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Neonatal diabetes is a rare disease, often caused by a monogenic abnormality. A male infant patient developed diabetic ketoacidosis at 2 months‐of‐age due to the heterozygous ABCC8 gene mutation (p.Pro1198Leu). After genetic diagnosis, insulin therapy was successfully transitioned to oral sulfonylurea therapy. For >6 years, oral sulfonylurea therapy has been safe and effective, and the required amount of sulfonylureas has progressively decreased. The mutation was transmitted in an autosomal‐dominant fashion across three generations of his family, but the severity of diabetes varied among members from neonatal diabetes to mild diabetes. One family member had normal glucose tolerance despite having the mutation. This case presentation could help in the understanding of neonatal diabetes caused by the ABCC8 gene mutation. [ABSTRACT FROM AUTHOR]

Objectives: Intravenous glibenclamide (GBC) exerts neuroprotection in both preclinical and preliminary clinical studies. This study explored the safety and potential efficacy of oral GBC in patients with acute hemispheric infarction. Materials & Methods: During January 2017 and August 2017, adult volunteers were recruited to receive oral GBC treatment, if they presented with an acute anterior ischemic stroke and a National Institute of Health Stroke Score of ≥8. Controls were those who met the above inclusion criteria and had not been on GBC or other sulfonylureas prior to stroke or after hospitalization. Propensity score matching (PSM) was performed to balance baseline characteristics. The primary endpoint was the score on the modified Rankin Scale (mRS) at 6 months. Results: We included 213 patients in the unmatched cohort (20 in the GBC group and 193 in the control group) and 40 patients (20 in each group) in the matched cohort. In both cohorts, GBC treatment did not increase the risks of early death, hypoglycemia, and early neurological deterioration. Although GBC did not substantially improve 6‐month functional outcome that measured in shift analysis of mRS, a slight trend toward less severe disability and death (mRS 5‐6) was observed. In the matched cohort, GBC treatment was associated with lighter brain edema, when CED score was used for evaluation. Conclusions: In this study, oral GBC is safe in treating acute hemispheric infarction and might have potential in preventing brain edema and consequential severe disability and death. An adequately powered and randomized trial is warranted. [ABSTRACT FROM AUTHOR]

Glibenclamide has a newly discovered role in inflammation regulation besides its antidiabetic effect. As an inhibitor of ATP-sensitive potassium (K) channel, glibenclamide antagonizes the relaxation of the tracheal smooth muscle. This indicates that glibenclamide might attenuate airway inflammation while aggravate airway hyperresponsiveness (AHR) in asthmatics. Clinically, many diabetics with asthma are prescribed with glibenclamide to control blood glucose. However, whether glibenclamide could exert any effects on asthmatic inflammation remains unknown. Using an ovalbumin (OVA)-induced mouse model of asthma, we evaluated the effects of glibenclamide on the AHR and inflammation. Interestingly, glibenclamide reduced all the cardinal features of asthma in OVA-challenged mice, including AHR, airway inflammation, and T-helper type 2 (Th2) cytokines. Glibenclamide also downregulated OVA-induced expressions of vascular cell adhesion molecule 1 (VCAM-1) and phosphorylated signal transducer and activator of transcription 6 (p-STAT6) in the lung. In addition, increased sulfonylurea receptor 1 (SUR1) expression in the lung was observed after the OVA challenge. These findings suggest that the classic sulfonylurea glibenclamide plays an important protective role in the development of asthma, which not only provides the evidence for the safety of prescribed glibenclamide in diabetics combined with asthma but also indicates a possible new therapeutic for asthma via targeting glibenclamide-related pathways. [ABSTRACT FROM AUTHOR]

