Elevated Blood Glucose Concentrations Research Articles

Caffeine and glucose homeostasis during rest and exercise in diabetes mellitus

Caffeine is a substance that has been used in our society for generations, primarily for its effects on the central nervous system that causes wakefulness. Caffeine supplementation has become increasingly more popular as an ergogenic aid for athletes and considerable scientific evidence supports its effectiveness. Because of their potential to alter energy metabolism, the effects of coffee and caffeine on glucose metabolism in diabetes have also been studied both epidemiologically and experimentally. Predominantly targeting the adenosine receptors, caffeine causes alterations in glucose homeostasis by decreasing glucose uptake into skeletal muscle, thereby causing elevations in blood glucose concentration. Caffeine intake has also been proposed to increase symptomatic warning signs of hypoglycemia in patients with type 1 diabetes and elevate blood glucose levels in patients with type 2 diabetes. Other effects include potential increases in glucose counterregulatory hormones such as epinephrine, which can also decrease peripheral glucose disposal. Despite these established physiological effects, increased coffee intake has been associated with reduced risk of developing type 2 diabetes in large-scale epidemiological studies. This review paper highlights the known effects of caffeine on glucose homeostasis and diabetes metabolism during rest and exercise.

Type 1 Diabetes Mellitus

1. Justin M. Gregory, MD* 2. Daniel J. Moore, MD, PhD† 3. Jill H. Simmons, MD‡ 1. *Pediatric Endocrinology Clinical Fellow, Ian Burr Division of Pediatric Endocrinology and Diabetes, Vanderbilt University School of Medicine, Nashville, TN. 2. †Assistant Professor of Pediatrics, Assistant Professor of Pathology, Microbiology, and Immunology, Ian Burr Division of Pediatric Endocrinology and Diabetes, Vanderbilt University School of Medicine, Nashville, TN. 3. ‡Assistant Professor of Pediatrics, Ian Burr Division of Pediatric Endocrinology and Diabetes, Vanderbilt University School of Medicine, Nashville, TN. * ADA: : American Diabetes Association DKA: : diabetic ketoacidosis HbA1c: : glycosylated hemoglobin I:C ratio: : insulin-to-carbohydrate ratio IV: : intravenous TDD: : total daily dose T1DM: : type 1 diabetes mellitus T2DM: : type 2 diabetes mellitus 1. All children with type 1 diabetes mellitus (T1DM) should have their blood sugar managed with basal-bolus insulin treatment by either multiple daily injections or an insulin pump. 2. All children with T1DM should have access to a pediatric endocrinologist with a diabetes management team with resources to support patients and families. 3. All children with T1DM should be monitored for symptoms and/or screened for commonly associated conditions such as thyroid and celiac disease. After completing this article, readers should be able to: 1. Recognize the presenting signs and symptoms of type 1 diabetes mellitus (T1DM). 2. Know the key principles of effective diabetes self-management and the diabetes care team’s role in facilitating effective self-management. 3. Know the acute and chronic complications of (T1DM). 4. Identify how different categories of insulin analogues are used in daily insulin regimens. True, it is a fight, but there is pleasure in the struggle. Victory comes to the courageous; and without courage and common sense, success awaits no one. I look upon the diabetic as charioteer and his chariot as drawn by three steeds named Diet, Insulin, and Exercise. It takes skill to drive one horse, intelligence to manage a team of two, but a man must be a very good teamster who can get all three to pull together.EP Joslin, 1933 Type 1 diabetes mellitus (T1DM) is a disorder of glucose homeostasis characterized by autoimmune destruction of the insulin-producing pancreatic β-cell that progressively leads to insulin deficiency and resultant hyperglycemia. If left untreated, insulin deficiency leads to progressive metabolic derangement, with worsening hyperglycemia, ketoacidosis, starvation, and death. In …

Type 1 Diabetes Mellitus

Type 1 Diabetes Mellitus

Hyperglycemia accelerates ATP‐binding cassette transporter A1 degradation via an ERK‐dependent pathway in macrophages

