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R S Sherwin

Publications and source records attributed to R S Sherwin.

At least 19 recordsLinked to original sources
PubMed2005

Targeted expression of the anti-apoptotic gene CrmA to NOD pancreatic islets protects from autoimmune diabetes.

The activation of apoptosis is a critical mechanism by which pancreatic beta cells are destroyed in type 1 diabetes (T1DM). Strategies aimed at interfering with the apoptotic pathways could therefore be of potential therapeutic value. To this end, we generated NOD transgenic mice with targeted expression of the anti-apoptotic gene Cytokine response modifier A (CrmA) to pancreatic beta cells using the rat insulin promoter and the reverse tetracycline transactivator to express CrmA in a temporally controlled manner. Two lines of transgenic mice were studied whose expression of CrmA occurred only after feeding doxycycline food. Islet expression of CrmA partially protected pancreatic beta cells from the cytokine-mediated cytotoxicity in vitro and reduced modestly the spontaneous development of diabetes in NOD mice in vivo. In addition, beta cells from NOD CrmA mice were significantly protected from the destruction by diabetogenic T cells after adoptive transfer. More strikingly, NODCrmA mice were significantly resistant to the diabetogenic activity of a potent insulin-specific CD8 T-cell clone. Since these adoptive transfer models mainly represent the effector phase rather than the initiation phase of autoimmune diabetes, our data suggest that the latter is more sensitive to CrmA protection. We conclude that anti-apoptotic genes such as CrmA might be potential candidates to enhance islet graft survival in T1DM.

Adoptive Transfer↗
PubMed2004

Influence of alcohol on cognitive performance during mild hypoglycaemia; implications for Type 1 diabetes.

AIMS: Alcohol and hypoglycaemia independently affect cognitive function. This may be relevant for insulin-treated diabetic patients who drive motor vehicles. The aim of this study was to examine the effect of mild hypoglycaemia (2.8 mmol/l) with modest alcohol intoxication (levels below UK driving limits) on intellectual performance in patients with Type 1 diabetes. METHODS: A hyperinsulinaemic glucose clamp (60 mU/m2) was used to study 17 subjects [age 35 +/- 8 years, HbA1c 8.1 +/- 1.4% (mean +/- sd)] on four occasions: (A) euglycaemia (4.5 mmol/l) with placebo, (B) euglycaemia with alcohol, (C) hypoglycaemia (2.8 mmol/l) with placebo, and (D) hypoglycaemia with alcohol. Cognitive performance was assessed using four-choice reaction time (4CRT, primary outcome), measurements of general intellectual skills [trail making B (TMB) and digit symbol substitution (DSST)], and visual information processing [visual change detection (VCD)]. A test related to driving performance (hazard perception) was also used. RESULTS: In experiments B and D the average blood alcohol level was 43 mg/dl. This was associated with deterioration in 4CRT [+ 35 ms [95% confidence interval (CI) 20, 50]] and TMB, whereas hypoglycaemia without alcohol increased 4CRT only [+ 39 ms (95% CI 5, 73)]. However, when alcohol was combined with hypoglycaemia, there was marked deterioration in all the cognitive function tests [4CRT 74 ms (95% CI 35, 113), TMB, DSST and VCD]. Hazard perception was not affected. The effect of alcohol was no different in euglycaemia than in hypoglycaemia, i.e. there was no interaction. Whereas hypoglycaemia did not reduce the likelihood that the subjects would drive, alcohol did. CONCLUSIONS: The cumulative effect of alcohol and hypoglycaemia on cognitive function together has implications for driving in patients with Type 1 diabetes. Both independently impair cognitive function and together the effects are additive. Patients with Type 1 diabetes should be educated about hypoglycaemia and driving and should avoid alcohol completely if planning to drive.

Adult↗
PubMed2003

Effects of recurrent antecedent hypoglycaemia and chronic hyperglycaemia on brainstem extra-cellular glucose concentrations during acute hypoglycaemia in conscious diabetic BB rats.

