Although the increased incidence of type 2 diabetes since the 1950s is thought to be primarily due to coincident alterations in lifestyle factors, another potential contributing factor in industrialized countries is exposure of the population to environmental pollutants and industrial chemicals. Exposure levels of many environmental toxicants have risen in the same time-frame as the disease incidence. Of particular interest in this regard is the metal lead. Although overall lead exposure levels have diminished in recent decades, there is an under-recognized but persistent occurrence of lead exposure in poor underserved urban populations. Although the neural developmental pathologies induced by lead exposures have been well documented, very little is known about the effect of lead exposure on the incidence of chronic metabolic diseases such as type 2 diabetes. Although our understanding of the metabolic health effects of lead exposure is incomplete, there are studies in model systems and a small amount of epidemiological data that together suggest a deleterious effect of environmental lead exposure on metabolic health. This article reviews the human, animal and in vitro studies that have examined the effects of lead exposure on the development of diabetes and related metabolic conditions.

The transcription factor peroxisome proliferator-activated receptor-γ (PPARγ) plays an important role in regulating lipid and glucose metabolism and improves insulin sensitivity in diabetic patients when activated by thiazolidinedione drugs. Several loss-of-function mutations in PPARγ have been identified that cause lipodystrophy and diabetes in humans. Because affected individuals are heterozygotes and have one normal PPARγ allele, it is of interest to know whether these mutations act in a dominant-negative fashion to inhibit the activity of the wild-type (WT) receptor. Here we compare the molecular phenotypes of two previously identified PPARγ mutations: P467L, reported to be dominant negative; and F388L, reported to be devoid of dominant-negative activity. We developed a competitive chromatin immunoprecipitation assay to measure the relative ability of mutant PPARγ to compete with WT receptor for binding to a PPAR regulatory element (PPRE)-containing promoter. By determining the ratio of mutant and WT receptors bound to a PPRE over time, we estimated the relative promoter turnover rate of each receptor. This assay demonstrated that PPARγ bearing the P467L had a reduced promoter turnover rate compared with the F388L receptor, and over time out-competed the WT receptor for promoter binding sites. We propose that the P467L receptor is dominant negative because in a cell containing both WT and mutant receptors, the majority of the PPAR-regulated promoters will be occupied by the transcriptionally defective mutant receptor. In contrast, the F388L mutation lacks dominant-negative activity because its more rapid promoter turnover rate prevented it from out-competing the WT receptor for promoter binding sites.

We demonstrate that the expression of glycine decarboxylase (the primary glycine degradative enzyme) is strongly induced by glucagon and that the elevation of its expression induces an increase in ce...

A novel class of antidiabetic agents, the thiazolidinediones, was developed in the 70s and 80s by screening newly synthesized compounds for their ability to lower blood glucose in diabetic rodents. Three molecules from this class, troglitazone, rosiglitazone and pioglitazone, were ultimately approved for the treatment of patients with type II diabetes. Although these compounds were developed without an understanding of their molecular mechanism of action, by the early 90s evidence began to accumulate linking the thiazolidinediones the nuclear receptor PPARγ (NR1C3). It was ultimately demonstrated that these molecules were high affinity ligands of PPARγ and that they increased the transcriptional activity of the receptor. Although many questions remain, multiple lines of evidence now indicate that the antidiabetic activities of the thiazolidinediones are mediated by their direct interaction with the receptor and the subsequent modulation of PPARγ target gene expression. The knowledge that PPARγ ligands can improve insulin resistance in diabetics, coupled with the availability of rapid assays for the identification and characterization of nuclear receptor ligands, has led to a virtual explosion in the number of new PPARγ ligands that are under development as antidiabetic agents. In this article we will briefly review the biology of PPARγ, and then provide an update of new synthetic PPARγ ligands that are under investigation or in development as antidiabetic drugs.

Type 2 diabetes (T2D) is accompanied by alterations in amino acid metabolism. Interestingly, in both humans and rodents, circulating glycine levels are significantly reduced in obesity, glucose intolerance and T2D identifying glycine as a biomarker of T2D and raising the possibility that altered glycine metabolism plays an active role in the etiology of the disease. The goals of our study are to determine if altered glycine metabolism plays a functional role in the development of diabetes. The glycine cleavage system (GCS) is the only biochemical route that degrades glycine in humans and loss‐of‐function mutations of GCS cause hyperglycinemia. Here, we show that the expression of the rate‐limiting enzyme of GCS, Glycine Decarboxylase (GLDC), is upregulated in livers of hyperinsulinemic mouse models of diabetes, and in hepatoma cell lines insulin stimulates transcription of the GLDC gene. We identified the insulin responsive transcription factor Sterol regulatory element binding protein 1c (SREBP‐1c) as the primary mediator of this insulin stimulatory effect. We also observed that altering GLDC expression levels strongly affected intracellular glutathione levels and levels of reactive oxygen species (ROS). Our findings suggest a working model in which Srebp1c‐mediated regulation of GLDC is responsible for the reduction of glycine levels seen in insulin resistant states and may play function as a compensatory mechanism to increase glutathione production as a defense against diabetes‐induced oxidative stress. Support or Funding Information This work is supported by NIH R21AG050741, and the Michigan Diabetes Research and Training Center. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .