Beta-cell adaptation and decompensation during the progression of diabetes.

Abstract

Inadequate ␤-cell function is an essential component of all forms of diabetes. The most obvious problem is a failure to maintain sufficient ␤-cell mass and function to cope with whatever insulin resistance is present. The most striking functional defect is a loss of acute glucose-induced insulin secretion (GIIS). This review discusses the ways in which ␤-cells successfully adapt to increased demand and then decompensate as diabetes develops. Successful adaptation is achieved through increased ␤-cell mass and increased insulin secretion. The hypothesis is explored that ␤-cells exposed to the diabetic milieu lose their differentiation, which leads to loss of specialized functions such as GIIS. This concept has been strengthened by the finding of dedifferentiation of ␤-cells in a rat model of partial pancreatectomy that includes a reduction of insulin gene expression, which may further contribute to decreased insulin production. Another finding was increased expression of c-Myc, which probably contributes to an increase in the expression of lactate dehydrogenase and the development of ␤-cell hypertrophy. Arguments are developed that the ␤-cell changes found in diabetes are better correlated with increased glucose levels than with nonesterified fatty acid levels, thus supporting the importance of glucose toxicity. Diabetes 50 (Suppl.

Dietary fatty acid composition during pregnancy and lactation in the rat programs growth and glucose metabolism in the offspring

“…Concomitantly, its responsivity to insulin greatly increases during weaning. After weaning, the plasticity and turnover of islets and of beta cells are diminished and this emphasizes the importance of adequate prenatal and early postnatal pancreatic development [33,34]. Both low protein diet and caloric restriction studies in animals have been shown to influence pancreatic development [27].…”

Development of diabetes in obese, insulin-resistant mice: essential role of dietary carbohydrate in beta cell destruction

“…Euglycaemichyperinsulinaemic clamps were performed as previously described [17] in 9-week old, conscious, catheterised mice that had fasted for 16 h. In vivo experiments lasted for 240 min and consisted of a 120-min basal period, directly followed by a 120-min euglycaemic-hyperinsulinaemic clamp. During the basal period a prime-continuous [3] glucose infusion (370 kBq bolus, 3.7 kBq/min) was started and continued to determine rates of whole-body glucose turnover. After the 120-min basal infusion period, a primecontinuous insulin infusion (10 mU kg −1 min −1 ) was started at time 0 min, raising insulin levels to within a physiological range.…”

“…Steady-state conditions for plasma glucose concentration and specific activity were achieved within 70 min and a single 2-deoxy-D-[1-14 C]glucose injection was administered at time 75 min. To determine plasma [3] glucose, 3 Histology of adipose tissue Adipose tissue was fixed in 4% buffered formaldehyde, rinsed in phosphate-buffered saline and dehydrated in a graded series of 50-100% ethanol followed by propylene oxide. Tissue was infiltrated with propylene/Epon-812 mixtures by gradually increasing the resin concentration.…”

“…Two different scenarios have been proposed as the mechanism of this pathophysiological process. First, it has been suggested that beta cell damage is due to oxidative stress exerted by elevated glucose levels [1][2][3]. Alternatively, it has been proposed that obesity-induced ectopic fat accumulation in the pancreas causes apoptosis of beta cells [4,5].…”

Cluster analysis of rat pancreatic islet gene mRNA levels after culture in low-, intermediate- and high-glucose concentrations

“…The ability of pancreatic beta cells to secrete insulin in response to nutrient stimulation depends on adequate expression of genes important for glycolysis, mitochondrial metabolism and insulin biosynthesis, such as preproinsulin, Glut2 (also known as Slc2a2) and glucokinase, and on the repression of genes potentially deleterious to beta cell function [1], including hexokinase 1 and lactate dehydrogenase A [2]. Besides acutely regulating insulin biosynthesis and secretion, subacute and prolonged changes in nutrient availability exert pleiotropic effects on the beta cell phenotype, such as altered function, survival, growth and differentiation [3][4][5][6].…”