scholarly journals The IgG Antibody Paradox in Insulin Resistance: Pathogenic and Therapeutic

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A443-A443
Author(s):  
Andrew Lipchik ◽  
Sooyeon Lee ◽  
Justin P Annes ◽  
Michael P Snyder
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Diabetic Mouse ◽  
High Dose ◽  
Low Grade ◽  
Igg Antibody ◽  
Glucose Levels ◽  
Insulin Dependent ◽  
High Doses ◽  
Systemic Nature

Abstract Chronic low-grade inflammation and mitochondrial dysfunction are hallmarks of insulin resistance. However, the mechanisms by which the immune system can propagate systemic insulin resistance remains poorly understood. IgG antibodies are a critical component of immunity and display paradoxical properties. IgG can propagate inflammation by crosslinking Fc receptors activating innate immune cells, and conversely, when given intravenously at high doses (1–2 g/kg intravenous immunoglobulin), actively suppress inflammation. Here, we demonstrate that IgG can exert similar paradoxical properties on glucose metabolism. IgG can elicit insulin resistance, and conversely, when given at high doses, promote insulin sensitivity in a diabetic mouse model. IgG, through its Fc-mediated interactions, suppresses insulin-induced mitochondrial function as well as insulin signaling. Modulation of insulin-dependent mitochondrial respiration by serum or purified IgG highly correlates (R2 = 0.70) with the quantitative measurement of insulin sensitivity accessed by the modified insulin suppression test. Our studies indicate that IgG antibody glycosylation is critically important to these conflicting actions. In mice and humans, the progression of insulin resistance is associated with reduced IgG Fc region sialylation, and administration of asialylated IgG is sufficient to cause insulin resistance in IgG null mice. On the other hand, a single administration of high-dose IgG significantly improved insulin and glucose tolerance as well as plasma glucose levels lasting over 72 days post-administration. These results demonstrate new insights into the systemic nature of insulin resistance, a novel mechanism of the disease, and an innovative therapeutic strategy for treating type 2 diabetes.

scholarly journals Dose- and time-dependent effects of 17beta-oestradiol on insulin sensitivity in insulin-dependent tissues of rat: implications of IRS-1

2003 ◽  
Vol 176 (3) ◽  
pp. 367-379 ◽  
Author(s):  
C Gonzalez ◽  
A Alonso ◽  
F Diaz ◽  
AM Patterson
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Plasma Concentrations ◽  
Hormonal Treatment ◽  
Late Gestation ◽  
Female Rats ◽  
High Dose ◽  
Insulin Dependent ◽  
Sensitivity Changes ◽  
Dose Dependent

Numerous studies have suggested that ovarian hormones are able to modulate insulin sensitivity, but their exact role remains unclear. We have investigated whether different doses of 17beta-oestradiol mediate changes in insulin sensitivity and if these changes could be related to modifications of insulin receptor substrate-1 (IRS-1). Female rats were ovariectomized and later separated into three groups: untreated; treated with a dose of 17beta-oestradiol sufficient to reproduce gestational plasma concentrations of 17beta-oestradiol (group E); and treated with a dose 100 times greater than that given to group E (group E2). A euglycaemic-hyperinsulinaemic clamp was used to measure insulin sensitivity. Changes in IRS-1 were analysed by Western blotting and RT-PCR assays. In group E we found a decrease in insulin sensitivity between days 11 and 16 of treatment as in late gestation, whereas in the untreated group and group E2, development of insulin resistance was observed throughout the treatment. In contrast, whereas in group E2 insulin resistance throughout the hormonal treatment was related to diminished expression and phosphorylation of IRS-1, in group E the decrease in insulin sensitivity between days 11 and 16 of treatment was not related to a decrease in IRS-1 expression. Our results suggest that the effects of oestradiol on insulin sensitivity were dose-dependent and that the insulin resistance associated with a high dose of 17beta-oestradiol was related to downregulation of IRS-1 expression.

scholarly journals Insulin resistance and liver histopathology in metabolically unhealthy subjects do not correlate with the hepatic abundance of NLRP3 inflammasome nor circulating IL-1β levels

2021 ◽  
Vol 9 (1) ◽  
pp. e001975
Author(s):  
Nicolas Quezada ◽  
Ilse Valencia ◽  
Javiera Torres ◽  
Gregorio Maturana ◽  
Jaime Cerda ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Liver Damage ◽  
Nlrp3 Inflammasome ◽  
Low Grade ◽  
Model Assessment ◽  
Alcoholic Fatty Liver ◽  
Protein Levels ◽  
Liver Histopathology ◽  
Inflammatory Status

