Glucose Toxicity Research Articles

High glucose inhibits myogenesis and induces insulin resistance by down-regulating AKT signaling

BackgroundA high glucose level is usually considered to be the factor that induces tissue and cell dysfunction and damage, commonly known as “glucose toxicity”. ObjectiveThis study aimed to explore the effects and the potential molecular mechanisms of high glucose on myoblast differentiation and insulin sensitivity. Materials and methodsC2C12 cells were cultured in differentiation medium containing 25, 40, or 60 mM glucose for 1, 3, or 5 days. E-MHC positive area and GLUT4 fluorescence were evaluated through Immunofluorescence. The expression of Myf5, MyoD, myogenin were measured by performing western blot and qRT-PCR. The protein expression of GLUT4 on cell membrane and glucose uptake in C2C12 myotubes were measured through western blot and 2-NBDG assay. AKT activator SC79 and inhibitor MK2206 was utilized to reveal the important role of AKT signaling in myogenesis and insulin sensitivity inhibited by high glucose. Results60 mM glucose inhibits myogenesis by decreasing the expression of MyoD and myogenin, and induces insulin resistance by reducing both basal and insulin-stimulated GLUT4 expressions and glucose uptakes. The influences of high glucose on myogenesis and IR was related to decreased AKT activation. SC79 rescued the inhibition of high glucose on myogenesis and attenuated IR. MK2206 inhibits the myogenic differentiation and induces IR. ConclusionThe present study reveals that high glucose inhibited myogenisis accompanied by inducing IR, through AKT signaling inhibition, which may help to further research for resisting degenerative muscular diseases caused by glucose metabolism disorders.

P722Glycemic control with canagliflozin, a SGLT-2 inhibitor, attenuates atherosclerosis and endothelial dysfunction in diabetic apolipoprotein e-deficient mice

Abstract Background Canagliflozin is a SGLT-2 inhibitor, a novel type of drug for type 2 diabetes mellitus treatment. Recent studies have shown that SGLT-2 inhibitors reduce cardiovascular events, although the mechanism is still unknown. Purpose The aim of our study was to examine the effect of canagliflozin on vascular endothelial cell. Method Eight-week-old apolipoprotein E-deficient (ApoE−/−) mice were treated with streptozotocin (STZ, 75 mg/kg/day) in three consecutive days by intraperitoneal injection to induce diabetes. Diabetic ApoE−/− mice were treated with canagliflozin (30 mg/kg/day) by gavage for 12 weeks or 8 weeks to examine its effect on atherosclerosis or endothelial function, respectively. Results Canagliflozin significantly decreased blood glucose level (P<0.001), triglyceride level (P<0.05), and total cholesterol level (P<0.05). Sudan IV staining on the aortic arch showed that canagliflozin decreased atherosclerotic lesion progression (P<0.05). Histological analyses using atherosclerotic lesions in the aortic root showed that canagliflozin reduced lipid disposition (P<0.01), macrophage accumulation (P<0.001, and expression of adhesion molecules such as ICAM-1, and VCAM-1 (P<0.01, and P<0.05 respectively). Canagliflozin also attenuated the development of endothelial dysfunction as determined by acetylcholine-dependent vasodilation (P<0.05), and reduced the expression of inflammatory molecules, such as ICAM-1 and VCAM-1 (P<0.01), also MCP-1, F4/80, IL6, and iNOS (P<0.05) in the aorta. Canagliflozin reduced oxidative stress as determined by the reduction of the expression of NOX2, NOX4, p22phox, p47phox in the aorta and by the urinary excretion of 8-OHdG. In in vitro experiment using human umbilical vein endothelial cells (HUVEC), methylglyoxal (MGO), a precursor of advanced glycation end products, significantly increased the expression of inflammatory molecules such as ICAM-1, MCP-1, and p22phox in (P<0.05, respectively). MGO also decreased the phosphorylation of eNOSser1177 and Akt, and increased phosphorylation of P38 MAPK in HUVEC. Conclusion Glucose lowering effect by canagliflozin attenuates the development of endothelial dysfunction and atherogenesis in diabetic ApoE−/− mice. Anti-inflammatory effect due to the reduction of glucose toxicity on endothelial cells might be one of the mechanisms.

Simplifying Complex Insulin Regimens While Preserving Good Glycemic Control in Type 2 Diabetes.

