 , then they have different B-cell function (i.e. different compensation for ambient insulin resistance). The best way to compare B-cell function between such groups in a quantitative fashion is to determine whether their sensitivitysecretion relationships are on the same or different hyperbolic lines. Taking advantage of the mathematical formula of a rectangular hyperbola (y ϭ ϫ * k, where y ϭ insulin release,
doi:10.1210/jc.86.3.989 pmid:11238474 fatcat:vem24qh5czbrnhwyucbna2qg6i