scholarly journals MECHANISMS IN ENDOCRINOLOGY: Biological role, clinical significance, and therapeutic possibilities of the recently discovered metabolic hormone fibroblastic growth factor 21

2012 ◽  
Vol 167 (3) ◽  
pp. 301-309 ◽  
Author(s):  
Pedro Iglesias ◽  
Rafael Selgas ◽  
Sara Romero ◽  
Juan J Díez
Keyword(s):  
Insulin Resistance ◽  
Blood Glucose ◽  
Growth Factor ◽  
Glucose Tolerance ◽  
Hepatic Insulin Resistance ◽  
Fibroblast Growth Factor 21 ◽  
Diabetic Patients ◽  
Glucose Transporter 1 ◽  
Insulin Resistant ◽  
The Metabolic Syndrome

Fibroblast growth factor 21 (FGF21), a 181 amino acid circulating protein, is a member of the FGF superfamily, with relevant metabolic actions. It acts through the interaction with specific FGF receptors and a cofactor called β-Klotho, whose expression is predominantly detected in metabolically active organs. FGF21 stimulates glucose uptake in adipocytes via the induction of glucose transporter-1. This action is additive and independent of insulin. β-Cell function and survival are preserved, and glucagon secretion is reduced by this protein, thus decreasing hepatic glucose production and improving insulin sensitivity. Lipid profile has been shown to be improved by FGF21 in several animal models. FGF21 increases energy expenditure in rodents and induces weight loss in diabetic nonhuman primates. It also exerts favorable effects on hepatic steatosis and reduces tissue lipid content in rodents. Adaptive metabolic responses to fasting, including stimulation of ketogenesis and fatty acid oxidation, seem to be partially mediated by FGF21. In humans, serum FGF21 concentrations have been found elevated in insulin-resistant states, such as impaired glucose tolerance and type 2 diabetes. FGF21 levels are correlated with hepatic insulin resistance index, fasting blood glucose, HbA1c, and blood glucose after an oral glucose tolerance test. A relationship between FGF21 levels and long-term diabetic complications, such as nephropathy and carotid atheromatosis, has been reported. FGF21 levels decreased in diabetic patients after starting therapy with insulin or oral agents. Increased FGF21 serum levels have also been found to be associated with obesity. In children, it is correlated with BMI and leptin levels, whereas in adults, FGF21 levels are mainly related to several components of the metabolic syndrome. Serum FGF21 levels have been found to be elevated in patients with ischemic heart disease. In patients with renal disease, FGF21 levels exhibited a progressive increase as renal function deteriorates. Circulating FGF21 levels seem to be related to insulin resistance and inflammation in dialysis patients. In summary, FGF21 is a recently identified hormone with antihyperglycemic, antihyperlipidemic, and thermogenic properties. Direct or indirect potentiation of its effects might be a potential therapeutic target in insulin-resistant states.

scholarly journals Changes in FGF21 Serum Concentrations and Liver mRNA Expression in an Experimental Model of Complete Lipodystrophy and Insulin-Resistant Diabetes

2014 ◽  
pp. 483-490 ◽  
Author(s):  
A. ŠPOLCOVÁ ◽  
M. HOLUBOVÁ ◽  
B. MIKULÁŠKOVÁ ◽  
V. NAGELOVÁ ◽  
A. ŠTOFKOVÁ ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Mrna Expression ◽  
Plasma Levels ◽  
Glucose Transporter ◽  
Liver Fat ◽  
Fibroblast Growth Factor 21 ◽  
Glucose Transporter 1 ◽  
Insulin Resistant

Patients with obesity and type 2 diabetes often display high levels of the anti-diabetic factor fibroblast growth factor-21 (FGF21), suggesting that the overproduction of FGF21 may result from increased adiposity in an attempt by white adipose tissue (WAT) to counteract insulin resistance. However, the production of FGF21 diabetes in the absence of WAT has not been examined. In this study, we investigated the effects of lipodystrophy in A-ZIP F-1 mice on FGF21 production in relation to diabetes. A-ZIP F-1 mice displayed high FGF21 plasma levels resulting from enhanced FGF21 mRNA expression in the liver. Concomitant enhancement of FGF21 receptor (FGFR1) and glucose transporter 1 (GLUT-1) mRNA expression was observed in the muscles of A-ZIP F-1 mice. Furthermore, the activation of hypothalamic NPY and AgRP mRNA expression positively correlated with plasma levels of FGF21 but not active ghrelin. Our study demonstrates that an increased FGF21 plasma level in lipodystrophic A-ZIP F-1 mice results mainly from up-regulated liver production but does not suffice to overcome the lipodystrophy-induced severe type 2-diabetes and insulin resistance in the liver linked to the augmented liver fat deposition.

scholarly journals Ceramide Content in Liver Increases Along with Insulin Resistance in Obese Patients

2019 ◽  
Vol 8 (12) ◽  
pp. 2197 ◽  
Author(s):  
Hady Razak Hady ◽  
Agnieszka U. Błachnio-Zabielska ◽  
Łukasz Szczerbiński ◽  
Piotr Zabielski ◽  
Monika Imierska ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Tolerance ◽  
Glycosylated Hemoglobin ◽  
Hepatic Insulin Resistance ◽  
Oral Glucose ◽  
Diabetic Patients ◽  
Obese Patients ◽  
Men And Women ◽  
Percentage Body Fat ◽  
Ceramide Content