IntroductionType 2 diabetic patients suffering from severe hyperglycemia are often assigned a regimen involving multiple daily injections (MDI) of insulin. If the glucose toxicity resolves, the regimen can potentially be simplified, but there are no guidelines for this, and many patients are left on the MDI regimen. We aimed to prospectively examine the safety and efficacy of switching from MDI to once-daily IDegLira, a fixed-ratio combination of insulin degludec and liraglutide, in relatively well controlled (HbA1c ≤ 7.5%) subjects with type 2 diabetes on a low total daily insulin dose (TDD).Methods62 adults with type 2 diabetes (baseline age 64.06 ± 10.24 years, HbA1c 6.42 ± 0.68%, BMI 33.53 ± 6.90 kg/m2, body weight 93.81 ± 19.26 kg, TDD 43.31 ± 10.99 IU/day, insulin requirement 0.47 ± 0.13 IU/kg, duration of diabetes 10.84 ± 7.50 years, mean ± SD) treated with MDI ± metformin were enrolled in our study. Previous insulins were stopped and once-daily IDegLira was started. IDegLira was titrated by the patients to achieve a self-measured pre-breakfast blood glucose concentration of < 6 mmol/L.ResultsAfter a mean follow-up period of 99.2 days, mean HbA1c had decreased by 0.30% to 6.12 ± 0.65% (p < 0.0001), body weight had decreased by 3.11 kg to 90.70 ± 19.12 kg (p < 0.0001), and BMI had reduced to 32.39 ± 6.71 kg/m2 (p < 0.0001). After 3 months of treatment, the mean dose of IDegLira was 20.76 ± 6.60 units and the mean insulin requirement had decreased to 0.23 ± 0.08 IU/kg. IDegLira ± metformin combination therapy was found to be safe and generally well tolerated. During the month before the baseline visit, 28 patients (45%) had at least one episode of documented or symptomatic hypoglycemia, while only 6 (9.67%) patients reported a total of 13 documented episodes during the follow-up.ConclusionIn everyday clinical practice, switching from low-dose MDI to IDegLira in patients with well-controlled type 2 diabetes is safe, may result in weight loss and similar or better glycemic control, and substantially reduces the insulin requirement. Simplifying complex treatment regimens decreases treatment burden and may improve adherence to therapy.Clinical Trial NumberNCT04020445.

Interleukin-6 (IL-6) mediates protection against glucose toxicity in human Müller cells via activation of VEGF-A signaling

Interleukin-6 (IL-6) has become a target of interest for drug development aiming to treat diabetic retinopathy. Since IL-6 signaling can promote beneficial as well as detrimental effects via two different signaling pathways, the objective of the present study was to investigate the effects of classical IL-6 and IL-6 trans-signaling on human Müller cells (HMC), which are important for the development of diabetic retinopathy. HMCs were cultured in normal (5 mmol/L) and high (25 mmol/L) glucose plus or minus IL-6 or IL-6/sIL-6R. IL-6 receptor expression using immunohistochemistry and flow cytometry and cytokine release using magnetic bead assays were determined. HMCs express the membrane bound form of the IL-6 receptor (mIL-6R), gp130, and can release the soluble forms sIL-6R and sgp130 demonstrating that HMCs are capable of responding to classical IL-6 and IL-6 trans-signaling. IL-6 protected HMCs from glucose toxicity via VEGF-A signaling. IL-6/sIL-6R caused only modest protection, which was not mediated by VEGF-A. Our data show for the first time that classical IL-6 signaling exerts its beneficial effects through VEGF-A action contrary to IL-6 trans-signaling, which was VEGF-A independent. These results have clinical implications for drug development targeting IL-6 since strict anti-IL-6 therapies might further decrease neuroretinal functions in the diabetic retina.

Growth environment and organ specific variation in in-vitro cytoprotective activities of Picea mariana in PC12 cells exposed to glucose toxicity: a plant used for treatment of diabetes symptoms by the Cree of Eeyou Istchee (Quebec, Canada)

BackgroundThe Cree of Eeyou Istchee (James Bay area of northern Quebec) suffer from a high rate of diabetes and its complications partly due to the introduction of the western lifestyle within their culture.As part of a search for alternative medicine based on traditional practice, this project evaluates the biological activity of Picea mariana (Mill.) Britton, Sterns & Poggenb. needle, bark, and cone, in preventing glucose toxicity to PC12-AC cells in vitro (a diabetic neurophathy model) and whether habitat and growth environment influence this activity.MethodsThree different organs (needle, bark, and cone) of P. mariana were collected at different geographical locations and ecological conditions and their 80% ethanolic extracts were prepared. Extracts were then tested for their ability to protect PC12-AC cells from hyperglycaemic challenge at physiologically relevant concentrations of 0.25, 0.5, 1.0 and 2.0 μg/mL. Folin-Ciocalteu method was used to determine the total phenolic content of P. mariana extracts.ResultsAll extracts were well-tolerated in vitro exhibiting LD50 of 25 μg/mL or higher. Extracts from all tested organs showed a cytoprotective concentration-dependent response. Furthermore, the cytoprotective activity was habitat- and growth environment-dependent with plants grown in bog or forest habitats in coastal or inland environments exhibiting different cytoprotective efficacies. These differences in activity correlated with total phenolic content but not with antioxidant activity. In addition, this paper provides the first complete Ultra-Performance Liquid Chromatography-quadrupole time-of-flight (UPLC-QTOF) mass spectrometry analysis of Picea mariana’s bark, needles and cones.ConclusionsTogether, these results provide further understanding of the cytoprotective activity of Canadian boreal forest plants identified by the Cree healers of Eeyou Istchee in a cell model of diabetic neuropathy. Their activity is relevant to diabetic peripheral neuropathic complications and shows that their properties can be optimized by harvesting in optimal growth environments.

