Gliquidone ameliorates hepatic insulin resistance in streptozotocin-induced diabetic Sur1-/- rats.

Gliquidone was suggested to exert hypoglycemic effect through enhancing hepatic insulin sensitivity. However, inadequate in vivo evidences make this statement controversial. The aim of the present study was to clarify the insulin-sensitizer role of gliquidone in liver and muscle, so as to confirm its extra-pancreatic effects in vivo. TALEN technique was used to create Sur1 knockout (Sur1-/-) rats. Diabetic Sur1-/- rat models were established by high-fat diet combined with streptozotocin, and which were randomly divided into three groups: gliquidone, metformin and saline, treated for 8 weeks. Fasting blood glucose (FBG) and body mass were tested each week. IPGTT, IPITT and hyperinsulinemic-euglycemic clamp tests were used to evaluate glucose tolerance and insulin sensitivity, respectively. Key mediators of glucose metabolism in liver and skeletal muscle and the activity of AKT and AMPK in these tissues were further analyzed. We found that gliquidone decreased FBG and increased insulin sensitivity without increasing insulin secretion in diabetic Sur1-/- rats. Further exploration implied that gliquidone mainly increased hepatic glycogen storage and decreased gluconeogenesis, which were accompanied with activation of AKT, but not enhanced muscle GLUT4 expression. However, both these effects were still weaker than that of metformin. These results suggested that gliquidone could exerts an extra-pancreatic hypoglycemic effect by improving insulin sensitivity, which might be largely attributes to its additional insulin sensitizer role in hepatic glucose metabolism.

Adult Proinsulinomatosis Associated With a MAFA Germline Mutation as a Rare Cause of Recurrent Hypoglycemia.

ABSTRACT: Sporadic adult insulinomatosis is an extremely rare clinical condition. Adult proinsulinomatosis has not yet been described. We report the case of a 48-year-old female patient with recurrent hypoglycemia caused by benign proinsulin-secreting pancreatic neuroendocrine neoplasias (pNENs) with no history of multiple endocrine neoplasia type 1. Initial workup revealed elevated serum proinsulin levels and a positive fasting test. Magnetic resonance imaging and endosonography visualized 2 pNENs in the pancreatic body and tail that were treated by robotic-assisted enucleation. After initial biochemical cure, the patient's hypoglycemia recurred 3 months after surgery. Imaging showed a new lesion in the pancreatic body, so that now a spleen-preserving subtotal distal pancreatectomy was performed. The pathological examination revealed 17 neuroendocrine microadenomas and 1 well-differentiated pNEN (Ki-67% 1%-2%) of 22-mm size as well as more than 200 (pro)insulin-producing ß-cell precursor lesions, confirming the diagnosis of adult proinsulinomatosis. Mutation analysis of the germline DNA identified the in-frame deletion mutation (p.His207del) in the MAFA gene on chromosome 8. The patient was biochemically cured 16 months after the last surgical resection. Similarly to adult insulinomatosis, the presence of proinsulin-secreting tumors causes recurrent hypoglycemia and might be associated with germline mutations in the MAFA gene.

Hypoglycaemic activity of Bauhinia holophylla through GSK3-ß inhibition and glycogenesis activation.

CONTEXT: Bauhinia L. species, including Bauhinia holophylla (Bong.) Steud. (Fabaceae), have traditionally been used to treat diabetes. Bauhinia is a complex botanical genus, and the indiscriminate use of the diverse Bauhinia species is reflected in the experimental divergence of their medicinal potential. OBJECTIVE: The hypoglycaemic and hypolipidaemic effects, molecular mechanism of action and phytochemical properties of an authentic extract of B. holophylla leaves were evaluated. MATERIALS AND METHODS: A phytochemical study of a 70% EtOH extract was performed using FIA-ESI-IT-MS/MSn and HPLC-PAD-ESI-IT-MS. The extract (200 or 400 mg/kg b.w.) was administered for 14 days to streptozotocin-induced diabetic Swiss mice. Glucose tolerance and insulin sensitivity, blood parameters, gene and protein expression, and the in vivo and in vitro inhibition of intestinal glucosidases were assessed. RESULTS: HPLC-PAD-ESI-IT-MS analysis identified flavonoid derivatives of quercetin, myricetin, luteolin and kaempferol. Treatment with 400 mg/kg of the extract reduced blood glucose (269.0 ± 32.4 mg/dL vs. 468.0 ± 32.2 mg/dL for diabetic animals), improved glucose tolerance, decreased cholesterol and triglyceride levels, and increased the mRNA expression of proteins involved in glucogenesis in the liver and muscle, such as PI3-K/Akt, GS, GSK3-ß (ser-9), AMPK and Glut4. The activity of intestinal maltase was inhibited in vitro (IC50: 43.0 µg/mL for the extract compared to 516.4 µg/mL for acarbose) and in vivo. DISCUSSION AND CONCLUSIONS: Treatment with B. holophylla was associated with a marked hypoglycaemic effect through the stimulation of glycogenesis and inhibition of gluconeogenesis and intestinal glucose absorption, without increasing basal insulinaemia.

