Effects of Perga on FGF21/Leptin/Insulin in Imparied Glucose Regulation

BackgroundThermogenesis is influenced by fluctuations in sex hormones during the menstrual cycle in premenopausal women. The thermogenic activity and mass of brown adipose tissue (BAT) are regulated by endocrine factors, including sex hormones and fibroblast growth factor 21 (FGF21). However, the relationship between human BAT and these endocrine fluctuations within individuals remains to be elucidated. This study aimed to assess variations in BAT activity between the luteal and follicular phases and identify correlations with circulating levels of sex hormones and FGF21.MethodsHealthy young women were enrolled in an observational study. Measurement of BAT activity and blood analyses were performed in both the follicular and luteal phases. BAT activity was analyzed using thermography with 2-h cold exposure. Plasma 17β-estradiol, progesterone, and FGF21 levels were determined by enzyme-linked immunosorbent assay. A comparative analysis within individuals was conducted in 13 women to compare the follicular and luteal phases. Furthermore, sensitivity analysis was carried out in 21 women during the follicular phase only.ResultsPlasma 17β-estradiol and progesterone levels were significantly higher in the luteal phase, whereas plasma FGF21 level was significantly higher in the follicular phase. Comparison analysis found no significant differences in cold-induced BAT activity between the follicular and luteal phases in young women. Correlation analysis in both comparison and sensitivity analyses found that plasma 17β-estradiol and progesterone levels were not associated with BAT activity, whereas plasma FGF21 levels were significantly and positively correlated with BAT activity only in the follicular phase. In addition, plasma 17β-estradiol levels in the follicular phase were significantly and positively associated with plasma FGF21 levels in both the comparison and sensitivity analyses.ConclusionsThe thermogenic activity of BAT during cold exposure was comparable between the follicular and luteal phases in young women. Higher BAT activity was associated with elevated levels of plasma FGF21 only in the follicular phase, which is related to increased plasma 17β-estradiol levels.

Fibroblast growth factor 21 (FGF21) is increased acutely by carbohydrate ingestion and is elevated in patients with type 2 diabetes (T2D). However, the physiological significance of increased FGF21 in humans remains largely unknown. We examined whether FGF21 contributed to the metabolic improvements observed following treatment of patients with T2D with either triple (metformin/pioglitazone/exenatide) or conventional (metformin/insulin/glipizide) therapy for 3 yr. Forty-six patients with T2D were randomized to receive either triple or conventional therapy to maintain HbA1c < 6.5%. A 2-h 75-g oral glucose tolerance test (OGTT) was performed at baseline and following 3 years of treatment to assess glucose tolerance, insulin sensitivity, and β-cell function. Plasma total and bioactive FGF21 levels were quantitated before and during the OGTT at both visits. Patients in both treatment arms experienced significant improvements in glucose control, but insulin sensitivity and β-cell function were markedly increased after triple therapy. At baseline, FGF21 levels were regulated acutely during the OGTT in both groups. After treatment, fasting total and bioactive FGF21 levels were significantly reduced in patients receiving triple therapy, but there was a relative increase in the proportion of bioactive FGF21 compared with that observed in conventionally treated subjects. Relative to baseline studies, triple therapy treatment also significantly modified FGF21 levels in response to a glucose load. These changes in circulating FGF21 were correlated with markers of improved glucose control and insulin sensitivity. Alterations in the plasma FGF21 profile may contribute to the beneficial metabolic effects of pioglitazone and exenatide in human patients with T2D.NEW & NOTEWORTHY In patients with T2D treated with a combination of metformin/pioglitazone/exenatide (triple therapy), we observed reduced total and bioactive plasma FGF21 levels and a relative increase in the proportion of circulating bioactive FGF21 compared with that in patients treated with metformin and sequential addition of glipizide and basal insulin glargine (conventional therapy). These data suggest that FGF21 may contribute, at least in part, to the glycemic benefits observed following combination therapy in patients with T2D.

