Proinflammatory cytokines in response to insulin-induced hypoglycemic stress in healthy subjects

Nematollahi, Laleh Razavi; Kitabchi, Abbas E.; Stentz, Frankie B.; Wan, Jim Y.; Larijani, Bagher; Tehrani, Mohammad Mohajer; Gozashti, Mohammad Hossein; Omidfar, Kobra; Taheri, Eghbal

doi:10.1016/j.metabol.2008.10.018

Cited by 189 publications

(142 citation statements)

References 24 publications

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“…There is evidence to support a proinflammatory state associated with hypoglycemia with increased inflammatory cytokines such as IL-6 and TNF-α [17,18,33], along with markers of endothelial dysfunction such as vascular adhesion molecules and reduced nitric oxide-induced vasodilation [18,19] and increased oxidative stress [33]. For reasons cited earlier, it is unclear to what extent brief episodes of hypoglycemia have on the development of atherosclerotic plaque formation as opposed to the more prolonged hyperglycemia, and studies in this area are urgently needed.…”

Section: Hypoglycemia and Endothelial Functionmentioning

confidence: 99%

Hypoglycaemia, thrombosis and vascular events in diabetes

King

Ajjan

2016

Expert Review of Cardiovascular Therapy

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Section: Hypoglycemia and Endothelial Functionmentioning

confidence: 99%

Hypoglycaemia, thrombosis and vascular events in diabetes

King

Ajjan

2016

Expert Review of Cardiovascular Therapy

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“…All of these are factors, which are known to contribute to the incidence and development of cardiovascular diseases. Hypoglycemia which is associated with intensive insulin therapy or starvation has been indicated in the elevation of oxidative stress in different hypoglycemic models (Razavi Nematollahi et al 2009, Bhardwaj et al 1998. A previous study has found that the depletion of scavenging agents for instance glutathione S-transferase (GST), glutathione peroxidase (GPx), and glutathione reductase (GR) promote oxidative stress in the brain, liver and kidney during RIIH or starvation (Bhardwaj et al 1998).…”

Section: Introductionmentioning

confidence: 99%

Recurrent insulin-induced hypoglycemia induces AngII and COX2 leading to renal (pro)renin receptor expression and oxidative stress

Alanazi¹,

Uddin²,

Fakhruddin

et al. 2017

IJM

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Background: Recurrent insulin-induced hypoglycemia (RIIH) is an avoidable consequence in the therapeutic management of diabetes mellitus. RIIH has been implicated in causing hypertension through an increase in renal and systemic AngII production. Objective: The present study was performed to assess the hypothesis that chronic insulin treatment enhances AngII and COX2 formation which in turn increases (pro) renin receptor (PRR) expression and NADPH oxidase-mediated oxidative stress, leading to renal and cardiac injury. Methods:The present studies were conducted in Male Sprague Dawley rats treated with daily subcutaneous injections of 7u/kg insulin or saline for 14 days. On the 14th day, surgery was performed for treatment infusion (captopril 12mg/kg, NS398 0.3mg/kg or vehicle), and renal interstitial fluid sample and urine collections for biomarker measurements. At the end of the experiments, kidneys and hearts were harvested to evaluate PRR and NOX2 (NADPH oxidase subunit) expression and oxidative stress. Results: We found that RIIH enhanced AngII and COX2 activity, leading to renal PRR expression and NADPH oxidase-induced oxidative stress in the heart and kidney. 8-isoprostane was evaluated as a renal biomarker of oxidative stress, which was induced in insulin treated animals and modulated by captopril and NS398. In addition, there was a slight increase in NGAL, a urinary biomarker of acute kidney injury (AKI), in insulin treated animals when compared to control. Conclusion: These results demonstrate that RIIH induces renal PRR expression and oxidative stress through increasing AngII and COX2 in the heart and kidney, leading to end-organ damage.

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“…The reasons for failure of the HbA 1c -based glycemic control strategies used in these more recent studies are not clear, but one possibility is that HbA 1c levels do not assess variability in plasma glucose levels; that is, HbA 1c does not directly reflect the frequency or severity of either hypoglycemic events or hyperglycemic increments after meals, both of which may cause physiologic changes that contribute to long-term risks. Possible mechanisms for such effects include systemic inflammation (8,9), oxidative stress (10), endothelial dysfunction (11,12), intimal-medial thickening (13), and cardiac ischemia or arrhythmias (14)(15)(16). Considerable literature linking various CVD risk markers with glycemic variability has been published (17,18).…”

mentioning

confidence: 99%

Design of FLAT-SUGAR: Randomized Trial of Prandial Insulin Versus Prandial GLP-1 Receptor Agonist Together With Basal Insulin and Metformin for High-Risk Type 2 Diabetes

Investigators¹,

Probstfield²,

Hirsch³

et al. 2015

Diabetes Care

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OBJECTIVEGlycemic variability may contribute to adverse medical outcomes of type 2 diabetes, but prior therapies have had limited success in controlling glycemic fluctuations, and the hypothesis has not been adequately tested. RESEARCH DESIGN AND METHODSPeople with insulin-requiring type 2 diabetes and high cardiovascular risk were enrolled during a run-in period on basal-bolus insulin (BBI), and 102 were randomized to continued BBI or to basal insulin with a prandial GLP-1 receptor agonist (GLIPULIN) group, each seeking to maintain HbA 1c levels between 6.7% and 7.3% (50-56 mmol/mol) for 6 months. The primary outcome measure was glycemic variability assessed by continuous glucose monitoring; other measures were HbA 1c , weight, circulating markers of inflammation and cardiovascular risk, albuminuria, and electrocardiographic patterns assessed by Holter monitoring. RESULTSAt randomization, the mean age of the population was 62 years, median duration of diabetes 15 years, mean BMI 34 kg/m 2 , and mean HbA 1c 7.9% (63 mmol/mol). Thirty-three percent had a prior cardiovascular event, 18% had microalbuminuria, and 3% had macroalbuminuria. At baseline, the continuous glucose monitoring coefficient of variation for glucose levels was similar in both groups. CONCLUSIONSFLAT-SUGAR is a proof-of-concept study testing whether, in a population of individuals with type 2 diabetes and high cardiovascular risk, the GLIPULIN regimen can limit glycemic variability more effectively than BBI, reduce levels of cardiovascular risk markers, and favorably alter albuminuria and electrocardiographic patterns. We successfully randomized a population that has sufficient power to answer the primary question, address several secondary ones, and complete the protocol as designed.

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Proinflammatory cytokines in response to insulin-induced hypoglycemic stress in healthy subjects

Cited by 189 publications

References 24 publications

Hypoglycaemia, thrombosis and vascular events in diabetes

Hypoglycaemia, thrombosis and vascular events in diabetes

Recurrent insulin-induced hypoglycemia induces AngII and COX2 leading to renal (pro)renin receptor expression and oxidative stress

Design of FLAT-SUGAR: Randomized Trial of Prandial Insulin Versus Prandial GLP-1 Receptor Agonist Together With Basal Insulin and Metformin for High-Risk Type 2 Diabetes

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