An elevation in blood glucose concentration leads to increased risk of developing diabetes-associated atherosclerotic cardiovascular disease due to an excessive accumulation of cholesterol in arterial macrophages. ATP-binding cassette transporter A1 (ABCA1) is an atheroprotective protein that mediates the export of cholesterol from macrophages. The present study aims to investigate the effect of hyperglycemia on the regulation of ABCA1 expression and to explore its underlying mechanisms of regulation in macrophages. Our results show that high glucose activates the extracellular signal-regulated kinases (ERK) signaling pathway via reactive oxygen species (ROS) production, which in turn down-regulates ABCA1 mRNA and protein expression. This down-regulation is mediated by accelerating ABCA1 mRNA and protein degradation in macrophages exposed to high concentrations of glucose. Our results provide evidence for the first time that hyperglycemia inhibits ABCA1 expression by ERK-modulated ABCA1 mRNA and protein stability. Overall, these results provide a mechanism for hyperglycemia-induced reduction in ABCA1 expression, which suggests a promising strategy for the treatment of diabetes-associated atherosclerosis.

Miniature Enzymatic Biosensors for Tear Glucose Measurement in Capillary Tubes

Miniature enzymatic electrochemical sensors were fabricated and applied to detect tear glucose concentrations in anesthetized rabbits. Three µL of tear fluid was sampled from under the lower eyelid via a glass capillary, and the miniature sensor was then inserted into the solution within the capillary for detection. Boluses of insulin were administrated to the rabbits to lower the elevated blood glucose concentrations caused from anesthesia. A significant correlation was found between tear and blood glucose levels, suggesting that tear glucose measurements are a potential, minimally invasive alternative for glucose monitoring.

GLP-1 receptor activated insulin secretion from pancreatic β-cells: mechanism and glucose dependence.

The major goal in the treatment of type 2 diabetes mellitus is to control the hyperglycaemia characteristic of the disease. However, treatment with common therapies such as insulin or insulinotrophic sulphonylureas (SU), while effective in reducing hyperglycaemia, may impose a greater risk of hypoglycaemia, as neither therapy is self-regulated by ambient blood glucose concentrations. Hypoglycaemia has been associated with adverse physical and psychological outcomes and may contribute to negative cardiovascular events; hence minimization of hypoglycaemia risk is clinically advantageous. Stimulation of insulin secretion from pancreatic β-cells by glucagon-like peptide 1 receptor (GLP-1R) agonists is known to be glucose-dependent. GLP-1R agonists potentiate glucose-stimulated insulin secretion and have little or no activity on insulin secretion in the absence of elevated blood glucose concentrations. This ‘glucose-regulated’ activity of GLP-1R agonists makes them useful and potentially safer therapeutics for overall glucose control compared to non-regulated therapies; hyperglycaemia can be reduced with minimal hypoglycaemia. While the inherent mechanism of action of GLP-1R agonists mediates their glucose dependence, studies in rats suggest that SUs may uncouple this dependence. This hypothesis is supported by clinical studies showing that the majority of events of hypoglycaemia in patients treated with GLP-1R agonists occur in patients treated with a concomitant SU. This review aims to discuss the current understanding of the mechanisms by which GLP-1R signalling promotes insulin secretion from pancreatic β-cells via a glucose-dependent process.

