Glycaemic patterns in healthy elderly individuals and in those with impaired glucose metabolism - exploring the relationship with nonglycaemic variables.

OBJECTIVE: The SENIORLABOR study data were explored (i) to examine the evolution during senescence of the differences between measured glycated haemoglobin (HbA1c) values and the values predicted by using regression to extrapolate from measured fructosamine levels; (ii) to scrutinise the relationship between the glycation gap and insulin resistance using a homeostasis model assessment, and between the glycation gap and a low-grade inflammation marker (C-reactive protein serum concentration); and (iii) to investigate the glycation gap ranges in relation to triglyceride levels and kidney function. SUBJECTS AND METHODS: A total of 1432 Swiss individuals aged >60 years and classified as healthy (547), prediabetic (701) or diabetic (184) based on their fasting plasma glucose and HbA1c values were included in the study. The glycation gap was evaluated and assigned to one of four categories: <−0.5; −0.5 to <0.0; 0.0 to ≤0.5; >0.5. RESULTS: In healthy and prediabetic participants, the homeostasis model assessment for estimation of insulin resistance (p <0.01), high-sensitivity C-reactive protein (p <0.001) and triglyceride (p = 0.02) values tended to increase with increasing glycation gap category and were highest in the glycation gap category >0.5. Homeostasis model assessment for estimation of insulin resistance, high-sensitivity C-reactive protein and triglyceride levels tended to increase with increasing glycation gap category and were highest in the glycation gap category >0.5. Significant differences (p <0.01) between glycation gap categories were seen among different high-sensitivity C-reactive protein concentration groups. Interestingly, in diabetic participants, homeostasis model assessment for estimation of insulin resistance values, triglyceride concentrations and estimation of glomerular filtration values all decreased with decreasing glycation gap category. In the group of participants with a glycation gap >0.5, high-sensitivity C-reactive protein values tended to increase with increasing glycation gap, whereas for participants with type 2 diabetes and in the glycation gap group >0.5, high-sensitivity C-reactive protein levels tended to decrease as the glycation gap increased. The percentage of participants with type 2 diabetes mellitus increased from 2% in the glycation gap category <−0.5 to 76% in the glycation gap category >0.5. In contrast, the percentage of healthy participants fell from 85% to 7%. CONCLUSION: This is the first time that a direct comparison of healthy, prediabetic and diabetic participants, all assessed under identical conditions and using identical methodology, has clearly demonstrated a different glycation gap pattern. Thus, we contribute evidence that the glycation gap might be of interest in the care of diabetic patients and their prophylaxis, while acknowledging that more studies are needed to confirm our findings. (Trial registration number ISRCTN53778569).

Inflammation Thread Runs across Medical Laboratory Specialities.

We work on the assumption that four major specialities or sectors of medical laboratory assays, comprising clinical chemistry, haematology, immunology, and microbiology, embraced by genome sequencing techniques, are routinely in use. Medical laboratory markers for inflammation serve as model: they are allotted to most fields of medical lab assays including genomics. Incessant coding of assays aligns each of them in the long lists of big data. As exemplified with the complement gene family, containing C2, C3, C8A, C8B, CFH, CFI, and ITGB2, heritability patterns/risk factors associated with diseases with genetic glitch of complement components are unfolding. The C4 component serum levels depend on sufficient vitamin D whilst low vitamin D is inversely related to IgG1, IgA, and C3 linking vitamin sufficiency to innate immunity. Whole genome sequencing of microbial organisms may distinguish virulent from nonvirulent and antibiotic resistant from nonresistant varieties of the same species and thus can be listed in personal big data banks including microbiological pathology; the big data warehouse continues to grow.

The cystatin C/creatinine ratio, a marker of glomerular filtration quality: associated factors, reference intervals, and prediction of morbidity and mortality in healthy seniors.