AIMS/HYPOTHESIS: Our aim was to determine whether the divergent effects of chronic exposure to hyperglycaemia or hypoglycaemia on the glycaemic threshold for auditory brainstem dysfunction are reflected in the extra-cellular fluid (ECF) concentrations of glucose in the inferior colliculus during hypoglycaemia in the diabetic BB rat. METHODS: Microdialysis was used to measure inferior colliculus ECF glucose concentrations under basal and hyperinsulinaemic (20 mU/kg.min) hypoglycaemic conditions. RESULTS: ECF glucose is increased under basal (hyperglycaemic) conditions and decreases during hypoglycaemia in both recurrently hypoglycaemic and chronically hyperglycaemic diabetic BB rats (to 0.5+/-0.1 and 0.8+/-0.2 mmol/L respectively), with no significant differences between groups. In both groups the plasma to ECF glucose ratio doubled during hypoglycaemia. CONCLUSION/INTERPRETATION: Prior exposure to recurrent hypoglycaemia does not lead to increased ECF glucose concentrations in the inferior colliculus of diabetic BB rats. The resistance to impaired brainstem function seen in recurrently hypoglycaemic rats during hypoglycaemia cannot simply be attributed to increased blood-brain barrier glucose transport within this brain region.

Animals↗
PubMed2002

Prevention of autoimmune diabetes by immunogene therapy using recombinant vaccinia virus expressing glutamic acid decarboxylase.

AIMS/HYPOTHESES: Type I (insulin-dependent) diabetes mellitus results from T-cell-mediated autoimmune destruction of pancreatic beta cells. Among the beta-cell autoantigens that have been implicated in triggering of beta-cell-specific autoimmunity, glutamic acid decarboxylase (GAD) is a strong candidate in both humans and the NOD mouse. We aimed to determine whether treatment with a recombinant vaccinia virus expressing GAD (rVV-GAD65) could prevent the development of diabetes in NOD mice. METHODS: Three-eight-to-nine-week-old female NOD mice were injected with various doses of rVV-GAD65 or rVV-MJ601as a control. We then examined the incidence of diabetes, T-cell proliferative response to GAD, amounts of anti-GAD IgGs, cytokine production and generation of regulatory cell populations. RESULTS: Administration of rVV-GAD65 to NOD mice prevented diabetes in an age-dependent and dose-dependent manner. Splenic T cells from rVV-GAD65-treated mice did not proliferate in response to GAD65. The amount of IgG1 was increased, whereas IgG2a amounts did not change in rVV-GAD65-treated NOD mice. The production of interleukin-4 increased, whereas the production of interferon-gamma decreased in rVV-GAD65-treated mice after stimulation with GAD. Furthermore, splenocytes from rVV-GAD65-treated NOD mice prevented the transfer of diabetes by splenocytes from acutely diabetic NOD mice in NOD. scid recipients. CONCLUSION/INTERPRETATION: Immunogene therapy using a recombinant vaccinia virus expressing GAD results in the prevention of autoimmune diabetes in NOD mice by the induction of immunological tolerance through active suppression of effector T cells, and this treatment might have therapeutic value for the prevention of Type I diabetes.

Adoptive Transfer↗
PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗
PubMed2002

Brain glucose levels are elevated in chronically hyperglycemic diabetic rats: no evidence for protective adaptation by the blood brain barrier.

