Search

Context The phosphate-regulating hormone fibroblast growth factor 23 (FGF23) has been linked to deregulations in glucose metabolism, but its role is insufficiently understood. Objective This study investigates potential crosstalk between FGF23 and glucose homeostasis. Methods First, we investigated the effect of glucose loading on plasma C-terminal FGF23 levels and its temporal relationship with changes in plasma phosphate in 45 overweight (body mass index [BMI] 25-30) individuals using time-lag analyses. Second, we studied cross-sectional associations of plasma C-terminal FGF23 levels with glucose homeostasis using multivariable linear regression in a population-based cohort. We also investigated associations of FGF23 with incident diabetes and obesity (BMI > 30) in individuals without diabetes or obesity at baseline, respectively, using multivariable Cox regression analyses. Finally, we explored whether the association between FGF23 and diabetes depends on BMI. Results After glucose loading, changes in FGF23 preceded changes in plasma phosphate (Ptime-lag = .04). In the population-based cohort (N = 5482; mean age 52 years, 52% women, median FGF23 69 RU/mL), FGF23 was associated with plasma glucose (β = .13 [.03-.23]; P = .01), insulin (β = .10 [.03-.17]; P < .001), and proinsulin (β = .06 [0.02-0.10]; P = .01) at baseline. On longitudinal analyses, a higher baseline FGF23 was independently associated with development of diabetes (199 events [4%]; fully adjusted hazard ratio [HR] 1.66 [95% CI, 1.06-2.60]; P = .03) and development of obesity (241 events [6%]; fully adjusted HR 1.84 [95% CI, 1.34-2.50]; P < .001). The association between FGF23 and incident diabetes lost significance after additional adjustment for BMI. Conclusion Glucose loading has phosphate-independent effects on FGF23 and, vice versa, FGF23 is associated with glucose, insulin and proinsulin levels, and obesity. These findings suggest crosstalk between FGF23 and glucose homeostasis, which may promote susceptibility to incident diabetes.

PurposeGlycA, a pro-inflammatory glycoprotein biomarker, associates with newly developed type 2 diabetes (T2D). We determined the association of plasma GlycA with the development of microvascular complications in patients with established T2D.MethodsPlasma GlycA was measured by nuclear magnetic resonance spectrometry in T2D patients without microvascular complications at baseline (n = 145) participating in a longitudinal cohort study of primary care-treated T2D patients (Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) study). Associations of GlycA with incident microvascular complications including nephropathy, retinopathy, and neuropathy, were determined by Cox proportional hazards regression analyses.ResultsAfter a median follow-up of 3.2 (interquartile range [IQR]: 2.9–3.4) years, 49 patients (33.8%) developed one or more microvascular complications. Median GlycA levels were 453.5 (IQR: 402.0–512.8) μmol/l. GlycA was associated with incident microvascular complications (hazard ratio [HR] per 1-SD increment: 1.28 [95% confidence interval [CI]:1.00–1.63], P = 0.048]), even after adjustment for potential confounders and high-sensitive C-reactive protein (hs-CRP), HR 1.79 [95%CI:1.25–2.57], P = 0.001). In contrast, hs-CRP levels were not significantly associated with the risk of developing microvascular complications (P = 0.792).ConclusionHigher plasma GlycA is associated with an increased risk of developing microvascular complications in T2D patients. Altered N-glycan branching associated with acute-phase reactive proteins may represent a preferred biomarker of systemic low-grade inflammation in predicting diabetic complications.

BACKGROUND AND AIMS Beta-hydroxybutyrate (BHB), a ketone body, has shown to be renoprotective in various disease-specific preclinical studies. The underlying mechanism of this renoprotective effect might be via the reduction of inflammation, apoptosis, oxidative stress, and fibrosis. Interest in the effects of this metabolite is rising because supplementation is possible as an intervention. We hypothesized that endogenous BHB is associated with better kidney function outcomes in the general population. The aim of this study is to assess the association between BHB and kidney function. METHOD We included 6127 participants with available plasma BHB data from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study, a prospective, population-based cohort of Dutch men and women. BHB was measured in fasting participants using nuclear magnetic resonance (NMR) spectroscopy. The association of BHB with estimated glomerular filtration rate (eGFR), calculated with the CKD-EPI creatinine cystatin C equation, was tested using multivariable linear regression for cross-sectional analyses and linear mixed modeling for longitudinal analyses. The analyses were adjusted for sex, age, BMI, smoking, diabetes type 2, hypertension and hyperlipidemia. RESULTS Overall, 50.6% of the included subjects were female, mean age was 53.6 ± 12.1 years. At baseline, the median BHB concentration was 121.5 μmol/L [inter quartile range (IQR) 92.8–169.2] and the mean eGFR was 92 ± 17 mL/min/1.73m2. In cross-sectional analyses, a higher BHB was associated with a lower eGFR, after adjustment for covariates (st.β= −0.041, P < 0.001). During a median follow-up of 7.5 years (IQR 7.2–8.0), the mean annual change in eGFR was −0.96 ± 0.52 mL/min/1.73m2/year. In longitudinal analyses, a higher BHB was associated with less eGFR decline in the fully adjusted model [0.17 (95% confidence interval, CI 0.01–0.33); P = 0.04]. After exclusion of participants with diabetes type 2, the association of BHB and eGFR decline became stronger [0.22 (95% CI 0.06–0.38); P = 0.01]. CONCLUSION Higher BHB levels were associated with less eGFR decline in this general population cohort. In combination with previous preclinical data, this data supports the hypothesis that BHB is renoprotective and forms a rationale to study whether supplementation with BHB attenuates kidney function decline in patients with chronic kidney disease.

