Incretins are gut hormones that are secreted from enteroendocrine cells into the blood within minutes after eating. One of their many physiological roles is to regulate the amount of insulin that is secreted after eating. In this manner, as well as others to be described in this review, their final common raison d'etre is to aid in disposal of the products of digestion. There are two incretins, known as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1), that share many common actions in the pancreas but have distinct actions outside of the pancreas. Both incretins are rapidly deactivated by an enzyme called dipeptidyl peptidase 4 (DPP4). A lack of secretion of incretins or an increase in their clearance are not pathogenic factors in diabetes. However, in type 2 diabetes (T2DM), GIP no longer modulates glucose-dependent insulin secretion, even at supraphysiological (pharmacological) plasma levels, and therefore GIP incompetence is detrimental to beta-cell function, especially after eating. GLP-1, on the other hand, is still insulinotropic in T2DM, and this has led to the development of compounds that activate the GLP-1 receptor with a view to improving insulin secretion. Since 2005, two new classes of drugs based on incretin action have been approved for lowering blood glucose levels in T2DM: an incretin mimetic (exenatide, which is a potent long-acting agonist of the GLP-1 receptor) and an incretin enhancer (sitagliptin, which is a DPP4 inhibitor). Exenatide is injected subcutaneously twice daily and its use leads to lower blood glucose and higher insulin levels, especially in the fed state. There is glucose-dependency to its insulin secretory capacity, making it unlikely to cause low blood sugars (hypoglycemia). DPP4 inhibitors are orally active and they increase endogenous blood levels of active incretins, thus leading to prolonged incretin action. The elevated levels of GLP-1 are thought to be the mechanism underlying their blood glucose-lowering effects.

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The Role of Incretins in Glucose Homeostasis and Diabetes Treatment

Purpose We evaluated whether the timing of fatal myocardial infarction (MI) was influenced by the administration of androgen suppression therapy (AST). Patients and Methods The study cohort comprised 1,372 men who were enrolled onto three randomized trials between February 1995 and June 2001. In the three trials, the men were randomly assigned to receive radiation therapy with 0 versus 3 versus 6, 3 versus 8, or 0 versus 6 months of AST. Fine and Gray's regression was used to determine the clinical factors associated with the time to fatal MI, and estimates of time to fatal MI were calculated using a cumulative incidence method. When comparing the cumulative incidence estimates using Gray's k-sample P values, increased weight was ascribed to the earlier data because recovery of testosterone is expected for most men within 2 years after short-course AST. Results Men age 65 years or older who received 6 months of AST experienced shorter times to fatal MIs compared with men in this age group who did not rece...

Influence of Androgen Suppression Therapy for Prostate Cancer on the Frequency and Timing of Fatal Myocardial Infarctions

Though gender-based differences in the development of protective or pathological adaptive host responses have been widely noted, it is becoming apparent that sex may also influence the early perception of microbial challenges and the generation of inflammatory immune responses. These differences may be due to the actions of reproductive hormones, and such a hypothesis is supported by the presence of receptors for these hormones in a variety of immune cell types. Androgens such as testosterone have been shown to decrease immune functions, including cytokine production. However, the mechanisms by which testosterone limits such responses remain undefined. In this study, we have investigated the acute effects of testosterone on the level of expression of a key trigger for inflammation and innate immunity, Toll-like receptor 4 (TLR4), on isolated mouse macrophages. We show that in vitro testosterone treatment of macrophages, generated in the absence of androgen, elicits a modest but significant decrease in TLR4 expression and sensitivity to a TLR4-specific ligand. In addition, we have studied the effect of in vivo removal of endogenous testosterone on TLR4 expression and endotoxin susceptibility. We report that orchidectomized mice were significantly more susceptible to endotoxic shock and show that macrophages isolated from these animals have significantly higher TLR4 cell surface expression than those derived from sham gonadectomized mice. Importantly, these effects were not apparent in orchidectomized animals that received exogenous testosterone treatment. As such, these data may represent an important mechanism underlying the immunosuppressive effects of testosterone.

