Glucose lowering and anti-atherogenic effects of incretin-based therapies: GLP-1 analogues and DPP-4-inhibitors

BACKGROUND: Type 2 diabetes is a chronic, progressive disease with a multi-faceted pathophysiology. Beyond the known defects of insulin resistance and beta-cell insufficiency, derangement of incretin hormones normally produced from the gut wall in response to food intake play an important role. In recent years, the 'incretin-based' therapies (IBTs) have been developed to address hyperglycemia through either mimicking the action of the endogenous incretin glucagon-like polypeptide (GLP-1) (GLP-1 receptor agonists) or by inhibiting the activity of the enzyme that degrades GLP-1 (the dipeptyl peptidase-4 inhibitors). OBJECTIVE: We reviewed available evidence on the glucose lowering and anti-atherogenic effects of IBT. RESULTS: In addition to their glucose-lowering and weight-neutral or weight-reducing actions, IBT decrease systolic blood pressure and improve fasting and postprandial lipid parameters by reducing total-cholesterol, low-density lipoprotein-cholesterol and triglycerides concentrations, and increasing high-density lipoprotein-cholesterol values. Reduced high-sensitivity C-reactive protein levels and improved endothelial dysfunction have been reported too. CONCLUSIONS: IBT have several beneficial effects on cardiovascular risk factors and, for this reason, it has been recently suggested to extend the use of these drugs in diabetic patients with cardiovascular complications. Yet, the long-term effects of IBT on subclinical or clinical atherosclerosis remain to be established by future studies

Hypoglycemia in response to glucose and glucagon in insulinoma patients with a negative prolonged fast: Functional and morphological properties

A negative 72-h fast is usually considered to preclude the diagnosis of insulinoma. The aim of this study was to describe the functional and morphological properties of two exceptional patients with an insulinoma who had exhibited pre-operatively a negative 72-h fast. Despite the ability of tumor cells to turn off insulin secretion in response to low plasma glucose during 72 h of fasting, hyperinsulinemic hypoglycemia occurred in both patients in response to stimulation by classical secretagogues. Pre-operatively, both patients underwent oral and iv glucose challenge tests and iv glucagon stimulation test. Insulin secretion was rapidly stimulated by these secretagogues to an exaggerated extent and thereby caused hypoglycemia due to an insulin mass effect. In contrast to the common functional features during suppression and stimulation tests, the tumors differed widely with regard to insulin and proinsulin response to calcium during ASVS tests and morphological properties. In patient 1, the immunohistochemical proinsulin distribution pattern resembled that of normal γ-cells, i.e. the staining was restricted to the perinuclear area; insulin and proinsulin were not stimulated by calcium during the ASVS test. In patient 2, the proinsulin staining pattern was abnormal, i.e. proinsulin was also found in the periphery of tumor cells; insulin and proinsulin were stimulated by calcium. We conclude that normal or exaggerated rather than defective glucose sensing may explain hypoglycemia in these exceptional insulinoma patients. Different functional characteristics of these tumors can be correlated with distinct morphological propertie

Rare jaw bone tumor: The importance of multidisciplinary management and minimally invasive treatment

Objective: The aim of this study was to present a mini review of oral Cementoblastoma and to report a particular case of this tumor. The Cementoblastoma is a rare benign lesion that represents less than 1-6% of all odontogenic tumors. Cementoblastoma, in the current WHO classification of odontogenic tumors, falls under the category of mesenchymal tumors (WHO 2017) and it is characterized by the proliferation of cementum-like tissue and, in all cases, tends to be associated with an erupting permanent tooth, most often the first molar. Case Presentation: A 15-year-old female presented a great Cementoblastoma with cortical expansion that affected the left mandibular body, extending from the canine to the first premolar (size 28x24 mm) and involving the mandibular canal. Surgery was performed under general anesthesia with total excision of the lesion, which was then sent for histological analysis. Due to the high risk of nerve injuries and the extreme fragility of the remaining bone after surgery, which required plates and intermaxillary blockage, the surgical site was regenerated with an iliac crest graft together with autologous and synthetic bone. Results: For the mini-review, 107 articles were found, but only 26 were selected. The patient was monitored for 12 months after surgery; a perfect healing was reported without complications, and she showed no signs of recurrence. Conclusions: This case report emphasizes the usefulness of clinical choices in a rare case of cementoblastoma of great size in a very young patient. In this condition, finding the most effective eradicative and reconstructive treatment, following the last published protocols, could achieve optimal clinical and psychological patient outcomes