Contribution of Impaired Insulin Signaling to the Pathogenesis of Diabetic Cardiomyopathy.

Diabetic cardiomyopathy (DCM) has emerged as a relevant cause of heart failure among the diabetic population. Defined as a cardiac dysfunction that develops in diabetic patients independently of other major cardiovascular risks factors, such as high blood pressure and coronary artery disease, the underlying cause of DCMremains to be unveiled. Several pathogenic factors, including glucose and lipid toxicity, mitochondrial dysfunction, increased oxidative stress, sustained activation of the renin-angiotensin system (RAS) or altered calcium homeostasis, have been shown to contribute to the structural and functional alterations that characterize diabetic hearts. However, all these pathogenic mechanisms appear to stem from the metabolic inflexibility imposed by insulin resistance or lack of insulin signaling. This results in absolute reliance on fatty acids for the synthesis of ATP and impairment of glucose oxidation. Glucose is then rerouted to other metabolic pathways, with harmful effects on cardiomyocyte function. Here, we discuss the role that impaired cardiac insulin signaling in diabetic or insulin-resistant individuals plays in the onset and progression of DCM.

Silence of lncRNA GAS5 alleviates high glucose toxicity to human renal tubular epithelial HK-2 cells through regulation of miR-27a

Renal tubular damage caused by persistent high glucose environment has been found to contribute to diabetic nephropathy. This study explored the effects of lncRNA growth arrest-specific 5 (GAS5) on high glucose-stimulated human renal tubular epithelial HK-2 damage, as well as the possible internal molecular mechanism. Viability and apoptosis of HK-2 cells were assessed with the help of CCK-8 assay and Annexin V-FITC/PI staining, respectively. Cell transfection was used to change the expression of GAS5, miR-27a and BNIP3. We found that high glucose stimulation suppressed HK-2 cell viability but induced cell apoptosis. The expression of GAS5 was increased in HK-2 cells under high glucose environment. Silence of GAS5 mitigated the high glucose-caused HK-2 cell viability reduction and apoptosis. Overexpression of miR-27a reversed the effects of GAS5 on high glucose-stimulated HK-2 cells. Overexpression of BNIP3 aggravated the high glucose-caused HK-2 cell viability reduction, apoptosis and activation of JNK pathway. Knockdown of BNIP3 had opposite effects. In conclusion, this research further confirmed the pro-apoptotic roles of GAS5 in renal tubular epithelial cells under high glucose environment. Silence of GAS5 alleviated high glucose toxicity to human renal tubular epithelial HK-2 cells might be via down-regulating miR-27a and BNIP3, and then inactivating JNK pathway.HighlightsHG suppresses HK-2 cell viability, but promotes cell apoptosis;HG enhances the expression of GAS5 in HK-2 cells;Silence of GAS5 alleviates the HG-caused HK-2 cell toxicity;miR-27a participates in the effects of GAS5 silencing on HG-stimulated HK-2 cells;BNIP3 is regulated by miR-27a and related to the HG toxicity to HK-2 cells.

410-P: An Impaired Mitophagy-Lysosome System Contributes to Hyperglycemia Cardiotoxicity

