Neuronal regulation of glucagon secretion and gluconeogenesis.

Hypoglycemia almost never develops in healthy individuals, because multiple hypoglycemia sensing systems, located in the periphery and in the central nervous system, trigger a coordinated counterregulatory hormonal response to restore normoglycemia. This involves not only the secretion of glucagon, but also of epinephrine, norepinephrine, cortisol and growth hormone. Increased hepatic glucose production is also stimulated by direct autonomous nervous connections to the liver that stimulate glycogenolysis and gluconeogenesis. This counterregulatory response, however, becomes deregulated in a significant fraction of diabetes patients that receive insulin therapy. This leads to the risk of developing hypoglycemic episodes, of increasing severity, which negatively impact the quality of life of the patients. How hypoglycemia is detected by the central nervous system is being actively investigated. Recent studies using novel molecular biological, optogenetic and chemogenetic techniques allow the characterization of glucose-sensing neurons, the mechanisms of hypoglycemia detection, the neuronal circuits in which they are integrated and the physiological responses they control. This review discusses recent studies aimed at identifying central hypoglycemia sensing neuronal circuits, how neurons are activated by hypoglycemia and how they restore normoglycemia

The SLC2 family of facilitated hexose and polyol transporters

The SLC2 family of glucose and polyol transporters comprises 13 members, the glucose transporters (GLUT) 1-12 and the H+-myo-inositol cotransporter (HMIT). These proteins all contain 12 transmembrane domains with both the amino and carboxy-terminal ends located on the cytoplasmic side of the plasma membrane and a N-linked oligosaccharide side-chain located either on the first or fifth extracellular loop. Based on sequence comparison, the GLUT isoforms can be grouped into three classes: class I comprises GLUT1-4; class II, GLUT6, 8, 10, and 12 and class III, GLUT5, 7, 9, 11 and HMIT. Despite their sequence similarity and the presence of class-specific signature sequences, these transporters carry various hexoses and HMIT is a H+/myo-inositol co-transporter. Furthermore, the substrate transported by some isoforms has not yet been identified. Tissue- and cell-specific expression of the well-characterized GLUT isoforms underlies their specific role in the control of whole-body glucose homeostasis. Numerous studies with transgenic or knockout mice indeed support an important role for these transporters in the control of glucose utilization, glucose storage and glucose sensing. Much remains to be learned about the transport functions of the recently discovered isoforms (GLUT6-13 and HMIT) and their physiological role in the metabolism of glucose, myo-inositol and perhaps other substrate

Intestinal absorption of glucose in mice as determined by positron emission tomography.

KEY POINTS:The goal was to determine the importance of the sodium-glucose cotransporter SGLT1 and the glucose uniporter GLUT2 in intestinal glucose absorption during oral glucose tolerance tests (OGTTs) in mice. Glucose absorption was determined in mice using positron emission tomography and three non-metabolizable glucose probes: one specific for SGLTs, one specific for GLUTs, and one a substrate for both SGLTs and GLUTs. Absorption was determined in wild-type, Sglt1-/- and Glut2-/- mice. Gastric emptying was a rate-limiting step in absorption. SGLT1, but not GLUT2, was important in fast glucose absorption. In the absence of SGLT1 or GLUT2, the oral glucose load delivered to the small intestine was slowly absorbed. Oral phlorizin only inhibited the fast component of glucose absorption, but it contributed to decreasing blood glucose levels by inhibiting renal reabsorption. ABSTRACT:The current model of intestinal absorption is that SGLT1 is responsible for transport of glucose from the lumen into enterocytes across the brush border membrane, and GLUT2 for the downhill transport from the epithelium into blood across the basolateral membrane. Nevertheless, questions remain about the importance of these transporters in vivo. To address these questions, we have developed a non-invasive imaging method, positron emission tomography (PET), to monitor intestinal absorption of three non-metabolized glucose tracers during standard oral glucose tolerance tests (OGTTs) in mice. One tracer is specific for SGLTs (α-methyl-4-[18 F]fluoro-4-deoxy-d-glucopyranoside; Me-4FDG), one is specific for GLUTs (2-deoxy-2-[18 F]fluoro-d-glucose; 2-FDG), and one is a substrate for both SGLTs and GLUTs (4-deoxy-4-[18 F]fluoro-d-glucose; 4-FDG). OGTTs were conducted on adult wild-type, Sglt1-/- and Glut2-/- mice. In conscious mice, OGTTs resulted in the predictable increase in blood glucose that was blocked by phlorizin in both wild-type and Glut2-/- animals. The blood activity of both Me-4FDG and 4-FDG, but not 2-FDG, accompanied the changes in glucose concentration. PET imaging during OGTTs further shows that: (i) intestinal absorption of the glucose load depends on gastric emptying; (ii) SGLT1 is important for the fast absorption; (iii) GLUT2 is not important in absorption; and (iv) oral phlorizin reduces absorption by SGLT1, but is absorbed and blocks glucose reabsorption in the kidney. We conclude that in standard OGTTs in mice, SGLT1 is essential in fast absorption, GLUT2 does not play a significant role, and in the absence of SGLT1 the total load of glucose is slowly absorbed

Role of Endogenous GLP-1 and GIP in Beta Cell Compensatory Responses to Insulin Resistance and Cellular Stress.