Blood spinal cord barrier (BSCB) disruption after spinal cord injury (SCI) leads to secondary injury and results in apoptosis of neurons and glia, leading to permanent neurological deficits. Here, we examined the effect of ghrelin on BSCB breakdown and hemorrhage after SCI. After moderate weight-drop contusion injury at T9 spinal cord, ghrelin (80 μg/kg) was administered via intraperitoneal injection immediately after SCI and then the same dose of ghrelin was treated every 6 h for 1 d. Our data showed that ghrelin treatment significantly inhibited the expression and activation of matrix metalloprotease-9 (MMP-9) at 1 d after SCI. The increases of sulfonylurea receptor 1 (SUR1) and transient receptor potential melastatin 4 (TrpM4) expressions at 1 h and 8 h after SCI respectively were also alleviated by ghrelin treatment. In addition, both BSCB breakdown and hemorrhage at 1 d after injury were significantly attenuated by ghrelin. In parallel, the infiltration of blood cells such as neutrophils and macrophages was inhibited by ghrelin treatment at 1 d and 5 d after SCI respectively. We also found that ghrelin receptor, growth hormone secretagogue receptor-1a (GHS-R1a), was expressed in the blood vessel of normal spinal tissue. Furthermore, the inhibitory effects of ghrelin on hemorrhage and BSCB disruption at 1 d after SCI were blocked by GHS-R1a antagonist, [D-Lys-3]-GHRP-6 (3 mg/kg). Thus, these results indicate that the neuroprotective effect by ghrelin after SCI is mediated in part by blocking BSCB disruption and hemorrhage through the down-regulation of SUR1/TrpM4 and MMP-9, which is dependent on GHS-R1a. [ABSTRACT FROM AUTHOR]

Abstract: Measuring changes in β-cell mass in vivo during progression of diabetes mellitus is important for understanding the pathogenesis, facilitating early diagnosis, and developing novel therapeutics for this disease. However, a non-invasive method has not been developed. A novel series of mitiglinide derivatives (o-FMIT, m-FMIT and p-FMIT; FMITs) were synthesized and their binding affinity for the sulfonylurea receptor 1 (SUR1) of pancreatic islets were evaluated by inhibition studies. (+)-(S)-o-FMIT had the highest affinity of our synthesized FMITs (IC50 =1.8μM). (+)-(S)-o-[18F]FMIT was obtained with radiochemical yield of 18% by radiofluorination of racemic precursor 7, hydrolysis, and optical resolution with chiral HPLC; its radiochemical purity was >99%. In biodistribution experiments using normal mice, (+)-(S)-o-[18F]FMIT showed 1.94±0.42% ID/g of pancreatic uptake at 5min p.i., and decreases in radioactivity in the liver (located close to the pancreas) was relatively rapid. Ex vivo autoradiography experiments using pancreatic sections confirmed accumulation of (+)-(S)-o-[18F]FMIT in pancreatic β-cells. These results suggest that (+)-(S)-o-[18F]FMIT meets the basic requirements for an radiotracer, and could be a candidate positron emission tomography tracer for in vivo imaging of pancreatic β-cells. [Copyright &y& Elsevier]

We studied a model of hemorrhagic encephalopathy of prematurity (EP) that closely recapitulates findings in humans with hemorrhagic EP. This model involves tandem insults of 20 min intrauterine ischemia (IUI) plus an episode of elevated venous pressure induced by intraperitoneal glycerol on post-natal day (P) 0. We examined Sur1 expression, which is upregulated after focal ischemia but has not been studied after brief global ischemia including IUI. We found that 20 min IUI resulted in robust upregulation of Sur1 in periventricular microvessels and tissues. We studied tandem insult pups from untreated or vehicle-treated dams (TI-CTR), and tandem insult pups from dams administered a low-dose, non-hypoglycemogenic infusion of the Sur1 blocker, glibenclamide, for 1 week after IUI (TI-GLIB). Compared to pups from the TI-CTR group, pups from the TI-GLIB group had significantly fewer and less severe hemorrhages on P1, performed significantly better on the beam walk and accelerating Rotarod on P35 and in tests of thigmotaxis and rapid learning on P35-49, and had significantly greater body and brain weights at P52. We conclude that low-dose glibenclamide administered to the mother at the end of pregnancy protects pups subjected to IUI from post-natal events of elevated venous pressure and its consequences. [ABSTRACT FROM AUTHOR]