Mitochondrial dysfunction plays an important role in diabetic heart damage. A healthy pool of mitochondria is maintained through a number of quality control mechanisms including mitophagy that degrades dysfunctional mitochondria through the lysosome. In the present study, we investigated the function of mitophagy-lysosome system in the diabetic heart and in cardiomyocytes cultured under high glucose. Streptozotocin-induced diabetes initiated mitophagy in the mouse heart but did not lead to its completion in the lysosome. Overexpression of the E3 ligase Parkin accelerated mitophagy flux and reduced diabetic cardiac injury. In contrast, Parkin gene deletion had the opposite effects, suggesting an essential role for mitophagy in maintaining cardiac homeostasis in diabetes. Lysophagy is the degradation of injured lysosomes by healthy lysosomes which is extremely important for all forms of autophagy. Using a novel dual fluorescent lysosome reporter, we showed that diabetes triggered lysosomal injury but reduced lysophagy flux, leading to the accumulation of injured lysosomes and the release of lysosomal enzymes such as cathepsin D. High glucose had similar effects in cultured cardiomyocytes. Enhancing lysophagy not only reduced high glucose toxicity but also accelerated mitophagy flux. Together, these results suggest that lysosomal dysfunction accounts at least partially for the reduced mitophagy flux and increased diabetic heart damage and that restoring lysosomal function may enhance mitochondrial quality control and reduce hyperglycemia cardiotoxicity. Disclosure S. Kobayashi: None. Y. Huang: None. T. Kobayashi: None. C. Li: None. F. Cai: None. Q. Liang: None. Funding National Institutes of Health

Fuzhuan Tea protects Caenorhabditis elegans from glucose and advanced glycation end products via distinct pathways

Abstract Fuzhuan Tea (FZT) protects against obesity and obesity-related disorders. However, little is known about its effects on high-sugar toxicity in Caenorhabditis elegans. Here, we find that FZT limits the life-shortening effects of a high-sugar (glucose, sucrose, galactose, and fructose) diet, but does not extend lifespan on a normal diet or protect against oxidative stress. FZT also can prolong healthspan and alleviate the detrimental effects of a glucose-rich diet. Furthermore, we report that effects of FZT on glucose toxicity and advanced glycation end products (AGEs) damage can be dissociated. Notably, FZT is dependent on DAF-16/FOXO and the insulin/IGF-1 signaling (IIS) pathway to promote lifespan and decrease fat content on a glucose-rich diet; concomitantly, FZT reduces AGEs levels by regulating SKN-1/Nrf and p38/mitogen-activated protein kinase (MAPK) pathway, independent of DAF-16/FOXO and IIS pathway. Our findings indicate that FZT protects against high glucose toxicity by a mechanism other than protection against AGEs damage.

Circulating Oxidative Stress Biomarkers in Clinical Studies on Type 2 Diabetes and Its Complications.

Type 2 diabetes (T2DM) and its complications constitute a major worldwide public health problem, with high rates of morbidity and mortality. Biomarkers for predicting the occurrence and development of the disease may therefore offer benefits in terms of early diagnosis and intervention. This review provides an overview of human studies on circulating biomarkers of oxidative stress and antioxidant defence systems and discusses their usefulness from a clinical perspective. Most case-control studies documented an increase in biomarkers of oxidative lipid, protein, and nucleic acid damage in patients with prediabetes and in those with a diagnosis of T2DM compared to controls, and similar findings were reported in T2DM with micro- and macrovascular complications compared to those without. The inconsistence of the results regarding antioxidant defence systems renders difficulty to draw a general conclusion. The clinical relevance of biomarkers of oxidative lipid and protein damage for T2DM progression is uncertain, but prospective studies suggest that markers of oxidative nucleic acid damage such as 8-hydroxy-2′-deoxyguanosine and 8-hydroxyguanosine are promising for predicting macrovascular complications of T2DM. Emerging evidence also points out the relationship between serum PON1 and serum HO1 in T2DM and its complications. Overall, enhanced oxidative damage represents an underlying mechanism of glucose toxicity in T2DM and its related micro- and macrovascular complications suggesting that it may be considered as a potential additional target for pharmacotherapy. Therefore, further studies are needed to understand whether targeting oxidative stress may yield clinical benefits. In this view, the measurement of oxidative stress biomarkers in clinical trials deserves to be considered as an additional tool to currently used parameters to facilitate a more individualized treatment of T2DM in terms of drug choice and patient selection.