Improving IV Insulin Administration in a Community Hospital

Diabetes mellitus is a major independent risk factor for increased morbidity and mortality in the hospitalized patient, and elevated blood glucose concentrations, even in non-diabetic patients, predicts poor outcomes. The 2008 consensus statement by the American Association of Clinical Endocrinologists (AACE) and the American Diabetes Association (ADA) states that "hyperglycemia in hospitalized patients, irrespective of its cause, is unequivocally associated with adverse outcomes." It is important to recognize that hyperglycemia occurs in patients with known or undiagnosed diabetes as well as during acute illness in those with previously normal glucose tolerance. The Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation (NICE-SUGAR) study involved over six thousand adult intensive care unit (ICU) patients who were randomized to intensive glucose control or conventional glucose control. Surprisingly, this trial found that intensive glucose control increased the risk of mortality by 14% (odds ratio, 1.14; p = 0.02). In addition, there was an increased prevalence of severe hypoglycemia in the intensive control group compared with the conventional control group (6.8% vs. 0.5%, respectively; p < 0.001). From this pivotal trial and two others, Wyoming Medical Center (WMC) realized the importance of controlling hyperglycemia in the hospitalized patient while avoiding the negative impact of resultant hypoglycemia. Despite multiple revisions of an IV insulin paper protocol, analysis of data from usage of the paper protocol at WMC shows that in terms of achieving normoglycemia while minimizing hypoglycemia, results were suboptimal. Therefore, through a systematical implementation plan, monitoring of patient blood glucose levels was switched from using a paper IV insulin protocol to a computerized glucose management system. By comparing blood glucose levels using the paper protocol to that of the computerized system, it was determined, that overall, the computerized glucose management system resulted in more rapid and tighter glucose control than the traditional paper protocol. Specifically, a substantial increase in the time spent within the target blood glucose concentration range, as well as a decrease in the prevalence of severe hypoglycemia (BG < 40 mg/dL), clinical hypoglycemia (BG < 70 mg/dL), and hyperglycemia (BG > 180 mg/dL), was witnessed in the first five months after implementation of the computerized glucose management system. The computerized system achieved target concentrations in greater than 75% of all readings while minimizing the risk of hypoglycemia. The prevalence of hypoglycemia (BG < 70 mg/dL) with the use of the computer glucose management system was well under 1%.

Improving IV Insulin Administration in a Community Hospital

Diabetes mellitus is a major independent risk factor for increased morbidity and mortality in the hospitalized patient, and elevated blood glucose concentrations, even in non-diabetic patients, predicts poor outcomes.1-4 The 2008 consensus statement by the American Association of Clinical Endocrinologists (AACE) and the American Diabetes Association (ADA) states that "hyperglycemia in hospitalized patients, irrespective of its cause, is unequivocally associated with adverse outcomes."5 It is important to recognize that hyperglycemia occurs in patients with known or undiagnosed diabetes as well as during acute illness in those with previously normal glucose tolerance. The Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation (NICE-SUGAR) study involved over six thousand adult intensive care unit (ICU) patients who were randomized to intensive glucose control or conventional glucose control.6 Surprisingly, this trial found that intensive glucose control increased the risk of mortality by 14% (odds ratio, 1.14; p=0.02). In addition, there was an increased prevalence of severe hypoglycemia in the intensive control group compared with the conventional control group (6.8% vs. 0.5%, respectively; p<0.001). From this pivotal trial and two others,7,8 Wyoming Medical Center (WMC) realized the importance of controlling hyperglycemia in the hospitalized patient while avoiding the negative impact of resultant hypoglycemia. Despite multiple revisions of an IV insulin paper protocol, analysis of data from usage of the paper protocol at WMC shows that in terms of achieving normoglycemia while minimizing hypoglycemia, results were suboptimal. Therefore, through a systematical implementation plan, monitoring of patient blood glucose levels was switched from using a paper IV insulin protocol to a computerized glucose management system. By comparing blood glucose levels using the paper protocol to that of the computerized system, it was determined, that overall, the computerized glucose management system resulted in more rapid and tighter glucose control than the traditional paper protocol. Specifically, a substantial increase in the time spent within the target blood glucose concentration range, as well as a decrease in the prevalence of severe hypoglycemia (BG < 40 mg/dL), clinical hypoglycemia (BG < 70 mg/dL), and hyperglycemia (BG > 180 mg/dL), was witnessed in the first five months after implementation of the computerized glucose management system. The computerized system achieved target concentrations in greater than 75% of all readings while minimizing the risk of hypoglycemia. The prevalence of hypoglycemia (BG < 70 mg/dL) with the use of the computer glucose management system was well under 1%.