Recent evidence suggests that brain function may be impaired by prolonged elevations of blood glucose, such as those that occur in poorly controlled diabetes. However, little is known about the effects of such hyperglycemia on brain metabolic substrate levels. Using microdialysis in awake, freely moving rats, we directly measured brain extracellular fluid (ECF) glucose, lactate, and beta-hydroxybutyrate (betaOHB) levels in the inferior colliculus in chronically hyperglycemic BB/wor diabetic rats and in control (Sprague-Dawley) rats during euglycemia and acute hyperglycemia. The ECF:plasma glucose ratio (0.27 to 0.34) was remarkably similar in animals from all 3 groups, resulting in proportional elevations of brain ECF glucose in the hyperglycemic groups. Moreover, brain ECF levels of lactate and beta-OHB were increased in diabetic (DM) rats as compared with controls. Our results suggest that no significant protective adaptation of the blood brain barrier (BBB) transfer of glucose occurs in chronic hyperglycemia. Hence, brain tissue may be chronically exposed to markedly elevated levels of glucose and other metabolic fuels during poorly controlled diabetes, and therefore it may be subject to the same long-term adverse effects of hyperglycemia seen in peripheral tissues.

3-Hydroxybutyric Acid↗
PubMed2002

AICAR and phlorizin reverse the hypoglycemia-specific defect in glucagon secretion in the diabetic BB rat.

Individuals with type 1 diabetes demonstrate a hypoglycemia-specific defect in glucagon secretion. To determine whether intraislet hyperinsulinemia plays a role in the genesis of this defect, glucagon-secretory responses to moderate hypoglycemia induced by either insulin or a novel combination of the noninsulin glucose-lowering agents 5-aminoimidazole-4-carboxamide (AICAR) and phlorizin were compared in diabetic BB rats (an animal model of type 1 diabetes) and nondiabetic BB rats. The phlorizin-AICAR combination was able to induce moderate and equivalent hypoglycemia in both diabetic and nondiabetic BB rats in the absence of marked hyperinsulinemia. Diabetic BB rats demonstrated impaired glucagon and epinephrine responses during insulin-induced hypoglycemia compared with nondiabetic rats. In contrast, both glucagon (9- to 10-fold increase) and epinephrine (5- to 6-fold increase) responses were markedly improved during phlorizin-AICAR hypoglycemia. Combining phlorizin, AICAR, and insulin attenuated the glucagon response to hypoglycemia by 70% in the diabetic BB rat. Phlorizin plus AICAR had no effect on counterregulatory hormones under euglycemic conditions. We conclude that alpha-cell glucagon secretion in response to hypoglycemia is not defective if intraislet hyperinsulinemia is prevented. This suggests that exogenous insulin plays a pivotal role in the etiology of this defect.

Aminoimidazole Carboxamide↗
PubMed2001

Cardiac responses to insulin-induced hypoglycemia in nondiabetic and intensively treated type 1 diabetic patients.

Insulin-induced hypoglycemia occurs commonly in intensively treated patients with type 1 diabetes, but the cardiovascular consequences of hypoglycemia in these patients are not known. We studied left ventricular systolic [left ventricular ejection fraction (LVEF)] and diastolic [peak filling rate (PFR)] function by equilibrium radionuclide angiography during insulin infusion (12 pmol. kg(-1). min(-1)) under either hypoglycemic (approximately 2.8 mmol/l) or euglycemic (approximately 5 mmol/l) conditions in intensively treated patients with type 1 diabetes and healthy nondiabetic subjects (n = 9 for each). During hypoglycemic hyperinsulinemia, there were significant increases in LVEF (DeltaLVEF = 11 +/- 2%) and PFR [DeltaPFR = 0.88 +/- 0.18 end diastolic volume (EDV)/s] in diabetic subjects as well as in the nondiabetic group (DeltaLVEF = 13 +/- 2%; DeltaPFR = 0.79 +/- 0.17 EDV/s). The increases in LVEF and PFR were comparable overall but occurred earlier in the nondiabetic group. A blunted increase in plasma catecholamine, cortisol, and glucagon concentrations occurred in response to hypoglycemia in the diabetic subjects. During euglycemic hyperinsulinemia, LVEF also increased in both the diabetic (DeltaLVEF = 7 +/- 1%) and nondiabetic (DeltaLVEF = 4 +/- 2%) groups, but PFR increased only in the diabetic group. In the comparison of the responses to hypoglycemic and euglycemic hyperinsulinemia, only the nondiabetic group had greater augmentation of LVEF, PFR, and cardiac output in the hypoglycemic study (P < 0.05 for each). Thus intensively treated type 1 diabetic patients demonstrate delayed augmentation of ventricular function during moderate insulin-induced hypoglycemia. Although diabetic subjects have a more pronounced cardiac response to hyperinsulinemia per se than nondiabetic subjects, their response to hypoglycemia is blunted.