Diabetes is associated with a strongly elevated risk of cardiovascular disease, which is even more pronounced in patients with diabetic nephropathy. Currently available guideline-based efforts to correct traditional risk factors are only partly able to attenuate this risk, underlining the urge to identify novel treatment targets. Emerging data point towards a role for disturbances in phosphate metabolism in diabetes. In this review, we discuss the role of phosphate and the phosphate-regulating hormone fibroblast growth factor 23 (FGF23) in diabetes. We address deregulations of phosphate metabolism in patients with diabetes, including diabetic ketoacidosis. Moreover, we discuss potential adverse consequences of these deregulations, including the role of deregulated phosphate and glucose as drivers of vascular calcification propensity. Finally, we highlight potential treatment options to correct abnormalities in phosphate and FGF23. While further studies are needed to more precisely assess their clinical impact, deregulations in phosphate and FGF23 are promising potential target in diabetes and diabetic nephropathy.

IntroductionDiabetic ketoacidosis (DKA) is a life-threatening complication of type 1 diabetes mellitus (T1DM) characterized by hyperglycemia and metabolic acidosis. Hypophosphatemia in DKA often occurs during hospital admittance for DKA. Literature on the magnitude, determinants and consequences of hypophosphatemia in DKA is scarce. Primary aim of this study was to investigate the incidence and consequences of hypophosphatemia during hospitalisation for DKA.Research design and methodsCohort study among individuals with T1DM who were admitted for DKA between 2005 and 2020 in an academic and a non-academic hospital. Multivariate regression models were performed to investigate determinants of the lowest phosphate during the treatment of DKA.ResultsA total of 127 episodes of DKA among 80 individuals were identified. Age at DKA presentation was 28 (22–46) years, 45% of the cases was female, diabetes duration was 13.2 (8.9–25.5) years with glycosylated hemoglobin levels of 91.9±26.2 mmol/mol. In 9% of all cases, DKA was the first presentation of T1DM. Lowest phosphate levelss reported during the treatment phase were 0.54 (0.32–0.83) mmol/L and hypophosphatemia was present in 74% (62/84). The time to lowest phosphate was 16 (8–23) hours. In multivariate analysis, baseline bicarbonate and hemoglobin at admission were significantly associated with the lowest phosphate level reported. No adverse effects of hypophosphatemia on hospital stay duration, morbidity or mortality were found, even if left untreated.ConclusionsHypophosphatemia during DKA is common and increases with severe acidosis. However, in this study it was not related to adverse outcomes. Although limitations of this retrospective study should be taken into account, the routine and repeated measurement of phosphate levels in DKA could be reconsidered, provided that possible symptoms related to hypophosphatemia are monitored.

IntroductionSerum calcification propensity is emerging as an independent predictor for cardiovascular outcomes in high-risk populations. Calcification propensity can be monitored by the maturation time of calciprotein particles in serum (T50 test). A low T50 value is an independent determinant of cardiovascular morbidity and mortality in various populations. Aim was to investigate the T50 and its relationship to type 2 diabetes mellitus.Research design and methodsUsing nephelometry, serum T50 was cross-sectionally measured in 932 stable patients with type 2 diabetes mellitus (55% male) with a median age of 66 (62–75) years, diabetes duration of 6.5 (3.0–10.2) years and hemoglobin A1c (HbA1c) of 49 (44–54) mmol/mol.ResultsSerum T50 was normally distributed with a mean value of 261±66 min. In linear regression, serum T50 was lower in women and current smokers. A lower T50 value was found in patients with a higher HbA1c or higher systolic blood pressure, insulin users and patients with a longer history of diabetes. The association with HbA1c was independent of other determinants in multivariable analysis. There was no association between T50 and previous macrovascular events or the presence of microvascular disease.ConclusionsSerum calcification propensity is independently associated with glycemic control, suggesting that a lower HbA1c may be associated with better cardiovascular outcomes. Retrospective analysis could not establish an association between a history of macrovascular events and T50, and prospective studies will have to be performed to address this hypothesis.Trial registration numberNCT01570140.