The evolution of β‐cell dysfunction and insulin resistance in type 2 diabetes

Abstract

Insulin resistance and beta-cell dysfunction have important roles in the pathogenesis and evolution of type 2 diabetes. The development of precise methods to measure these factors has helped us to define the relationship between them and evidence is reviewed that changes in insulin sensitivity are compensated by inverse changes in beta-cell responsiveness such that the product of insulin sensitivity and insulin secretion (the disposition index) remains constant. While the disposition index promises to be a useful tool to predict individuals at high risk of developing type 2 diabetes, other factors that contribute to beta-cell dysfunction and mark disease onset and progression include impairments in proinsulin processing and insulin secretion, decreased beta-cell mass and islet amyloid deposition. Emerging data indicate that anti-diabetic agents, such as the thiazolidinediones that simultaneously target insulin resistance and beta-cell dysfunction, may have a beneficial impact on disease onset and progression. Several landmark clinical studies are underway to investigate if their initial promise is supported by data from large-scale trials.

Beta-cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study

“…In populations with a high prevalence of T2DM, insulin resistance is well established long before the development of any impairment in glucose homeostasis [1,2,3,5,6,9,10,11,12]. As long as the beta cell is able to secrete sufficient amounts of insulin to offset the severity of insulin resistance, glucose tolerance remains normal [1,2,3,13,14,15,16,17,18]. This dynamic interaction between insulin secretion and insulin resistance is essential to the maintenance of NGT [1,3,6,7,9,14,15,16,17,18] and interruption of this cross-talk between the beta cell and peripheral tissues results in the progressive deterioration of glucose homeostasis [1,3,14,17,18,19].…”

“…As long as the beta cell is able to secrete sufficient amounts of insulin to offset the severity of insulin resistance, glucose tolerance remains normal [1,2,3,13,14,15,16,17,18]. This dynamic interaction between insulin secretion and insulin resistance is essential to the maintenance of NGT [1,3,6,7,9,14,15,16,17,18] and interruption of this cross-talk between the beta cell and peripheral tissues results in the progressive deterioration of glucose homeostasis [1,3,14,17,18,19]. Among individuals with NGT it has been proposed that about 20% are insulin resistant [15,20,21,22].…”

Hyperthyroidism impairs pancreatic beta cell adaptations to late pregnancy and maternal liporegulation in the rat

“…This may involve common factors contributing to both insulin resistance and pancreatic beta cell function, or factors influencing insulin sensitivity, pancreatic beta cell function and the feedback mechanisms that link them [3]. Inadequate compensatory hypersecretion of insulin to counter insulin resistance is critical to the pathology of type 2 diabetes [3].…”

“…This may involve common factors contributing to both insulin resistance and pancreatic beta cell function, or factors influencing insulin sensitivity, pancreatic beta cell function and the feedback mechanisms that link them [3]. Inadequate compensatory hypersecretion of insulin to counter insulin resistance is critical to the pathology of type 2 diabetes [3]. Pregnancy is a progressive state of maternal insulin resistance [4][5][6] (reviewed in [7]), which in healthy pregnancies is accompanied by reciprocal increases in insulin secretion (see [5,8]).…”

“…Pregnancy is a progressive state of maternal insulin resistance [4][5][6] (reviewed in [7]), which in healthy pregnancies is accompanied by reciprocal increases in insulin secretion (see [5,8]). Gestational diabetes occurs in women who secrete insufficient insulin to compensate for lowered in-sulin sensitivity during the third trimester [9] (reviewed in [3]). …”