Adult↗
PubMed2001

Oral glucose augments the counterregulatory hormone response during insulin-induced hypoglycemia in humans.

It has been suggested that the counterregulatory hormone (CRH) response to acute hypoglycemia is triggered via glucose sensors situated in either the hypothalamus or the portohepatic area. If the latter were critical during hypoglycemia, one would anticipate that ingestion of glucose, by raising glucose levels in the portal circulation, should attenuate CRH responses previously described in animal studies. To evaluate the effect of raising portal, but not peripheral, glucose levels during insulin-induced hypoglycemia, we performed hypoglycemic clamp studies in five healthy adult males on two occasions. On one occasion, subjects received oral glucose (OG) (25 g) during hypoglycemia; and on one occasion, noncarbohydrate-containing drink of equal volume, while maintaining plasma glucose at 55 +/- 2 mg/dL (3.08 mmol/L). As a result, there were no significant differences in systemic plasma glucose levels between the two hypoglycemic clamp studies, and basal CRH concentrations were also similar. As expected, there was a brisk rise in all CRH during the control (hypoglycemia+noncarbohydrate drink) study. In the experimental study, administration of OG (hypoglycemia+OG), to raise intraportal glucose levels during systemic hypoglycemia, did not attenuate CRH responses. Indeed, OG enhanced the rise in epinephrine, glucagon, and GH. Increases in cortisol and norepinephrine did not differ between the two studies. Therefore, our data suggest that increasing the level of glucose in the portal vein above that in the systemic circulation, during hypoglycemia, enhances (rather than suppresses) CRH responses. Thus, ingestion of glucose may reverse hypoglycemia directly by provision of substrate, as well as indirectly by stimulating counteregulatory mechanisms.

Administration, Oral↗
PubMed2001

The effect of evening alcohol consumption on next-morning glucose control in type 1 diabetes.

OBJECTIVE: Alcohol is associated with acute hypoglycemia in patients with type 1 diabetes. After drinking alcohol in the evening, delayed hypoglycemia has also been described, although its cause is unknown. We performed a controlled study to investigate this phenomenon. RESEARCH DESIGN AND METHODS: We admitted six men with type 1 diabetes (aged 19-51 years, HbA(1c) 7.0-10.3%) on two occasions, from 5:00 P.M. to 12:00 noon the following day. They received regular insulin injections before standardized meals, at 6:00 P.M. and 8:00 A.M., and a basal insulin infusion (0.15 mU x kg(-1) x min(-1)) from 11:00 P.M. They drank either dry white wine (0.75 g/kg alcohol) or mineral water at 9:00 P.M. over 90 min. Blood glucose, alcohol, insulin, cortisol, growth hormone, and glucagon levels were measured. RESULTS: Blood ethanol reached a mean (SEM) peak of 19.1 (1.2) mmol/l and was undetectable by 8:00 A.M. There were no significant differences in evening or overnight blood glucose levels between the studies. In the morning, fasting and postprandial blood glucose levels were significantly lower after consumption of wine (postprandial peak 8.9 [1.7] vs. 15 [1.5] mmol/l, P < 0.01), and from 10:00 A.M., five subjects required treatment for hypoglycemia (nadir 1.9-2.9 mmol/l). None of the subjects had hypoglycemia after consumption of water. After consumption of wine, growth hormone secretion was significantly reduced between midnight and 4:00 A.M. (area under the curve 2.1 [1.1] vs. 6.5 [2.1] microg. l(-1) x h(-1), P = 0.04). There were no differences in insulin or other hormone levels. CONCLUSIONS: In type 1 diabetes, moderate consumption of alcohol in the evening may predispose patients to hypoglycemia after breakfast the next morning. This is associated with reduced nocturnal growth hormone secretion. Patients should be informed of this risk and advised regarding appropriate preventative measures.