The integrated glucose insulin minimal model: An improved version.

This paper describes the improved integrated minimal model for healthy subjects and patients with type 2 diabetes and the work leading up to this model. The original integrated minimal model characterizes simultaneously glucose and insulin following intravenous glucose tolerance test (IVGTT) in healthy subjects and provides apart from estimates of indices for insulin sensitivity (Si) and glucose effectiveness (SG), also full simulation capabilities. However, this model was developed using IVGTT data of total glucose and consequently, the model cannot separate hepatic glucose production from glucose disposal. By fitting the original integrated minimal model to IVGTT data of labelled and total glucose, we show that all parameter estimates of the glucose sub-model were significantly different between the fits, in particular, SG, which was ~3 fold higher with total, compared to labelled glucose. In addition, the time profiles of hepatic glucose production, obtained from the model, were unphysiological in most subjects. To correct these flaws, we developed the improved integrated minimal model based on the non-integrated, two-compartment minimal model. The improved integrated minimal model showed physiologically plausible dynamic time profiles of hepatic glucose production and all parameter estimates were compatible with those reported in original publication of the non-integrated minimal model. The integrated minimal model offers the benefits of the original integrated minimal model with simulation capabilities, in presence of endogenous insulin, combined with the benefits of the non-integrated minimal model, which accurately estimates the clinical indices of insulin sensitivity and glucose effectiveness. In addition, the improved integrated minimal model describes, apart from healthy subjects, also patients with type 2 diabetes.

Association Between Blood Glucose and Functional Outcome in Intracerebral Hemorrhage: A Systematic Review and Meta-Analysis.

BACKGROUND: Intracerebral hemorrhage (ICH) is a devastating subtype of stroke. Patients with ICH have poor functional outcomes. The association between blood glucose level and functional outcome in ICH remains unclear. This systematic review and meta-analysis aimed to investigate the association between blood glucose level and functional outcomes in patients with ICH. METHODS: Literature was searched systemically in PubMed, EMBASE, Web of Science, and Cochrane Library. Published cohort studies evaluating the association between blood glucose and functional outcome in patients with ICH were included. This meta-analysis was performed using odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: A total of 16 studies were included in our meta-analysis. Our data show that hyperglycemia defined by cutoff values was significantly associated with unfavorable functional outcome (OR, 1.80; 95% CI, 1.36-2.39; P < 0.001). Our analysis also suggested a significant association between increased blood glucose levels and functional outcomes (OR, 1.05; 95% CI, 1.03-1.07; P < 0.001). CONCLUSIONS: High blood glucose level is significantly associated with poor functional outcome in ICH. Further studies with larger sample sizes, more time points, and longer follow-up times are necessary to confirm this association.

Impact of C-Peptide Status on the Response of Glucagon and Endogenous Glucose Production to Induced Hypoglycemia in T1DM.

