IL-1 Receptor Antagonist (IL-1Ra) Levels and Management of Metabolic Disorders.

Low-grade inflammation is a major player in obesity and the metabolic syndrome predicting development of type 2 diabetes (T2DM). The interleukin-1 receptor antagonist (IL-1Ra) is a vital and natural anti-inflammatory factor and mediator in glucose homeostasis disturbances. The predictive role is independent of multiple confounders, and elevated levels appear few years before T2DM. The role of IL-1Ra is important for accumulated risk factors, dysregulated metabolism and glucose homeostasis, and dietary interventions. Longitudinal and cross-sectional population study cohorts have enabled the approximation of IL-1Ra limit values for metabolic dysregulation and guide further analysis as a potential biomarker. The limit value of IL-1Ra is reaching 400 pg/mL with prediabetes and before T2DM. However, subjects with metabolic syndrome are suggested to have lower limit values, especially among men. Future research may evaluate the role of IL-1Ra in actual glucose homeostasis together with routine fasted laboratory tests, such as glucose and C-reactive protein (CRP) instead of the oral glucose tolerance test. The significance of intermediate low IL-1Ra levels in metabolic abnormalities should be further analyzed. It is possible to specify the impact of multiple lifestyle and metabolic parameters together with age and sex. IL-1Ra could be studied in multiple approaches including interventional studies of metabolic diseases.

Associations of overweight and metabolic health with successful aging: 32-year follow-up of the Helsinki Businessmen Study.

BACKGROUND & AIMS: Prognostic significance of metabolically healthy overweight and obesity (MHO) is under debate. However the relationship between MHO and health-related quality of life (HRQoL) is less studied. We compared successful aging (longevity plus HRQoL) in men with MHO, metabolically healthy normal weight (MHN) and metabolically unhealthy overweight and obesity (MUO). METHODS: In the Helsinki Businessmen Study longitudinal cohort, consisting of men born 1919 to 1934. In 1985/86, overweight (BMI≥25 kg/m2) and metabolic health were determined in 1309 men (median age 60 years). HRQoL was assessed using RAND-36/SF-36 in 2000 and 2007, and all-cause mortality retrieved from registers up to 2018. The proportion of men reaching 90 years was also calculated. RESULTS: Of the men, 469 (35.8%), 538 (41.1%), 276 (21.1%), and 26 (2.0%) were MHN, MHO, MUO and MUN, respectively. During the 32-year follow-up, 72.3% men died. With MHN as reference, adjusted hazard ratio with all-cause mortality was 1.08 (95% confidence interval [CI] 0.93 to 1.27) for MHO, and 1.18 (95% CI 0.95 to 1.47) for MUO. During follow-up, 273 men reached 90 years. With MHN as reference, adjusted odds ratio for MHO was 0.82 (95% CI 0.59 to 1.14) and 0.62 (95% CI 0.41 to 0.95) for MUO. Men in MHN group scored generally highest in RAND-36 HRQoL subscales in 2000 and 2007, of those significantly better in Physical functioning, Role physical, Role emotional, Bodily Pain, and General health sub-scales compared to MHO group in 2000. CONCLUSIONS: As compared to MHN, MHO in late midlife does not increase mortality, but impairs odds for successful aging.

Statin treatment, phenotypic frailty and mortality among community-dwelling octogenarian men: the HBS cohort.

BACKGROUND: statin treatment has increased also among people aged 80 years and over, but adverse effects potentially promoting frailty and loss of resilience are frequent concerns. METHODS: in the Helsinki Businessmen Study, men born in 1919-34 (original n = 3,490) have been followed up since the 1960s. In 2011, a random subcohort of home-living survivors (n = 525) was assessed using questionnaires and clinical (including identification of phenotypic frailty) and laboratory examinations. A 7-year mortality follow-up ensued. RESULTS: we compared 259 current statin users (median age 82 years, interquartile range 80-85 years) with 266 non-users (83; 80-86 years). Statin users had significantly more multimorbidity than non-users (prevalencies 72.1% and 50.4%, respectively, P < 0.0001) and worse glucose status than non-users (prevalencies of diabetes 19.0% and 9.4%, respectively, P = 0.0008). However, there was no difference in phenotypic frailty (10.7% versus 11.2%, P = 0.27), and statin users had higher plasma prealbumin level than non-users (mean levels 257.9 and 246.3 mg/L, respectively, P = 0.034 adjusted for age, body mass index and C-reactive protein) implying better nutritional status. Despite morbidity difference, age-adjusted 7-year mortality was not different between the two groups (98 and 103 men among users and non-users of statins, respectively, hazard ratio 0.96, 95% confidence interval 0.72-1.30). CONCLUSIONS: our study suggests that male octogenarian statin users preserved resilience and survival despite multimorbidity, and this may be associated with better nutritional status among statin users.