Adult↗
PubMed2000

Inhibition of NF-kappaB activity and enhancement of apoptosis by the neuropeptide calcitonin gene-related peptide.

Calcitonin gene-related peptide (CGRP) is a neuropeptide produced by the central and peripheral nervous systems and by endocrine cells. CGRP exerts diverse biological effects on the cardiovascular, gastrointestinal, respiratory, central nervous and immune systems. Little is known, however, about the molecular mechanisms that mediate CGRP effects. Using the NFkappaB-luciferase reporter transgenic mice, here we show that CGRP selectively inhibits NF-kappaB-mediated transcription in thymocytes in vitro and in vivo. In contrast, CGRP does not affect transcription mediated by the AP-1 and NFAT transcription factors. CGRP inhibits the accumulation of NF-kappaB complexes in the nucleus by preventing phosphorylation and degradation of the NF-kappaB inhibitor IkappaB. Inhibition of NF-kappaB activity is associated with the induction of apoptosis by CGRP in thymocytes. Together these results demonstrate for the first time the selective implication of the NF-kappaB signaling pathway in the regulatory function of the neuropeptide CGRP. Our study suggests a potential molecular mechanism by which CGRP can induce cell death in thymocytes.

Animals↗
PubMed2000

Effects of hypoglycemia on functional magnetic resonance imaging response to median nerve stimulation in the rat brain.

The authors studied the effects of a standardized mild-moderate hypoglycemic stimulus (glucose clamp) on brain functional magnetic resonance imaging (fMRI) responses to median nerve stimulation in anesthetized rats. In the baseline period (plasma glucose 6.6 +/- 0.3 mmol/L), the MR signal changes induced by median nerve activation were determined within a fixed region of the somatosensory cortex from preinfusion activation maps. Subsequently, insulin and a variable glucose infusion were administered to decrease plasma glucose. The goal was to produce a stable hypoglycemic plateau (2.8 +/- 0.2 mmol/L) for 30 minutes. Thereafter, plasma glucose was restored to euglycemic levels (6.0 +/- 0.3 mmol/L). In the early phase of insulin infusion (15 to 30 minutes), before hypoglycemia was reached (4.7 +/- 0.3 mmol/L), the activation signal was unchanged. However, once the hypoglycemic plateau was achieved, the activation signal was significantly decreased to 57 +/- 6% of the preinfusion value. Control regions in the brain that were not activated showed no significant changes in MR signal intensity. Upon return to euglycemia, the activation signal change increased to within 10% of the original level. No significant activation changes were noted during euglycemic hyperinsulinemic clamp experiments. The authors concluded that fMRI can detect alterations in cerebral function because of insulin-induced hypoglycemia. The signal changes observed in fMRI activation experiments were sensitive to blood glucose levels and might reflect increases in brain metabolism that are limited by substrate deprivation during hypoglycemia.

Animals↗
PubMed2000

Augmentation of alimentary insulin secretion despite similar gastric inhibitory peptide (GIP) responses in juvenile obesity.