https://bioone.org/journals/Biology-of-Reproduction/volume-78/issue-3/biolreprod.107.063545/Testosterone-Reduces-Macrophage-Expression-in-the-Mouse-of-Toll-Like/10.1095/biolreprod.107.063545.pdf

Testosterone Reduces Macrophage Expression in the Mouse of Toll-Like Receptor 4, a Trigger for Inflammation and Innate Immunity

Background— Immune responses participate in several phases of atherosclerosis; there is, in fact, increasing evidence that both adaptive immunity and innate immunity tightly regulate atherogenesis. Pentraxins are a superfamily of acute-phase proteins that includes short pentraxins such as C-reactive protein or long pentraxins such as PTX3, a molecule acting as the humoral arm of innate immunity. To address the potential role of PTX3 in atherogenesis, we first investigated the expression of PTX3 during atherogenesis, generated double-knockout mice lacking PTX3 and apolipoprotein E, and then studied the effect of murine PTX3 deficiency on plasma lipids, atherosclerosis development, and gene expression pattern in the vascular wall. Methods and Results— PTX3 expression increases in the vascular wall of apolipoprotein E–knockout mice from 3 up to 18 months of age. Double-knockout mice lacking PTX3 and apolipoprotein E were fed an atherogenic diet for 16 weeks. Aortic lesions were significantly increased in dou...

Deficiency of the Long Pentraxin PTX3 Promotes Vascular Inflammation and Atherosclerosis

A considerable body of evidence exists suggesting a link among reduced testosterone plasma levels, type 2 diabetes (T2D), and insulin resistance (IR). Hypogonadal men are at higher risk for T2D. Here we evaluate the relationships between testosterone, metabolic syndrome (MetS), T2D, and IR and discuss the relationships among androgen deficiency and these factors, especially as it ultimately relates to the development of cardiovascular disease and erectile dysfunction (ED). Thus, a comprehensive literature search was carried out using PubMed, and relevant articles pertinent to androgen deficiency, T2D, IR, MetS, and ED were reviewed and discussed. Low testosterone precedes elevated fasting insulin, glucose, and hemoglobin A1c (HbA1C) values and may even predict the onset of diabetes. Treatment of prostate cancer patients with surgical or medical castration exacerbates IR and glycemic control, strengthening the link between testosterone deficiency and onset of T2D and IR. Androgen therapy of hypogonadal men improves insulin sensitivity, fasting glucose, and HbA1c levels. We suggest that androgen deficiency is associated with IR, T2D, MetS, and with increased deposition of visceral fat, which serves as an endocrine organ, producing inflammatory cytokines and thus promoting endothelial dysfunction and vascular disease.

https://onlinelibrary.wiley.com/doi/pdf/10.2164/jandrol.108.005751

The Dark Side of Testosterone Deficiency: II. Type 2 Diabetes and Insulin Resistance

Context: An increasing body of evidence suggests that testosterone may exert beneficial effects on the development of atherosclerosis. It was suggested that testosterone may act after conversion into estradiol and activation of the estrogen receptors; however, a direct role of androgens on the vascular wall has been proposed. Objective: We investigated the effects of dihydrotestosterone on the proinflammatory response observed in human endothelial cells. Design: Human endothelial cells isolated from umbilical cords were incubated with lipopolysaccharide or TNFα in the presence or absence of dihydrotestosterone (DHT). mRNA and cellular proteins were processed for gene expression studies, and transient transfection experiments were performed to investigate molecular mechanisms involved in the effects observed. Setting: These studies took place at the Department of Pharmacological Sciences, University of Milan, Milan, Italy. Results: Lipopolysaccharide and TNFα induced VCAM-1 and ICAM-1 mRNA and protein expr...

Paul Maria Seccomandi

Papers

Dihydrotestosterone Decreases Tumor Necrosis Factor-α and Lipopolysaccharide-Induced Inflammatory Response in Human Endothelial Cells