Atherogenic forms of dyslipidaemia in women with polycystic ovary syndrome

OBJECTIVE: Dyslipidaemia is very common in patients with polycystic ovary syndrome (PCOS) but, beyond plasma lipids, atherogenic lipoprotein (Lp) and apolipoprotein (apo) alterations are still ill defined. DESIGN: We measured concentrations of apoB, Lp(a) and small, dense low-density lipoprotein (LDL) in 42 patients with PCOS [age: 28 +/- 7 years, body mass index (BMI): 27 +/- 5 kg/m(2)] vs. 37 age- and BMI-matched healthy controls. METHODS: Elevated Lp(a) levels considered were those > 30 mg/dl while elevated apoB concentrations were those > 100 g/l. RESULTS: Polycystic ovary syndrome showed increased triglycerides levels (p = 0.0011) and lower high-density lipoprotein (HDL)-cholesterol concentrations (p = 0.0131) while total- and LDL cholesterol were similar. PCOS also showed smaller LDL size (p = 0.0005), higher levels of total small, dense LDL (p < 0.0001), higher concentrations of Lp(a), as considered as absolute values (p = 0.0143) and log-transformed (p = 0.0014), while no differences were found in apoB levels. Elevated Lp(a) concentrations were found in 24% of PCOS, while elevated apoB levels were relatively uncommon (14%). Spearman correlation analysis revealed that Lp(a) concentrations were weakly correlated only with HDL-cholesterol levels (r = -0.378, p = 0.0431). In addition, 36% of patients with PCOS with normal plasma lipid profile showed elevated levels of Lp(a), apoB or small, dense LDL. CONCLUSIONS: Atherogenic Lp abnormalities may be found in one-third of women with PCOS who have a normal lipid pattern. Future prospective studies are needed to test to which extent such atherogenic forms of dyslipidaemia may contribute to the increased cardiovascular risk in young women with PCOS

Recurrent aphthous stomatitis: Treatment and management

Background: Recurrent aphthous stomatitis consists of the presence of abrasions or ulcerations located on mucosae (oral or genital). Objectives: The aim of this article is to review the current literature providing the main causes related to recurrent aphthous stomatitis and insights into treatment and management of this clinical condition Methods: Articles matching terms that correlated with "recurrent aphthous stomatitis"were searched on PubMed, EMBASE, and Cochrane Library and selected according to their pertinence. Results: Several forms of aphthous stomatitis have been described, based on the extent (minor, major), morphology (herpetiform) and associations to other signs (Beh\ue7et syndrome or more complex inflammatory syndromes). Topical as well as systemic treatments have been described to obtain a faster remission of the aphthosis or to reduce associated symptoms such as pain. Conclusions: Recurrent aphthous stomatitis can have a mild-to-severe clinical appearance, being mainly localized on the oral mucosa or at the level of the genital area. Different strategies have been described so far for its management and treatment

Glucose-stimulated insulin production in mice deficient for the PAS kinase PASKIN.

The Per-ARNT-Sim (PAS) domain serine/threonine kinase PASKIN, or PAS kinase, links energy flux and protein synthesis in yeast and regulates glycogen synthase in mammals. A recent report suggested that PASKIN mRNA, protein, and kinase activity are increased in pancreatic islet beta-cells under hyperglycemic conditions and that PASKIN is necessary for insulin gene expression. We previously generated Paskin knockout mice by targeted replacement of the kinase domain with the beta-geo fusion gene encoding beta-galactosidase reporter activity. Here we show that no 5-bromo-4-chloro-3-indolyl-ss-d-galactopyranoside (X-gal) staining was observed in islet beta-cells derived from Paskin knockout mice, irrespective of the ambient glucose concentration, whereas adenoviral expression of the lacZ gene in beta-cells showed strong X-gal staining. No induction of PASKIN mRNA could be detected in insulinoma cell lines or in islet beta-cells. Increasing glucose concentrations resulted in PASKIN-independent induction of insulin mRNA levels and insulin release. PASKIN mRNA levels were high in testes but undetectable in pancreas and in islet beta-cells. Finally, blood glucose levels and glucose tolerance after intraperitoneal glucose injection were indistinguishable between Paskin wild-type and knockout mice. These results suggest that Paskin gene expression is not induced by glucose in pancreatic beta-cells and that glucose-stimulated insulin production is independent of PASKIN