Here, we examined the chronic effects of two cannabinoid receptor-1 (CB1) inverse agonists, rimonabant and ibipinabant, in hyperinsulinemic Zucker rats to determine their chronic effects on insulinemia. Rimonabant and ibipinabant (10 mg·kg-1·day-1) elicited body weightindependent improvements in insulinemia and glycemia during 10 wk of chronic treatment. To elucidate the mechanism of insulin lowering, acute in vivo and in vitro studies were then performed. Surprisingly, chronic treatment was not required for insulin lowering. In acute in vivo and in vitro studies, the CB1 inverse agonists exhibited acute K channel opener (KCO; e.g., diazoxide and NN414)-like effects on glucose tolerance and glucose-stimulated insulin secretion (GSIS) with approximately fivefold better potency than diazoxide. Followup studies implied that these effects were inconsistent with a CB1- mediated mechanism. Thus effects of several CB1 agonists, inverse agonists, and distomers during GTTs or GSIS studies using perifused rat islets were unpredictable from their known CB1 activities. In vivo rimonabant and ibipinabant caused glucose intolerance in CB1 but not SUR1-KO mice. Electrophysiological studies indicated that, compared with diazoxide, 3 μM rimonabant and ibipinabant are partial agonists for K channel opening. Partial agonism was consistent with data from radioligand binding assays designed to detect SUR1 KATP KCOs where rimonabant and ibipinabant allosterically regulated 3Hglibenclamide- specific binding in the presence of MgATP, as did diazoxide and NN414. Our findings indicate that some CB1 ligands may directly bind and allosterically regulate Kir6.2/SUR1 KATP channels like other KCOs. This mechanism appears to be compatible with and may contribute to their acute and chronic effects on GSIS and insulinemia. [ABSTRACT FROM AUTHOR]

Subarachnoid hemorrhage (SAH) causes secondary brain injury due to vasospasm and inflammation. Here, we studied a rat model of mild-to-moderate SAH intended to minimize ischemia/hypoxia to examine the role of sulfonylurea receptor 1 (SUR1) in the inflammatory response induced by SAH. mRNA for Abcc8, which encodes SUR1, and SUR1 protein were abundantly upregulated in cortex adjacent to SAH, where tumor-necrosis factor-α (TNFα) and nuclear factor (NF)κB signaling were prominent. In vitro experiments confirmed that Abcc8 transcription is stimulated by TNFα. To investigate the functional consequences of SUR1 expression after SAH, we studied the effect of the potent, selective SUR1 inhibitor, glibenclamide. We examined barrier permeability (immunoglobulin G, IgG extravasation), and its correlate, the localization of the tight junction protein, zona occludens 1 (ZO-1). SAH caused a large increase in barrier permeability and disrupted the normal junctional localization of ZO-1, with glibenclamide significantly reducing both effects. In addition, SAH caused large increases in markers of inflammation, including TNFα and NFκB, and markers of cell injury or cell death, including IgG endocytosis and caspase-3 activation, with glibenclamide significantly reducing these effects. We conclude that block of SUR1 by glibenclamide may ameliorate several pathologic effects associated with inflammation that lead to cortical dysfunction after SAH.Journal of Cerebral Blood Flow & Metabolism (2009) 29, 317–330; doi:10.1038/jcbfm.2008.120; published online 15 October 2008 [ABSTRACT FROM AUTHOR]

Pancreatic α-cells, like β-cells, express ATP-sensitive K+ (KATP) channels. To determine the physiological role of KATP channels in α-cells, we examined glucagon secretion in mice lacking the type 1 sulfonylurea receptor (Sur1). Plasma glucagon levels, which were increased in wild-type mice after an overnight fast, did not change in Sur1 null mice. Pancreas perfusion studies showed that Sur1 null pancreata lacked glucagon secretory responses to hypoglycemia and to synergistic stimulation by arginine. Pancreatic a-cells isolated from wild-type animals exhibited oscillations of intracellular free Ca2+ concentration ([Ca2+]i) in the absence of glucose that became quiescent when the glucose concentration was increased. In contrast, Sur1 null a-cells showed continuous oscillations in [Ca2+]i regardless of the glucose concentration. These findings indicate that KATP channels in α-cells play a key role in regulating glucagon secretion, thereby adding to the paradox of how mice that lack KATP channels maintain euglycemia. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • Gliquidone decreases the level of blood glucose through extra-pancreatic actions in diabetic Sur1 −/− rats. • Gliquidone alleviates hepatic insulin resistance by increasing glycogen synthesis and decreasing gluconeogenesis in vivo. • The mechanism of gliquidone might be related to the activation of AKT, rather than AMPK. [ABSTRACT FROM AUTHOR]