Insulin secretion rates are greater after oral glucose than after parenteral administration of an equivalent glucose load. This augmented beta-cell secretory response to an oral glucose load results from the release of mainly two gut hormones: gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1, which potentiate glucose-induced insulin secretion. Because of their insulinotropic action, their abnormal secretion may be involved in the pathogenesis of the hyperinsulinemia of childhood obesity. In this study, we used the hyperglycemic clamp with a small oral glucose load to assess the effect of childhood obesity on GIP response in seven prepubertal lean and 11 prepubertal obese children and in 14 lean adolescents and 10 obese adolescents. Plasma glucose was acutely raised to 11 mM by infusing i.v. glucose and kept at this concentration for 180 min. Each subject ingested oral glucose (30 g) at 120 min, and the glucose infusion was adjusted to maintain the plasma glucose plateau. Basal insulin and C-peptide concentrations and insulin secretion rates (calculated by the deconvolution method) were significantly greater in obese children compared with lean children (p < 0.001). Similarly, during the first 120 min of the clamp, insulin secretion rates were higher in obese than lean children. After oral glucose, plasma insulin, C-peptide, and insulin secretion rates further increased in all four groups. This incretin effect was 2-fold greater in obese versus lean adolescents (p < 0.001). Circulating plasma GIP concentrations were similar at baseline in all four groups and remained unchanged during the first 120 min of the clamp. After oral glucose, plasma GIP concentrations rose sharply in all groups (p < 0.002). Of note, the rise in GIP was similar in both lean and obese children. In conclusion, under conditions of stable hyperglycemia, the ingestion of a small amount of glucose elicited equivalent GIP responses in both lean and obese children. However, despite similar GIP responses, insulin secretion was markedly augmented in obese adolescents. Thus, in juvenile obesity, excessive alimentary beta-cell stimulation may be independent of the increased release of GIP.

Administration, Oral↗
PubMed2000

Impaired in vivo stimulation of lipolysis in adipose tissue by selective beta2-adrenergic agonist in obese adolescent girls.

Studies performed in adults with long-standing obesity suggest a reduced lipolytic sensitivity to catecholamines in subcutaneous abdominal adipose tissue (AT). We used microdialysis to study the in situ lipolytic effects of dobutamine (selective beta1-agonist) and terbutaline (selective beta2-agonist) on glycerol release (lipolytic index) in abdominal subcutaneous AT in 10 obese girls aged 13-17 years, BMI 38 +/- 2.1 kg/m2, and in 7 lean girls aged 11-17 years, BMI 21 +/- 1.1 kg/m2, and compared them with 10 obese women aged 21-39 years, BMI 36 +/- 1.6 kg/m2, and 10 lean women aged 18-42 years, BMI 21 +/- 0.4 kg/m2. Terbutaline at 10(-6) mol/l stimulated glycerol release more efficiently in lean girls than in obese girls (peak response approximately 350 vs. 150% of control, P < 0.01). At the lower concentration of agonist, no significant difference was seen. In women, terbutaline was more effective in lean than in obese women in stimulating glycerol release at both 10(-8) mol/l (peak response lean approximately 175% vs. obese 125% of control) and 10(-6) mol/l (approximately 300 vs. 150% of control, P < 0.05). No significant difference in glycerol release between obese and lean girls or women was detected with selective beta1-stimulation. Our data demonstrate a specific impairment in the capacity of beta2-adrenergic agonists to promote lipolysis in subcutaneous abdominal adipose tissue of obese adolescent girls and women. Thus, decreased mobilization of fat during activation of the adrenergic system might be present early in the development of adolescent obesity.

Abdomen↗
PubMed1999

Control of autoimmune diabetes in NOD mice by GAD expression or suppression in beta cells.

Glutamic acid decarboxylase (GAD) is a pancreatic beta cell autoantigen in humans and nonobese diabetic (NOD) mice. beta Cell-specific suppression of GAD expression in two lines of antisense GAD transgenic NOD mice prevented autoimmune diabetes, whereas persistent GAD expression in the beta cells in the other four lines of antisense GAD transgenic NOD mice resulted in diabetes, similar to that seen in transgene-negative NOD mice. Complete suppression of beta cell GAD expression blocked the generation of diabetogenic T cells and protected islet grafts from autoimmune injury. Thus, beta cell-specific GAD expression is required for the development of autoimmune diabetes in NOD mice, and modulation of GAD might, therefore, have therapeutic value in type 1 diabetes.

Adoptive Transfer↗