Testosterone is associated with insulin resistance index independently of adiposity in women with polycystic ovary syndrome.

OBJECTIVE: To study the associations between androgens, glucose homeostasis, inflammation and statin treatment in women with polycystic ovary syndrome (PCOS). DESIGN AND METHODS: Oral glucose tolerance tests, androgens, hs-CRP and interleukin-1 receptor antagonist (IL-1Ra) were analyzed at baseline and after 6 months of atorvastatin (20 mg/d) or placebo treatment in 27 women with PCOS. RESULTS: Testosterone associated with insulin resistance measured with ISIMatsuda independently of BMI, age and SHBG concentrations and the full model, including IL-1Ra, hs-CRP and HDL-C, also showed independency of BMI and waist circumference (p ≤ .042). Free androgen index (FAI) associated with ISIMatsuda independently of adiposity (p ≤ .025) but in the full model with waist circumference the association was insignificant. ISIMatsuda decreased with testosterone >1.2 nmol/l compared with lower levels at baseline (p = .043) and at six months (p = .003). Accordingly, 30-minute insulin levels were increased with moderately elevated testosterone independently of adiposity (p ≤ .046). Increased fasting glucose and AUC insulin associated with statin treatment independently of adiposity and the associations attenuated after adjusting for testosterone. CONCLUSIONS: Moderately elevated testosterone concentrations together with obesity-related inflammatory factors modify glucose homeostasis by increasing insulin resistance and early insulin secretion.

IL-1 receptor antagonist levels are associated with glucose tolerance in polycystic ovary syndrome.

OBJECTIVE: To investigate serum interleukin-1 receptor antagonist (IL-1Ra) levels in women with polycystic ovary syndrome (PCOS). SUBJECTS AND METHODS: Serum IL-1Ra levels were measured at baseline in 73 women with PCOS and 45 control subjects (18-47 years), and in 27 women with PCOS who underwent oral and intravenous glucose tolerance tests (OGTTs and IVGTTs). RESULTS: IL-1Ra concentrations predicted OGTT 2-h glucose levels independently of BMI and insulin resistance (P ≤ 0·001) in women with PCOS. Serum IL-1Ra concentration was elevated in women with PCOS compared with controls [mean (SD): 309·5 (208·8) vs 199·1 (81·4) ng/l, P < 0·001], but the difference disappeared after adjusting for BMI. An increment of five BMI units raised IL-1Ra levels by 108·5 ng/l [95% confidence interval (CI): 85·5-131·5, r(2) = 0·603] in women with PCOS and only by 77·0 ng/l (95% CI: 50·5-103·5, r(2) = 0·512) in controls when adjusted for BMI and age. Levels of IL-1Ra in obese women with PCOS reflected decreasing OGTT-derived insulinogenic index (P = 0·032) and disposition index (P = 0·046) independently of BMI. Increased levels of IL-1Ra correlated with indices showing increasing insulin resistance and AUC insulin (P ≤ 0·002). CONCLUSIONS: Increased IL-1Ra levels in women with PCOS were largely explained by increasing adiposity. However, serum IL-1Ra concentrations predicted 2-h glucose levels independently of BMI suggesting that increased IL-1Ra may be associated with disturbed glucose metabolism.

Genetic determinants of circulating interleukin-1 receptor antagonist levels and their association with glycemic traits.

The proinflammatory cytokine interleukin (IL)-1ß is implicated in the development of insulin resistance and ß-cell dysfunction, whereas higher circulating levels of IL-1 receptor antagonist (IL-1RA), an endogenous inhibitor of IL-1ß, has been suggested to improve glycemia and ß-cell function in patients with type 2 diabetes. To elucidate the protective role of IL-1RA, this study aimed to identify genetic determinants of circulating IL-1RA concentration and to investigate their associations with immunological and metabolic variables related to cardiometabolic risk. In the analysis of seven discovery and four replication cohort studies, two single nucleotide polymorphisms (SNPs) were independently associated with circulating IL-1RA concentration (rs4251961 at the IL1RN locus [n = 13,955, P = 2.76 × 10(-21)] and rs6759676, closest gene locus IL1F10 [n = 13,994, P = 1.73 × 10(-17)]). The proportion of the variance in IL-1RA explained by both SNPs combined was 2.0%. IL-1RA-raising alleles of both SNPs were associated with lower circulating C-reactive protein concentration. The IL-1RA-raising allele of rs6759676 was also associated with lower fasting insulin levels and lower HOMA insulin resistance. In conclusion, we show that circulating IL-1RA levels are predicted by two independent SNPs at the IL1RN and IL1F10 loci and that genetically raised IL-1RA may be protective against the development of insulin resistance.