Naturally improving insulin resistance with amorfrutins

The incidence of type 2 diabetes (T2D), recognized in 2006 as a global health priority by the United Nations, is increasing worldwide. According to the International Diabetes Federation, approximately 190 million people are affected by T2D worldwide, a number expected to nearly double in the coming 20 y. Traditionally an age-related disease, there is today an alarming increased prevalence of T2D in adolescent subjects, which calls urgently for preventive measures. T2D is diagnosed by the presence of elevated blood glucose concentrations, as measured by elevated fasting plasma glucose, 2-h postload glucose, and HbA1c levels.

Carbohydrate-Electrolyte Drink Ingestion and Skill Performance During and After 2 hr of Indoor Tennis Match Play

Twenty-two tennis players were individually studied on 2 occasions. They performed a prematch skill test, a 2-hr tennis match against an equally ranked opponent, and a postmatch skill test. A carbohydrate-electrolyte (CHO-E; Lucozade Sport) or flavor-matched placebo-electrolyte (PL) beverage was administered in a double-blind fashion. During the trials, heart-rate and movement intensity were monitored, and the match was recorded for performance analysis. There were no differences in skill-test scores pre- to postmatch or between trials (154±38 pre- and 160±35 postmatch on PL, 155±36 pre- and 165±33 postmatch on CHO-E). CHO-E ingestion elevated blood glucose concentration throughout the match, and participants reported feeling more energetic (general activation) and more tense (high activation) 1 hr into the match than at baseline (p<.05). Participants in the CHO-E trial spent more time in moderate-intensity activity and less time in low-intensity activity than on PL. Performance analysis revealed that CHO-E ingestion increased overall serve success (M±SD, 68%±7% for CHO-E vs. 66%±7% for PL; p<.05) and success of first serves (65%±9% for CHO-E, 61%±7% for PL; p<.01) and serves to the advantage side (70%±9% for CHO-E, 66%±7% for PL; p<.05). Return success was greater during the second set of the match (p<.05) in the CHO-E trial. Differences in serve and return success were not associated with blood glucose response to CHO or player ability.

Therapeutic potential of metals in managing diabetes mellitus: a review

Diabetes mellitus (DM) represents one of the greatest threats to modern global health. Diabetes mellitus is characterized by chronic elevation of blood glucose concentration as a consequence of decreased blood insulin levels or decreased action of insulin. In order to prevent or delay the onset of such complications, tight control of fasting and postprandial blood glucose levels is a central aspect of diabetes treatment. Development of new therapies that are able to improve glycemia management, cure diabetes, and can even protect from it, are of great interest. Metal compounds proposed to have the potential to elicit beneficial effect in the pathogenesis and complication of the disease. The idea of using metal ions for the treatment of diabetes originates from the report in 1899. Vanadium, chromium, copper, cobalt, tungsten and zinc were found to be effective for treating diabetes in experimental animals. Results from long-term trials are needed in order to assess the safety and beneficial role of these metals as complementary therapies in the management of diabetes. The present review includes the therapeutic potential of some metals showing promising result in the treatment of diabetes.

The Metabolic Syndrome and Risk of Chronic Kidney Disease: Pathophysiology and Intervention Strategies

Metabolic syndrome is characterized by a clustering of cardiovascular risk factors, including abdominal obesity, elevated blood pressure and glucose concentrations, and dyslipidemia. The presence of this clinical entity is becoming more pervasive throughout the globe as the prevalence of obesity increases worldwide. Moreover, there is increased recognition of the complications and mortality related to this syndrome. This paper looks to examine the link between metabolic syndrome and the development of chronic kidney disease.

Emerging perspectives on essential amino acid metabolism in obesity and the insulin-resistant state.