Role of GLP-1 and GIP in beta cell compensatory responses to beta cell attack and insulin resistance were examined in C57BL/6 mice lacking functional receptors for GLP-1 and GIP. Mice were treated with multiple low dose streptozotocin or hydrocortisone. Islet parameters were assessed by immunohistochemistry and hormone measurements were determined by specific enzyme linked immunoassays. Wild-type streptozotocin controls exhibited severe diabetes, irregularly shaped islets with lymphocytic infiltration, decreased Ki67/TUNEL ratio with decreased beta cell and increased alpha cell areas. GLP-1 and GIP were co-expressed with glucagon and numbers of alpha cells mainly expressing GLP-1 were increased. In contrast, hydrocortisone treatment and induction of insulin resistance increased islet numbers and area, with enhanced beta cell replication, elevated mass of beta and alpha cells, together with co-expression of GLP-1 and GIP with glucagon in islets. The metabolic responses to streptozotocin in GLP-1RKO and GIPRKO mice were broadly similar to C57BL/6 controls, although decreases in islet numbers and size were more severe. In contrast, both groups of mice lacking functional incretin receptors displayed substantially impaired islet adaptations to insulin resistance induced by hydrocortisone, including marked curtailment of expansion of islet area, beta cell mass and islet number. Our observations cannot be explained by simple changes in circulating incretin concentrations, suggesting that intra-islet GLP-1 and GIP make a significant contribution to islet adaptation, particularly expansion of beta cell mass and compensatory islet compensation to hydrocortisone and insulin resistance

Effects of inhaled salmeterol and salbutamol (albuterol) on morning dips compared in intensive care patients recovering from an acute severe asthma attack

Objective: To assess the effect of a long-acting inhaled β 2-agonist, salmeterol (SM), compared to a short-acting inhaled β 2-agonist, salbutamol (or albuterol, SB), on the occurrence of morning dip (MD) in patients recovering from an acute severe asthma attack (ASA). Design: Prospective study Setting: 18-bed, medical intensive care unit (ICU) in a university hospital. Patients: 19 patients suffering from an ASA. Interventions: Serial measurements of the peak expiratory flow rate (PEFR), arterial blood gases, vital capacity and forced expiratory volume in one second (FEV1) were performed from admission. All patients were first treated with i. v. methyl prednisolone and i.v. SB. Once the PEFR was stable and > 35 % of predicted value, i. v. SB was stopped while i. v. steroids were maintained, and patients were randomised to either inhaled SB (9 patients, 400 μg every 4 h) or inhaled SM (10 patients, 100 μg every 12 h). Results: The mean admission PEFR was 26.1 ± 11.7 % of the predicted value and was not different between the two groups. MD was more frequent with SB (6/9 patients) than with SM (4/10). The severity of MD, expressed in 1/min fall in PEFR, was higher in SB than in SM (106 ± 25 vs 55±37;p<0.05). Discussion: MD is frequent in ASA. In ASA, SM appears to reduce the frequency and the severity of MD more than SB. The clinical implications of this observation, particularly a lowering of mortality and a shortening of the ICU stay, remain to be investigate

Attitudes toward psychopharmacology among hospitalized patients from diverse ethno-cultural backgrounds

<p>Abstract</p> <p>Background</p> <p>Biological factors influencing individual response to drugs are being extensively studied in psychiatry. Strikingly, there are few studies addressing social and cultural differences in attitudes toward psychotropic medications. The objective of this study was to investigate ethno-culturally determined beliefs, expectations and attitudes toward medication among a sample of hospitalized psychiatric patients.</p> <p>Methods</p> <p>An ad hoc questionnaire was designed to assess patients' expectations, attitudes and prejudice toward medication. The study included 100 adult patients hospitalized in Geneva, Switzerland.</p> <p>Results</p> <p>Patients were in majority male (63%), originated from Switzerland (54%) and spoke the local language fluently (93%). They took on the average 3 different psychotropic drugs. Sixty-eight percent of patients expected side effects and 60% were ready to stop medication because of them. Thirty percent of patients expected negative personal changes with treatment and 34% thought that their mental disorder could have been treated without drugs. Thirty six percent of the sample used alternative or complementary medicines. 35% of immigrant patients believed that medication had different effects on them than on local patients. When compared with Swiss patients, they more often reported that significant others had an opinion about medication (p = 0.041) and more frequently valued information provided by other patients about treatment (p = 0.010).</p> <p>Conclusion</p> <p>Patients' attitudes toward medication should be investigated in clinical practice, as specific expectations and prejudice exist. Targeted interventions, especially for immigrant patients, might improve adherence.</p

SY30-3THE USE OF SOPHISMS IN SUSTAINING DISULFIRAM

Disulfiram's use is not supported by scientific evidence but nevertheless largely advocated and used. This would be less odd in case of lacking or just preliminary evidence. What is peculiar in the case of disulfiram's prescription is its persistence against evidence. Hence arise the question how it is possible that its use can be supported, i.e. by what type of arguments. The goal of an argument is to persuade, the goal of logic and argumentation is additionally to persuade for good reasons. In this sense, a good argument would give good reasons to believe the conclusion. Fallacies are bad arguments, either because they have weak logic, or because they rely on a false premise. Sophisms are intentionally used fallacies, an attempt to persuade opponents that a specific conclusion is true, by means other than by proposing relevant evidence. Proponents of fallacious arguments may use them either because they are incapable or because they are unwilling to accept their arguments to be fallacious. We therefore formulate the hypothesis that the frequency use of fallacious arguments within our otherwise supposedly evidence based discipline may be indicative of (a) a scientifically immature discipline, and/or (b) a moralistically intermingled disciplin