scholarly journals Effect of Denosumab on Glucose Homeostasis in Postmenopausal Women with Breast Cancer Treated with Aromatase Inhibitors: A Pilot Study

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Alessandro Rossini ◽  
Sofia Frigerio ◽  
Elena Dozio ◽  
Roberto Trevisan ◽  
Gianluca Perseghin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Insulin Sensitivity ◽  
Pilot Study ◽  
Glucose Metabolism ◽  
Aromatase Inhibitors ◽  
Glucose Homeostasis ◽  
Glycated Haemoglobin ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Sensitivity Index

Background. Aromatase inhibitors in women with breast cancer have been associated with cancer treatment-induced bone loss (CTIBL), increased fracture risk, and impairment of glucose metabolism. Denosumab (Dmab), a monoclonal antibody against RANKL, which is a key regulator of the osteoclast activity, is effective as an antiresorptive agent in the treatment of CTIBL. Since RANKL/RANK pathway may contribute to the pathogenesis of glucometabolic disorders, it has been suggested that Dmab may improve glucose homeostasis. Our pilot study evaluated the effect of a single administration of 60 mg Dmab on glucose metabolism in a cohort of women with breast cancer treated with aromatase inhibitors. Methods. Fifteen postmenopausal nondiabetic women were prospectively enrolled. Oral glucose tolerance test (OGTT) and metabolic parameters, including FGF21, were assessed at baseline and one month after Dmab injection. Midterm glucose control was evaluated by measuring glycated haemoglobin (HbA1c) levels 5 months after Dmab. Results. Parameters of glucose metabolism were not different one month after Dmab but circulating FGF21 levels significantly decreased (128.5 ± 46.8 versus 100.2 ± 48.8 pg/mL; p = 0.016 ). Considering patients with insulin resistance at baseline (HOMA-IR > 2.5 and Matsuda Index < 2.5; n = 5), reduced mean fasting insulin levels (16.3 ± 4.9 versus 13.5 ± 3.5 mcU/mL; p = 0.029 ) and increased insulin sensitivity index QUICKI (0.317 ± 0.013 versus 0.327 ± 0.009; p = 0.025 ) were found. Nonetheless, HbA1c increased 5 months after Dmab (36.0 ± 2.3 versus 39.6 ± 3.1 mmol/mol; p = 0.01 ). Conclusions. Although RANKL blockade induced a short-term positive effect on insulin sensitivity, particularly in insulin-resistant patients, a benefit on long-term glucose metabolism was not evident. In conclusion, Dmab is safe for glucose metabolism in aromatase inhibitor-treated women with breast cancer.

scholarly journals Higher Insulin Resistance and Adiposity in Postmenopausal Women With Breast Cancer Treated With Aromatase Inhibitors

2019 ◽  
Vol 104 (9) ◽  
pp. 3670-3678 ◽  
Author(s):  
Fraser W Gibb ◽  
J Michael Dixon ◽  
Catriona Clarke ◽  
Natalie Z Homer ◽  
Abdullah M M Faqehi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Aromatase Inhibitors ◽  
Glucose Tolerance Test ◽  
Postmenopausal Breast Cancer ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Oral Glucose Tolerance

Abstract Context Aromatase deficiency causes obesity and insulin resistance in aromatase knockout mice and humans with rare mutations of the aromatase gene (CYP19). Aromatase inhibitors are a commonly prescribed therapy for postmenopausal breast cancer. Objective We hypothesized that aromatase inhibitors induce obesity and insulin resistance when used in treatment of breast cancer. Design Case-control study. Setting University teaching hospital. Participants Patients with postmenopausal breast cancer (n = 20) treated with aromatase inhibitors and 20 age-matched control subjects. Main outcome measures The primary outcome measure was insulin sensitivity index – Matsuda, derived from a 75-g oral glucose tolerance test. Body composition was assessed by dual energy x-ray absorptiometry and biopsy specimens of subcutaneous adipose tissue obtained for assessment of mRNA transcript levels. Data are reported as mean ± SEM (patients receiving inhibitors vs control group, respectively). Results Aromatase inhibitor therapy was associated with significantly lower insulin sensitivity (5.15 ± 0.45 vs 6.80 ± 0.64; P = 0.041), higher peak insulin concentration after oral glucose tolerance test (693.4 ± 78.6 vs 527.6 ± 85.5 pmol/L; P = 0.035), greater percentage of body fat (38.4% ± 1.0% vs 34.6% ± 1.3%; P = 0.026), and higher plasma leptin concentration (23.5 ± 2.8 vs 15.5 ± 2.3 ng/mL; P = 0.035). Conclusion Women who received aromatase inhibitors for postmenopausal breast cancer had greater percentage body fat and insulin resistance compared with control subjects with no history of breast cancer.

