Lowered fasting chenodeoxycholic acid correlated with the decrease of fibroblast growth factor 19 in Chinese subjects with impaired fasting glucose.
ABSTRACT: The gut-derived hormone Fibroblast growth factor 19 (FGF19) could regulate glucose metabolism and is induced by bile acids (BAs) through activating Farnesoid X Receptor (FXR). FGF19 was found to decrease in subjects with isolated-impaired fasting glucose (I-IFG) and type 2 diabetes mellitus (T2DM). However, the reason for the change of FGF19 in subjects with different glucometabolic status remained unclear. Here we measured six BAs including chenodeoxycholic acid (CDCA), cholic acid, deoxycholic acid, their glycine conjugates and FGF19 levels during oral glucose tolerance test (OGTT) in normal glucose tolerance (NGT), isolated-impaired glucose tolerance, I-IFG, combined glucose intolerance (CGI) and T2DM subjects. After OGTT, serum FGF19 peaked at 120?min in all subjects. Glycine conjugated BAs peaked at 30?min, while free BAs did not elevated significantly. Consistent with the decrease trend in FGF19 levels, fasting serum CDCA levels in subjects with I-IFG, CGI and T2DM were significantly lower than NGT subjects (P?
Project description:<h4>Context</h4>People with prediabetes are at high risk of developing diabetes.<h4>Objective</h4>The objective of this study was to determine the pathogenesis of fasting and postprandial hyperglycemia in prediabetes.<h4>Design</h4>Glucose production, gluconeogenesis, glycogenolysis, and glucose disappearance were measured before and during a hyperinsulinemic clamp using [6,6-(2)H2]glucose and the deuterated water method corrected for transaldolase exchange.<h4>Setting</h4>The study was conducted at the Mayo Clinic Clinical Research Unit.<h4>Participants</h4>Subjects with impaired fasting glucose (IFG)/normal glucose tolerance (NGT) (n = 14), IFG/impaired glucose tolerance (IGT) (n = 18), and normal fasting glucose (NFG)/NGT (n = 16) were studied.<h4>Intervention</h4>A hyperinsulinemic clamp was used.<h4>Outcome measures</h4>Glucose production, glucose disappearance, gluconeogenesis, and glycogenolysis were measured.<h4>Results</h4>Fasting glucose production was higher (P < .0001) in subjects with IFG/NGT than in those with NFG/NGT because of increased rates of gluconeogenesis (P = .003). On the other hand, insulin-induced suppression of glucose production, gluconeogenesis, glycogenolysis, and stimulation of glucose disappearance all were normal. Although fasting glucose production also was increased (P = .0002) in subjects with IFG/IGT, insulin-induced suppression of glucose production, gluconeogenesis, and glycogenolysis and stimulation of glucose disappearance were impaired (P = .005).<h4>Conclusions</h4>Fasting hyperglycemia is due to excessive glucose production in people with either IFG/NGT or IFG/IGT. Both insulin action and postprandial glucose concentrations are normal in IFG/NGT but abnormal in IFG/IGT. This finding suggests that hepatic and extrahepatic insulin resistance causes or exacerbates postprandial glucose intolerance in IFG/IGT. Elevated gluconeogenesis in the fasting state in IFG/NGT and impaired insulin-induced suppression of both gluconeogenesis and glycogenolysis in IFG/IGT suggest that alteration in the regulation of these pathways occurs early in the evolution of type 2 diabetes.
Project description:To examine the relationship between hormones involved in bone remodeling and glucose metabolism alterations in prediabetes.Individuals (n = 43) with NGT (BMI = 31.1 ± 1.1 kg/m2) and individuals (n = 79) with impaired glucose regulation (IGR) (BMI = 31.9 ± 1.2 kg/m2) including subjects with IFG, IGT, and IFG-IGT underwent OGTT and DXA. Osteopontin (OPN), osteocalcin (OCN), osteoprotegerin (OPG), and PTH levels were measured at fasting. Beta-cell function was calculated using C-peptide deconvolution. Dynamic indexes of insulin sensitivity were calculated from OGTT. A subgroup underwent to a euglycemic hyperinsulinemic clamp with 3-3H-glucose to estimate the endogenous glucose production (EGP) and insulin-mediated body glucose disposal (TGD/SSPI).OPN was higher in IGR compared to NGT (5.3 ± 0.5 vs. 3.3 ± 0.2 ?g/mL; p = 0.008) and in isolated IGT compared to IFG and IFG-IGT (6.3 ± 0.5 vs. 4.5 ± 0.3 and 5.4 ± 0.5 ?g/mL; p = 0.02). OCN was similar in IFG and NGT but lower in IGT and IFG-IGT compared to NGT (7.2 ± 0.3 and 5.4 ± 0.2 vs. 8.3 ± 0.3 ng/mL; p < 0.01). OPN was positively correlated with HbA1c, fasting and 2 h plasma glucose and PTH. OCN was negatively correlated with body fat, 2 h plasma glucose, insulin and positively correlated with Stumvoll index. OPG correlated with TGD/SSPI (r = - 0.29; p < 0.05), EGP, and hepatic insulin resistance index in IGR (r = 0.51, r = 0.43; p < 0.01). There was no correlation between PTH and insulin sensitivity or Beta-cell function parameters.In prediabetes, hormones known to be involved in bone remodeling may affect glucose metabolism before overt T2DM occurs with tissue-specific mechanisms.
