scholarly journals Quantitative Measurement of Full-Length and C-Terminal Proteolyzed RBP4 in Serum of Normal and Insulin-Resistant Humans using a Novel Mass Spectrometry Immunoassay

Endocrinology ◽  
2012 ◽  
Vol 153 (3) ◽  
pp. 1519-1527 ◽  
Author(s):  
Qin Yang ◽  
Iratxe Eskurza ◽  
Urban A. Kiernan ◽  
David A. Phillips ◽  
Matthias Blüher ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Metabolic Syndrome ◽  
Full Length ◽  
Clinical Severity ◽  
Glucose Disposal ◽  
Insulin Resistant ◽  
Glucose Disposal Rate

Serum retinol-binding protein 4 (RBP4) levels are increased in insulin-resistant humans and correlate with severity of insulin resistance in metabolic syndrome. Quantitative Western blotting (qWestern) has been the most accurate method for serum RBP4 measurements, but qWestern is technically complex and labor intensive. The lack of a reliable, high-throughput method for RBP4 measurements has resulted in variability in findings in insulin-resistant humans. Many commonly used ELISAs have limited dynamic range. Neither the current ELISAs nor qWestern distinguish among full-length and carboxyl terminus proteolyzed forms of circulating RBP4 that are altered in different medical conditions. Here, we report the development of a novel quantitative mass spectrometry immunoaffinity assay (qMSIA) to measure full-length and proteolyzed forms of RBP4. qMSIA and qWestern of RBP4 were performed in identical serum aliquots from insulin-sensitive/normoglycemic or insulin-resistant humans with impaired glucose tolerance or type 2 diabetes. Total RBP4 qMSIA measurements were highly similar to qWestern and correlated equally well with clinical severity of insulin resistance (assessed by clamp glucose disposal rate, r = −0.74), hemoglobin A1c (r = 0.63), triglyceride/high-density lipoprotein (r = 0.55), waist/hip (r = 0.61), and systolic blood pressure (r = 0.53, all P < 0.001). Proteolyzed forms of RBP4 accounted for up to 50% of total RBP4 in insulin-resistant subjects, and des(Leu)-RBP4 (cleavage of last leucine) correlated highly with insulin resistance (assessed by glucose disposal rate, r = −0.69). In multiple regression analysis, insulin resistance but not glomerular filtration rate was the strongest, independent predictor of serum RBP4 levels. Thus, qMSIA provides a novel tool for accurately measuring serum RBP4 levels as a biomarker for severity of insulin resistance and risk for type 2 diabetes and metabolic syndrome.

scholarly journals Estimated glucose disposal rate and risk of stroke and mortality in type 2 diabetes: a nationwide cohort study

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Alexander Zabala ◽  
Vladimer Darsalia ◽  
Marcus Lind ◽  
Ann-Marie Svensson ◽  
Stefan Franzén ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Cohort Study ◽  
Cox Regression ◽  
Glucose Disposal ◽  
Risk Of Death ◽  
Increased Risk ◽  
Estimated Glucose Disposal Rate ◽  
Glucose Disposal Rate

Abstract Background and aims Insulin resistance contributes to the development of type 2 diabetes (T2D) and is also a cardiovascular risk factor. The aim of this study was to investigate the potential association between insulin resistance measured by estimated glucose disposal rate (eGDR) and risk of stroke and mortality thereof in people with T2D. Materials and methods Nationwide population based observational cohort study that included all T2D patients from the Swedish national diabetes registry between 2004 and 2016 with full data on eGDR and categorised as following: < 4, 4–6, 6–8, and ≥ 8 mg/kg/min. We calculated crude incidence rates and 95% confidence intervals (CIs) and used multiple Cox regression to estimate hazard ratios (HRs) to assess the association between the risk of stroke and death, according to the eGDR categories in which the lowest category < 4 (i.e., highest grade of insulin resistance), served as a reference. The relative importance attributed of each factor in the eGDR formula was measured by the R2 (± SE) values calculating the explainable log-likelihoods in the Cox regression. Results A total of 104 697 T2D individuals, 44.5% women, mean age of 63 years, were included. During a median follow up-time of 5.6 years, 4201 strokes occurred (4.0%). After multivariate adjustment the HRs (95% CI) for stroke in patients with eGDR categories between 4–6, 6–8 and > 8 were: 0.77 (0.69–0.87), 0.68 (0.58–0.80) and 0.60 (0.48–0.76), compared to the reference < 4. Corresponding numbers for the risk of death were: 0.82 (0.70–0.94), 0.75 (0.64–0.88) and 0.68 (0.53–0.89). The attributed relative risk R2 (± SE) for each variable in the eGDR formula and stroke was for: hypertension (0.045 ± 0.0024), HbA1c (0.013 ± 0.0014), and waist (0.006 ± 0.0009), respectively. Conclusion A low eGDR (a measure of insulin resistance) is associated with an increased risk of stroke and death in individuals with T2D. The relative attributed risk was most important for hypertension.

