Mechanisms for the antihyperglycemic effect of sitagliptin in patients with type 2 diabetes

Context: Dipeptidyl peptidase IV (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes. The underlying mechanisms (incretin effect, β-cell function, endogenous glucose production) are not well known. Objective: The aim of the study was to examine mechanisms of the antihyperglycemic effect of DPP-4 inhibitors. Design, Setting, and Patients: We administered a mixed meal with glucose tracers ([6,6-(2)H(2)]-glucose infused, [1-(2)H]-glucose ingested), and on a separate day, a glucose infusion matched the glucose responses to the meal (isoglycemic test) in 50 type 2 diabetes patients (hemoglobin A(1c) = 7.4 ± 0.8%) and seven controls; 47 diabetic completers were restudied after 6 wk. Glucose fluxes were calculated, and β-cell function was assessed by mathematical modeling. The incretin effect was calculated as the ratio of oral to iv insulin secretion. Intervention: We conducted a 6-wk, double-blind, randomized treatment with sitagliptin (100 mg/d; n = 25) or placebo (n = 22). Results: Relative to placebo, meal-induced changes in fasting glucose and glucose area under the curve (AUC) were greater with sitagliptin, in parallel with a lower appearance of oral glucose [difference (post-pre) AUC = -353 ± 915 vs. +146 ± 601 μmol · kg(-1) · 5 h] and greater suppression of endogenous glucose production. Insulin sensitivity improved 10%, whereas total insulin secretion was unchanged. During the meal, β-cell glucose sensitivity improved (+19[29] vs. 5[21] pmol · min(-1) · m(-2) · mm(-1); median [interquartile range]) and glucagon AUC decreased (19.6 ± 7.5 to 17.3 ± 7.1 ng · ml(-1) · 5 h), whereas intact glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 AUC increased with sitagliptin vs. placebo. The incretin effect was unchanged because sitagliptin increased β-cell glucose sensitivity also during the isoglycemic test. Conclusions: Chronic sitagliptin treatment improves glycemic control by lowering the appearance of oral glucose, postprandial endogenous glucose release, and glucagon response, and by improving insulin sensitivity and β-cell glucose sensing in response to both oral and iv glucose.     

An observational study addressing the anatomic basis of mesosigmoidopexy as a rational treatment of non-gangrenous sigmoid volvulus

Sigmoid volvulus is a common cause of bowel obstruction. We describe mesosigmoidopexy, an accepted surgical technique for the management of non-gangrenous sigmoid volvulus, and provide anatomic correlations supporting the therapy. Mesosigmoidopexy should be considered as a rational alternative to resection and anastomosis when operating on non-gangrenous sigmoid volvulus.     

Child maltreatment: variation in trends and policies in six developed countries

We explored trends in six developed countries in three types of indicators of child maltreatment for children younger than 11 years, since the inception of modern child protection systems in the 1970s. Despite several policy initiatives for child protection, we recorded no consistent evidence for a decrease in all types of indicators of child maltreatment. We noted falling rates of violent death in a few age and country groups, but these decreases coincided with reductions in admissions to hospital for maltreatment-related injury only in Sweden and Manitoba (Canada). One or more child protection agency indicators increased in five of six countries, particularly in infants, possibly as a result of early intervention policies. Comparisons of mean rates between countries showed five-fold to ten-fold differences in rates of agency indicators, but less than two-fold variation in violent deaths or maltreatment-related injury, apart from high rates of violent child death in the USA. These analyses draw attention to the need for robust research to establish whether the high and rising rates of agency contacts and out-of-home care in some settings are effectively reducing child maltreatment.     

Mapping of alpha-neo-endorphin- and neurokinin B-immunoreactivity in the human brainstem

We have studied the distribution of alpha-neo-endorphin- or neurokinin B-immunoreactive fibres and cell bodies in the adult human brainstem with no prior history of neurological or psychiatric disease. A low density of alpha-neo-endorphin-immunoreactive cell bodies was only observed in the medullary central gray matter and in the spinal trigeminal nucleus (gelatinosa part). Alpha-neo-endorphin-immunoreactive fibres were moderately distributed throughout the human brainstem. A high density of alpha-neo-endorphin-immunoreactive fibres was found only in the solitary nucleus (caudal part), in the spinal trigeminal nucleus (caudal part), and in the gelatinosa part of the latter nucleus. Neurokinin B-immunoreactive cell bodies (low density) were found in the periventricular central gray matter, the reticular formation of the pons and in the superior colliculus. The distribution of the neurokinin-immunoreactive fibres was restricted. In general, for both neuropeptides the density of the immunoreactive fibres was low. In the human brainstem, the proenkephalin system was more widely distributed than the prodynorphin system, and the preprotachykinin A system (neurokinin A) was more widely distributed than the preprotachykinin B system (neurokinin B).     