Project description:BACKGROUND:The optimal reference range of homeostasis model assessment of insulin resistance (HOMA-IR) in normal Chinese population has not been clearly defined. Here we address this issue using the Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS), a prospective population-based cohort study with long-term follow-up. MATERIAL & METHODS:In this study, normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) were defined according to the 1998 World Health Organization criteria. Dysglycemia referred to IFG, IGT or T2DM. This study comprised two parts. Part one was a cross-sectional study involving 2,649 Hong Kong Chinese subjects, aged 25-74 years, at baseline CRISPS-1 (1995-1996). The optimal HOMA-IR cut-offs for dysglycemia and T2DM were determined by the receiver-operating characteristic (ROC) curve. Part two was a prospective study involving 872 subjects who had persistent NGT at CRISPS-4 (2010-2012) after 15 years of follow-up. RESULTS:At baseline, the optimal HOMA-IR cut-offs to identify dysglyceia and T2DM were 1.37 (AUC = 0.735; 95% confidence interval [CI] = 0.713-0.758; Sensitivity [Se] = 65.6%, Specificity [Sp] = 71.3%] and 1.97 (AUC = 0.807; 95% CI = 0.777-0.886; Se = 65.5%, Sp = 82.9%) respectively. These cut-offs, derived from the cross-sectional study at baseline, corresponded closely to the 75th (1.44) and 90th (2.03) percentiles, respectively, of the HOMA-IR reference range derived from the prospective study of subjects with persistent NGT. CONCLUSIONS:HOMA-IR cut-offs, of 1.4 and 2.0, which discriminated dysglycemia and T2DM respectively from NGT in Southern Chinese, can be usefully employed as references in clinical research involving the assessment of insulin resistance.
Project description:BACKGROUND: The bile acid-activated nuclear receptor Farnesoid X Receptor (FXR) is critical in maintaining intestinal barrier integrity and preventing bacterial overgrowth. Patients with Crohn's colitis (CC) exhibit reduced ileal FXR target gene expression. FXR agonists have been shown to ameliorate inflammation in murine colitis models. We here explore the feasibility of pharmacological FXR activation in CC. METHODS: Nine patients with quiescent CC and 12 disease controls were treated with the FXR ligand chenodeoxycholic acid (CDCA; 15 mg/kg/day) for 8 days. Ileal FXR activation was assessed in the fasting state during 6 hrs after the first CDCA dose and on day 8, by quantification of serum levels of fibroblast growth factor (FGF) 19. Since FGF19 induces gallbladder (GB) refilling in murine models, we also determined concurrent GB volumes by ultrasound. On day 8 ileal and cecal biopsies were obtained and FXR target gene expression was determined. RESULTS: At baseline, FGF19 levels were not different between CC and disease controls. After the first CDCA dose, there were progressive increases of FGF19 levels and GB volumes during the next 6 hours in CC patients and disease controls (FGF19: 576 resp. 537% of basal; GB volumes: 190 resp. 178% of basal) without differences between both groups, and a further increase at day 8. In comparison with a separate untreated control group, CDCA affected FXR target gene expression in both CC and disease controls, without differences between both groups. CONCLUSIONS: Pharmacological activation of FXR is feasible in patients with CC. These data provide a rationale to explore the anti-inflammatory properties of pharmacological activation of FXR in these patients. TRIAL REGISTRATION: TrialRegister.nl NTR2009.
