Fibroblast Growth Factor 23, Glucose Homeostasis, and Incident Diabetes: Findings of 2 Cohort Studies.

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 (ß = .13 [.03-.23]; P = .01), insulin (ß = .10 [.03-.17]; P < .001), and proinsulin (ß = .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.

Glucose Loading Enhances the Value of 18F-FDG PET/CT for the Characterization and Delineation of Cerebral Gliomas.

This study aimed to assess how to enhance the value of 18F-Fluorodeoxyglucose (FDG) PET/CTs for glioma grading and better delineation of the tumor boundary by glucose loading. In mouse models of brain tumor using U87MG cells, 18F-FDG-PET images were obtained after fasting and after glucose loading. There was a significant difference in the tumor-to-normal cortex-uptake ratio (TNR) between the fasting and glucose-loading scans. 14C-2-Deoxy-D-glucose (14C-DG) uptake was measured in vitro using U87MG, U373MG and primary neurons cultured with different concentrations of glucose. The tumor-to-neuron ratio of 14C-DG uptake increased with up to 10 mM of glucose. Finally, 10 low-grade and 17 high-grade glioma patients underwent fasting and glucose loading 18F-FDG PET/CT and the TNR was compared between scans. The effect of glucose loading was significant in high-grade but not in low-grade gliomas. The receiver operating characteristic curve analyses with a cut-off TNR of 0.81 showed a higher area under the curve after glucose loading than fasting for differentiating low-grade versus high-grade gliomas. In addition, the glucose loading PET/CT was more useful than the fasting PET/CT for the discrimination of oligodendrogliomas from IDH-wildtype glioblastomas. Glucose loading resulted in a greater reduction in 18F-FDG uptake in the normal cortex than in tumors, which increases the usefulness of 18F-FDG PET/CT for grading.

Status of F-18 fluorodeoxyglucose uptake in normal and hibernating myocardium after glucose and insulin loading.

OBJECTIVE: F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) has been increasingly used in myocardial viability imaging. In routine PET viability studies, oral glucose and intravenous insulin loading is commonly utilized. In an optimal study, glucose and insulin loading is expected to cause FDG uptake both in hibernating and normal myocardium. However, in routine studies it is not uncommon to see absent or reduced FDG uptake in normal myocardium. In this retrospective study we further analyzed our PET viability images to evaluate FDG uptake status in myocardium under the oral glucose and intravenous insulin loading protocol that we use in our hospital. METHODS: Patients who had both myocardial perfusion single photon emission computed tomography (SPECT) and FDG PET cardiac viability studies were selected for analysis. FDG uptake status in normal and abnormal myocardial segments on perfusion SPECT was evaluated. Based on SPECT and PET findings, patients were divided into two main groups and four subgroups. Group 1 included PET viable studies and Group 2 included PET-nonviable studies. Subgroups based on FDG uptake in normal myocardium were 1a and 2a (normal uptake) and 1b and 2b (absent or significantly reduced uptake). RESULTS: Seventy-one patients met the inclusion criteria. Forty-two patients were PET-viable and 29 were PET-nonviable. In 33 of 71 patients (46.4%) there was absent or significantly reduced FDG uptake in one or more normal myocardial segments, which was identified more in PET-viable than PET-nonviable patients (59.5% vs. 27.5%, p = 0.008). This finding was also more frequent in diabetic than nondiabetic patients (53% vs. 31.8%), but the difference was not significant (p = 0.160). CONCLUSIONS: In nearly half of our patients, one or more normal myocardial segments showed absent or significantly reduced FDG uptake. This finding, particularly if it is diffuse, could be from suboptimal study, inadequacy of current glucose and insulin loading protocols, or various other patient-related causes affecting FDG uptake both in the normal and hibernating myocardium. In cases with significantly reduced FDG uptake in normal myocardium, PET images should be interpreted cautiously to prevent false-negative results for viability.

Impact of Glucose Loading on Variations in CD4+ and CD8+ T Cells in Japanese Participants with or without Type 2 Diabetes.

OBJECTIVE: The aim of this study was to examine the fluctuations in CD4+ T cells, CD8+ T cells, and natural CD4+CD25+FoxP3+T-regulatory (Treg) cells following an oral glucose tolerance test (OGTT) in participants with and those without type 2 diabetes (T2DM). METHODS: 19 Japanese participants with T2DM (DM group) and 21 participants without diabetes (non-DM group) were recruited and underwent a 75-g OGTT. The cell numbers of leukocytes, lymphocytes, and the T cell compartment, such as CD4+, CD8+, and Treg, were calculated for blood samples obtained after an overnight 12 h fast and during a 75-g OGTT at 60 and 120 min. RESULTS: Before glucose loading, no differences in the cell numbers of leukocytes, lymphocytes, CD4+, CD8+, and Treg were observed between the DM group and the non-DM group. The proportion of CD8+ was significantly reduced, whereas the proportion of CD4+ was significantly increased, after 120 min of glucose loading in both groups. The proportion of Treg was not affected. Furthermore, a significant positive correlation was observed between the AUC0-120 min of CD8+ and the change in the free fatty acid level following the OGTT (ρ = 0.39, P < 0.05), but not that of glucose or insulin. CONCLUSION: The proportion of CD4+ T cells was increased and that of CD8+ T cells was reduced after glucose loading in both subjects with and without diabetes. These findings suggest that glucose loading dynamically affects the balance of the circulating T lymphocyte subset, regardless of glucose tolerance.

Factors associated with fibroblast growth factor 19 increment after oral glucose loading in patients who were previously admitted for coronary angiography.

BACKGROUND: We investigated factors associated with fibroblast growth factor 19 (FGF-19) increment after oral glucose loading (OGL) in human subjects. METHODS: A total of 240 outpatients without known diabetes who were previously admitted for coronary angiography underwent an oral glucose tolerance test. FGF-19 increment (pg/ml) was calculated as FGF-19 2h after OGL minus fasting FGF-19. RESULTS: Overall, FGF-19 significantly increased after OGL (from 123 [78-201] to 141 [80-237], p=0.001). By age tertiles (≦ 54, 55-64, ≧ 65), FGF-19 significantly increased only in patients aged ≧ 65 (from 143 [98-209] to 189 [124-332], p<0.001). By glucose regulation status, FGF-19 significantly increased in patients with normal glucose tolerance (from 117 [78-211] to 153 [106-325], p=0.014) and in patients with prediabetes (from 117 [73-179] to 123 [70-204], p=0.043), but not in patients with diabetes (from 181 [102-243] to 178 [111-275], p=0.139). FGF-19 significantly increased in patients on statin treatment (from 120 [78-207] to 145 [86-264], p<0.001), but not in patients not on statin therapy (from 125 [86-196] to 128 [68-230] pg/ml, p=0.676). These findings remained significant after adjustment for confounders. CONCLUSIONS: FGF-19 increment after OGL was positively associated with age, and negatively associated with abnormal glucose regulation and statin treatment.