Dysregulation of insulin action is most often considered in the context of impaired glucose homeostasis, with the defining feature of diabetes mellitus being elevated blood glucose concentration. Complications arising from the hyperglycemia accompanying frank diabetes are well known and epidemiological studies point to higher risk toward development of metabolic disease in persons with impaired glucose tolerance. Although the central role of proper blood sugar control in maintaining metabolic health is well established, recent developments have begun to shed light on associations between compromised insulin action [obesity, prediabetes, and type 2 diabetes mellitus (T2DM)] and altered intermediary metabolism of fats and amino acids. For amino acids, changes in blood concentrations of select essential amino acids and their derivatives, in particular BCAA, sulfur amino acids, tyrosine, and phenylalanine, are apparent with obesity and insulin resistance, often before the onset of clinically diagnosed T2DM. This review provides an overview of these changes and places recent observations from metabolomics research into the context of historical reports in the areas of biochemistry and nutritional biology. Based on this synthesis, a model is proposed that links the FFA-rich environment of obesity/insulin resistance and T2DM with diminution of BCAA catabolic enzyme activity, changes in methionine oxidation and cysteine/cystine generation, and tissue redox balance (NADH/NAD+).

Maternal Gestational Dietary Fat has Minimal Effects on Serum Lipid Profiles and Hepatic Glucose Transporter 2 and No Effect on Glucokinase Expression in Neonatal Wistar Rat Offspring

The study investigated the effects of maternal diets, varying in fat content, on lipid profiles and the expression of hepatic glucose transporter 2 (GLUT2) and glucokinase (GK) in neonatal Wistar rat offspring. Dams were maintained on diets of 10% (control), 20% (20F), 30% (30F) and 40% (40F) fat as energy throughout gestation; daily food intakes and weekly body weights were measured. Circulating fasting glucose, insulin and glucagon concentrations were determined in dams and their neonatal offspring. In neonates, total serum triglyceride, total and individual serum fatty acid concentrations, hepatic GLUT2 and GK mRNA and protein expression were determined. In dams, overall food intake of 20F (645.50 ± 25.26 g) and 40F (716.30 ± 14.15 g) dams was reduced compared to control (1007.00 ± 44.83 g) and 30F (924.50 ± 21.16 g) dams. The 20F neonates displayed elevated blood glucose concentrations (4.63 ± 0.153 mmol/l) compared to control neonates (4.14 ± 0.112 mmol/l). In 30F neonates, serum palmitoleic acid was reduced (1.63 ± 0.21% vs. 3.56 ± 0.38%) whereas stearic acid was elevated (10.05 ± 0.40% vs. 7.40 ± 0.72%) compared to control neonates. Further, the palmitoleic acid/palmitic acid ratio was reduced in 30F neonates (0.085 ± 0.009% vs. 0.165 ± 0.020% in control neonates). The 40F neonates displayed elevated GLUT2 immunoreactivity (22.86 ± 0.760%) compared to 20F (11.46 ± 2.701%) and 30F (6.45 ± 1.759%) neonates. Gestational programming with different dietary fat proportions minimally affects lipid profiles and hepatic GLUT2 immunoreactivity in neonatal offspring.

Blood glucose and nocturnal blood pressure in African and Caucasian men: The SABPA study

AimTo investigate the relationship between nocturnal blood pressure and chronically elevated blood glucose to determine if these elevated blood glucose concentrations contribute to a non-dipping blood pressure, especially in high-risk groups such as Africans. MethodsNocturnal blood pressures and blood glucose levels of 41 non-dipping African and 28 non-dipping Caucasian men were investigated. Ambulatory systolic (SBP) and diastolic blood pressure (DBP) were measured and blood collected in sodium fluoride tubes from the antebrachial vein to determine serum glucose and glycosylated hemoglobin A1c (HbA1c) percentage. The estimated average glucose (eAG) was determined from HbA1c percentage with a regression formula. ResultsThe African non-dippers had higher blood pressures (p<0.001) and elevated HbA1c (p=0.037) and eAG (p=0.041) levels compared to the Caucasians. In single, partial and multiple regression analyses nighttime (00:00–04:00) SBP correlated positively with HbA1c (p=0.069) and eAG (p<0.001) in the African men. No correlations were found in the Caucasian men. Sensitivity analysis confirmed that the association between nighttime SBP (00:00–04:00) and eAG was independent of carotid intima-media thickness in the African men (R2=0.617; β=0.438; p=0.008). ConclusionThe blunted nocturnal decline in SBP during the early morning hours is associated with chronically elevated blood glucose in non-dipper African men.