Context: Complete loss of ß-cell function in patients with type 1 diabetes mellitus (T1DM) may lead to an increased risk of severe hypoglycemia. Objective: We aimed to determine the impact of C-peptide status on glucagon response and endogenous glucose production (EGP) during hypoglycemia in patients with T1DM. Design and Setting: We conducted an open, comparative trial. Patients: Ten C-peptide positive (C-pos) and 11 matched C-peptide negative (C-neg) patients with T1DM were enrolled. Intervention: Plasma glucose was normalized over the night fast, and after a steady-state (baseline) plateau all patients underwent a hyperinsulinemic, stepwise hypoglycemic clamp with glucose plateaus of 5.5, 3.5, and 2.5 mmol/L and a recovery phase of 4.0 mmol/L. Blood glucagon was measured with a specific and highly sensitive glucagon assay. EGP was determined with a stable isotope tracer technique. Main Outcome Measure: Impact of C-peptide status on glucagon response and EGP during hypoglycemia. Results: Glucagon concentrations were significantly lower in C-pos and C-neg patients than previously reported. At baseline, C-pos patients had higher glucagon concentrations than C-neg patients (8.39 ± 4.6 vs 4.19 ± 2.4 pmol/L, P = 0.016, mean ± standard deviation) but comparable EGP rates (2.13 ± 0.2 vs 2.04 ± 0.3 mg/kg/min, P < 0.391). In both groups, insulin suppressed glucagon levels, but hypoglycemia revealed significantly higher glucagon concentrations in C-pos than in C-neg patients. EGP was significantly higher in C-pos patients at hypoglycemia (2.5 mmol/L) compared with C-neg patients. Conclusions: Glucagon concentrations and EGP during hypoglycemia were more pronounced in C-pos than in C-neg patients, which indicates that preserved ß-cell function may contribute to counterregulation during hypoglycemia in patients with T1DM.

Maternal Early Pregnancy Plasma Concentration of 25-Hydroxyvitamin D and Risk of Gestational Diabetes Mellitus.

We examined whether 25-Hydroxyvitamin D [25(OH) D] concentrations, measured at the first prenatal visit, would be associated with risk of gestational diabetes mellitus (GDM). From July 2015 to June 2016, consecutive women who admitted to the two-obstetrics center in china were included. Relevant data were collected between 24 and 28 weeks of gestation, including fasting plasma glucose (FPG) and 25(OH) D concentrations at the first prenatal visit and the one-step GDM screened with 75-g oral glucose tolerance test (OGTT). Blood from women at first prenatal visit was available for 827 women and 101 of them developed GDM (12.2%). The GDM distribution across the 25(OH) D quartiles ranged between 3.9% (fourth quartile, Q4) and 26.1% (first quartile, Q1). The median plasma concentration of 25(OH) D at first prenatal visit was significantly lower in women who developed GDM compared with those not developed (p < 0.001). In multivariate models comparing the 25(OH) D of Q1, second (Q2) and third quartiles (Q3) against the Q4, it observed that concentrations of 25(OH) D in Q1 and Q2 were associated with later developed GDM, and risk of GDM was increased by 240 and 48%, respectively. The women group with combined vitamin D deficiency and obesity had an OR of 4.66 [95% CI (2.91-8.15); p < 0.001] for GDM compared to those without vitamin D deficiency and obesity. Low 25(OH) D concentrations at the first prenatal visit were associated with increased risk of GDM and might be useful in identifying women at risk of GDM for performing early prevention strategies.

Glucose homeostasis in two degrees of sepsis lethality induced by caecum ligation and puncture in mice.

Sepsis is associated with high mortality. Both critically ill humans and animal models of sepsis exhibit changes in their glucose homeostasis, that is, hypoglycaemia, with the progression of infection. However, the relationship between basal glycaemia, glucose tolerance and insulin sensitivity is not well understood. Thus, we aimed to evaluate this glucose homeostasis triad at the late stage of sepsis (24 h after surgery) in male Swiss mice subjected to lethal and sublethal sepsis by the caecal ligation and puncture (CLP) model. The percentage of survival 24 h after CLP procedure in the Lethal and Sublethal groups was around 66% and 100% respectively. Both Lethal and Sublethal groups became hypoglycaemic in fasting and fed states 24 h after surgery. The pronounced fed hypoglycaemia in the Lethal group was not due to worsening anorexic behaviour or hepatic inability to deliver glucose in relation to the Sublethal group. Reduction in insulin sensitivity in CLP mice occurred in a lethality-dependent manner and was not associated with glucose intolerance. Analysis of oral and intraperitoneal glucose tolerance tests, as well as the gastrointestinal motility data, indicated that CLP mice had reduced intestinal glucose absorption. Altogether, we suggest cessation of appetite and intestinal glucose malabsorption are key contributors to the hypoglycaemic state observed during experimental severe sepsis.

Effects of encapsulated porcine islets on glucose and C-peptide concentrations in diabetic nude mice 6 months after intraperitoneal transplantation.