scholarly journals Measurement of bioactive osteocalcin in humans using a novel immunoassay reveals association with glucose metabolism and β-cell function

2020 ◽  
Vol 318 (3) ◽  
pp. E381-E391 ◽  
Author(s):  
Julie Lacombe ◽  
Omar Al Rifai ◽  
Lorraine Loter ◽  
Thomas Moran ◽  
Anne-Frédérique Turcotte ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Glucose Metabolism ◽  
Cell Function ◽  
Fasting Glucose ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Sensitivity Index ◽  
Model Assessment ◽  
Β Cell

Osteocalcin (OCN) is a bone-derived hormone involved in the regulation of glucose metabolism. In serum, OCN exists in carboxylated and uncarboxylated forms (ucOCN), and studies in rodents suggest that ucOCN is the bioactive form of this hormone. Whether this is also the case in humans is unclear, because a reliable assay to measure ucOCN is not available. Here, we established and validated a new immunoassay (ELISA) measuring human ucOCN and used it to determine the level of bioactive OCN in two cohorts of overweight or obese subjects, with or without type 2 diabetes (T2D). The ELISA could specifically detect ucOCN concentrations ranging from 0.037 to 1.8 ng/mL. In a first cohort of overweight or obese postmenopausal women without diabetes ( n = 132), ucOCN correlated negatively with fasting glucose (r = −0.18, P = 0.042) and insulin resistance assessed by the homeostatic model assessment of insulin resistance (r = −0.18, P = 0.038) and positively with insulin sensitivity assessed by a hyperinsulinemic-euglycemic clamp (r = 0.18, P = 0.043) or insulin sensitivity index derived from an oral glucose tolerance test (r = 0.26, P = 0.003). In a second cohort of subjects with severe obesity ( n = 16), ucOCN was found to be lower in subjects with T2D compared with those without T2D (2.76 ± 0.38 versus 4.52 ± 0.06 ng/mL, P = 0.009) and to negatively correlate with fasting glucose (r = −0.50, P = 0.046) and glycated hemoglobin (r = −0.57, P = 0.021). Moreover, the subjects with ucOCN levels below 3 ng/mL had a reduced insulin secretion rate during a hyperglycemic clamp ( P = 0.03). In conclusion, ucOCN measured with this novel and specific assay is inversely associated with insulin resistance and β-cell dysfunction in humans.

Analysis of candidate genes in Polish families with obesity

2004 ◽  
Vol 42 (5) ◽  
Author(s):  
Malgorzata Malczewska-Malec ◽  
Iwona Wybranska ◽  
Iwona Leszczynska-Golabek ◽  
Lukasz Partyka ◽  
Jadwiga Hartwich ◽  
...  
Keyword(s):  
Risk Factors ◽  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Body Mass ◽  
Tolerance Test ◽  
Whole Body ◽  
Oral Glucose ◽  
Sensitivity Index ◽  
Model Assessment ◽  
The Metabolic Syndrome

AbstractThis study analyzes the relationship between risk factors related to overweight/obesity, insulin resistance, lipid tolerance, hypertension, endothelial function and genetic polymorphisms associated with: i) appetite regulation (leptin, melanocortin-3-receptor (MCR-3), dopamine receptor 2 (D2R)); ii) adipocyte differentiation and insulin sensitivity (peroxisome proliferator-activated receptor-γThe 122 members of 40 obese Caucasian families from southern Poland participated in the study. The genotypes were analyzed by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) or by direct sequencing. Phenotypes related to obesity (body mass index (BMI), fat/lean body mass composition, waist-to-hip ratio (WHR)), fasting lipids, glucose, leptin and insulin, as well as insulin during oral glucose tolerance test (OGTT) (4 points within 2 hours) and during oral lipid tolerance test (OLTT) (5 points within 8 hours) were assessed. The insulin sensitivity indexes: homeostasis model assessment of insulin resistance, whole body insulin sensitivity index, hepatic insulin sensitivity and early secretory response to an oral glucose load (HOMA-IR, ISI-COMP, ISI-HOMA and DELTA) were calculated.The single gene mutations such as CWe conclude that the polymorphisms we investigated were weakly correlated with obesity but significantly modified the risk factors of the metabolic syndrome.