Project description:Objective:To quantify glucose-mediated glucose disposal with and without basal insulin replacement and insulin-mediated glucose disposal in subjects with impaired fasting glucose (IFG). Research Design and Methods:We used the hyperglycemic/pancreatic clamp and stepped euglycemic clamp techniques to quantify glucose disposal and suppression of endogenous glucose production (EGP) in those with normal glucose tolerance (NGT; n = 14) and those with IFG (n = 14). Results:Total body glucose-mediated glucose uptake, measured with the hyperglycemic/pancreatic clamp, was not significantly affected by the basal plasma insulin levels in subjects with IFG and those with NGT. Compared with subjects with NGT, those with IFG had significantly lower glucose-mediated glucose uptake (by 15%) during the hyperglycemic clamp performed with and without basal insulin replacement. In contrast, insulin-mediated glucose disposal was comparable in both groups. The suppression of EGP by hyperglycemia was similar in both groups. However, the suppression of EGP by insulin was attenuated in those with IFG compared with those with NGT. Conclusions:The results of the present study have demonstrated that (i) glucose-mediated glucose disposal is impaired in those with IFG; (ii) insulin-mediated glucose uptake in IFG is normal; and (iii) insulin action to suppress EGP is impaired.
Project description:Diurnal carbohydrate and fat distribution modulates glycaemic control in rodents. In humans, the optimal timing of both macronutrients and its effects on glycaemic control after prolonged consumption are not studied in detail. In this cross-over trial, 29 non-obese men were randomized to two four-week diets: (1) carbohydrate-rich meals until 13.30 and fat-rich meals between 16.30 and 22.00 (HC/HF) versus (2) inverse sequence of meals (HF/HC). After each trial period two meal tolerance tests were performed, at 09.00 and 15.40, respectively, according to the previous intervention. On the HF/HC diet, whole-day glucose level was increased by 7.9% (p?=?0.026) in subjects with impaired fasting glucose and/or impaired glucose tolerance (IFG/IGT, n?=?11), and GLP-1 by 10.2% (p?=?0.041) in normal glucose-tolerant subjects (NGT, n?=?18). Diet effects on fasting GLP-1 (p?=?0.009) and PYY (p?=?0.034) levels were observed in IFG/IGT, but not in NGT. Afternoon decline of glucose tolerance was more pronounced in IFG/IGT and associated with a stronger decrease of postprandial GLP-1 and PYY levels, but not with changes of cortisol rhythm. In conclusion, the HF/HC diet shows an unfavourable effect on glycaemic control in IFG/IGT, but not in NGT subjects. Consequently, large, carbohydrate-rich dinners should be avoided, primarily by subjects with impaired glucose metabolism.
Project description:<h4>Background</h4>To assess the impact of changes in different glucose tolerance states on risk of incident cardiovascular disease (CVD)/coronary heart disease (CHD).<h4>Methods</h4>A total of 4094 Iranians (43.9% men) aged???30 years, without diabetes and CVD at enrolment were included. The following categories were defined both at baseline visit and 3 years later (second visit): normal fasting glucose (NFG), normal glucose tolerance (NGT), NFG and NGT (NFG/NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and IFG and/or IGT (IFG/IGT). Changes in the categories, i.e. regression to normoglycemia, remaining in previous status and progression to diabetes were assessed. We used Cox's proportional hazard models adjusted for traditional risk factors and their changes, to estimate the hazard ratio (HR) with 95% confidence interval (CI) of different changing categories for incident CVD/CHD.<h4>Results</h4>During a median follow-up of 12.42 years, 428 subjects (men?=?265) experienced CVD. Considering persistent NFG/NGT as reference, participants who shifted from NFG/NGT to IFG/IGT showed a lower hazard of CVD in the fully adjusted model, HR 0.72 [95% CI 0.52-0.996, P?=?0.048]. Moreover, subjects who shifted from IFG, IGT and IFG/IGT to diabetes had an increased risk of CVD/CHD. The risk however, was only statistically significant for those with IFG/IGT, 1.61 [(1.03-2.51), P?=?0.04] for CVD and 1.75 [(1.10-2.78), P?=?0.02] for CHD; considering IFG/IGT at both visits as reference. Furthermore, those who regressed from IFG/IGT to normoglycemia were at the same risk as those remained in IFG/IGT state, 1.12 [(0.79-1.60), P?=?0.52] for CVD and 1.04 [(0.70-1.53), P?=?0.85] for CHD. Among a subgroup of population with insulin data (n?=?803) those with insulin resistance (IR) that converted to diabetes showed a higher risk for CVD, 3.68 [(1.49-9.06), P?=?0.01] and CHD, 2.76 [(1.00-7.60), P?=?0.05] events in the fully adjusted model.<h4>Conclusions</h4>Among participants with IFG, IGT or IFG/IGT at baseline, only those who developed diabetes had a higher risk of developing CVD/CHD. Persistent IFG/IGT was not associated with higher risk, compared with those reverted to normoglycemia. Moreover, subjects who converted from NFG/NGT to incident IFG/IGT showed a signal for lower risk of CVD/CHD.