BACKGROUND: In patients with type 1 diabetes, allogeneic islet transplantation can provide normal HbA1c concentrations, but it requires immunosuppression. Transplanting encapsulated islets into the peritoneal cavity could reduce or eliminate the need for immunosuppression. One of the uncertain features of intraperitoneal islet transplantation is the difficulty of measuring C-peptide concentrations in peripheral blood, which is often used for the marker of islet function. We hypothesized that secreted C-peptide from intraperitoneally transplanted islets was mostly consumed in the peritoneal cavity, which resulted in low C-peptide concentrations in peripheral blood. METHODS: In each of two experiments, encapsulated neonatal porcine islets were intraperitoneally transplanted into four nude mice with streptozotocin-induced diabetes. Three diabetic nude mice without transplanted islets were used as diabetic controls, and three untreated healthy nude mice were used as normal controls. Islet functions were monitored for 2 months in the first experiment and 6 months in the second experiment. Encapsulated islets were retrieved after each experiment and evaluated by fluorescein diacetate/propidium iodide tests for the viability and static glucose-stimulated insulin release tests for the function. C-peptide concentrations from the blood and from the intraperitoneal cavity at 6 months were compared. RESULTS: In both experiments, diabetes was reversed in all transplanted mice, and oral glucose tolerance test showed improved profiles. In general, retrieved islets were viable and functional. However, blood porcine C-peptide concentrations were low at both 2 and 6 months, and concentrations in the ascites of peritoneal cavity were 40 times as high as those in blood. CONCLUSIONS: The peripheral blood sampling for c-peptide, though highly informative in vascularized grafts, may not be the primary tool for monitoring the health and function of encapsulated products when transplanted into intraperitoneal cavity. Our results might explain the clinical feature of the low C-peptide blood concentrations after successful intraperitoneal encapsulated islet transplantation.

Gamma-glutamyltransferase, fatty liver index and hepatic insulin resistance are associated with incident hypertension in two longitudinal studies.

OBJECTIVE: We hypothesized that liver markers and the fatty liver index (FLI) are predictive of incident hypertension and that hepatic insulin resistance plays a role. METHODS: The association between liver markers and incident hypertension was analysed in two longitudinal studies of normotensive individuals, 2565 from the 9-year data from an epidemiological study on the insulin resistance cohort and the 321 from the 3-year 'Relationship between Insulin Sensitivity and Cardiovascular disease' cohort who had a measure of endogenous glucose production. The FLI is calculated from BMI, waist circumference, triglycerides and gamma-glutamyltransferase (GGT) and the hepatic insulin resistance index from endogenous glucose production and fasting insulin. RESULTS: The incidence of hypertension increased across the quartiles groups of both baseline GGT and alanine aminotransferase. After adjustment for sex, age, waist circumference, fasting glucose, smoking and alcohol intake, only GGT was significantly related with incident hypertension [standardized odds ratio: 1.21; 95% confidence interval (1.10-1.34); P = 0.0001]. The change in GGT levels over the follow-up was also related with an increased risk of hypertension, independently of changes in body weight. FLI analysed as a continuous value, or FLI at least 60 at baseline were predictive of incident hypertension in the multivariable model. In the RISC cohort, the hepatic insulin resistance index was positively related with the risk of 3-year incident hypertension [standardized odds ratio: 1.54 (1.07-2.22); P = 0.02]. CONCLUSION: Baseline GGT and FLI, as well as an increase in GGT over time, were associated with the risk of incident hypertension. Enhanced hepatic insulin resistance predicted the onset of hypertension and may be a link between liver markers and hypertension.

Glucose Tolerance in Non-Diabetic Adult Subjects of an Urban West-African Population.

