The presence of circulating microbiome in blood has been reported in both physiological and pathological conditions, although its origins, identities and function remain to be elucidated. This... Show moreThe presence of circulating microbiome in blood has been reported in both physiological and pathological conditions, although its origins, identities and function remain to be elucidated. This study aimed to investigate the presence of blood microbiome by quantitative real-time PCRs targeting the 16S rRNA gene. To our knowledge, this is the first study in which the circulating microbiome has been analyzed in such a large sample of individuals since the study was carried out on 1285 Randomly recruited Age-Stratified Individuals from the General population (RASIG). The samples came from several different European countries recruited within the EU Project MARK-AGE in which a series of clinical biochemical parameters were determined. The results obtained reveal an association between microbial DNA copy number and geographic origin. By contrast, no gender and age-related difference emerged, thus demonstrating the role of the environment in influencing the above levels independent of age and gender at least until the age of 75. In addition, a significant positive association was found with Free Fatty Acids (FFA) levels, leukocyte count, insulin, and glucose levels. Since these factors play an essential role in both health and disease conditions, their association with the extent of the blood microbiome leads us to consider the blood microbiome as a potential biomarker of human health. Show less
Tripolino, C.; Ciaffi, J.; Pucino, V.; Ruscitti, P.; Leeuwen, N. van; Borghi, C.; ... ; Ursini, F. 2021
Inflammatory arthritis is burdened by an increased risk of metabolic disorders. Cytokines and other mediators in inflammatory diseases lead to insulin resistance, diabetes and hyperlipidemia.... Show moreInflammatory arthritis is burdened by an increased risk of metabolic disorders. Cytokines and other mediators in inflammatory diseases lead to insulin resistance, diabetes and hyperlipidemia. Accumulating evidence in the field of immunometabolism suggests that the cause-effect relationship between arthritis and metabolic abnormalities might be bidirectional. Indeed, the immune response can be modulated by various factors such as environmental agents, bacterial products and hormones. Insulin is produced by pancreatic cells and regulates glucose, fat metabolism and cell growth. The action of insulin is mediated through the insulin receptor (IR), localized on the cellular membrane of hepatocytes, myocytes and adipocytes but also on the surface of T cells, macrophages, and dendritic cells. In murine models, the absence of IR in T-cells coincided with reduced cytokine production, proliferation, and migration. In macrophages, defective insulin signaling resulted in enhanced glycolysis affecting the responses to pathogens. In this review, we focalize on the bidirectional cause-effect relationship between impaired insulin signaling and arthritis analyzing how insulin signaling may be involved in the aberrant immune response implicated in arthritis and how inflammatory mediators affect insulin signaling. Finally, the effect of glucose-lowering agents on arthritis was summarized. Show less
Boels, A.M.; Rutten, G.; Cleveringa, F.; Avendonk, M. van; Vos, R. 2021
IntroductionMany individuals with type 2 diabetes mellitus (T2DM) experience "psychological insulin resistance". Consequently, it could be expected that insulin therapy may have negative effects on... Show moreIntroductionMany individuals with type 2 diabetes mellitus (T2DM) experience "psychological insulin resistance". Consequently, it could be expected that insulin therapy may have negative effects on psychological outcomes and well-being. Therefore, this study compared health status and psychosocial functioning of individuals with T2DM using only oral antihyperglycemic agents (OHA) and on insulin therapy (with or without OHA).Materials and MethodsIn this cross-sectional study, we used baseline data of a cluster randomized controlled trial conducted in 55 Dutch general practices in 2005. Health status was measured with the Short Form (SF)-36 (scale 0-100) and psychosocial functioning with the Diabetes Health Profile (DHP, scale 0-100). To handle missing data, we performed multiple imputation. We used linear mixed models with random intercepts per general practice to correct for clustering at practice level and to control for confounding.ResultsIn total, 2,794 participants were included in the analysis, their mean age was 65.8 years and 50.8% were women. Insulin-users (n = 212) had a longer duration of T2DM (11.0 versus 5.6 years) and more complications. After correcting for confounders and multiple comparisons, insulin-users reported significantly worse outcomes on vitality (SF-36, adjusted difference -5.7, p=0.033), general health (SF-36, adjusted difference -4.8, p=0.043), barriers to activity (DHP, adjusted difference -7.2, p<0.001), and psychological distress (DHP, adjusted difference -3.7, p=0.004), all on a 0-100 scale.DiscussionWhile previous studies showed similar or better health status in people with type 2 diabetes receiving insulin therapy, we found that vitality, general health and barriers to activity were worse in those on insulin therapy. Although the causality of this association cannot be established, our findings add to the discussion on the effects of insulin treatment on patient-reported outcomes in daily practice. Show less
Simple SummaryThe insulin-like growth factor-1 receptor (IGF1R) is a receptor commonly overexpressed and overactivated in a variety of cancers, including Ewing sarcoma, and promotes cell growth and... Show moreSimple SummaryThe insulin-like growth factor-1 receptor (IGF1R) is a receptor commonly overexpressed and overactivated in a variety of cancers, including Ewing sarcoma, and promotes cell growth and survival. After promising results with targeting and inhibiting the receptor in vitro, multiple different IGF1R targeting compounds have been clinically tried but showed limited efficacy. Here we discuss several possible resistance mechanisms which could explain why IGF1R targeting fails in the clinic and discuss possible ways to overcome these resistances.Insulin-like growth factor-1 receptor (IGF1R) inhibitors are effective in preclinical studies, but so far, no convincing benefit in clinical studies has been observed, except in some rare cases of sustained response in Ewing sarcoma patients. The mechanism of resistance is unknown, but several hypotheses are proposed. In this review, multiple possible mechanisms of resistance to IGF-targeted therapies are discussed, including activated insulin signaling, pituitary-driven feedback loops through growth hormone (GH) secretion and autocrine loops. Additionally, the outcomes of clinical trials of IGF1-targeted therapies are discussed, as well as strategies to overcome the possible resistance mechanisms. In conclusion, lowering the plasma insulin levels or blocking its activity could provide an additional target in cancer therapy in combination with IGF1 inhibition. Furthermore, because Ewing sarcoma cells predominantly express the insulin receptor A (IRA) and healthy tissue insulin receptor B (IRB), it may be possible to synthesize a specific IRA inhibitor. Show less
Uitbeijerse, B.S.; Nijhoff, M.F.; Sont, J.K.; Koning, E.J.P. de 2020
In order to assess beta cell secretory capacity after islet transplantation, standardized mixed meal stimulation tests are often used. But these tests are cumbersome and the effect of exogenous... Show moreIn order to assess beta cell secretory capacity after islet transplantation, standardized mixed meal stimulation tests are often used. But these tests are cumbersome and the effect of exogenous insulin on the test results is unclear. The aim of our study was to determine to what extent fasting glycemic indices can estimate stimulated beta cell function in islet transplant recipients with and without basal insulin. In total 100 mixed meal stimulation tests, including 31 with concurrent basal insulin treatment, were performed in 36 islet transplant recipients. In a multivariate model, fasting C-peptide and fasting glucose together estimated peak C-peptide withR(2) = .87 and area under the curve (AUC) C-peptide with aR(2) = .93. There was a larger increase of glucose during tests in which exogenous insulin was used (+7.9 vs +5.3 mmol/L,P < .001) and exogenous insulin use was associated with a slightly lower estimated peak C-peptide (relative change: -15%,P = .02). In islet transplant recipients the combination of fasting C-peptide and glucose can be used to accurately estimate stimulated beta cell function after a mixed meal stimulation test, whether exogenous basal insulin is present or not. These data indicate that graft function can be reliably determined during exogenous insulin treatment and that regular islet graft stimulation tests can be minimized. Show less
Huet, C.; Boudaba, N.; Guigas, B.; Viollet, B.; Foretz, M. 2020
The cellular energy sensor AMP-activated protein kinase (AMPK) is a metabolic regulator that mediates adaptation to nutritional variations to maintain a proper energy balance in cells. We show here... Show moreThe cellular energy sensor AMP-activated protein kinase (AMPK) is a metabolic regulator that mediates adaptation to nutritional variations to maintain a proper energy balance in cells. We show here that suckling-weaning and fasting-refeeding transitions in rodents are associated with changes in AMPK activation and the cellular energy state in the liver. These nutritional transitions were characterized by a metabolic switch from lipid to glucose utilization, orchestrated by modifications in glucose levels and the glucagon/insulin ratio in the bloodstream. We therefore investigated the respective roles of glucose and pancreatic hormones on AMPK activation in mouse primary hepatocytes. We found that glucose starvation transiently activates AMPK, whereas changes in glucagon and insulin levels had no impact on AMPK. Challenge of hepatocytes with metformin-induced metabolic stress strengthened both AMPK activation and cellular energy depletion under limited-glucose conditions, whereas neither glucagon nor insulin altered AMPK activation. Although both insulin and glucagon induced AMPK? phosphorylation at its Ser(485/491) residue, they did not affect its activity. Finally, the decrease in cellular ATP levels in response to an energy stress was additionally exacerbated under fasting conditions and by AMPK deficiency in hepatocytes, revealing metabolic inflexibility and emphasizing the importance of AMPK for maintaining hepatic energy charge. Our results suggest that nutritional changes (i.e. glucose availability), rather than the related hormonal changes (i.e. the glucagon/insulin ratio), sensitize AMPK activation to the energetic stress induced by the dietary transition during fasting. This effect is critical for preserving the cellular energy state in the liver. Show less