IntroductionSystemic chronic low-grade inflammation has been linked to insulin resistance (IR) and non-alcoholic steatohepatitis (NASH). NOD-like receptor protein 3 (NLRP3) inflammasome and its final product, interleukin (IL)-1β, exert detrimental effects on insulin sensitivity and promote liver inflammation in murine models. Evidence linking hepatic NLRP3 inflammasome, systemic IR and NASH has been scarcely explored in humans. Herein, we correlated the hepatic abundance of NLRP3 inflammasome components and IR and NASH in humans.Research design and methodsMetabolically healthy (MH) (n=11) and metabolically unhealthy (MUH) (metabolic syndrome, n=21, and type 2 diabetes, n=14) subjects were recruited. Insulin sensitivity (homeostatic model assessment of IR (HOMA-IR) and Oral Glucose Sensitivity (OGIS120)), glycemic (glycated hemoglobin), and lipid parameters were determined by standard methods. Plasma cytokines were quantified by Magpix. Hepatic NLRP3 inflammasome components were determined at the mRNA and protein levels by reverse transcription–quantitative PCR and western blot, respectively. Liver damage was assessed by histological analysis (Non-alcoholic Fatty Liver Disease Activity Score (NAS) and Steatosis, Inflammatory Activity, and Fibrosis (SAF) scores). IR and liver histopathology were correlated with NLRP3 inflammasome components as well as with liver and plasma IL-1β levels.ResultsBody Mass Index, waist circumference, and arterial hypertension frequency were significantly higher in MUH subjects. These patients also had increased high-sensitivity C reactive protein levels compared with MH subjects. No differences in the plasma levels of IL-1β nor the hepatic content of Nlrp3, apoptosis-associated speck-like (Asc), Caspase-1, and IL-1β were detected between MUH and MH individuals. MUH subjects had significantly higher NAS and SAF scores, indicating more severe liver damage. However, histological severity did not correlate with the hepatic content of NLRP3 inflammasome components nor IL-1β levels.ConclusionOur results suggest that NLRP3 inflammasome activation is linked neither to IR nor to the inflammatory status of the liver in MUH patients.

scholarly journals A Male with Extreme Subcutaneous Insulin Resistance: A Case Report

2016 ◽  
Vol 23 (2) ◽  
pp. 209-213 ◽  
Author(s):  
Zuhayer Ahmed ◽  
Indrajit Prasad ◽  
Hafizur Rahman ◽  
Jalil Ansari ◽  
Khaled Hassan
Keyword(s):  
Insulin Resistance ◽  
Blood Glucose ◽  
Underdeveloped Country ◽  
Hypoglycemic Agents ◽  
High Dose ◽  
Subcutaneous Insulin ◽  
Oral Hypoglycemic Agents ◽  
Glucose Levels ◽  
Medical Issues ◽  
Insulin Autoantibody

AbstractIntroduction: Though insulin has no upper limit in dosage, we do not encounter very high dose requirements too often. The reported case is the first in Bangladesh to require more than 1000 international units (IU) of subcutaneous insulin per day.Case presentation: A 44-year old male diabetic patient from Bangladesh presented with unusually uncontrolled diabetes mellitus due to extreme insulin resistance. Despite dramatic increase in insulin step by step up to 1110 IU of concomitant short and intermediate acting insulin per day by subcutaneous route, his blood glucose remained over 12 mmol/L persistently, in all the fasting, pre-prandial, postprandial and random samples. He was also treated with several oral hypoglycemic agents including metformin, vildagliptin, glimepiride, pioglitazone and miglitol along with insulin but blood glucose levels remained almost unchanged. However, intravenous infusion of insulin over 4 hours caused a plummet in the glucose level. His blood test for insulin autoantibody was negative.Conclusion: This paper provides a scope to review literatures on extreme subcutaneous insulin resistance and its management. It also reveals the limitations of management due to lack of facilities in an underdeveloped country, which hinders proper exploration to many medical issues.

scholarly journals Immunosuppressive Therapy in Treatment of Refractory Hypoglycemia in Type B Insulin Resistance: A Case Report

2017 ◽  
Vol 1 (12) ◽  
pp. 1435-1439 ◽  
Author(s):  
Lavanya Viswanathan ◽  
Imali Sirisena
Keyword(s):  
Insulin Resistance ◽  
African American ◽  
Insulin Receptor ◽  
American Woman ◽  
High Serum ◽  
Future Research ◽  
High Dose ◽  
Type B ◽  
Glucose Levels ◽  
Receptor Antibodies

