The estrogen receptor α-selective agonist propyl pyrazole triol improves glucose tolerance in ob/ob mice: potential molecular mechanisms

The authors and journal apologise for an error in the above paper, which appeared in volume 199 part 2, pages 275­286. The error relates to Fig. 10, given on page 283.

The estrogen receptor {alpha}-selective agonist propyl pyrazole triol improves glucose tolerance in ob/ob mice; potential molecular mechanisms.

The aim of this study was to validate the role of estrogen receptor alpha (ERalpha) signaling in the regulation of glucose metabolism, and to compare the molecular events upon treatment with the ERalpha-selective agonist propyl pyrazole triol (PPT) or 17beta-estradiol (E(2)) in ob/ob mice. Female ob/ob mice were treated with PPT, E(2) or vehicle for 7 or 30 days. Intraperitoneal glucose and insulin tolerance tests were performed, and insulin secretion was determined from isolated islets. Glucose uptake was assayed in isolated skeletal muscle and adipocytes. Gene expression profiling in the liver was performed using Affymetrix microarrays, and the expression of selected genes was studied by real-time PCR analysis. PPT and E(2) treatment improved glucose tolerance and insulin sensitivity. Fasting blood glucose levels decreased after 30 days of PPT and E(2) treatment. However, PPT and E(2) had no effect on insulin secretion from isolated islets. Basal and insulin-stimulated glucose uptake in skeletal muscle and adipose tissue were similar in PPT and vehicle-treated ob/ob mice. Hepatic lipid content was decreased after E(2) treatment. In the liver, treatment with E(2) and PPT increased and decreased the respective expression levels of the transcription factor signal transducer and activator of transcription 3, and of glucose-6-phosphatase. In summary, our data demonstrate that PPT exerts anti-diabetic effects, and these effects are mediated via ERalpha.

Expression of glucose-6-phosphatase system genes in murine cortex and hypothalamus.

The glucose-6-phosphatase (G6Pase) system participates in the regulation of glucose homeostasis by converting glucose-6-phosphate (G6P) into glucose and inorganic phosphates. We have used an RT-PCR-based cloning and sequencing approach to study the expression of components of the G6Pase system in the hypothalamus and cortex tissues of the ob/ob mouse. We observed the expression of hepatic G6Pase catalytic subunit, G6PC, in both tissues, although increased template inputs were required for its detection. Conversely, expression of both the mouse homologue of the previously-described brain-specific G6P translocase T1 (G6PT1) variant and of the hepatic G6PT1 isoform was easily detectable in hypothalamus and cortex tissues. Of the proposed G6Pase catalytic subunit homologues, the expression of murine ubiquitous G6Pase catalytic subunit-related protein (UGRP, G6PC3) was also easily detectable in both tissues. However, islet-specific G6Pase catalytic subunit-related protein (IGRP, G6PC2) was expressed in a tissue-specific manner, and was detectable only in hypothalamus tissue at increased template inputs. We conclude that cells within ob/ob mouse hypothalamus and cortex tissues express genes with either established or proposed roles in G6P hydrolysis.

Overview of incretin hormones.

Incretins are hormones released by nutrients from the GI tract. They amplify glucose-induced insulin release. By raising circulating incretin levels, oral glucose provokes a higher insulin response than that resulting from intravenous glucose. The two most important incretin hormones are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). In patients with type 2 diabetes, the incretin effect is decreased, mainly due to loss of the GIP-regulated second phase of insulin secretion, and because of a decreased secretion of GLP-1. In addition to its insulinotropic effect, GLP-1 inhibits glucagon release, prolongs gastric emptying, and leads to decreases in body-weight, all of which explain the marked antidiabetogenic effect of this incretin hormone.

Low interleukin-1alpha messenger RNA levels predict decreased overall survival time of patients with urinary bladder carcinoma.

Due to our inability to exactly characterize tumours, many patients with urinary bladder cancer undergo unnecessary surgery or cytostatic therapy. We have here studied the expression of the cytokine interleukin-1alpha (IL-1alpha ) in 73 human bladder carcinomas in relation to patient survival, and examined possible relationships between IL-1alpha and urokinase plasminogen activator (uPA) expression. Expression levels of IL-1alpha and uPA mRNA were determined by RT-PCR using the quantitative TaqMan technique. The levels of IL-1alpha mRNA expression did not differ significantly between tumours of different grade or stage. Calculation of the overall survival rates showed a decreased overall survival time for patients with low levels of IL-1alpha mRNA in their tumours (log rank; P = 0.0002, median follow up: 37 months). Low tumoral IL-1alpha expression predicted decreased survival of patients with poorly differentiated tumours (P< 0.005) and of patients with invasive tumours (P = 0.02). uPA expression was about 4-fold increased in poorly differentiated tumours. High levels of uPA mRNA were associated with decreased overall survival times (log rank; P = 0.032, n = 60). We conclude that IL-1alpha is important for bladder cancer biology, and that measurements of this cytokine may be useful in pre-treatment characterization of urinary bladder cancer.

Diabetes mellitus due to viruses--some recent developments.

Many different viruses belonging to several genera have the potential to damage beta cells. The mechanisms they employ are varied, and infection may result in either a direct destruction of islets and rapid insulin deficiency, or in a more gradual loss of functioning islets with the onset of diabetes many years later. Several case histories involving extensive cytolysis of beta cells can be directly linked to viral infection, whilst an example of diabetes occurring many years after viral infection is found in individuals who had a congenital infection with rubella virus. Here, the virus induces an autoimmune reaction against beta cells. Autoimmune phenomena have also been observed in islets following infections with viruses other than rubella, and thus activation of autoimmune mechanisms leading to beta-cell destruction may be a relatively frequent occurrence. Recent evidence shows that picornaviruses are not exclusively lytic, and can induce more subtle, long-term changes in beta cells, which may be important in the aetiology of diabetes. The exact mechanisms involved are not known, but it is clear that several viruses can directly inhibit insulin synthesis and induce the expression of other proteins such as interferons, and the HLA antigens. Strain differences in viruses are important since not all variants are tropic for the beta cells. Several laboratories are in the process of identifying the genetic determinants of tropism and diabetogenicity, especially amongst the Coxsackie B (CB) virus group. The sequence of one such diabetogenic CB4 strain virus has been determined.(ABSTRACT TRUNCATED AT 250 WORDS)

Coxsackie B4 viruses with the potential to damage beta cells of the islets are present in clinical isolates.

Infections with Coxsackie viruses (especially Coxsackie B4) are thought to be involved in the pathogenesis of diabetes. Many interdependent variables determine the outcome of an infection with a Coxsackie virus, one of them being the tropism of the virus for a specific tissue. The extent to which Beta cell tropic variants of Coxsackie B4 virus occur naturally was assessed. Human isolates of this virus were tested in an in vitro system in which elevated insulin release from infected islets incubated at a non-stimulatory (2 mmol/l) glucose concentration appears to be related to viral attack. Using this technique, 8/24 isolates tested, impaired secretory function in mouse islets. Some strains of Coxsackie B4 virus, therefore, will directly infect mouse islets in vitro leading to changes in islet cell function. In conclusion, these findings confirm that variants of Coxsackie B4 virus with the potential to damage Beta cells occur quite frequently in the natural population. In certain circumstances the damage they inflict on Beta cells may cause destruction of these cells, or precipitate overt diabetes.