scholarly journals FRI0052 INFLUENCE OF RHEUMATOID ARTHRITIS ON THE CLINICAL AND BIOLOGICAL PROFILE OF TYPE-2 DIABETES MELLITUS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 601.2-602
Author(s):  
J. Avouac ◽  
M. Elhai ◽  
M. Forien ◽  
J. Sellam ◽  
F. Eymard ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Requirement ◽  
Multivariate Logistic Regression ◽  
Biological Profile ◽  
Research Support ◽  
Insulin Resistant ◽  
Research Grant

Background:Type-2 diabetes and rheumatoid arthritis (RA) are two chronic diseases characterized by tissue inflammation and insulin resistance. To date, no data have evaluated the influence of RA-induced joint and systemic inflammation on the course of type-2 diabetes.Objectives:To study the impact of RA on type-2 diabetesMethods:Observational, multicenter, cross-sectional usual-care study, including 7 rheumatology centers. This study included over a 24-month period consecutive patients with type-2 diabetes and RA, fulfilling the 2010 ACR / EULAR criteria, and diabetic controls with osteoarthritis (OA). The following data were collected: demographics, disease activity and severity indices, current treatment for RA and diabetes, history and complications of diabetes. A systematic blood test was performed, assessing inflammatory (CRP levels) and metabolic (fasting glycemia and insulin levels, HbA1c) parameters. The HOMA2%B (insulin secretion) and HOMA2%S (tissue insulin sensitivity) indices (HOMA calculator, © Diabetes Trials Unit, University of Oxford) were used to assess insulin resistance. Ra and OA patients were compared using parametric tests after adjusting for age and BMI. A multivariate logistic regression was performed ti identify factors independently associated with insulin resistance.Results:We included 122 RA patients (74% women, mean age 64+/-11 years, mean disease duration 15+/-11 11 years, 75% with positive ACPA antibodies and 64% with erosive disease) and 54 controls with OA. 64% of RA patients were treated with oral corticosteroids <10 mg/day, 65% received methotrexate and 53% received targeted biological therapies.The characteristics of type-2 diabetes in the 54 OA patients corresponded to severe insulin-resistant diabetes: age> 65 years, high BMI> 30 kg/m2, mean HbA1c 7.3%+/-11 1.3%, 30% of insulin requirement, high frequency of other cardiovascular risk factors, macroangiopathy found in almost half of patients and biological criteria of insulin resistance (elevation of HOMA2%B and decrease of HOMA2%S).RA patients with type-2 diabetes had a younger age (64+/-11 years vs. 68+/-12 years, p=0.031) and lower BMI (27.7+/-11 5.5 vs. 31.5+/-11 6.3, p<0.001). These patients also had severe diabetes (HbA1c 7.0%+/-11 1.2%, 29% of insulin requirement, 43% of macroangiopathy) with an insulin resistance profile identical to OA controls. After adjusting for age and BMI, RA patients had a significantly increased insulin secretion compared to OA patients (HOMA2%B: 83.1+/-11 65.2 vs. 49.3+/-11 25.7, p=0.023) as well as a significant reduction of insulin sensitivity (HOMA2%S: 61.1+/-11 31.6 vs. 92.9+/-11 68.1, p=0.016). This insulin resistance was associated with the inflammatory activity of RA, with a negative correlation between the HOMA2%S and the DAS28 (r=-0.28, p=0.027). The multivariate logistic regression confirmed the independent association between the HOMA2%S index and DAS28 (OR: 3.93, 95% CI 1.02-15.06), as well as high blood pressure (OR: 1.29, 95% CI 0.33-1.99 CI).Conclusion:RA patients with type-2 diabetes displayed severe, poorly controlled diabetes, highlighting the burden of comorbidities associated with RA. The clinical-biological profile of diabetic RA patients was severe insulin-resistant diabetes, with a biological profile of insulin resistance linked to the inflammatory activity of the disease. These findings may have therapeutic implications, with the potential targeting of insulin resistance through the treatment of joint and systemic inflammation.Acknowledgments:Société Française de Rhumatologie (research grant)Bristol Myers Squibb (research grant)Disclosure of Interests:Jérôme Avouac Grant/research support from: Pfizer, Bristol Myers Squibb, Consultant of: Sanofi, Bristol Myers Squibb, Abbvie, Boerhinger, Nordic Pharma, Speakers bureau: Sanofi, Bristol Myers Squibb Abbvie, MSD, Pfizer, Nordic Pharma, Muriel ELHAI: None declared, Marine Forien: None declared, Jérémie SELLAM: None declared, Florent Eymard Consultant of: Regenlab, Anna Moltó Grant/research support from: Pfizer, UCB, Consultant of: Abbvie, BMS, MSD, Novartis, Pfizer, UCB, Laure Gossec Grant/research support from: Lilly, Mylan, Pfizer, Sandoz, Consultant of: AbbVie, Amgen, Biogen, Celgene, Janssen, Lilly, Novartis, Pfizer, Sandoz, Sanofi-Aventis, UCB, Frédéric Banal: None declared, Joel Daminano: None declared, Philippe Dieudé: None declared, Yannick Allanore Shareholder of: Sanofi, Roche, Consultant of: Actelion, Bayer, BMS, Boehringer Ingelheim, Inventiva, Sanofi

scholarly journals The effects of metformin plus sulfonylurea therapy on clinical features of the metabolic syndrome