Abstract Type B insulin resistance is a rare syndrome characterized by fluctuating glucose levels (ranging from hyperglycemia with extreme insulin resistance to intractable hypoglycemia without exogenous insulin administration), high serum insulin levels, and insulin receptor autoantibodies. Most cases occur in the African American population in association with other underlying autoimmune systemic diseases. Treatments with high-dose steroids, immunosuppressants, and plasmapheresis have been used, with variable outcomes, in patients without spontaneous remission. We report the case of a 60-year-old African American woman with history of systemic lupus erythematosus presenting with extreme fluctuations in glucose levels, ranging from severe hyperglycemia to refractory hypoglycemia, with high serum concentration of insulin in both phases. Her presentation and phenotype were very similar to those seen in known cases of type B insulin resistance associated with insulin receptor antibodies. Treatment in other reported cases used a combination of high-dose steroids and immunosuppressants. We tried high-dose steroids, azathioprine, and intravenous immunoglobulins, which resulted in improvement and barely detectable insulin receptor antibody. We present a case of type B insulin resistance with abnormally low titers of insulin receptor antibodies despite a typical clinical course and response. Future research is needed to improve diagnosis and treatment in this rare disease.

Fractionated proton radiation therapy of chordoma and low-grade chondrosarcoma of the base of the skull

1989 ◽  
Vol 70 (1) ◽  
pp. 13-17 ◽  
Author(s):  
Mary Austin-Seymour ◽  
John Munzenrider ◽  
Michael Goitein ◽  
Lynn Verhey ◽  
Marcia Urie ◽  
...  
Keyword(s):  
Disease Free Survival ◽  
Local Control Rate ◽  
High Dose ◽  
Low Grade ◽  
Proton Radiation ◽  
Content Type ◽  
Biological Effectiveness ◽  
High Doses ◽  
Disease Free Survival Rate ◽  
Base Of The Skull

✓ Sixty-eight patients with chordoma or low-grade chondrosarcoma at the base of the skull received fractionated high-dose postoperative radiation delivered with a 160-MeV proton beam. Protons have favorable physical characteristics which allow the delivery of high doses of radiation to these critically located tumors. The methods employed for these treatments are described. These patients have been followed for at least 17 months and for a median of 34 months. The median tumor dose was 69 CGE (cobalt Gy equivalent): CGE is the dose in proton Gy multiplied by 1.1, which is the relative biological effectiveness for protons compared to cobalt-60. The daily dose was 1.8 to 2.1 CGE. For this group the 5-year actuarial local control rate is 82% and disease-free survival rate is 76%. The incidence of treatment-related morbidity has been acceptable.

scholarly journals Suppression of Prolactin Secretion Partially Explains the Antidiabetic Effect of Bromocriptine in ob/ob Mice

Endocrinology ◽  
2018 ◽  
Vol 160 (1) ◽  
pp. 193-204 ◽  
Author(s):  
Isadora C Furigo ◽  
Miriam F Suzuki ◽  
João E Oliveira ◽  
Angela M Ramos-Lobo ◽  
Pryscila D S Teixeira ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Glucose ◽  
Insulin Sensitivity ◽  
Glucose Homeostasis ◽  
Prolactin Secretion ◽  
Dopamine Receptor Agonist ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Insulin Tolerance ◽  
Promising Therapeutic Approach

Abstract Previous studies have shown that bromocriptine mesylate (Bromo) lowers blood glucose levels in adults with type 2 diabetes mellitus; however, the mechanism of action of the antidiabetic effects of Bromo is unclear. As a dopamine receptor agonist, Bromo can alter brain dopamine activity affecting glucose control, but it also suppresses prolactin (Prl) secretion, and Prl levels modulate glucose homeostasis. Thus, the objective of the current study was to investigate whether Bromo improves insulin sensitivity via inhibition of Prl secretion. Male and female ob/ob animals (a mouse model of obesity and insulin resistance) were treated with Bromo and/or Prl. Bromo-treated ob/ob mice exhibited lower serum Prl concentration, improved glucose and insulin tolerance, and increased insulin sensitivity in the liver and skeletal muscle compared with vehicle-treated mice. Prl replacement in Bromo-treated mice normalized serum Prl concentration without inducing hyperprolactinemia. Importantly, Prl replacement partially reversed the improvements in glucose homeostasis caused by Bromo treatment. The effects of the Prl receptor antagonist G129R-hPrl on glucose homeostasis were also investigated. We found that central G129R-hPrl infusion increased insulin tolerance of male ob/ob mice. In summary, our findings indicate that part of Bromo effects on glucose homeostasis are associated with decrease in serum Prl levels. Because G129R-hPrl treatment also improved the insulin sensitivity of ob/ob mice, pharmacological compounds that inhibit Prl signaling may represent a promising therapeutic approach to control blood glucose levels in individuals with insulin resistance.