Mitiglinide treatment may decreases plasma fibroblast growth factor-21 levels in individuals with new-onset T2DM

The effect of dietary phosphorus (P) on fibroblast growth factor 21 (FGF21)/β-klotho axis was investigated in rats that were fed diets with: Normal (NP) or high P (HP) and either normal (NC), high (HC) or low calories (LC). Sampling was performed at 1, 4 and 7 months. Plasma FGF21 concentrations were higher (p < 0.05) in NC and HC than in LC groups. Increasing P intake had differing effects on plasma FGF21 in rats fed NC and HC vs. rats fed LC at the three sampling times. When compared with the NP groups, FGF21 concentrations decreased at the three sampling points in rats fed NC-HP (80 vs. 194, 185 vs. 382, 145 vs. 403 pg/mL) and HC-HP (90 vs. 190, 173 vs. 353, 94 vs. 434 pg/mL). However, FGF21 did not decrease in rats fed LC-HP (34 vs. 20, 332 vs. 164 and 155 vs. 81 pg/mL). In addition, LC groups had a much lower liver FGF21 messenger ribonucleic acid/glyceraldehyde 3-phosphate dehydrogenase (mRNA/GAPDH) ratio (0.51 ± 0.08 and 0.56 ± 0.07) than the NC-NP (0.97 ± 0.14) and HC-NP (0.97 ± 0.22) groups. Increasing P intake reduced liver FGF21 mRNA/GAPDH in rats fed NC and HC to 0.42 ± 0.05 and 0.37 ± 0.04. Liver β-klotho mRNA/GAPDH ratio was lower (p < 0.05) in LC groups (0.66 ± 0.06 and 0.59 ± 0.10) than in NC (1.09 ± 0.17 and 1.03 ± 0.14) and HC (1.19 ± 0.12 and 1.34 ± 0.19) groups. A reduction (p < 0.05) in β-klotho protein/α-tubulin ratio was also observed in LC groups (0.65 ± 0.05 and 0.49 ± 0.08) when compared with NC (1.12 ± 0.11 and 0.91 ± 0.11) and HC (0.93 ± 0.17 and 0.87 ± 0.09) groups. In conclusion β-klotho is potently regulated by caloric restriction but not by increasing P intake while FGF21 is regulated by both caloric restriction and increased P intake. Moreover, increased P intake has a differential effect on FGF21 in calorie repleted and calorie depleted rats.

Insufficient expression of hepatic fibroblast growth factor 21 (FGF21) and stromal cell-derived factor 2 like 1 (Sdf2l1) reportedly leads to insulin resistance and hepatosteatosis in obesity and type 2 diabetes. On the other hand, increased expression of hepatic serotonin receptor 2a (htr2a) in diet-induced obesity contributes to hepatosteatosis. Here we show that increases in circulating FGF21 levels and expression of hepatic FGF21 preceded weight gain, hyperinsulinemia, and hyperglycemia in C57BLJ6 mice fed a high-fat diet. Expression of hepatic htr2a and Sdf2l1 increased in insulin-resistant mice fed a high-fat diet. Intake of whey protein isolate decreased plasma FGF21 levels and expression of hepatic FGF21 in mice fed either a high-fat diet or a chow diet, whereas it only suppressed the overexpression of hepatic Sdf2 and htr2a in insulin-resistant mice fed a high-fat diet. Moreover, intake of whey protein isolate decreased plasma serotonin levels in mice fed either a high-fat diet or a chow diet. Genetic inhibition of tryptophan hydroxylase 1 decreased hepatic FGF21 expression and plasma FGF21 levels in mice. These findings suggest that increased hepatic FGF21 production precedes diet-induced weight gain, hyperinsulinemia, and hyperglycemia, and that intake of whey protein isolate could inhibit hepatic FGF21 production by suppressing peripheral serotonin synthesis.

PurposeMalnutrition during childhood precedes growth failure and affects the child’s well-being later in life. This study aims to investigate the potency of iron-fortified klutuk banana (Musa balbisiana Colla) flour on growth parameters and fibroblast growth factor 21 (FGF21) expression in malnourished rat model.Design/methodology/approachRats were allocated into normal control (NC), untreated malnutrition (MC), malnutrition + iron-fortified klutuk banana flour (IBF) and malnutrition + Indonesian Government-issued biscuit (GB). Malnutrition was induced by an isoenergetic low-protein diet for five weeks. The IBF and GB groups were supplemented with IBF 1.2 g/200 gBW and GB 1.2 g/200 gBW, respectively, via gavage daily for three weeks. The body weight and length, the levels of plasma and liver FGF21 and red blood cell indices were analyzed.FindingsAfter three weeks of supplementation, the IBF group showed higher body weight (245 ± 13.6 g vs 201.8 ± 16.3 g; p = 0.0004) and length (20.9 ± 0.5 cm vs 19.8 ± 0.5 cm; p = 0.021) compared with the untreated group. The plasma FGF21 level decreased in the IBF group (p = 0.034). The IBF group altered mean corpuscular volume and mean corpuscular hemoglobin, suggesting the IBF might attenuate malnutrition-induced anemia. Overall, the IBF prevented growth failure in malnourished condition. This might be mediated by the suppression of FGF21 expression, along with the prevention of malnutrition and anemia.Originality/valueThis study provides preliminary information about the potential use of rarely consumed banana, klutuk banana, as a supplement to treat malnutrition. This study might help the developing countries to eliminate the widespread malnutrition in economically challenged communities.