scholarly journals Validation of Insulin Sensitivity Indices from Oral Glucose Tolerance Test Parameters in Obese Children and Adolescents

2004 ◽  
Vol 89 (3) ◽  
pp. 1096-1101 ◽  
Author(s):  
Catherine W. Yeckel ◽  
Ram Weiss ◽  
James Dziura ◽  
Sara E. Taksali ◽  
Sylvie Dufour ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Glucose Tolerance Test ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Sensitivity Index ◽  
Intramyocellular Lipid ◽  
Insulin Sensitivity Index ◽  
Obese Youth ◽  
Intramyocellular Lipid Content

Abstract Given the extreme increase in prediabetes, type 2 diabetes, and the potential for metabolic syndrome in obese youth, identifying simplified indexes for assessing stimulated insulin sensitivity is critical. The purpose of this study was validation of two surrogate indexes of insulin sensitivity determined from the oral glucose tolerance test (OGTT): the composite whole body insulin sensitivity index (WBISI) and the insulin sensitivity index (ISI). An obese population (aged 8–18 yr) of normal and impaired glucose tolerance individuals was studied. One group (n = 38) performed both the euglycemic-hyperinsulinemic clamp and OGTT for comparison of insulin sensitivity measurements as well as 1H-magnetic resonance spectroscopy estimates of intramyocellular lipid content. Another larger (n = 368) cohort participated only in an OGTT. Both the WBISI and ISI represented good estimates (r = 0.78 and 0.74; P &lt; 0.0005) for clamp-derived insulin sensitivity (glucose disposed, M-value), respectively. In the large cohort, the surrogate indexes demonstrated the shift toward poorer function and increased risk profile as a function of insulin resistance. Additionally, the WBISI and ISI correlated with intramyocellular lipid content (r = −0.74 and −0.71; P &lt; 0.0001), a tissue marker for insulin resistance. Insulin sensitivity can be estimated using plasma glucose and insulin responses derived from the OGTT in obese youth with normal and impaired glucose tolerance.

scholarly journals A Single 60 mg Dose of Denosumab Might Improve Hepatic Insulin Sensitivity in Postmenopausal Nondiabetic Severe Osteoporotic Women

2015 ◽  
Vol 2015 ◽  
pp. 1-5 ◽  
Author(s):  
Elena Passeri ◽  
Stefano Benedini ◽  
Elena Costa ◽  
Sabrina Corbetta
Keyword(s):  
Insulin Sensitivity ◽  
Glucose Metabolism ◽  
Serum Alkaline Phosphatase ◽  
Resistance Index ◽  
Tolerance Test ◽  
Hepatic Insulin Resistance ◽  
Oral Glucose ◽  
Insulinogenic Index ◽  
Glucose Response ◽  
Hepatic Insulin Sensitivity

Background. The RANKL/RANK/OPG signaling pathway is crucial for the regulation of osteoclast activity and bone resorption being activated in osteoporosis. The pathway has been also suggested to influence glucose metabolism as observed in chronic low inflammation.Aim. To test whether systemic blockage of RANKL by the monoclonal antibody denosumab influences glucose metabolism in osteoporotic women.Study Design. This is a prospective study on the effect of a subcutaneously injected single 60 mg dose of denosumab in 14 postmenopausal severe osteoporotic nondiabetic women evaluated at baseline and 4 and 12 weeks after their first injection by an oral glucose tolerance test.Results. A single 60 mg dose of denosumab efficiently inhibited serum alkaline phosphatase while it did not exert any significant variation in fasting glucose, insulin, or HOMA-IR at both 4 and 12 weeks. No changes could be detected in glucose response to the glucose load, Matsuda Index, or insulinogenic index. Nonetheless, 60 mg denosumab induced a significant reduction in the hepatic insulin resistance index at 4 weeks and in HbA1c levels at 12 weeks.Conclusions. A single 60 mg dose of denosumab might positively affect hepatic insulin sensitivity though it does not induce clinical evident glucose metabolic disruption in nondiabetic patients.