Cerebral edema is a clinical problem that frequently follows ischemic infarcts. Sulfonylurea receptor 1 (SUR1) is an inducible protein that can form a heteromultimeric complex with aquaporin 4 (AQP4) that mediate the ion/water transport involved in brain tissue swelling. Transcription of the Abcc8 gene coding for SUR1 depends on the activity of transcriptional factor SP1, which is modulated by the cellular redox environment. Since oxidative stress is implicated in the induced neuronal damage in ischemia and edema formation, the present study aimed to evaluate if the antioxidant resveratrol (RSV) prevents the damage by reducing the de novo expression of SUR1 in the ischemic brain. Male Wistar rats were subjected to 2 h of middle cerebral artery occlusion followed by different times of reperfusion. RSV (1.9 mg/kg; i.v.) was administered at the onset of reperfusion. Brain damage and edema formation were recognized by neurological evaluation, time of survival, TTC (2,3,5-Triphenyltetrazolium chloride) staining, Evans blue extravasation, and water content. RSV mechanism of action was studied by SP1 binding activity measured through the Electrophoretic Mobility Shift Assay, and Abcc8 and Aqp4 gene expression evaluated by qPCR, immunofluorescence, and Western blot. We found that RSV reduced the infarct area and cerebral edema, prevented blood-brain barrier damage, improved neurological performance, and increased survival. Additionally, our findings suggest that the antioxidant activity of RSV targeted SP transcription factors and inhibited SUR1 and AQP4 expression. Thus, RSV by decreasing SUR1 expression could contribute to reducing edema formation, constituting a therapeutic alternative for edema reduction in stroke. • Resveratrol reduces brain edema formation and increases survival in the MCAO model of ischemia. • Resveratrol reduces DNA binding activity of the transcription factor SP1 in cerebral ischemia. • Induced-SUR1 expression in the brain during ischemia is down-regulated by resveratrol. [ABSTRACT FROM AUTHOR]

Background: Sulfonylurea receptor 1 (SUR1) is primarily responsible for glucose regulation in normal conditions. Here, we sought to investigate the glucose metabolism characteristics of SUR1−/− rats. Methods: The TALEN technique was used to construct a SUR1 gene deficiency rat model. Rats were grouped by SUR1 gene knockout or not and sex difference. Body weight; glucose metabolism indicators, including IPGTT, IPITT, glycogen contents and so on; and other molecule changes were examined. Results: Insulin secretion was significantly inhibited by knocking out the SUR1 gene. SUR1−/− rats showed lower body weights compared to wild-type rats, and even SUR1−/− males weighed less than wild-type females. Upon SUR1 gene knockout, the rats showed a peculiar plasma glucose profile. During IPGTT, plasma glucose levels were significantly elevated in SUR1−/− rats at 15 min, which could be explained by SUR1 mainly working in the first phase of insulin secretion. Moreover, SUR1−/− male rats showed obviously impaired glucose tolerance than before and a better insulin sensitivity in the 12th week compared with females, which might be related with excess androgen secretion in adulthood. Increased glycogen content and GLUT4 expression and the inactivation of GSK3 were also observed in SUR1−/− rats, which suggested an enhancement of insulin sensitivity. Conclusions: These results reconfirm the role of SUR1 in systemic glucose metabolism. More importantly, our SUR1−/− rat model might be applied in other fields, such as for exploring other hypoglycaemic functions of sulfonylureas. [ABSTRACT FROM AUTHOR]

Abstract: We recently published a description of the molecular mechanism involved in “progressive hemorrhagic necrosis”, a pathological process that evolves during several hours after spinal cord injury, that is attributable to progressive capillary fragmentation, and that is due to upregulation and activation of SUR1-regulated channels in microvascular endothelium. In this commentary, we reflect on the independent replication of our original experiment by Dr. Phillip Popovich and colleagues, and how their initial attempt at replication led to the unexpected finding that anisotropy of spinal cord tissues strongly influences the patterns of both primary and secondary hemorrhage that are observed after impact injury to the spinal cord. [Copyright &y& Elsevier]