Excessive Food Intake, Obesity and Inflammation Process in Zucker fa/fa Rat Pancreatic Islets

Inappropriate food intake-related obesity and more importantly, visceral adiposity, are major risk factors for the onset of type 2 diabetes. Evidence is emerging that nutriment-induced β-cell dysfunction could be related to indirect induction of a state of low grade inflammation. Our aim was to study whether hyperphagia associated obesity could promote an inflammatory response in pancreatic islets leading to ß-cell dysfunction. In the hyperphagic obese insulin resistant male Zucker rat, we measured the level of circulating pro-inflammatory cytokines and estimated their production as well as the expression of their receptors in pancreatic tissue and β-cells. Our main findings concern intra-islet pro-inflammatory cytokines from fa/fa rats: IL-1β, IL-6 and TNFα expressions were increased; IL-1R1 was also over-expressed with a cellular redistribution also observed for IL-6R. To get insight into the mechanisms involved in phenotypic alterations, abArrays were used to determine the expression profile of proteins implicated in different membrane receptors signaling, apoptosis and cell cycle pathways. Despite JNK overexpression, cell viability was unaffected probably because of decreases in cleaved caspase3 as well as in SMAC/DIABLO and APP, involved in the induction and amplification of apoptosis. Concerning β-cell proliferation, decreases in important cell cycle regulators (Cyclin D1, p35) and increased expression of SMAD4 probably contribute to counteract and restrain hyperplasia in fa/fa rat islets. Finally and probably as a result of IL-1β and IL-1R1 increased expressions with sub-cellular redistribution of the receptor, islets from fa/fa rats were found more sensitive to both stimulating and inhibitory concentrations of the cytokine; this confers some physiopathological relevance to a possible autocrine regulation of β-cell function by IL-1β. These results support the hypothesis that pancreatic islets from prediabetic fa/fa rats undergo an inflammatory process. That the latter could contribute to β-cell hyperactivity/proliferation and possibly lead to progressive β-cell failure in these animals, deserves further investigations

Simultaneous islet-kidney vs pancreas-kidney transplantation in type 1 diabetes mellitus: a 5 year single centre follow-up

AIMS/HYPOTHESIS: The aim of this study was to compare the long-term outcomes-in terms of glucose control, renal function and procedure-related complications-of simultaneous islet-kidney (SIK) transplantation with those of simultaneous pancreas-kidney (SPK) transplantation in patients with type 1 diabetes mellitus. METHODS: HbA(1c), need for insulin, GFR and complication rate were compared between 13 recipients of SIK and 25 recipients of SPK transplants at the same institution. The mean follow-up was 41 months. RESULTS: Two primary organ non-functions occurred in the SIK group. HbA(1c) did not differ at any time point during follow-up in the SIK group compared with the SPK group (mean during follow-up 6.3 vs 5.9%). Similarly, kidney function over time was not different between the two groups. A higher rate of insulin independence following SPK transplantation (after 1 year 96 vs 31% in the SIK group) was counterbalanced by a higher rate of serious adverse events (40% relaparotomies vs 0% in the SIK group). CONCLUSIONS/INTERPRETATION: The endogenous insulin production achieved by islet transplantation, combined with optimal insulin therapy, was sufficient for maintaining near-normal glucose levels. In terms of glucose control, islet transplantation provides results comparable to those achieved with pancreas transplantation. However, SPK results in a higher rate of insulin independence, albeit at the cost of more surgical complications. These results have led to a new paradigm in islet transplantation at our institution, where the primary goal is not insulin independence, but good glucose control and avoidance of severe hypoglycaemia

Diabetes melitus Typ 1 - neue Entwicklungen in der intensivierten Insulintherapie

Die intensivierte Insulintherapie wurde durch das Mittel der kontinuierlichen Glukosemessung erweitert. Die Kombination von Insulinpumpe und kontinuierlicher Glukosemessung verbessert die Blutzuckerkontrolle, bedarf aber nach wie vor der Bedienung durch den Patienten. Für die Berechnung der notwendigen Insulinboli steht eine breite Palette von Bolusrechnern zur Verfügung