Estimation of β-cell function from the data of the oral glucose tolerance test

2007 ◽  
Vol 292 (6) ◽  
pp. E1575-E1580 ◽  
Author(s):  
Shinji Sakaue ◽  
Shinji Ishimaru ◽  
Daisuke Ikeda ◽  
Yoshinori Ohtsuka ◽  
Toshiro Honda ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Glucose Tolerance Test ◽  
Cell Function ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Sensitivity Index ◽  
Β Cell ◽  
Β Cell Function ◽  
The Relationship

Although a hyperbolic relationship between insulin secretion and insulin sensitivity has been shown, the relationship has been often questioned. We examined the relationship using oral glucose tolerance test (OGTT)-derived indexes. A total of 374 Japanese subjects who had never been given a diagnosis of diabetes underwent a 75-g OGTT. In subjects with normal glucose tolerance (NGT), the ln [insulinogenic index (IGI)] was described by a linear function of ln ( x) ( x, insulin sensitivity index) in regression analysis when the reciprocal of the insulin resistance index in homeostasis model assessment, Matsuda's index, and oral glucose insulin sensitivity index were used as x. Because the 95% confidence interval of the slope of the regression line did not necessarily include −1, the relationships between IGI and x were not always hyperbolic, but power functions IGI × xα = a constant. We thought that IGI × xα was an appropriate β-cell function estimate adjusted by insulin sensitivity and referred to it as β-cell function index (BI). When Matsuda's index was employed as x, the BI values were decreased in subjects without NGT. Log BI had a better correlation with fasting plasma glucose (PG; FPG) and 2-h PG in non-NGT subjects than in NGT subjects. In subjects with any glucose tolerance, log BI was linearly correlated with 1-h PG and glucose spike (the difference between maximum PG and FPG). In conclusion, the relationship between insulin secretion and insulin sensitivity was not always hyperbolic. The BI is a useful tool in the estimation of β-cell function with a mathematical basis.

scholarly journals Growth hormone receptor antagonism with pegvisomant in insulin resistant non-diabetic men: A phase II pilot study

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 614 ◽  
Author(s):  
Ada P. Lee ◽  
Kathleen Mulligan ◽  
Morris Schambelan ◽  
Elizabeth J. Murphy ◽  
Ethan J. Weiss
Keyword(s):  
Insulin Resistance ◽  
Growth Hormone ◽  
Insulin Sensitivity ◽  
Pilot Study ◽  
Glucose Metabolism ◽  
Phase Ii ◽  
Whole Body ◽  
Sensitivity Index ◽  
Insulin Resistant ◽  
Gh Receptor

Background: Growth hormone (GH) is known to affect insulin and glucose metabolism.  Blocking its effects in acromegalic patients improves diabetes and glucose metabolism. We aimed to determine the effect of pegvisomant, a GH receptor antagonist, on insulin resistance, endogenous glucose production (EGP) and lipolysis in insulin resistant non-diabetic men.  Methods: Four men between the ages of 18-62 with a BMI of 18-35kg/m2, with insulin resistance as defined by a HOMA-IR > 2.77, were treated for four weeks with pegvisomant 20 mg daily.  Inpatient metabolic assessments were performed before and after treatment. The main outcome measurements were: change after pegvisomant therapy in insulin sensitivity as measured by hyperinsulinemic euglycemic clamp; and EGP and lipolysis assessed by stable isotope tracer techniques. Results: Insulin like growth factor-1 (IGF-1) concentrations decreased from 134.0 ± 41.5 (mean ± SD) to 72.0 ± 11.7 ng/mL (p = 0.04) after 4 weeks of therapy. Whole body insulin sensitivity index (M/I 3.2 ± 1.3 vs. 3.4 ± 2.4; P = 0.82), as well as suppression of EGP (89.7 ± 26.9 vs. 83.5 ± 21.6%; p = 0.10) and Ra glycerol (59.4 ± 22.1% vs. 61.2 ± 14.4%; p = 0.67) during the clamp were not changed significantly with pegvisomant treatment. Conclusions: Blockade of the GH receptor with pegvisomant for four weeks had no significant effect on insulin/glucose metabolism in a small phase II pilot study of non-diabetic insulin resistant participants without acromegaly.

scholarly journals Risk Factors for Spontaneously Self-Reported Postprandial Hypoglycemia After Bariatric Surgery