Project description:β-Cell function (BCF) declines over the course of type 2 diabetes, but little is known about BCF changes across glucose tolerance status (GTS) categories, and comparisons of direct vs surrogate measures.To assess longitudinal changes in BCF across GTS.The Insulin Resistance Atherosclerosis Study is a multicenter, observational, epidemiologic study.Four clinical centers in the US that could identify subjects likely to have impaired fasting glucose (IFG) or impaired glucose tolerance (IGT).We compared longitudinal changes in BCF in 1052 subjects over 5 years. Subjects were categorized according to baseline GTS: normal glucose tolerance (NGT: n = 547), impaired fasting glucose or impaired glucose tolerance (IFG/IGT: n = 341), and newly diagnosed type 2 diabetes (n = 164).None.BCF was assessed from a frequently sampled iv glucose tolerance test (AIR, acute insulin response), and the homeostasis model assessment of BCF (HOMA B).NGT and IFG/IGT subjects increased their insulin secretion over time, whereas those with type 2 diabetes experienced either decline or little change in BCF. After adjustment for demographic variables and change in insulin resistance, change in HOMA B underestimated the magnitude of changes in BCF, as assessed by change in AIR. Relative to NGT, the 5-year change in insulin secretion in IFG/IGT and type 2 diabetes was 31% and 70% lower (by HOMA B) and 50% and 80% lower (by AIR).The decline in BCF over time in IFG/IGT and type 2 diabetes may be more pronounced than previously estimated; HOMA B may underestimate this decline significantly.
Project description:<h4>Background</h4>Bile salts likely contribute to liver injury in patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC). Fibroblast growth factor 19 (FGF19) is a bile salt-induced enterokine with hepatoprotective potential as it suppresses de novo bile salt synthesis. Here, we evaluated the bile salt receptor FXR/FGF19 gut-liver axis in PSC and PBC patients.<h4>Methods</h4>Fasted patients with PSC (n = 12) and PBC (n = 10), and healthy controls (HC; n = 10) were orally challenged with the natural FXR agonist chenodeoxycholic acid (CDCA 15 mg/kg). Blood was sampled hourly until 8 h afterwards. Serum FGF19 and bile salt excursions were determined. Serum levels of 7?-hydroxy-4-cholesten-3-one (C4), reflecting bile salt synthesis, were measured as a biomarker of FGF19 response.<h4>Results</h4>Baseline serum FGF19 levels were comparable between groups, while fasted bile salt levels in PSC patients were elevated. Upon CDCA challenge, HC and PBC patients showed a serum FGF19 peak after 4 h followed by a decline. PSC patients showed a prolonged and elevated serum FGF19 response up to 8 h, combined with a sustained serum elevation of CDCA and other bile salts. In general, C4 levels declined following FGF19 elevation. In PSC patients with less favorable prognosis, baseline C4 levels were drastically suppressed and did not further decline.<h4>Conclusion</h4>Following an oral CDCA challenge, PSC patients showed an impaired clearance of CDCA and a prolonged serum FGF19 response. FXR agonist therapy in PSC could cause prolonged exposure to elevated levels of FGF19, and we propose careful monitoring for detrimental side effects in patient studies.
Project description:This study investigated the clinical characteristics and associated risk factors of prediabetes in the southwestern region of Korea. A total of 323 subjects from 13 prediabetes studies were included in the data analysis. Subjects with prediabetes were divided into the following subtypes: (1) normal glucose tolerance (NGT) with HbA1c 5.7%-6.4%; (2) isolated impaired fasting glucose (I-IFG); (3) isolated impaired glucose tolerance (I-IGT); and (4) combined I-IFG and I-IGT (C-IFG/IGT). Clinical and biochemical variables were compared among subtypes, and multivariate logistic regression analysis was used to identify risk factors for prediabetes subtypes. The overall proportion of subjects with NGT, I-IFG, I-IGT and C-IFG/IGT was 8.4%, 20.7%, 33.1% and 37.8%, respectively. In men, C-IFG/IGT was the most common subtype, while in women, I-IGT was the most common. The parameters related to dysglycemia, atherosclerosis and liver dysfunction were higher in subjects in the C-IFG/IGT subtype than in other subtypes. Multiple linear regression analysis revealed independent risk factors for increased FPG, 2h-PPG and HbA1c levels. This study identified the clinical features and independent risk factors for prediabetes subtypes.