LEVELS OF DIABETES BLOOD SUGAR WITH TYPE OF CATARACT

Diabetes mellitus was a disease with macro and micro risk of angiopathy, which includes the impact of causing cataracts. Diabetic patients with high sugar levels have a greater chance of developing cataracts at a younger age and certain tendencies towards cataract type. The aim of the study was to analyze the correlation between diabetes blood sugar levels and cataract type. The research design was correlation analysis with Cross-Sectional approach. Samples in the study were some cataract patients who had a history of diabetes mellitus in Surabaya Undaan Eye Hospital as many as 125 people, it was taken using consecutive sampling technique, and fulfilling the criteria of the study (age range 45 - 65 years, have complete medical records related to the continuity of sugar examination results in blood, the incidence of cataracts is not caused by congenital cataracts, juveniles, due to trauma, chemical exposure to UV radiation). Independent variable was the blood sugar level of Diabetes mellitus and the Dependent variable was cataract type. The instruments used were laboratory tests related to blood sugar levels, and medical diagnosis related to cataract type. Data were analyzed by Spearman rho, with a significant value &lt;0.05. The results showed a close association between diabetes and cataracts, where as many as 47.2% with high blood sugar levels, 40% with nuclear cataract type and from 59 respondents with high blood sugar levels 26 people experienced nuclear cataract type, with rho value = 0.001. The mechanism of glucose toxicity in Diabetes Mellitus which causes cataracts can go through three paths: increased activity of the aldose reductase enzyme which causes the formation of sugar alcohol, sorbitol and galactitol in crystalline lenses; through the non-enzymatic replication process; and at high blood glucose levels a glucose oxidation process will occur which causes oxidative stress conditions. Maintenance of managing blood sugar levels must be a concern for diabetics.&#x0D; &#x0D; Keywords: Blood Sugar Level, Diabetes Mellitus, Type of Cataract &#x0D;

LEVELS OF DIABETES BLOOD SUGAR WITH TYPE OF CATARACT

Diabetes mellitus was a disease with macro and micro risk of angiopathy, which includes the impact of causing cataracts. Diabetic patients with high sugar levels have a greater chance of developing cataracts at a younger age and certain tendencies towards cataract type. The aim of the study was to analyze the correlation between diabetes blood sugar levels and cataract type. The research design was correlation analysis with Cross-Sectional approach. Samples in the study were some cataract patients who had a history of diabetes mellitus in Surabaya Undaan Eye Hospital as many as 125 people, it was taken using consecutive sampling technique, and fulfilling the criteria of the study (age range 45 - 65 years, have complete medical records related to the continuity of sugar examination results in blood, the incidence of cataracts is not caused by congenital cataracts, juveniles, due to trauma, chemical exposure to UV radiation). Independent variable was the blood sugar level of Diabetes mellitus and the Dependent variable was cataract type. The instruments used were laboratory tests related to blood sugar levels, and medical diagnosis related to cataract type. Data were analyzed by Spearman rho, with a significant value &lt;0.05. The results showed a close association between diabetes and cataracts, where as many as 47.2% with high blood sugar levels, 40% with nuclear cataract type and from 59 respondents with high blood sugar levels 26 people experienced nuclear cataract type, with rho value = 0.001. The mechanism of glucose toxicity in Diabetes Mellitus which causes cataracts can go through three paths: increased activity of the aldose reductase enzyme which causes the formation of sugar alcohol, sorbitol and galactitol in crystalline lenses; through the non-enzymatic replication process; and at high blood glucose levels a glucose oxidation process will occur which causes oxidative stress conditions. Maintenance of managing blood sugar levels must be a concern for diabetics.&#x0D; &#x0D; Keywords: Blood Sugar Level, Diabetes Mellitus, Type of Cataract &#x0D;

The protective effects of a novel polysaccharide from Lentinus edodes mycelia on islet β (INS-1) cells damaged by glucose and its transportation mechanism with human serum albumin

High glucose can lead to toxicity on islet β cells. The protective effects of a novel Lentinus edodes mycelia polysaccharide (LMP) on INS-1 cells damaged by glucose were investigated. Cell viability, lactate dehydrogenase (LDH) release, cell apoptosis, intracellular reactive oxygen species (ROS), superoxide dismutase (SOD) activity, and malondialdehyde (MDA) content were detected. P38 MAPK, JNKand NF-κB pathways were analyzed to reveal the inhibitory mechanism of LMP on glucose-induced INS-1 cells toxicity. The results showed that LMP could decrease cellular oxidative stress, reduce intracellular ROS levels, decrease MDA content and increase SOD activity. Furthermore, the glucose-induced cell apoptosis in cells were inhibited by regulating the expression of Bax, Bcl-2, cleaved caspase‑3 and cleaved caspase‑1. Cell signaling pathway analysis revealed that LMP could inhibit the activation of p38 MAPK, JNK, NF-κB pathways and activate Nrf2 pathway. To further explore the possible transportation mechanism of LMP with human serum albumin (HSA), ultraviolet-visible absorption spectroscopy and fluorescence spectroscopy were used to evaluate the interaction between LMP and HSA. The results showed that LMP-HSA complex was formed, which would be helpful for explaining the transportation mechanism in vivo. These results suggested that LMP might be a new therapeutic candidate to alleviate the high glucose toxicity.