Introduction With increased duration of type 2 diabetes, most people have a growing need of glucose-lowering medication and eventually might require insulin. Presumptive evidence is reported that... Show moreIntroduction With increased duration of type 2 diabetes, most people have a growing need of glucose-lowering medication and eventually might require insulin. Presumptive evidence is reported that early detection (eg, by population-based screening) and treatment of hyperglycemia will postpone the indication for insulin treatment. A treatment legacy effect of population-based screening for type 2 diabetes of about 3 years is estimated. Therefore, we aim to compare insulin prescription and glycemic control in people with screen-detected type 2 diabetes after 10 years with data from people diagnosed with type 2 diabetes seven (treatment legacy effect) and 10 years before during care-as-usual.Research design and methods Three cohorts were compared: one screen-detected cohort with 10 years diabetes duration (Anglo-Danish-Dutch study of Intensive Treatment in People with Screen-Detected Diabetes in Primary care (ADDITION-NL): n=391) and two care-as-usual cohorts, one with 7-year diabetes duration (Groningen Initiative to Analyze Type 2 Diabetes Treatment (GIANTT) and Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC): n=4473) and one with 10-year diabetes duration (GIANTT and ZODIAC: n=2660). Insulin prescription (primary outcome) and hemoglobin A1c (HbA1c) of people with a known diabetes duration of 7 years or 10 years at the index year 2014 were compared using regression analyses.Results Insulin was prescribed in 10.5% (10-year screen detection), 14.7% (7-year care-as-usual) and 19.0% (10-year care-as-usual). People in the 7-year and 10-year care-as-usual groups had a 1.5 (95% CI 1.0 to 2.1) and 1.8 (95% CI 1.3 to 2.7) higher adjusted odds for getting insulin prescribed than those after screen detection. Lower HbA1c values were found 10 years after screen detection (mean 50.1 mmol/mol (6.7%) vs 51.8 mmol/mol (6.9%) and 52.8 mmol/mol (7.0%)), compared with 7 years and 10 years after care-as-usual (MDadjusted: 1.6 mmol/mol (95% CI 0.6 to 2.6); 0.1% (95% CI 0.1 to 0.2) and 1.8 mmol/mol (95% CI 0.7 to 2.9); and 0.2% (95% CI 0.1 to 0.3)).Conclusion Population-based screen-detected type 2 diabetes is associated with less need for insulin after 10 years compared with people diagnosed during care-as-usual. Glycemic control was better after screen detection but on average good in all groups. Show less
Objectives To determine at what glycated haemoglobin (HbA1c) level physicians from eight European countries would initiate insulin in type 2 diabetes, which physician or practice related factors... Show moreObjectives To determine at what glycated haemoglobin (HbA1c) level physicians from eight European countries would initiate insulin in type 2 diabetes, which physician or practice related factors influenced this level and whether physicians would differentiate between a younger uncomplicated patient and an older patient with comorbidities.Design Cross-sectional study with data from the Guideline Adherence to Enhance Care study.Setting and participants 410 physicians from both primary and secondary care from Belgium, France, Germany, Italy, Ireland, Sweden, the Netherlands and the UK.Outcome measures Physicians were asked at which HbA1c level they would initiate insulin for a young, uncomplicated patient (vignette 1) and for an older, complicated patient (vignette 2). We evaluated differences in HbA1c levels between physicians from different countries using analysis of variance. To identify physician and practice related factors associated with HbA1c level at initiation of insulin, we performed multivariable linear regression. Multiple imputation was used to deal with missing data.Results In Germany, Ireland, Sweden, the Netherlands and the UK, the HbA1c levels for initiating insulin in vignette 2 (range: 60.0 to 66.0mmol/mol; 7.6% to 8.2%) were higher than for vignette 1 (range: 57.2 to 64.2mmol/mol; 7.4% to 8.0%). In multivariable analysis, the HbA1c level at which insulin was initiated only differed between countries (vignette 1): Dutch physicians initiated insulin at a lower HbA1c level compared with Belgium, France and the UK. No physician or practice factors were independently associated with HbA1c level at insulin initiation.Conclusions When deciding on individualised HbA1c targets for insulin initiation, physicians from five countries took patient's age and comorbidity into account. The HbA1c level at which physicians would initiate insulin therapy differed between countries. Show less
Background: In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the... Show moreBackground: In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear.Methods: We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium.Results: All sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p = 5.09 x 10(-4)], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p = 4.02 x 10(-4)), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p = 5.05 x 10(-19)) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p = 9.22 x 10(-6)). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer.Conclusions: We confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer. Show less