2010 ◽  
Vol 63 (9-10) ◽  
pp. 611-615 ◽  
Author(s):  
Branka Koprivica ◽  
Teodora Beljic-Zivkovic ◽  
Tatjana Ille
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Type 2 Diabetes ◽  
Metabolic Syndrome ◽  
Body Mass Index ◽  
Waist Circumference ◽  
Glycemic Control ◽  
Body Mass ◽  
Combined Therapy

Introduction. Insulin resistance is a well-known leading factor in the development of metabolic syndrome. The aim of this study was to evaluate metabolic effects of metformin added to sulfonylurea in unsuccessfully treated type 2 diabetic patients with metabolic syndrome. Material and methods. A group of thirty subjects, with type 2 diabetes, secondary sulfonylurea failure and metabolic syndrome were administered the combined therapy of sulfonylurea plus metformin for six months. Metformin 2000 mg/d was added to previously used sulfonylurea agent in maximum daily dose. Antihypertensive and hypolipemic therapy was not changed. The following parameters were assessed at the beginning and after six months of therapy: glycemic control, body mass index, waist circumference, blood pressure, triglycerides, total cholesterol and its fractions, homeostatic models for evaluation of insulin resistance and secretion (HOMA R, HOMA B) and C- peptide. Results. Glycemic control was significantly improved after six months of the combined therapy: (fasting 7.89 vs. 10.61 mmol/l. p<0.01; postprandial 11.12 vs. 12.61 mmol/l. p<0.01, p<0.01; glycosylated hemoglobin 6.81 vs. 8.83%. p<0.01). the body mass index and waist circumference were significantly lower (26.7 vs. 27.8 kg/m2, p<0.01 and 99.7 vs. 101.4 cm for men, p<0.01; 87.2 vs. 88.5 for women, p<0.01). Fasting plasma triglycerides decreased from 3.37 to 2.45 mmol/l (p<0.001) and HOMA R from 7.04 to 5.23 (p<0.001). No treatment effects were observed on blood pressure, cholesterol, and residual insulin secretion. Conclusion. Administration of metformin in type 2 diabetes with metabolic syndrome decreased cardiovascular risk factors by reducing glycemia, triglycerides, BMI, central obesity and insulin resistance.

Lipid-Induced Insulin Resistance Mechanisms: The Link to Inflammation and Type 2 Diabetes.

2021 ◽  
pp. 1-9
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Fatty Acid ◽  
Molecular Mechanisms ◽  
Laboratory Data ◽  
Phosphatidyl Inositol ◽  
Resistance Mechanisms ◽  
Cellular Mechanisms ◽  
Insulin Resistant

1. Abstract Insulin Resistance is the leading cause of Type 2 diabetes mellitus [T2DM] onset. It occurs as a result of disturbances in lipid metabolism and increased levels of circulating free fatty acids [FFAs]. FFAs accumulate within the insulin sensitive tissues such as muscle, liver and adipose tissues exacerbating different molecular mechanisms. Increased fatty acid flux has been documented to be strongly associated with insulin resistant states and obesity causing inflammation that eventually causes type 2-diabetes development. FFAs appear to cause this defect in glucose transport by inhibiting insulin –stimulated tyrosine phosphorylation of insulin receptor substrate-1 [IRS-1] and IRS-1 associated phosphatidyl-inositol 3-kinase activity. A number of different metabolic abnormalities may increase intramyocellular or intrahepatic fatty acid metabolites that induce insulin resistance through different cellular mechanisms. The current review point out the link between enhanced FFAs flux and activation of PKC and how it impacts on both the insulin signaling in muscle and liver as shown from our laboratory data and highlighting the involvement of the inflammatory pathways importance. This embarks the importance of measuring the inflammatory biomarkers in clinical settings.

IL-6 as a Surrogate Biomarker: The IL-6 Clinical Value for the Diagnosis of Insulin Resistance and Type 2 Diabetes.

2021 ◽  
pp. 1-13
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Molecular Mechanisms ◽  
Diagnostic Value ◽  
Low Grade ◽  
Clinical Value ◽  
Insulin Resistant ◽  
Tnf Α ◽  
Low Grade Inflammation

1. Abstract Insulin Resistance is the leading cause of Type 2 diabetes mellitus (T2D). It occurs as a result of lipid disorders and increased levels of circulating free fatty acids (FFAs). FFAs accumulate within the insulin sensitive tissues such as muscle, liver and adipose tissues exacerbating different molecular mechanisms. Increased levels fatty acid has been documented to be strongly associated with insulin resistant states and obesity causing inflammation that eventually causes type 2-diabetes. Among the biomarkers that are accompanying low grade inflammation include IL-1β, IL-6 and TNF-α. The current review point out the importance of measuring the inflammatory biomarkers especially focusing on the conductance and measurement for IL-6 as a screening laboratory test and its diagnostic value in clinical practice.

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