MON-151 Hypertriglyceridemia and Acute Pancreatitis Leading to Ketoacidosis in a Patient with Type 2 Diabetes

Introduction: We describe a case of type 2 diabetes presenting with acute pancreatitis (AP), hypertriglyceridemia, and diabetic ketoacidosis (DKA). Clinical Case: A 34-year-old Caucasian male presented to the emergency room with worsening intractable nausea and vomiting for 2 days. Medical problems included obesity, hypertension, hyperlipidemia, and fatty liver disease. He had a history of polysubstance use (denied recent alcohol intake) and noncompliance with self-care and was a known carrier for hemochromatosis. He gave a history of 30-lb weight loss over the past 6 weeks with associated polydipsia, polyuria, and abdominal pain. Six days prior to admission, the patient had been seen by his primary care physician for headache, nausea and vomiting, found to have a hemoglobin A1c of 13.5% (n=4.2-5.8%) and was started on metformin for newly-diagnosed T2DM. Physical exam revealed him to be afebrile, tachycardic (heart rate 145 bpm), and with a BP of 146/98 mmHg. Laboratory tests were significant for sodium 125 mmol/L (n=135-145mmol/L), potassium 4.0 mmol/L (n=3.5-5.1 mmol/L), anion gap 25 mmol/L (n=2-14 mmol/L), glucose 330 mg/dL (n=70-99 mg/dL), creatinine 1.5 mg/dL (n=0.5-1.3 mg/dL), lipase 268 U/L (n=8-78 U/L), triglyceride 1619 mg/dl (n<150 mg/dL), and negative alcohol and cardiac markers. Urine testing was positive for ketones with a negative drug screen. Arterial blood gas showed a pH of 7.27 (n=7.35-7.45), pCO2 19 mmHg (n= 35-45 mmHg), and pO2 111 mmHg (n=80-100 mmHg). CT of the abdomen revealed inflammation surrounding the pancreatic head, consistent with pancreatitis. The patient was admitted to the intensive-care unit for DKA and AP. He was treated with intravenous fluids and required an insulin drip for 72 hours before transitioning to subcutaneous insulin with resumption of oral nutrition as the pancreatic inflammation and gastrointestinal symptoms resolved. He was discharged on basal-bolus insulin therapy and lipid-lowering medications. Conclusion: Both DKA and AP are serious medical conditions with a high mortality rate when these two disorders occur simultaneously. Treatment requires aggressive fluid resuscitation with replacement of electrolytes and initiation of insulin. Identifying the potential trigger is key to preventing future occurrences. In the case presented, it is likely that primary hypertriglyceridemia, worsened by elevated glucose levels, was the etiologic factor for the onset of AP, which in turn precipitated DKA. However, it is also possible, though less likely, that uncontrolled hyperglycemia, glucose toxicity, and relative insulin deficiency led to increased production of very-low-density lipoprotein (VLDL) in the liver and its reduced clearance from the plasma, thus predisposing to hypertriglyceridemia. Close monitoring and appropriate therapy are required to control the latter and prevent future recurrences of AP and possibly DKA.

MON-143 Diabetic Ketoacidosis Confounding Diagnosis of Acromegaly with Microadenoma

Introduction: Acromegaly is a chronic endocrine disorder caused by excess secretion of GH. Due to the pulsatile nature of GH secretion, random GH levels do not necessarily correlate with the disease severity. Diagnosis of acromegaly is suggestive when IGF-1 levels are elevated. It can be further confirmed by demonstrating the failure of GH suppression with oral glucose tolerance test. Diabetes is a common complication of Acromegaly due to the GH hormone’s anti- insulin effect. However, the diagnosis of Acromegaly with co-existent uncontrolled DM may prove to be challenging. In the setting of uncontrolled DM, IGF-1 level may be normal, thus confounding the diagnosis of acromegaly. Case: Here we report a case of a newly diagnosed Acromegaly presenting with DKA as its initial manifestation with normal IGF-1 level and subsequently found to have microadenoma on imaging study. IGF-1 levels were confirmed to be elevated on subsequent visits after glucose optimization. Discussion: Manifestations of acromegaly present insidiously and evolve over many years, thus eluding a prompt diagnosis. The mean delay of acromegaly diagnosis from the onset of symptoms is approximately 9 years. Acromegaly is a disease process that has multiple negative consequences including impaired glucose tolerance, resistance and diabetes. Approximately 1% of patients with acromegaly present with DKA as its initial manifestation. Combination of lipotoxicity and glucose toxicity as a result of excess Growth Hormone may lead to a relatively insulin deficient state, predisposing to the development of DKA. IGF-1 levels can be altered by malnutrition, anorexia nervosa, liver cirrhosis, renal failure inflammatory diseases, malignant tumors and uncontrolled DM. Normal IGF-1 levels in the setting of DKA or uncontrolled diabetes can therefore erroneously lead a practitioner to exclude the diagnosis of acromegaly. Re-measuring IGF-1 levels after glucose control is imperative. Conclusion: Even though acromegaly with normal IGF-1 levels in the context of uncontrolled DM has been described in the literature, DKA and concomitant acromegaly is a rare presentation. According to literature review there are 22 reported cases where patients presented with DKA in combination with Acromegaly. Notably all cases were found to have pituitary macro-adenoma on MRI. We are reporting the case of Acromegaly presenting with DKA, microadenoma on MRI and normal IGF-1. Our case illustrates that normal IGF-1 levels in the setting of uncontrolled DM/DKA does not exclude acromegaly. As a result, the diagnosis of Acromegaly in the setting of DKA can be challenging. A clinician must be very vigilant and pursue further investigative workup if the clinical suspicion for acromegaly is high in patients presenting with DKA and normal IGF-1 levels.