The present study was carried out to determine glucose tolerance and insulin sensitivity in adult subjects of a west African population. 103 subjects recruited in the town of Cotonou were included in the study. After anthropometric measurement, they were subjected to an oral glucose tolerance test (OGTT). Serum glucose and insulin levels were determined throughout the OGTT. Homeostatic model of assessment of insulin resistance (HOMA-IR), MATSUDA insulin sensitivity index (MATSUDA-ISI) and insulinogenic index (IGI) have been determined to evaluate insulin sensitivity and beta cells function. Normal glucose tolerance (NGT), isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT) and combined glucose intolerance (CGI) were observed in respectively 53.40%, 1.94%, 35.92% and 8.74% of subjects. The prevalence of IFG and or IGT (IFG/IGT) was higher in obese subjects (66.67%) than in subjects with normal BMI (41.17%). Fasting hyperinsulinemia was observed in 82% of subjects. Mean values of HOMA-IR were not significantly different in NGT (6.86 ± 0.7) and in IFG/IGT subjects (7.47 ± 0.57). In contrast to HOMA-IR, mean value of Matsuda-ISI was significantly lower in IFG/IGT than in NGT subjects (1.47 ± 0.1 versus 1.96 ± 0.13, p<0.01). Matsuda-ISI values were also significantly lower in obese subjects (1.33 ± 0.12) than in subjects with normal BMI (1.93 ± 0.13). The mean insulinogenic index value in IFG/IGT subjects (42.5 ± 4.36) was not significantly different of that in NGT subjects (50.3 ± 5.21). These data show that the glucose tolerance disorders observed in subjects of the present study are more related to a decrease in insulin sensitivity than to an alteration of the beta cells function.

Calorie restriction and not glucagon-like peptide-1 explains the acute improvement in glucose control after gastric bypass in Type 2 diabetes.

AIMS: To compare directly the impact of glucagon-like peptide-1 secretion on glucose metabolism in individuals with Type 2 diabetes listed for Roux-en-Y gastric bypass surgery, randomized to be studied before and 7 days after undergoing Roux-en-Y gastric bypass or after following a very-low-calorie diet. METHODS: A semi-solid meal test was used to investigate glucose, insulin and glucagon-like peptide-1 response. Insulin secretion in response to intravenous glucose and arginine stimulus was measured. Hepatic and pancreatic fat content was quantified using magnetic resonance imaging. RESULTS: The decrease in fat mass was almost identical in the Roux-en-Y gastric bypass and the very-low-calorie diet groups (3.0±0.3 and 3.0±0.7kg). The early rise in plasma glucose level and in acute insulin secretion were greater after Roux-en-Y gastric bypass than after a very-low-calorie diet; however, the early rise in glucagon-like peptide-1 was disproportionately greater (sevenfold) after Roux-en-Y gastric bypass than after a very-low-calorie diet. This did not translate into a greater improvement in fasting glucose level or area under the curve for glucose. The reduction in liver fat was greater after Roux-en-Y gastric bypass (29.8±3.7 vs 18.6±4.0%) and the relationships between weight loss and reduction in liver fat differed between the Roux-en-Y gastric bypass group and the very-low-calorie diet group. CONCLUSIONS: This study shows that gastroenterostomy increases the rate of nutrient absorption, bringing about a commensurately rapid rise in insulin level; however, there was no association with the large post-meal rise in glucagon-like peptide-1, and post-meal glucose homeostasis was similar in the Roux-en-Y gastric bypass and very-low-calorie diet groups. (Clinical trials registry number: ISRCTN11969319.).

Mechanisms of improved glucose handling after metabolic surgery: the big 6.

For some time, it has been clear that elevated glucose is detrimental to the organism. A plethora of medicines have been introduced to reduce the fasting and postprandial glucose levels (including insulin, glucagon-like peptide receptor 1 [GLP-1] agonists, and sodium-glucose co-transporter 2 [SGLT2] inhibitors, among others). Although these medications are useful to reduce tissue exposure to glucose, no single compound and no combination have been able to totally normalize the blood sugar. Thus, it was astonishing when it was reported that surgery of the gastrointestinal tract could not only reduce obesity but also normalize the blood sugar. These discoveries have transformed diabetes research. What is it about bariatric surgery that causes the remarkable amelioration of glucose homeostasis dysregulation? The answer to this million dollar question is a billion dollar answer. However, a new perspective could shed some light and help provide a clear path for investigation. Instead of asking what does bariatric surgery do to change the pathophysiology, we can ask what pathophysiology and risk factors confer a greater success with remission and improved disease state after surgery. Work from our laboratory and others can help to offer a physiologic basis for which mechanisms may be put into play when the anatomy is altered during surgery. Here, we do not offer an explanation of the mechanism of action of bariatric surgery, but rather provide a background on the regulation of blood glucose and how it is altered during both the diseased state and, as available, the remission state.

The impact of glutamine supplementation on the symptoms of ataxia-telangiectasia: a preclinical assessment.