scholarly journals Early postnatal oestradiol exposure causes insulin resistance and signs of inflammation in circulation and skeletal muscle

2009 ◽  
Vol 201 (1) ◽  
pp. 49-58 ◽  
Author(s):  
Camilla Alexanderson ◽  
Elias Eriksson ◽  
Elisabet Stener-Victorin ◽  
Malin Lönn ◽  
Agneta Holmäng
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Uncoupling Protein ◽  
Female Rats ◽  
Whole Body ◽  
Low Grade ◽  
Expression Of Genes ◽  
Genes Encoding

Early postnatal events can predispose to metabolic and endocrine disease in adulthood. In this study, we evaluated the programming effects of a single early postnatal oestradiol injection on insulin sensitivity in adult female rats. We also assessed the expression of genes involved in inflammation and glucose metabolism in skeletal muscle and adipose tissue and analysed circulating inflammation markers as possible mediators of insulin resistance. Neonatal oestradiol exposure reduced insulin sensitivity and increased plasma levels of monocyte chemoattractant protein-1 (MCP-1) and soluble intercellular adhesion molecule-1. In skeletal muscle, oestradiol increased the expression of genes encoding complement component 3 (C3), Mcp-1, retinol binding protein-4 (Rbp4) and transforming growth factor β1 (Tgfβ1). C3 and MCP-1 are both related to insulin resistance, and C3, MCP-1 and TGFβ1 are also involved in inflammation. Expression of genes encoding glucose transporter-4 (Glut 4), carnitine-palmitoyl transferase 1b (Cpt1b), peroxisome proliferator-activated receptor δ (Ppard) and uncoupling protein 3 (Ucp3), which are connected to glucose uptake, lipid oxidation, and energy uncoupling, was down regulated. Expression of several inflammatory genes in skeletal muscle correlated negatively with whole-body insulin sensitivity. In s.c. inguinal adipose tissue, expression of Tgfβ1, Ppard and C3 was decreased, while expression of Rbp4 and Cpt1b was increased. Inguinal adipose tissue weight was increased but adipocyte size was unaltered, suggesting an increased number of adipocytes. We suggest that early neonatal oestrogen exposure may reduce insulin sensitivity by inducing chronic, low-grade systemic and skeletal muscle inflammation and disturbances of glucose and lipid metabolism in skeletal muscle in adulthood.

scholarly journals Increased basal level of Akt-dependent insulin signaling may be responsible for the development of insulin resistance

2009 ◽  
Vol 297 (4) ◽  
pp. E898-E906 ◽  
Author(s):  
Hui-Yu Liu ◽  
Tao Hong ◽  
Ge-Bo Wen ◽  
Jianmin Han ◽  
Degen Zuo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Insulin Signaling ◽  
Kinase Inhibitor ◽  
Phosphatidylinositol 3 Kinase ◽  
Akt Phosphorylation ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Triglyceride Content

A majority of subjects with insulin resistance and hyperinsulinemia can maintain their blood glucose levels normal for the whole life presumably through protein kinase B (Akt)-dependent insulin signaling. In this study, we found that the basal Akt phosphorylation level was increased in liver and gastrocnemius of mice under the high-fat diet (HFD). Levels of mitochondrial DNA and expression of some mitochondrion-associated genes were decreased by the HFD primarily in liver. Triglyceride content was increased in both liver and gastrocnemius by the HFD. Oxidative stress was induced by the HFD in both liver and gastrocnemius. Insulin sensitivity was decreased by the HFD. All of these changes were largely or completely reversed by treatment of animals with the phosphatidylinositol 3-kinase inhibitor LY-294002 during the time when animals usually do not eat. Consequently, the overall insulin sensitivity was increased by treatment with LY-294002. Together, our results indicate that increased basal Akt-dependent insulin signaling suppresses mitochondrial production, increases ectopic fat accumulation, induces oxidative stress, and desensitizes insulin signaling in subjects with insulin resistance and hyperinsulinemia.