2016 ◽  
Vol 101 (10) ◽  
pp. 3600-3607 ◽  
Author(s):  
Monica Nannipieri ◽  
Anna Belligoli ◽  
Daniela Guarino ◽  
Luca Busetto ◽  
Diego Moriconi ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Cell Function ◽  
Tolerance Test ◽  
The Body ◽  
Oral Glucose ◽  
Sensitivity Index ◽  
Β Cell ◽  
Fasting Glycemia ◽  
Glucose Sensitivity ◽  
Cell Glucose

Context: Postprandial hypoglycemia (PPHG) is a recognized complication of Roux-en-Y gastric bypass (RYGB) surgery. Data on PPHG after laparoscopic sleeve gastrectomy (LSG) are scant. Objective: The objective of the study was to identify preoperative predictors of PPHG in subjects spontaneously self-reporting PPHG after RYGB or LSG. Patients, Setting, and Intervention: Nondiabetic patients spontaneously self-reporting symptoms/signs of PPHG (PPHG group, 21 RYGB and 11 LSG) were compared in a case-control design with subjects who never experienced spontaneous or oral glucose tolerance test (OGTT)-induced hypoglycemia over 24 months after surgery (No-PPHG group, 13 RYGB and 40 LSG). Paired pre- and postoperative 3-hour OGTTs were analyzed in all participants. Main Outcome Measures: Insulin sensitivity was assessed by the oral glucose insulin sensitivity index and β-cell function by mathematical modeling of the C-peptide response to glucose. Results: Before surgery, the body mass index was lower in PPHG than No-PPHG patients in the RYGB (P = .002) and trended similarly in the LSG group (P = .08). Fasting glycemia and the glucose-OGTT nadir were lower in the PPHG than the No-PPHG subjects in both surgery groups. Before surgery, insulin sensitivity was higher in PPHG than No-PPHG in the RYGB (393 ± 55 vs 325 ± 44 mL/min−1 · m−2, P = .001) and LSG groups (380 ± 48 vs 339 ± 60 mL/min−1 · m−2, P = .05) and improved to a similar extent in all groups after surgery. Before surgery, β-cell glucose sensitivity was higher in PPHG than No-PPHG in both RYGB (118 ± 67 vs 65 ± 24 pmol/min−1 · m2 · mM−1) and LSG patients (114 ± 32 vs 86 ± 33) (both P = .02) and improved in all subjects after surgery. Conclusions: In subjects self-reporting PPHG after surgery, lower presurgery plasma glucose concentrations, higher insulin sensitivity, and better β-cell glucose sensitivity are significant predictors of PPHG after both RYGB and LSG.

scholarly journals Carbohydrate-induced manipulation of insulin sensitivity independently of intramyocellular lipids

2003 ◽  
Vol 89 (3) ◽  
pp. 365-374 ◽  
Author(s):  
Louise M. Goff ◽  
Gary S. Frost ◽  
Gavin Hamilton ◽  
E. Louise Thomas ◽  
Waljit S. Dhillo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Healthy Volunteers ◽  
Dietary Intervention ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Resonance Spectroscopy ◽  
Sensitivity Index ◽  
Intramyocellular Lipids ◽  
Post Intervention

Subjects with insulin resistance have been shown to have higher storage levels of intramyocellular lipid (IMCL) than their insulin-sensitive counterparts. It has been proposed that elevated IMCL stores may be the main cause of insulin resistance. The aim of the present study was to ascertain whether there is a causal relationship between IMCL storage and insulin resistance. IMCL storage was assessed using magnetic resonance spectroscopy and insulin sensitivity was assessed by performing an oral glucose tolerance test. A 4-week intervention of reduction of dietary glycaemic index was used to manipulate insulin sensitivity in a cohort of healthy volunteers; the effects of this intervention on IMCL were measured after 4 weeks of intervention. Significant improvements in the insulin sensitivity index occurred following the dietary intervention (baseline 7·8 (sem 1·11) v. post-intervention 9·7 (sem 1·11), P=0·02). However, there were no changes in IMCL storage levels, suggesting that insulin sensitivity can be manipulated independently of IMCL. This suggests that in healthy volunteers, insulin sensitivity is independent of IMCL storage and the high storage levels that have been found in insulin-resistant subjects may occur as a consequence rather than a cause of insulin resistance.

Sign in / Sign up

Export Citation Format

Share Document