BACKGROUND: Our previous studies of Alzheimer's disease (AD) suggested that glutamine broadly improves cellular readiness to respond to stress and acts as a neuroprotectant both in vitro and in AD mouse models. We now expand our studies to a second neurodegenerative disease, ataxia-telangiectasia (A-T). Unlike AD, where clinically significant cognitive decline does not typically occur before age 65, A-T symptoms appear in early childhood and are caused exclusively by mutations in the ATM (A-T mutated) gene. RESULTS: Genetically ATM-deficient mice and wild type littermates were maintained with or without 4 % glutamine in their drinking water for several weeks. In ATM mutants, glutamine supplementation restored serum glutamine and glucose levels and reduced body weight loss. Lost neurophysiological function assessed through the magnitude of hippocampal long term potentiation was significantly restored. Glutamine supplemented mice also showed reduced thymus pathology and, remarkably, a full one-third extension of lifespan. In vitro assays revealed that ATM-deficient cells are more sensitive to glutamine deprivation, while supra-molar glutamine (8 mM) partially rescued the reduction of BDNF expression and HDAC4 nuclear translocation of genetically mutant Atm(-/-) neurons. Analysis of microarray data suggested that glutamine metabolism is significantly altered in human A-T brains as well. CONCLUSION: Glutamine is a powerful part of an organism's internal environment. Changes in its concentrations can have a huge impact on the function of all organ systems, especially the brain. Glutamine supplementation thus bears consideration as a therapeutic strategy for the treatment of human A-T and perhaps other neurodegenerative diseases.

Changes in the Fracture Resistance of Bone with the Progression of Type 2 Diabetes in the ZDSD Rat.

Individuals with type 2 diabetes (T2D) have a higher fracture risk compared to non-diabetics, even though their areal bone mineral density is normal to high. Identifying the mechanisms whereby diabetes lowers fracture resistance requires well-characterized rodent models of diabetic bone disease. Toward that end, we hypothesized that bone toughness, more so than bone strength, decreases with the duration of diabetes in ZDSD rats. Bones were harvested from male CD(SD) control rats and male ZDSD rats at 16 weeks (before the onset of hyperglycemia), at 22 weeks (5-6 weeks of hyperglycemia), and at 29 weeks (12-13 weeks of hyperglycemia). There were at least 12 rats per strain per age group. At 16 weeks, there was no difference in either body weight or glucose levels between the two rat groups. Within 2 weeks of switching all rats to a diet with 48 % of kcal from fat, only the ZDSD rats developed hyperglycemia (>250 mg/dL). They also began to lose body weight at 21 weeks. CD(SD) rats remained normoglycemic (<110 mg/dL) on the high-fat diet and became obese (>600 g). From micro-computed tomography (µCT) analysis of a lumbar vertebra and distal femur, trabecular bone volume did not vary with age among the non-diabetic rats but was lower at 29 weeks than at 16 weeks or at 22 weeks for the diabetic rats. Consistent with that finding, µCT-derived intra-cortical porosity (femur diaphysis) was higher for ZDSD following ~12 weeks of hyperglycemia than for age-matched CD(SD) rats. Despite an age-related increase in mineralization in both rat strains (µCT and Raman spectroscopy), material strength of cortical bone (from three-point bending tests) increased with age only in the non-diabetic CD(SD) rats. Moreover, two other material properties, toughness (radius) and fracture toughness (femur), significantly decreased with the duration of T2D in ZDSD rats. This was accompanied by the increase in the levels of the pentosidine (femur). However, pentosidine was not significantly higher in diabetic than in non-diabetic bone at any time point. The ZDSD rat, which has normal leptin signaling and becomes diabetic after skeletal maturity, provides a pre-clinical model of diabetic bone disease, but a decrease in body weight during prolonged diabetes and certain strain-related differences before the onset of hyperglycemia should be taken into consideration when interpreting diabetes-related differences.

Suprachiasmatic Nucleus Neuropeptides and Their Control of Endogenous Glucose Production.