Molecular repair of a defective CFTR protein in cystic fibrosis

We analyse a paper, which reports an entirely novel approach to the treatment of cystic fibrosis, consisting in "repairing" the defective mutant protein. Patients with cystic fibrosis have a mutation of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), an epithelial chloride channel involved in salt and fluid transport in multiple organs, including the lungs and pancreas. The mutations have different effects on the CFTR protein, such as misfolding for the ΔF508 mutation (the most common), or defective opening of the chloride channel for the G551D-CFTR mutation, found in 4 to 5% of the patients. The authors of this work have shown that VX-770, an agent known previously to increase the activity of wild-type and G551D-CFTR cell surface protein in vitro, was able, when given orally to 39 cystic fibrosis patients during 14 and 28 days, to partially restore chloride conductance, as measured by nasal epithelium potential difference. Similarly, the agent partially restored chloride transport in sweat glands, as measured by the sweat chloride concentration. Clinically, VX-770 increased the forced expiratory volume per second (FEVi). Side effects included macular skin rash, elevation of blood glucose concentration and glycosuria. All side effects resolved after discontinuation of the drug. VX-770 has also been shown to increase the activity of ΔF508-CFTR channels in vitro, provided they reach the cell surface. This study appears to be a milestone in the treatment of cystic fibrosis and possibly other genetic diseases.

Bacteremia in Kenyan children presenting with malaria.

Since the etiologies and clinical outcomes of bacteremia in children with Plasmodium falciparum infections, particularly in areas of holoendemic malaria transmission, are largely unexplored, blood cultures and comprehensive clinical, laboratory, hematological, and nutritional parameters for malaria-infected children (aged 1 to 36 months, n = 585 patients) were investigated at a rural hospital in western Kenya. After the exclusion of contaminant microorganisms, the prevalence of bacteremia was 11.7% in the cohort (n = 506), with nontyphoidal Salmonella spp. being the most common isolates (42.4%). Bacteremia was found to occur in a significantly higher proportion of females than males and was associated with elevated blood glucose concentrations and lowered malaria parasite and hemoglobin (Hb) levels compared to those in abacteremic participants. In addition, the incidences of respiratory distress and severe malarial anemia (SMA; Hb level of <6.0 g/dl) were nonsignificantly greater in children with bacteremia. Mortality was 8.5-fold higher in children with bacteremia. Multivariate logistic regression analyses revealed that bacteremia was significantly associated with reduced incidences of high-density parasitemia (HDP; ≥ 10,000/μl) and increased incidences of malnutrition (i.e., underweight; weight-for-age Z score of <-2 using the NCHS system). Since previous studies showed that bacteremia caused by Gram-negative organisms is associated with enhanced anemia and mortality, multivariate logistic regression was also performed separately for randomly age- and gender-matched children with bacteremia caused by Gram-negative organisms (n = 37) and for children found to be abacteremic (n = 74). These results revealed that the presence of bacteremia caused by Gram-negative organisms was significantly associated with reduced HDP, enhanced susceptibility to respiratory distress, SMA (Hb level of <6.0 g/dl), and being underweight (Z score, <-2). Data presented here from a region of holoendemic P. falciparum transmission demonstrate that although bacteremia is associated with reduced malaria parasitemia, a number of unfavorable clinical outcomes, including malnutrition, respiratory distress, anemia, and mortality, are elevated in children with bacteremia, particularly in cases of Gram-negative origin.