BackgroundHuman brown adipose tissue (BAT) activity is associated with lower body fatness and favorable glucose metabolism. Previous studies reported that oral fructose loading induces postprandial fibroblast growth factor 21 (FGF21) secretion. FGF21 is a known inducer of adipose tissue thermogenesis; however, the effects of diet-induced FGF21 secretion on BAT thermogenesis remain to be elucidated.MethodsThe effects of both single load and daily consumption of fructose on BAT activity were examined using a randomized cross-over trial and a 2-week randomized controlled trial (RCT), respectively. In the cross-over trial, 15 young men consumed a single dose of fructose solution or water and then consumed the other on a subsequent day. The RCT enrolled 22 young men, and the participants were allocated to a group that consumed fructose and a group that consumed water daily for 2 weeks. BAT activity was analyzed using thermography with cold exposure. Plasma FGF21 level was determined by enzyme-linked immunosorbent assay.ResultsIn the cross-over single-load trial, plasma FGF21 levels were significantly increased at 2 h after oral fructose load (p < 0.01); however, there was no significant difference in BAT activity between the fructose load and drinking water. The 2-week RCT revealed that both plasma FGF21 levels and BAT activity were not significantly increased by daily fructose consumption compared to water. Correlation analyses revealed that BAT activity at the baseline and the final measurements were strongly and positively associated with the RCT (r = 0.869, p < 0.001). Changes in BAT activity were significantly and negatively correlated with changes in plasma glucose levels during the 2-week intervention (r = − 0.497, p = 0.022).ConclusionsOral fructose load induces a temporary increase in circulating FGF21 levels; however, this does not activate BAT thermogenesis in healthy young men. Further studies are needed to elucidate the effect of endogenous FGF21 on physiological function.Trial registrationThis study is registered with the University Hospital Medical Information Network in Japan (number 000051761, registered 1 August 2023, retrospectively registered, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000052680).

Objective To investigate the relationship between plasma fibroblast growth factor 21 (FGF-21) levels and body mass index(BMI), plasma glucose, plasma insulin levels, as well as other factors in newly diagnosed type 2 diabetes mellitus (T2DM). Methods 180 subjects who visited Department of endocrinology, Chaoyang Hospital, Capital Medical University from January to July in 2013 were enrolledand divided into newly diagnosed T2DM group (DM group, n=136) and Impaired glucose tolerance (IGR group, n=44). We selected 52 healthy volunteer as control group (NCM group). Plasma FGF-21 levels were determined by ELISA. The association between plasma FGF-21 levels and BMI, plasma glucose, blood lipids, plasma insulin levels, homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment of insulin sensitivity index(HOMA-ISI) and other factors were also analyzed. We use independent-samples t test, Pearson's correlations, multivariate linear regression analysis. Results Plasma FGF-21 levels in newly diagnosed T2DM patients were significantly higher than those of healthy individuals (319.2±2.5 vs 223.09±1.43, t=2.804, P<0.05). Plasma FGF-21 levels positively correlated with triglyceride (TG) in newly diagnosed T2DM patients and healthy individuals (r=0.26, 0.38, respectively, P< 0.05 all above). Plasma FGF-21 levels positively correlated with BMI in IGR group (r=0.33, P<0.05). Multiple regression analysis suggested that HOMA-ISI was an independent related factor influencing plasma FGF-21 levels. Conclusion FGF-21 in newly diagnosed T2DM patients is associated with triglyceride levels, insulin resistance. Key words: Diabetes mellitus, type 2; Insulin resistance; Fibroblast growth factor 21