Defective control of endogenous glucose production is an important factor responsible for hyperglycaemia in the diabetic individual. During the past decade, progressively more evidence has appeared indicating a strong and potentially causal relationship between disturbances of the circadian system and defects of metabolic regulation, including glucose metabolism. The detrimental effects of disturbed circadian rhythms may have their origin in disturbances of the molecular clock mechanisms in peripheral organs, such as the pancreas and liver, or in the central brain clock in the hypothalamic suprachiasmatic nuclei (SCN). To assess the role of SCN output per se on glucose metabolism, we investigated (i) the effect of several SCN neurotransmitters on endogenous glucose production and (ii) the effect of SCN neuronal activity on hepatic and systemic insulin sensitivity. We show that silencing of SCN neuronal activity results in decreased hepatic insulin sensitivity and increased peripheral insulin sensitivity. Furthermore, both oxytocin neurones in the paraventricular nucleus of the hypothalamus (PVN) and orexin neurones in the lateral hypothalamus may be important targets for the SCN control of glucose metabolism. These data further highlight the role of the central clock in the pathophysiology of insulin resistance.

Evaluación de la eficacia de un protocolo destinado a mejorar el control glucémico de los pacientes con hiperglucemia ingresados en servicios hospitalarios de medicina interna / Evaluation of the effectiveness of a protocol designed to improve glycemic control in hospitalized internal medicine patients with hyperglycemia

Objetivos: Los objetivos del presente trabajo fueron evaluar si la difusión de un protocolo de manejo de la hiperglucemia sería capaz de incrementar el uso de insulina programada y mejorar el control glucémico durante la estancia hospitalaria. Pacientes y métodos: Estudio observacional de cohortes retrospectivo analítico. Se comparan 2 grupos de pacientes dados de alta con un diagnóstico relacionado con diabetes (DM) en servicios de Medicina Interna, antes (grupoPRE) y después (grupoPOS) de la implantación de un protocolo de actuación. Las respuestas analizadas fueron indicadores de proceso (probabilidad de permanecer sin insulina programada, evaluada mediante curvas de Kaplan-Meier), y de resultados (diferencias ajustadas (grupoPOS - grupoPRE) de control glucémico, evaluadas mediante regresión lineal múltiple). Resultados: Hubo 228 pacientes en el grupoPRE y 127 en el grupoPOS. La mediana del tiempo hasta el inicio de insulina programada fue de un día (IC 95%: 0-2,5) en el grupoPOS y de cuatro días (IC 95%: 2-6) en el grupoPRE (p=0,056). La glucemia en las primeras 48 horas de ingreso entre los pacientes que no recibieron insulina programada fue inferior en el grupoPOS respecto al grupoPRE (163,9 vs 186,7 mg/dl; p=0,025). La glucemia media las primeras 24 horas fue inferior en el grupoPOS (diferencia: -24,8 mg/dl (IC 95%: -40,5-(-9); p=0,002)). En análisis estratificado, la diferencia en glucemia media durante el ingreso fue significativa en los pacientes en ayunas (-29,8 mg/dl; IC 95%: -58,9-(-0,6); p=0,045) pero no en aquellos con ingesta conservada. Conclusión: Un protocolo específico puede mejorar la calidad en la asistencia hospitalaria al paciente con DM (AU)

Background: Our aims were to assess the effectiveness of a diabetes (DM) management protocol to increase scheduled insulin therapy and to improve glycemic inpatient control. Patients and methods: We designed an analytical retrospective cohort study comparing 2 groups of medical services hospitalized patients with a primary or secondary discharge diagnosis of DM, before (group PRE) and after (group POS) the delivery of a DM management protocol. We analyzed the quality of attention by process indicators (cumulative probability of receive scheduled insulin therapy, evaluated with Kaplan-Meier analysis) and result indicators (adjusted glucose differences (group POS - group PRE), evaluated with multivariate regression models). Results: A number of patients (355) were included (228 group PRE and 127 group POS). The median time to scheduled insulin regimen beginning was 1 (CI 95%: 0-2.5) day in group POS and 4 (CI 95%: 2-6) days in group PRE (p=0.056). First 48 hours mean glucose in patients without scheduled insulin therapy was lower in group POS than in group PRE (163.9 versus 186.7 mg/dl; p=0.025). The first 24 hours mean glucose was significantly lower in patients of group POS, with a difference between both groups of -24.8 mg/dl (CI 95%: -40.5-(-9); p=0.002). Stratified analysis showed statistically significant mean in-hospital glucose difference only in the nothing by mouth situation (-29.8 mg/dl; CI 95%: -58.9-(-0.6); p=0.045). Conclusion: The delivery of an institutional protocol can improve hospitalized DM patients management quality (AU)

Evaluación de la respuesta sistémica en el postoperatorio de las cardiopatías congénitas / Evaluation of the postoperative systemic response in congenital heart defects

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