Glucose Metabolism and Erythropoietin Stimulation of Erythroid Progenitor Cells

AbstractAbstract 4232Erythropoietin (EPO) is known for its activity in stimulating erythroid progenitor cell survival, proliferation and differentiation. EPO is produced in the interstitial cells of the kidney in a hypoxic responsive manner and is used in treatment of anemia in patients with chronic kidney disease. Suggestions that EPO may affect metabolic parameters led to a recent report that high dose erythropoietin treatment in mice resulted in reduced blood glucose level in addition to increased hematocrit (Hojman et al., Plos One 2009). To examine the link between EPO and metabolic processes further, we treated wild type C57Bl/6 mice fed normal diet (11 kcal% fat) and high fat diet (45 kcal% fat) with EPO (3,000 U/kg three times a week for 3 weeks). As expected from the stimulation of erythropoiesis by exogenous EPO, both groups showed the expected increase in hematocrit up to 80%. We also found that EPO decreased fasting blood glucose level in both normal diet fed mice and high fat diet fed mice, compared with mice treated with saline. An improvement in glucose tolerance was also observed. Since hematopoietic tissue is the major target of EPO, we speculate that EPO may stimulate glucose uptake in hematopoietic tissue, especially during erythropoiesis. To examine EPO stimulation and glucose uptake in vitro, we used cultures of primary human adult erythroid progenitor cells isolated from peripheral blood. We found that with EPO stimulation, glucose uptake per cell increased with erythroid differentiation and peaked in late erythroid progenitor cells at day 8 to 10, then decreased during terminal differentiation. This pattern was observed at both 21% O2 and 5% O2. EPO increased glucose uptake in a dose dependent manner up to 10 U/ml. Cellular glucose uptake appeared to follow EpoR expression and was maximal when EpoR levels, and therefore EPO response, were highest. Glucose uptake decreased as EpoR levels decreased with the progression of erythroid maturation. These data suggest that EPO stimulation regulates glucose uptake in erythroid progenitor/precursor cells depending on the stage of erythroid differentiation and that glucose uptake is reduced in late erythroid precursor cells with the down regulation of EpoR and loss of EPO dependence as the cells differentiate into mature erythrocytes. We also examined the effect of high glucose concentration on EPO response in primary human adult erythroid progenitor cell cultures. We found that high glucose concentration in erythroid progenitor cell cultures inhibited EPO stimulated differentiating erythroid progenitor cell proliferation. The combination of EPO with high dose glucose increased hemoglobinization as determined by the increase in benzidine positive cells, suggesting premature hemoglobin accumulation and differentiation. This activity of elevated glucose level suggests that elevated blood glucose concentration contributes to the blunted EPO response, giving rise to EPO resistance. The findings from this study provide us with new insight on EPO stimulation of erythropoiesis and the potential interplay between erythropoiesis and glucose metabolism. Disclosures:No relevant conflicts of interest to declare.

Impact of 6 weeks of treatment with low-dose metformin and atorvastatin on glucose-induced changes of endothelial function in adults with newly diagnosed type 2 diabetes mellitus: A single-blind study