The ratio of cystatin C (cysC) to creatinine (crea) is regarded as a marker of glomerular filtration quality associated with cardiovascular morbidities. We sought to determine reference intervals for serum cysC-crea ratio in seniors. Furthermore, we sought to determine whether other low-molecular weight molecules exhibit a similar behavior in individuals with altered glomerular filtration quality. Finally, we investigated associations with adverse outcomes. A total of 1382 subjectively healthy Swiss volunteers aged 60 years or older were enrolled in the study. Reference intervals were calculated according to Clinical & Laboratory Standards Institute (CLSI) guideline EP28-A3c. After a baseline exam, a 4-year follow-up survey recorded information about overall morbidity and mortality. The cysC-crea ratio (mean 0.0124 ± 0.0026 mg/µmol) was significantly higher in women and increased progressively with age. Other associated factors were hemoglobin A1c, mean arterial pressure, and C-reactive protein (P < 0.05 for all). Participants exhibiting shrunken pore syndrome had significantly higher ratios of 3.5-66.5 kDa molecules (brain natriuretic peptide, parathyroid hormone, ß2-microglobulin, cystatin C, retinol-binding protein, thyroid-stimulating hormone, α1-acid glycoprotein, lipase, amylase, prealbumin, and albumin) and creatinine. There was no such difference in the ratios of very low-molecular weight molecules (urea, uric acid) to creatinine or in the ratios of molecules larger than 66.5 kDa (transferrin, haptoglobin) to creatinine. The cysC-crea ratio was significantly predictive of mortality and subjective overall morbidity at follow-up in logistic regression models adjusting for several factors. The cysC-crea ratio exhibits age- and sex-specific reference intervals in seniors. In conclusion, the cysC-crea ratio may indicate the relative retention of biologically active low-molecular weight compounds and can independently predict the risk for overall mortality and morbidity in the elderly.

Impaired glucose metabolism and type 2 diabetes in apparently healthy senior citizens.

STUDY PRINCIPLE: To estimate the prevalence of unknown impaired glucose metabolism, also referred to as prediabetes (PreD), and unknown type 2 diabetes mellitus (T2DM) among subjectively healthy Swiss senior citizens. The fasting plasma glucose (FPG) and glycated haemoglobin A(1c) (HbA(1c)) levels were used for screening. A total of 1 362 subjects were included (613 men and 749 women; age range 60-99 years). Subjects with known T2DM were excluded. METHODS: The FPG was processed immediately for analysis under standardised preanalytical conditions in a cross-sectional cohort study; plasma glucose levels were measured by means of the hexokinase procedure, and HbA(1c) was measured chromatographically and classified using the current American Diabetes Association (ADA) criteria. RESULTS: The crude prevalence of individuals unaware of having prediabetic FPG or HbA(1c) levels, was 64.5% (n = 878). Analogously, unknown T2DM was found in 8.4% (n = 114) On the basis of HbA(1c) criteria alone, significantly more subjects with unknown fasting glucose impairment and laboratory T2DM could be identified than with the FPG. The prevalence of PreD as well as of T2DM increased with age. The mean HOMA indices (homeostasis model assessment) for the different age groups, between 2.12 and 2.59, are consistent with clinically hidden disease and are in agreement with the largely orderly Body Mass Indices found in the normal range. CONCLUSIONS: Laboratory evidence of impaired glucose metabolism and, to a lesser extent, unknown T2DM, has a high prevalence among subjectively healthy older Swiss individuals. Laboratory identification of people with unknown out-of-range glucose values and overt diabetic hyperglycaemia might improve the prognosis by delaying the emergence of overt disease.

Vitamin B12 and folate levels in healthy Swiss senior citizens: a prospective study evaluating reference intervals and decision limits.

BACKGROUND: The vitamin B12 and folate status in nonanaemic healthy older persons needs attention the more so as decrease in levels may be anticipated from reduced haematinic provision and/or impaired intestinal uptake. METHODS: A total of 1143 subjectively healthy Swiss midlands participants (637 females and 506 males), ≥60 years of age were included in this study. Levels of vitamin B12, holotranscobalamin (holoTC), methylmalonic acid (MMA), homocysteine (Hcy), serum folate, red blood cell (RBC) folate were measured. Further, Fedosov's wellness score was determined. Associations of age, gender, and cystatin C/creatinine-based estimated kidney function, with the investigated parameters were assessed. Reference intervals were calculated. Further, ROC analysis was done to assess accuracy of the individual parameters in recognizing a deficient vitamin B12 status. Finally, decision limits for sensitive, specific and optimal recognition of vitamin B12 status with individual parameters were derived. RESULTS: Three age groups: 60-69, 70-79 and ≥ 80 had median B12 (pmol/L) levels of 237, 228 and 231 respectively (p = 0.22), holoTC (pmol/L) of 52, 546 and 52 (p = 0.60) but Hcy (µmol/L) 12, 15 and 16 (p < 0.001), MMA (nmol/L) 207, 221 and 244 (p < 0.001). Hcy and MMA (both p < 0.001), but not holoTC (p = 0.12) and vitamin B12 (p = 0.44) were found to be affected by kidney function. In a linear regression model Fedosov's wellness score was independently associated with kidney function (p < 0.001) but not with age. Total serum folate and red blood cell (RBC) folate drift apart with increasing age: whereas the former decreases (p = 0.01) RBC folate remains in the same bandwidth across all age groups (p = 0.12) A common reference interval combining age and gender strata can be obtained for vitamin B12 and holoTC, whereas a more differentiated approach seems warranted for serum folate and RBC folate. CONCLUSION: Whereas the vitamin B12 and holoTC levels remain steady after 60 years of age, we observed a significant increment in MMA levels accompanied by increments in Hcy; this is better explained by age-related reduced kidney function than by vitamin B12 insufficiency. Total serum folate levels but not RBC folate levels decreased with progressing age.