Findings from animal studies indicate that growth hormone (GH) may stimulate the production of the putative metabolic regulator fibroblast growth factor 21 (FGF21). We investigated whether circulating FGF21 levels are altered in patients with GH deficiency and characterized how levels of this growth factor are influenced by acute and long-term administration of GH, and the potential relationship between FGF21 and nonesterified fatty acids (NEFAs). GH-deficient patients (n = 9) were studied prior to and during 1 year of replacement with GH. Healthy subjects (n = 8) received an intravenous bolus of GH with or without concomitant oral glucose. Healthy subjects and patients with heterozygous familial hypercholesterolaemia (n = 23) were monitored following increasing doses of GH for 3 weeks. The main outcome measures were serum FGF21 and NEFA levels. Studies were performed at two academic centres. GH-deficient patients had FGF21 levels within the normal range, and GH replacement did not influence circulating FGF21 or NEFA concentrations. Acute GH administration to healthy control subjects did not change FGF21 levels, whereas an oral glucose load increased serum FGF21 by 25% and reduced NEFA levels by 48%. Similar effects were seen on administration of glucose together with GH. However, FGF21 levels increased dose dependently up to 3.7-fold in control subjects treated with GH for 3 weeks; simultaneously NEFA levels were increased by 47%. GH is not critical for the maintenance of basal serum FGF21 levels in humans, but circulating FGF21 levels increase following administration of GH to healthy individuals. There is no correlation between plasma NEFA and circulating FGF21 levels.

Plasma fibroblast growth factor-21 levels in patients with inborn errors of metabolism

Introduction. Fibroblast growth factor-21 (FGF21) regulates glucose, lipid, and energy homeostasis. Retinol-binding protein-4 (RBP4) controls metabolic and proliferative cell functions. Aims and methods. Aims of the study were to assess (1) serum FGF21 and RBP4 levels in 75 non-obese chronic hepatitis C (CHC) patients and 41 healthy controls similar in age and BMI; (2) the relationship between their serum concentration and insulin resistance, liver histology, and biochemical parameters; (3) their effectiveness as diagnostic markers. Results. FGF21 levels increased significantly in CHC patients compared with controls (p = 0.04). CHC patients with steatosis had significantly higher FGF21 levels compared with those without steatosis (p = 0.01). FGF21 concentration was positively related to steatosis grade (r = 0.39, p = 0.007). RBP4 levels did not differ between CHC patients and controls, but were negatively associated with necro-inflammatory activity grade (r = (-0.34), p = 0.04), with significantly higher levels in patients with minimal inflammatory activity (G1 vs. G2/3, p < 0.001; G1 vs. G2, p = 0 < 001; G1 vs. G3, p = 0.01). After stepwise linear regression analysis adjusting for potential confounders, RBP4 levels retained their independent significance as a predictor of necro-inflammatory activity (β = -0.31; t = -2.15, p = 0.035) and FGF21 levels as a predictor of steatosis (β = 0.34; t = 2.31, p = 0.024). Serum FGF21 correlated with serum RBP4 levels (r = 0.32, p = 0.02). Conclusions. Serum FGF21 levels increased in CHC patients, especially in those with steatosis and were associated with steatosis grade. FGF21 seems to be a useful diagnostic marker in determining hepatic steatosis in CHC. A negative association between serum RBP4 and necro-inflammatory activity indicates that disease severity may determine RBP4 levels.

Anemia and malaria are global health problems affecting >50% of pregnant women in sub-Saharan Africa and are associated with intrauterine growth restriction. The hormones fibroblast growth factor 21 (FGF-21) and growth differentiation factor 15 (GDF-15) are involved in metabolic regulation and are expressed in the placenta. No studies exist on FGF-21 and GDF-15 responses to exposures of malaria and anemia in pregnancy. Using a prospective, longitudinal pregnancy and birth cohort of women with an average age of 26 years from a rural region in northeastern Tanzania, we examined if FGF-21 and GDF-15 levels in maternal blood at week 33 ± 2 (n = 301) and in cord blood at birth (n = 353), were associated with anemia and malaria exposure at different time points in pregnancy and with neonatal anthropometry. Among mothers at gestation week 33 ± 2, lower FGF-21 levels were observed after exposure to malaria in the first trimester, but not anemia, whereas GDF-15 levels at week 33 ± 2 were not associated with malaria nor anemia. In cord blood, moderate to severe anemia at any time point in pregnancy was associated with higher levels of FGF-21, whereas malaria exposure in the third trimester was associated with lower FGF-21 levels in cord blood. Negative associations were observed between cord blood FGF-21 and GDF-15 levels and neonatal skinfold thicknesses and birthweight. Our results suggest that moderate to severe anemia throughout pregnancy associates with higher FGF-21 levels, and malaria in last trimester associates with lower FGF-21 levels, in the neonates, thereby potentially affecting the future cardiometabolic health of the child.

