Progress in the oral treatment of type 2 diabetes: update on DPP-IV inhibitors.

Abstract: Glucagon-like peptide-1 (GLP-1) is a gut hormone that plays an important role in regulating glucose homeostasis by both its pancreatic and extrapancreatic activity. Defects of GLP-1 characterize type 2 diabetes as a primary or perhaps consequent phenomenon, resulting in inappropriately low insulin secretion after oral ingestion of nutrients. The discovery that cleavage by the ubiquitous enzyme dipeptidyl peptidase-IV (DPP-IV) is the primary route of GLP-1 metabolism formed the rationale behind the proposal to prevent degradation of endogenously released GLP-1 by DPP-IV inhibition as a novel approach to the management of type 2 diabetes. Enhanced insulin secretion as well as delayed gastric emptying, reduced glucagon secretion, and inhibited apoptosis of beta cells resulting from blockade of incretin degradation, have been proposed as the major actions of DPP-IV inhibitors as antidiabetic agents. Clinical studies to date indicate that DPP-IV inhibitors effectively ameliorate islet dysfunction and improve glucose control in patients with type 2 diabetes. They appear to have excellent therapeutic effectiveness as monotherapy in patients inadequately controlled with diet and exercise and as add-on therapy in combination with metformin, thiazolidinediones, and insulin. Their pharmacokinetic and pharmacodynamic profiles support once-daily dosing, with relatively few adverse effects

Ultrastructural mucosal alterations and increased intestinal permeability in non-celiac, type I diabetic patients

Background. Increased intestinal permeability was described in several intestinal auto-immune conditions. There are very few and con- tradictory reports about type I diabetes mellitus, an auto-immune condition sometimes associated with celiac disease. Aims. To investigate intestinal permeability in type I diabetes mellitus patients with no concomitant celiac disease, with a comparison to ultra-structural aspects of duodenal mucosa. Patients. 46 insulin dependent diabetes mellitus, non-celiac, patients (18 females and 28 males, mean age 15.8 ± 5.3 [S.D.] years) were enrolled. The mean duration of the disease was 5.7 years. Methods. The morphological aspect of the small bowel mucosa, at standard light microscopy and electron transmission microscopy, along with intestinal permeability (by lactulose/mannitol test) were studied. Lactulose and mannitol urinary excretion were determined by means of high performance anion exchange chromatography–pulsed amperometric detection. Results. The lactulose/mannitol ratio was 0.038 [0.005 − 0.176] (median and range) in 46 patients compared to 0.014 [0.004 − 0.027] in 23 controls: insulin dependent diabetes mellitus group values being significantly higher than those of the controls (P < 0.0001, Mann–Whitney test). Eight insulin dependent diabetes mellitus patients underwent endoscopy and biopsies were analysed by means of light microscopy and transmission electron microscopy. At the light microscopy level, none of the biopsy samples showed any sign of atrophy nor inflammation, whereas transmission electron microscopy analysis showed remarkable ultra-structural changes in six out of the eight patients. Four parameters were evaluated: height and thickness of microvilli, space between microvilli and thickness of tight junctions. Conclusions. This alteration of intestinal barrier function in non-celiac type I diabetes mellitus, frequently associated with mucosal ultra-structural alterations, could suggest that a loss of intestinal barrier function can be a pathogenetic factor in a subset of insulin dependent diabetes mellitus patients

Acute pressor and hormonal effects of beta-endorphin at high doses in healthy and hypertensive subjects: role of opioid receptor agonism.

Context: The opioid system is involved in blood pressure regulationin both normal humans and patients with essential hypertension. Objective: The objective of the study was to investigate the effects of a high-dose infusion of *-endorphin, an opioid peptide, on blood pressure and on the hormonal profile in healthy subjects and in hypertensive patients and the mediation played by opioid receptor agonism. Design, Setting, and Participants: According to a randomized double- blind design, 11 healthy subjects (controls) and 12 hypertensive inpatients(mean age, 38.9 and 40.4 yr, respectively) received 1-h iv infusion of *-endorphin (250 *g/h) and, on another occasion, the same infusion protocol preceded by the opioid antagonist naloxone (8 mg). Main Outcome Measures: Hemodynamic and hormonal measurements were performed at established times during the infusion protocols. Results: At baseline, circulating *-endorphin, norepinephrine, and endothelin-1 in hypertensive patients were significantly (P * 0.05) higher than in controls. In controls, *-endorphin reduced blood pressure(P * 0.01) and circulating norepinephrine (P * 0.02) and increased plasma atrial natriuretic factor (P * 0.003) and GH (P * 0.0001). In hypertensive patients, *-endorphin decreased systemic vascular resistance (P * 0.0001), blood pressure (P * 0.0001), and plasma norepinephrine (P * 0.0001) and endothelin-1 (P * 0.0001) and raised circulating atrial natriuretic factor (P * 0.0001), GH (P * 0.0001), and IGF-I (P * 0.0001). These hemodynamic and hormonal responses to *-endorphin in hypertensive patients were significantly (P * 0.0001) greater than in controls but were annulled in all individuals when naloxone preceded *-endorphin infusion. Conclusions: High doses of *-endorphin induce hypotensive and beneficial hormonal effects in humans, which are enhanced in essential hypertension and are mediated by opioid receptor

The Vascular Smooth Muscle Cells Apoptosis in Asymptomatic Diabetic Carotid Plaques: Role of Glycemic Control

Although it has been demonstrated that diabetes mellitus may enhance apoptosis in myocardial (4) and endothelial cells (5), still, no evidence exists in humans about the potential role of diabetes in the evolution of diabetic atherosclerotic plaques toward instability by enhancing VSMC apoptosis. We hypothesize that by enhancing the proinflammatory cytokines, diabetes may exert proapoptotic effects on VSMCs of atherosclerotic plaque. To address these issues, cell death by apoptosis and expression and localization of TNF-9 and IL-1b was evaluated in carotid plaques of asymptomatic diabetic and nondiabetic patients. The study group consisted of 26 type 2 diabetic and 30 nondiabetic patients enlisted to undergo carotid endarterectomy for asymptomatic extracranial high-grade (.70%) internal carotid artery stenosi