The serum uromodulin level is associated with kidney function.

BACKGROUND: In chronic kidney diseases of various etiologies, the urinary excretion of uromodulin is usually decreased in parallel with the glomerular filtration rate. This study aimed to investigate whether serum uromodulin is associated with kidney function. METHODS: Within the framework of the Seniorlabor study, a subset of subjectively healthy individuals 60 years of age and older were included in the study. Serum uromodulin was measured with ELISA. The relationship between serum uromodulin and different stages of kidney function (i.e., cystatin C-based 2012-CKD-EPI eGFRCysC>90 mL/min/1.73 m2, 60-89 mL/min/1.73 m2, 45-59 mL/min/1.73 m2, and <45 mL/min/1.73 m2) was investigated. Furthermore, the relationship between serum uromodulin and other markers of kidney function (i.e., creatinine, cystatin C, and urea) was assessed. RESULTS: In total, 289 participants (140 males/149 females; mean age 71±7 years) were included in the study. There were significant differences in serum uromodulin among the four groups according to different kidney function stages (p<0.001). Serum uromodulin displayed inverse relationships with creatinine (r=-0.39), cystatin C (r=-0.42), and urea (r=-0.30) and, correspondingly, a positive relationship with eGFRCysC (r=0.38, p<0.001 for all). These associations remained intact when fitting a regression model that incorporated age, gender, body mass index, and current smoking status as covariates. CONCLUSIONS: Serum uromodulin behaves in a manner opposite that of the different conventional renal retention markers by displaying lower concentrations with decreasing kidney function. As uromodulin is produced by the cells of the thick ascending limb of the loop of Henle, lower uromodulin serum levels may reflect a reduction in number or function of these cells in chronic kidney disease.

Factors other than the glomerular filtration rate that determine the serum beta-2-microglobulin level.

BACKGROUND: ß2-microglobulin has been increasingly investigated as a diagnostic marker of kidney function and a prognostic marker of adverse outcomes. To date, non-renal determinants of ß2-microglobulin levels have not been well described. Non-renal determinants are important for the interpretation and appraisal of the diagnostic and prognostic value of any endogenous kidney function marker. METHODS: This cross-sectional analysis was performed within the framework of the www.seniorlabor.ch study, which includes subjectively healthy individuals aged ≥ 60 years. Factors known or suspected to have a non-renal association with kidney function markers were investigated for a non-renal association with serum ß2-microglobulin. As a marker of kidney function, the Berlin Initiative Study equation 2 for the estimation of the estimated glomerular filtration rate (eGFR(BIS2)) in the elderly was employed. RESULTS: A total of 1302 participants (714 females and 588 males) were enrolled in the study. The use of a multivariate regression model adjusting for age, gender and kidney function (eGFR(BIS2)) revealed age, male gender, and C-reactive protein level to be positively associated with ß2-microglobulin levels. In addition, there was an inverse non-renal relationship between systolic blood pressure, total cholesterol and current smoking status. No association with markers of diabetes mellitus, body stature, nutritional risk, thyroid function or calcium and phosphate levels was observed. CONCLUSIONS: Serum ß2-microglobulin levels in elderly subjects are related to several non-renal factors. These non-renal factors are not congruent to those known from other markers (i.e. cystatin C and creatinine) and remind of classical cardiovascular risk factors.