SAT-175 (-)-Epicatechin Modulates Cellular Signaling and Mitochondrial Redox in Endothelium

Diabetes mellitus affects 451 million people worldwide, and people with diabetes are 3-5 times more likely to develop cardiovascular disease. In vascular tissue, mitochondrial function is important for vasodilation and arterial stiffness, both of which are abnormal in diabetes. Diabetes-mediated generation of excess reactive oxygen species (ROS) may be contributing to this problem. We have identified (-)-epicatechin (EPICAT), a plant compound and known vasodilator, as a potential therapy. We hypothesized that mitochondrial ROS accumulation in cells treated with high glucose (HG) or antimycin A (AA, a compound targeting complex III) could be diminished by EPICAT. We further hypothesized that reduction of ROS would correlate with improved mitochondrial dynamics and cellular signaling. To test this hypothesis, we employed human umbilical vein endothelial cells (HUVEC) treated with HG, AA, and/or 0.1 or 1.0 µM of EPICAT, and measured mitochondrial and cellular superoxide, mitochondrial dynamics, and cellular signaling upstream of mitochondrial function. AA significantly increased mitochondrial width (p=0.012) and decreased mitochondrial length (p=0.0001), but we observed no impact of EPICAT. We measured superoxide production by electron paramagnetic resonance spectroscopy using two spin probes specific to mitochondrial (Mito-TEMPO-H) and total cell (CMH) superoxide. No impact of HG treatment was detected in the total cell superoxide; however, an increase in mitochondrial superoxide was measured in cells treated with HG as compared to control (0.42 µM superoxide vs. 0.31 µM superoxide, respectively). We found that both concentrations of EPICAT significantly attenuated mitochondrial superoxide production when treated with HG (HG alone=0.44 µM superoxide, HG + 0.1 µM EPICAT=0.34 µM superoxide, HG + 1.0 µM EPICAT= 0.34 µM superoxide, p=0.02 EPICAT effect), but not with AA treatment. We found that in combination with HG, 0.1 µM EPICAT significantly increased eNOS expression (p<0.05). At 1.0 µM, EPICAT also increased peNOS expression (p<0.05) and attenuated a decrease in pAMPK (p<0.05) in response to HG. EPICAT at both concentrations significantly increased mitochondrial complex II expression (p<0.05 for both). In summary, HG-induced mitochondrial ROS is responsive to EPICAT, whereas AA-induced ROS is not, suggesting that EPICAT is useful in mitigating moderate ROS concentrations and may be modulating mitochondrial activity upstream of complex III. Our data further illustrate that EPICAT may be a tool to modulate both cellular and mitochondrial glucose toxicity through the regulation of AMPK and eNOS, upstream of mitochondrial activity, as well as bolstering endogenous antioxidant defenses.

Glucose toxicity: The worldwide problem and the all-natural solution

Glucose toxicity is aworldwide epidemic leading to the insulin resistance and the development of obesity and Type 2 diabetes in both children and adults. In addition to poor health and early death, this is costing our healthcare systems a fortune to treat diabetes and its complications. Glucose is not a passive bystander in our bloodstream but is a toxic and reactive compound. Glucose reacts with all of the proteins in our body forming glycated proteins. These glycated proteins progress to become what is known as Advanced Glycation Endproducts (AGEs). These AGEs are known to be the culprits associated with kidney failure, blindness, amputations and cardiovasular disease. Protein glycation is also the cause of insulin resistance which can lead to insulin depletion. When this happens, we have to resort to injection of insulin in an attempt to keep our blood glucose levels in the normal range. In over 20 years of R&D and clinical studies, nutritional supplements have been proven to combat glucose toxicity. Three important supplements having this ability are LYSINE, ZINC and VITAMIN C. These three supplements are now in one tablet, Lysulin® to combat glucose toxicity and protein glycation. Unlike the available prescription drugs for type 2 diabetes which are directed at the symptoms of diabetes (high blood glucose), Lysulin is directed at the problem, which is protein glycation. Clinical studies have proven that Lysulin supplementation lowers HbA1c better than most prescription drugs for diabetes. Historically, supplements have had a bad reputation because many of them have made unsubstantiated claims. Conversely, Lysulin is firmly grounded on a foundation published literature and clinical studies proving that Lysulin will lower blood glucose and glycated proteins. The history of studies proving the effectiveness of Lysulin will be presented along with recent data from double blind placebo controlled studies.