Development of an animal model to investigate optimal laparoscopic trocar site fascial closure

Background

The rate of hernia formation after closure of 10–12 mm laparoscopic trocar sites is grossly under-reported. Using an animal model, we have developed a method to assess trocar site fascial dehiscence and the strength of different methods of fascial closure.

Materials and methods

Pigs (n = 9; 17 ± 2.5 lbs) underwent placement of 12 mm Hasson trocars with pneumoperitoneum maintained for 1 h. Three closure techniques (Figure-of-eight; simple interrupted; pulley) were compared with no fascial closure and to native fascia at five randomly allocated abdominal wall midline locations. Necropsy was performed on the fourth postoperative d. Statistical comparisons of tensile strength and breaking strength based on closure type and trocar location were made using ANOVA with Tukey’s tests.

Results

The mean (SD) force (Newtons) required for fascial disruption varied significantly with closure type [Native Fascia 170 (39), Figure-of-eight 169 (31), Pulley 167 (59), Simple Interrupted 151 (27), No Closure 108 (28)]; P = 0.007. The mean force required for fascial disruption was significantly increased for Native Fascia, Figure-of-eight, and Pulley relative to No Closure (P = 0.013, P = 0.015, P = 0.023, respectively). The mean (SD) force (in Newtons) required for fascial disruption also varied significantly with location of trocar [subxiphoid 181 (43), supraumbilical 151 (23), Umbilical 146 (23), infraumbilical 168 (62), suprapubic 120 (38)]; P = 0.03. The mean force for subxiphoid location was significantly increased relative to the suprapubic location (P = 0.021).

Conclusions

We have developed a novel assessment model that reliably detects differences in fascial integrity after laparoscopic trocar placement and closure. This model will allow for further testing of various trocars and closure techniques, and facilitate hernia prevention strategies.     

Resultados de la esofagectomía por cáncer tras la creación de un Comité de Tumores Esofagogástricos

Introduction

Treatment of oesophageal cancer with curative intent requires a multidisciplinary approach. Neoadjuvant therapy, the radicality of resection and extension of lymphadenectomy have been associated with increased operative morbidity and mortality. The aim of this study was to assess the results of surgical treatment of oesophageal cancer since the presence of an interdisciplinary esophagogastric tumour board.

Methods

Patients with cancer of the oesophagus and oesophagogastric junction who underwent oesophagectomy between January 2005 and March 2012 were included in this retrospective study. Data concerning type of resection, postoperative complications, mortality and survival were analysed.

Results

Of the 392 patients with a diagnosis of oesophageal cancer over the study period, 100 underwent oesophagectomy. Seventy-four patients received neoadjuvant treatment. Eighty-two patients underwent transthoracic resection while a transhiatal was used in 10 patients. Colon interposition was required in 8 cases. An R0 resection was achieved in 98 patients. Anastomotic leaks developed in 15 patients, 9 were intrathoracic and 6 were cervical. Postoperative morbidity occurred in 42% of patients, and intra-hospital and 90-day mortality was 2%. Median length of hospital stay was 16 days. The respective actuarial survival at 1 and 5 years were 82% and 56%.

Conclusions

Surgical treatment with curative intention for oesophageal cancer is only possible in a quarter of patients diagnosed. The high morbidity rate was mainly due to intrathoracic complications.     

Obesidomics: contribution of adipose tissue secretome analysis to obesity research

Obesity is presently reaching pandemic proportions and it is becoming a major health concern in developed and developing countries due to its comorbidities like type II diabetes, cardiovascular pathologies, and some cancers. The discovery of the adipose tissue role as an endocrine gland able to secrete adipokines that affects whole-body energy homeostasis has become a key break-through toward a better molecular understanding of obesity. Among the known adipokines involved in the regulation of energy metabolism very few have been clearly seen as central regulators of insulin sensitivity, metabolism, and energy homeostasis. Thus, the discovery and characterization of new adipocyte-derived factors is still in progress. Proteomics technology has emerged as a useful tool to analyze adipose tissue secretion (secretome) dynamics giving a wider picture into the molecular events that control body weight. Besides the identification of new secreted proteins, the advantage of using this approach is the possibility to detect post-translational modifications and protein interactions that generally cannot be predicted by genome studies. In this review, we summarize the recent efforts to identify new bioactive adipokines by proteomics especially in pathological situations such as obesity.