Fibroblast growth factor 21 (FGF21) is a stress-inducible hormone that regulates nutrient and metabolic homeostasis. Inflammatory state is one of the stimulators of FGF21 secretion. The aim of the study was to assess correlations between serum FGF21 level and inflammatory markers as well as nutritional status indicators in patients with inflammatory bowel disease (IBD). Fasting serum FGF21 level was measured using ELISA test in 105 IBD patients and 17 healthy controls. There were 31 subjects with active ulcerative colitis (UC), 16 with inactive UC, 36 with active Crohn's disease (CD), and 22 with inactive CD. Clinical and endoscopic activity of IBD was evaluated based on validated scales and indices. Fecal calprotectin, serum CRP, and selected parameters of nutritional status were tested in all patients. Serum FGF21 level was characterized by fluctuations depending on the IBD activity. FGF21 level was significantly higher in both active UC and CD compared to inactive phases of the diseases and to the controls. A correlation between FGF21 and fecal calprotectin levels was also found in UC and CD. Additionally, in CD, FGF21 level positively correlated with CRP level. In both UC and CD, a negative correlation was noted between FGF21 level and nutritional status parameters including cholesterol, protein, albumin levels, and BMI. The intensity of intestinal inflammation is related to FGF21 level, which correlates negatively with nutritional status indicators in IBD. The disturbances in FGF21 secretion may contribute to the multifactorial pathogenesis of malnutrition and weight loss in IBD patients.

Fibroblast growth factor-21 (FGF21) is a novel endocrine and paracrine regulator of metabolic homeostasis. The aim of our study was to measure its serum concentrations in patients with obesity, obesity and type 2 diabetes mellitus (T2DM) and healthy subjects (C), and to assess the changes of its circulating levels and mRNA expression after dietary and pharmacological interventions. We measured biochemical parameters, serum FGF21, adiponectin, leptin and insulin levels by commercial ELISA and RIA kits, and mRNA expression in the liver, subcutaneous and visceral fat by RT PCR in 26 obese patients, 11 T2DM patients and 32 control subjects. The interventions were acute hyperinsulinaemia during isoglycaemic-hyperinsulinaemic clamp, very low calorie diet (VLCD) and 3 months treatment with PPAR-alpha agonist fenofibrate. Baseline serum FGF21 levels were significantly higher in both obese and T2DM patients relative to healthy controls. FGF21 levels in obesity did not significantly differ from T2DM group. Both 3 weeks of VLCD and 3 months of fenofibrate treatment significantly increased FGF21 levels. FGF21 mRNA expression in visceral fat was twofold higher in obesity relative to C group, while it did not differ in subcutaneous fat. VLCD significantly increased FGF21 mRNA expression in subcutaneous fat of obesity. 3-h hyperinsulinaemia during the clamp increased FGF21 levels in T2DM but not in C group. An increase in FGF21 levels after VLCD and fenofibrate treatment may contribute to positive metabolic effect of these interventions and suggests the possibility of direct positive metabolic effects of FGF21 in humans.

Objective To observe the expression of FGF19 ( fibroblast growth factor 19) and PEDF (pigment epithelium-derived factor) in the serum of type 2 diabetic retinopathy (DR) patients and discuss their significance. Methods Total 89 patients with type 2 diabetes were selected and divided into two groups according to whether they were combined with diabetic retinopathy: 45 patients with type 2 diabetes alone (DM group) and 44 patients with type 2 diabetes mellitus combined with retinopathy (DR group). At the same time, 40 healthy people were selected as the control group (NDM group). The serum levels of FGF19 and PEDF and their biochemical indexes were detected and compared in each group. The correlation between the indexes and the relationship between FGF19, PEDF and DR were analyzed. Results Compared with NDM group, serum FGF19 level in DM group and DR group decreased, while C-reactive protein (CRP) and PEDF level in DM group and DR group increased (P 0.05); the levels of Hcy, triacylglycerol (TG) and CRP in DR group were higher than those in DM and NDM group (P 12.76 mg/L, the sensitivity and specificity of PEDF dignosing DR were 80.9% and 56.7% respectively. Conclusions In patients with DR, serum FGF19 level decreased and serum PEDF levels increased. The level of both changes is closely related to DR and may be involved in the development of DR. Key words: Diabetic retinopathy; Diabetes mellitus, type 2; Fibroblast growth factor 19; Pigment epithelium derived factor