The effect of high-dose sodium salicylate on chronically elevated plasma nonesterified fatty acid-induced insulin resistance and β-cell dysfunction in overweight and obese nondiabetic men

2009 ◽  
Vol 297 (5) ◽  
pp. E1205-E1211 ◽  
Author(s):  
Changting Xiao ◽  
Adria Giacca ◽  
Gary F. Lewis
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Sodium Salicylate ◽  
Insulin Clearance ◽  
High Dose ◽  
Β Cell ◽  
Nonesterified Fatty Acids ◽  
Lipid Infusion ◽  
Cell Dysfunction ◽  
Oral Sodium

Prolonged elevation of plasma nonesterified fatty acids (NEFA) induces insulin resistance and impairs pancreatic β-cell adaptation to insulin resistance. Studies in rodents suggest that inflammation may play a role in this “lipotoxicity.” We studied the effects of sodium salicylate, an anti-inflammatory agent, on lipid-induced alterations in β-cell function and insulin sensitivity in six overweight and obese nondiabetic men. Each subject underwent four separate studies, 4–6 wk apart, in random order: 1) SAL, 1-wk placebo followed by intravenous (iv) infusion of saline for 48 h; 2) IH, 1-wk placebo followed by iv infusion of intralipid plus heparin for 48 h to raise plasma NEFA approximately twofold; 3) IH + SS, 1-wk sodium salicylate (4.5 g/day) followed by 48-h IH infusion; and 4) SS, 1-wk oral sodium salicylate followed by 48-h saline infusion. After 48-h saline or lipid infusion, insulin secretion and sensitivity were assessed by hyperglycemic clamp and euglycemic hyperinsulinemic clamp, respectively, in sequential order. Insulin sensitivity was reduced by lipid infusion (IH = 67% of SAL) and was not improved by salicylate (IH + SS = 56% of SAL). Lipid infusion also reduced the disposition index ( P < 0.05), which was not prevented by sodium salicylate. Salicylate reduced insulin clearance. These data suggest that oral sodium salicylate at this dose impairs insulin clearance but does not ameliorate lipid-induced insulin resistance and β-cell dysfunction in overweight and obese nondiabetic men.

scholarly journals Effıcacy and safety of dapagliflozin on diabetic patients receiving high-doses of insulin

2019 ◽  
Vol 35 (2) ◽  
Author(s):  
Meltem Sertbas ◽  
Yasar Sertbas ◽  
Nalan Okuroglu ◽  
Ali Burkan Akyildiz ◽  
Seda Sancak ◽  
...  
Keyword(s):  
Insulin Dose ◽  
Fasting Blood Glucose ◽  
Insulin Requirement ◽  
Diabetic Patients ◽  
High Dose ◽  
Efficacy And Safety ◽  
Serum Electrolyte ◽  
Glucose Levels ◽  
Antidiabetic Treatment ◽  
High Doses

Objective: In this study we aimed to investigate the efficacy and safety of dapagliflozin addition to diabetic patients using high dose insulin. Methods: The current study was carried out in the outpatient diabetic clinics of Fatih Sultan Mehmet Education and Research Hospital. Thirty diabetic patients who were receiving high dose (>0.5U/kg) insulin and oral antidiabetic treatment (other than SGLT 2 inhibitors) were included in this study. Primary end point was the change in HbA1c, insulin doses and serum electrolyte from the addition of dapagliflozin 10 mg to the week 12. Results: At the end of three month BMI were obviously decreased from 33.31±4.51 to 32.14±4.66 (p: 0.001). There was also an evident decrease of insulin requirement from 76±23.15 U/kg to 57.60±17.61 U/day (p<0.001). As well as the decrease in insulin doses, there was also a significant decline in HbA1c (Δ 1.6 %) and fasting blood glucose levels (Δ68.6 mg/dl) (p<0.001). Among serum electrolyte levels slight but meaningful increase of blood urea nitrogen (BUN) and sodium (Na) levels were seen (p: 0.044 and p: 0.026). There were no significant changes in serum cholesterol levels with electrolytes such as potassium, calcium, phosphorus magnesium and vitamin D (p>0.05). Conclusion: In diabetic patients with inadequately controlled glucose regulation despite high-dose insulin therapy, dapagliflozin may be an alternative combination choice to decrease the need of insulin dose and obtain an optimal HbA1c, fasting plasma glucose levels and weight without major side effects. How to cite this:Sertbas M, Sertbas Y, Okuroglu N, Akyildiz AB, Sancak S, Ozdemir A. Effıcacy and safety of dapagliflozin on diabetic patients receiving high-doses of insulin. Pak J Med Sci. 2019;35(2):---------. doi: https://doi.org/10.12669/pjms.35.2.21 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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