Background: Statin treatment has been reported to improve survival in patients with atherosclerosis, partly by improving vascular endothelial function. Elevation of blood glucose concentrations impairs endothelial function and promotes atherogenesis, but the effect of statins on glucose-induced endothelial dysfunction is unknown. Endothelium-dependent dilation (EDD) measured by gauge-strain plethysmography in the forearm is considered to be a reliable marker of endothelial function in forearm resistance vessels. Objective: This study examined the combined effects of metformin and atorvastatin treatment on glucose-induced endothelial dysfunction (as EDD) in patients with newly diagnosed type 2 diabetes mellitus (DM). Methods: Patients with newly diagnosed DM were recruited and were randomly assigned to receive metformin 850 mg/d or metformin 850 mg/d + atorvastatin 10 mg/d for 6 weeks in a single-blind study. All patients underwent glucose loading (75 g oral glucose after 12 hours of fasting) at baseline and at the end of the treatment period. Blood samples were obtained at baseline before glucose loading and 3 hours after loading to de- termine serum concentrations of cholesterol, lipoproteins, triglycerides, glucose, and glycosylated hemoglobin. EDD was evaluated at baseline and at 1, 2, and 3 hours after loading. The investigators were blinded to the treatment group assignments, and all analyses were performed in a blinded manner. Adverse events (eg, gastrointestinal disorders, myopathy, liver disorders) were monitored based on reported symptoms or signs (eg, myalgias, muscle cramps), clinical examination, and laboratory parameters (eg, increased liver and muscle enzymes). Results: Thirty-two white patients with newly diagnosed type 2 DM were randomly assigned to receive metformin 850 mg/d (n = 17 [12 men]; mean [SD] age, 53.88 [45] years; body mass index [BMI], 28.7 [4.5] kg/m 2) or metformin 850 mg/d + atorvastatin 10 mg/d (n = 15 [6 men]; mean age, 52.53 [37] years; BMI, 28.5 [2.1] kg/m 2). At baseline, EDD was reduced 1 and 2 hours after glucose loading in both study groups ( P < 0.01). Glucose loading was associated with an elevation of blood glucose concentrations at 1 and 2 hours ( P < 0.01 vs resting levels before loading), and concentrations returned to resting levels at 3 hours, in both groups at baseline and after treatment. Metformin alone or in combination with atorvastatin was associated with a significant reduction in resting glucose concentrations after 6 weeks (both, P < 0.05 vs baseline), but only the combination of metformin + atorvastatin partly prevented the glucose-induced elevation of serum glucose at 1 hour after loading and the glucose-induced decrease in EDD (both, P < 0.01 vs baseline). Conclusions: Glucose loading blunted endothelial function, with a deterioration in EDD, in these patients with newly diagnosed type 2 DM. However, combined treatment with metformin and atorvastatin for 6 weeks partly prevented the glucose-induced impairment of EDD in these patients, with a significant difference compared with monotherapy with metformin.

Insulin facilitates repetitive spike firing in rat insular cortex via phosphoinositide 3-kinase but not mitogen activated protein kinase cascade

The insular cortex (IC) processes gustatory and visceral information, which functionally correlate to feeding behavior. Insulin, a well-known hormone controlling glucose metabolism, is released by elevation of blood glucose concentration following feeding behavior. The IC expresses dense insulin receptors and receives projection from the hypothalamus, which monitors changes in glucose concentration. Therefore, it is likely that insulin modulates neural properties in the IC. However, little is known about the effects of insulin on electrophysiological properties of the neocortex including the IC. To explore the effects of insulin on subthreshold responses and action potential properties in the IC, intracellular recording with sharp glass electrodes was performed from IC pyramidal cells using slice preparations. Although application of insulin (100 nM) had little effect on the resting membrane potential, input resistance and rheobase, insulin significantly increased the frequency of repetitive spike firing in response to a long depolarizing current pulse injection: the slope of the frequency-current curve was increased from 23.7±2.3 Hz/nA to 29.5±3.4 Hz/nA. Insulin slightly decreased the action potential threshold without affecting the amplitude of medium-duration and slow afterhyperpolarization (sAHP) s. The insulin-induced facilitation of repetitive spike firing was dose-dependent and blocked by pre-application of 200 nM lavendustin A, a tyrosine kinase inhibitor. Moreover, when combined with 200 nM wortmannin, a phosphoinositide 3-kinase (PI3-K) inhibitor, or 500 nM deguelin, an inhibitor of protein kinase B (PKB/Akt) downstream of PI3-K, insulin failed to increase the frequency of repetitive spike firing. In contrast, co-application of insulin and (10 μM) PD 98059, an inhibitor of mitogen activated protein kinase (MAPK), exerted facilitation of repetitive spike firing. These results suggest that acute insulin-induced facilitation of firing frequency is at least partially induced by hyperpolarizing effects on the action potential threshold, and that this facilitation is induced by activation of PI3-K but not MAPK cascade.