Evolution of β-cell dysfunction in impaired glucose tolerance and diabetes

Abstract

Patients with overt Type 2 diabetes consistently have alterations in insulin secretion, including reduced insulin secretory responses to glucose, delayed and blunted meal-induced insulin secretion, increased pro-insulin and abnormal insulin secretory oscillations. More recently, it has become evident that abnormal insulin secretion antedates the onset of overt hyperglycaemia and is present in people with impaired glucose tolerance, i.e. normal fasting glucose and glycohaemoglobin concentrations. These defects are subtle and include shifts to the right in the dose-response curves that relate to glucose and insulin secretion, reduced ability of the beta-cell to detect and respond to oscillatory changes in the plasma glucose concentration and impaired beta-cell compensation for insulin resistance. In order to define the factors responsible for these defects in secretion, we have infused human patients with a lipid emulsion and heparin to raise plasma free fatty acid concentrations. This is associated with reduced ability of the beta-cell to detect and respond to small changes in the plasma glucose concentration. In summary, defects in insulin secretion are consistently present in patients with impaired glucose tolerance and play a critical role in the progression from impaired glucose tolerance to diabetes.

Pulsatile insulin secretion, impaired glucose tolerance and type 2 diabetes

“…Readers with a special interest in ultradian insulin oscillations (period ≈ 80–180 minutes) are directed to other reviews [12]. …”

Mathematical investigation of diabetically impaired ultradian oscillations in the glucose–insulin regulation

“…This work solely focuses on the modelling of these ultradian oscillations, which were first discovered in [10] and have been observed during fasting, meal ingestion, continuous enteral nutrition, and under a constant glucose infusion [33] (the condition upon which we will perform our analysis). For a review of ultradian oscillations, readers are directed to [26,33]. In [17,35,37] mathematical analysis of the dynamics of models taking into account physiological time delays suggested that the delayed feedback loop between glucose and insulin can account for the ultradian rhythms within the system, without the technical need for an internal pulsatile insulin pacemaker.…”

Glucose‐lowering action through targeting islet dysfunction in type 2 diabetes: Focus on dipeptidyl peptidase‐4 inhibition

“…As shown in Figure 1, key defects for the development of glucose dysregulation in type 2 diabetes is insufficient release of insulin from islet β‐cells in association of exaggerated release of glucagon from islet α‐cells. This conclusion has been possible to establish from the results of several clinical studies, showing defective insulin secretion 50‐55 or inappropriately high glucagon secretion in type 2 diabetes 56‐59 . The impaired insulin secretion results in inappropriately low circulating levels of insulin, leading to impaired stimulation of glucose utilization in peripheral tissues, and the inappropriately high glucagon levels result in exaggerated hepatic glucose production and release.…”