Genetic variation of the interleukin-1 family and nongenetic factors determining the interleukin-1 receptor antagonist phenotypes.

The natural anti-inflammatory protein interleukin-1 receptor antagonist (IL-1Ra) inhibits the activity of IL-1 and is associated with vascular injury and metabolic disorders. We analyzed genetic and nongenetic determinants of the IL-1Ra phenotype. Fifteen haplotype-tagging single nucleotide polymorphisms (SNPs) in the IL-1α (IL1A), IL-1ß (IL1B), and IL-1 receptor antagonist (IL-1RN) genes were determined in the Health 2000 survey (n = 6771) and European myocardial infarction (MI) survivors (n = 972). Three SNPs were genotyped in the FINRISK97 (FR97) study (n = 7222). We found 3 IL1RN variants that were associated with the IL-1Ra phenotype in the study populations and remained significant after Bonferroni correction with increasing significance in meta-analysis (P values for rs3213448,rs315952, rs315949, respectively: 5.5 x 10(-11), 1.5 x 10(-11), and 4.0 x 10(-14)). Minor allele of the rare IL1B variant rs1143642 was associated with decreased IL-1Ra levels in the Health 2000 and FR97 populations, and the association strengthened in the meta-analysis (P = 9.4 x 10(-7)). The proportion of variance explained by the IL1RN variant was larger in MI survivors (5.0%) than in the unselected population (0.5%). Body mass index was the strongest nongenetic predictor of the IL-1Ra phenotype, explaining 11.8% of the variance in Health 2000, 18.1% in FR97, and 25% in MI survivors. In conclusion, 3 IL1RN SNPs and 1 IL1B variant were determining IL-1Ra phenotype independently of body mass index and other metabolic phenotypes. The proportion of phenotypic variation in IL-1Ra explained by the genetic variants was, however, modest compared with the proportion explained by the body mass index.

Association of variation in the interleukin-1 gene family with diabetes and glucose homeostasis.

OBJECTIVE: Proinflammatory cytokine IL-1beta is capable of decreasing insulin-induced glucose transport. Therefore, we hypothesized that genetic variation in the IL-1 gene family is associated with measures of glucose homeostasis and diabetes. DESIGN AND OUTCOME MEASURES: Fifteen haplotype-tagging single-nucleotide polymorphisms in the IL-1alpha, IL-1beta, and IL-1 receptor antagonist genes were determined in a Finnish population survey (n = 6771). Glucose and insulin concentrations were measured, and indices of insulin resistance and beta-cell function were calculated using the homeostasis model assessment. Two-hour oral glucose tolerance tests were carried out on a subsample of 1390 participants. Associations with prevalent diabetes were tested for replication in a sample of European myocardial infarction survivors (n = 972). RESULTS: The minor allele of the IL-1beta rs1143634(G-->A) was associated with higher blood glucose than the major allele: 5.37, 5.41, and 5.48 mmol/liter for the GG, AG, and AA genotypes, respectively (multivariate adjusted P for trend <0.0001; Bonferroni corrected P = 0.00096). The 2-h glucose was also higher (6.45 and 7.20 mmol/liter for the GG vs. AA; P = 0.003, Bonferroni corrected P = 0.045). The haplotype ACG of rs1143634, rs3917356, and rs16944 associated with higher glucose, higher homeostasis model assessment for insulin resistance index, higher 2-h insulin, and prevalent diabetes (adjusted rate ratio = 1.54; 95% confidence interval = 1.03-2.30; P = 0.037). The association with prevalent diabetes was replicated among European myocardial infarction survivors (rate ratio = 2.09; 95% confidence interval = 1.17-3.76; P = 0.013). CONCLUSIONS: These results suggest that genetic variation in the IL-1 gene family is associated with measures of glucose homeostasis and prevalent diabetes.