Epidemiological Evidence of the Relationship Between Diabetes and Dementia.

Growing epidemiological evidence has suggested that subjects with diabetes mellitus are at an increased risk for the development of dementia. However, the results for the subtypes of dementia are inconsistent. This review examined the risk of dementia in subjects with diabetes mellitus and discusses the possible mechanism underlying this association. Diabetes mellitus is associated with a 1.5- to 2.5-fold greater risk of dementia among community-dwelling elderly people. Notably, diabetes mellitus is a significant risk factor for not only vascular dementia but also Alzheimer's disease. The mechanisms underlying the association are unclear, but it may be multifactorial in nature, involving factors such as cardiovascular risk factors, glucose toxicity, changes in insulin metabolism, and inflammation. The optimal management of these risk factors in early life may be important to prevent future dementia. Furthermore, novel therapeutic strategies will be needed to prevent or reduce the development of dementia in subjects with diabetes mellitus.

The investigation of protective effects of glucagon-like peptide-1 (GLP-1) analogue exenatide against glucose and fructose-induced neurotoxicity

Diabetes mellitus (DM) is one of the most common metabolic disorders characterized by hyperglycemia due to insufficiency of insulin and/or insulin resistance. Clinical studies have revealed a higher risk of neurodegenerative disorders such as Alzheimer’s disease or Parkinson’s disease in diabetic patients. Recently, glucagon-like peptide-1 (GLP-1) is an attractive potential treatment modality for various neurodegenerative diseases. In our study, we aimed to investigate whether exenatide, a GLP-1 analogue, has neuroprotective effects against glucose and fructose-induced toxicity in human SH-SY5Y neuroblastoma cell line. Neurotoxicity was induced by incubating SH-SY5Y cells with different doses (25–100 mM) of glucose and fructose for 24, 48 and 72 hours. Following determination of the significant toxic doses of glucose and fructose, the cells were treated with various doses of exenatide (10–250 nM) in the presence or absence of glucose and fructose. Neurotoxicity was evaluated by MTT assay and Hoechst 33258 staining. Caspase-3 activity and the levels of advanced glycation end products (AGEs) were determined in the cytosolic fractions of treated cells. Our results demonstrated that both glucose and fructose treatments decreased cell viability in neuronal cells dose and time-dependently. Glucose and fructose-treated groups showed increased numbers of apoptotic cells, caspase-3 activity and AGEs levels. Treatment of the cells with exenatide significantly prevented cell death. The most prominent effect was observed at 100 nM exenatide-treated cultures. Our results suggest that high doses of glucose and fructose may lead to neurotoxicity, and exenatide may have protective effects against neuronal damage through its anti-apoptotic feature.

Hydroxysafflor yellow A attenuates high glucose-induced pancreatic β-cells oxidative damage via inhibiting JNK/c-jun signaling pathway

Pancreatic β-cells apoptosis and dysfunction induced by glucose toxicity were attributed to the formation of excess oxidative damage. Some studies have found that hydroxysafflor yellow A has strong effects to scavenge oxidative stress and inhibit apoptosis. In order to explore the influence of HSYA on oxidative stress induced by high glucose and the potential mechanisms, we set up a high glucose damage model and induced oxidative stress in INS-1 rat insulinoma cells. N-acetylcysteine was added as a group of oxidative stress scavenger. After 72 h of cultivation, the related indexes of oxidative stress (reactive oxygen species, catalase, glutathione peroxidase, lipid peroxidation, and superoxide dismutase), apoptosis (caspase3, parp) and the function of glucose stimulated insulin secretion were determined. In addition, the signaling pathway proteins of C-Jun NH2 -terminal kinases (JNK), phosphorylated JNK, C-jun, phosphorylated C-jun were evaluated. Fluorescence microscopy, qRT-PCR, western blotting were the main methods used in the experiment. Our results showed that hydroxysafflor yellow A reduced pancreatic β-cells apoptosis by attenuating oxidative damage, and JNK/c-Jun signaling pathway was involved. It indicated a significant mechanism for the positive impacts of HSYA on oxidative stress induced by high glucose, and provide important basis for using HSYA in diabetic prevention and therapy.