The liver plays a central role in the glucose and lipid metabolism. Studies performed on animal models have shown an important role of lipid accumulation in the induction of insulin resistance. We sought to explain whether in obese humans, the insulin resistance is associated with hepatic ceramide accumulation. The experiments were conducted on obese men and women. Each gender was divided into three groups: Normal glucose tolerance group (NGT), Impaired glucose tolerance group (IGT), and Type 2 diabetic subjects (T2D). Ceramide (Cer) content was analyzed with the use of LC/MS/MS. An oral glucose tolerance test (OGTT), glycosylated hemoglobin (HbA1c), percentage body fat (FAT%), and body mass index (BMI) was also measured. Total hepatic ceramide was significantly higher in T2D females as compared to NGT females (p < 0.05), whereas in males, total ceramide was significantly higher in IGT and T2D as compared to NGT (p < 0.05). In both, men and women, the highest increase in T2D subjects, was observed in C16:0-Cer, C18:0:-Cer, C22:0-Cer, and C24:0-Cer (p < 0.05) as compared to NGT group. Interestingly, glucose (at 0′ and at 120′ in OGTT) and HbA1c positively correlated with the ceramide species that most increased in T2D patients (C16:0-Cer, C18:0-Cer, C22:0-Cer, and C24:0-Cer). In men glucose and HbA1c significantly correlated with only C22:0-Cer. This is one of the few studies comparing hepatic ceramide content in severely obese patients. We found that, ceramide content increased in diabetic patients, both in men and women, and the content of ceramide correlated with glycemic parameters. These data indicate ceramide contribution to the induction of hepatic insulin resistance.

scholarly journals Skeletal muscle insulin resistance in zebrafish induces alterations in β-cell number and glucose tolerance in an age- and diet-dependent manner

2015 ◽  
Vol 308 (8) ◽  
pp. E662-E669 ◽  
Author(s):  
Lisette A. Maddison ◽  
Kaitlin E. Joest ◽  
Ryan M. Kammeyer ◽  
Wenbiao Chen
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Blood Glucose ◽  
Glucose Tolerance ◽  
Fasting Blood Glucose ◽  
Β Cells ◽  
Β Cell ◽  
Muscle Insulin Resistance ◽  
Insulin Resistant ◽  
Skeletal Muscle Insulin Resistance

Insulin resistance creates an environment that promotes β-cell failure and development of diabetes. Understanding the events that lead from insulin resistance to diabetes is necessary for development of effective preventional and interventional strategies, and model systems that reflect the pathophysiology of disease progression are an important component toward this end. We have confirmed that insulin enhances glucose uptake in zebrafish skeletal muscle and have developed a zebrafish model of skeletal muscle insulin resistance using a dominant-negative IGF-IR. These zebrafish exhibit blunted insulin signaling and glucose uptake in the skeletal muscle, confirming insulin resistance. In young animals, we observed an increase in the number of β-cells and normal glucose tolerance that was indicative of compensation for insulin resistance. In older animals, the β-cell mass was reduced to that of control with the appearance of impaired glucose clearance but no elevation in fasting blood glucose. Combined with overnutrition, the insulin-resistant animals have an increased fasting blood glucose compared with the control animals, demonstrating that the β-cells in the insulin-resistant fish are in a vulnerable state. The relatively slow progression from insulin resistance to glucose intolerance in this model system has the potential in the future to test cooperating genes or metabolic conditions that may accelerate the development of diabetes and provide new therapeutic targets.

scholarly journals The Impact of Metabolic Syndrome Defined by IDF or Revised NCEP on Glycemic control in Malaysians with Type 2 Diabetes

2020 ◽  
Author(s):  
Riyadh Saif-Ali ◽  
Nor Azmi Kamaruddin ◽  
Molham AL-Habori ◽  
Sami A Al-Dubai ◽  
Wan Zurinah Wan Ngah
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Metabolic Syndrome ◽  
Blood Glucose ◽  
Glycemic Control ◽  
Diabetic Patients ◽  
C Peptide ◽  
The Metabolic Syndrome ◽  
Type 2 Dm

Abstract BackgroundChronic complication of Type 2 diabetes mellitus such as macrovascular disease is amplified with the increase in the number of the metabolic syndrome (MeS) risk factors. Specific criteria for diagnosis of metabolic syndrome are essential to help in glycemic control and reduce cardiovascular morbidity and mortality in diabetic patients with metabolic syndrome.Methods The study involved 485 Type 2 DM patients who are receiving treatment at the University Kebangsaan Malaysia Medical Center (UKMMC), Kuala Lumpur, Malaysia. Metabolic syndrome among the Type 2 DM patients was diagnosed based on IDF and NCEP-R criteria. The C-peptide and glycated hemoglobin (HbA1c) levels were determined by an automated quantitative immunoassay analyzer and high-performance liquid chromatography respectively. The metabolic syndrome factors, glucose, triglyceride and HDL cholesterol were measured by spectrophotometerResultsApplication of IDF and NCEP-R criteria respectively resulted in 73% and 85% of Type 2 DM subjects being diagnosed with metabolic syndrome. The concordance of these criteria in diagnosing metabolic syndrome among Type 2 DM was low (kappa=0.33, P<0.001). Both IDF and NCEP-R criteria indicated that Type 2 DM with five criteria of metabolic syndrome had higher insulin resistance (P=2.1×10-13, P=1.4×10-11), C-peptide (P=1.21×10-13; 4.1×10-11), blood glucose (P=0.01; 0.021) and HbA1c (P=0.039; 0.018) than those Type 2 DM without metabolic syndrome respectively.ConclusionHowever, there is a low concordance between IDF and NCEP-R criteria in the diagnosis of metabolic syndrome among Type 2 DM, both criteria showed that type 2 DM with five criteria of metabolic syndrome had higher insulin resistance, blood glucose and HbA1c.

scholarly journals Relationship of Metabolic Syndrome Defined by IDF or Revised NCEP with Glycemic Control among Malaysians with Type 2 Diabetes

2020 ◽  
Author(s):  
Riyadh Saif-Ali ◽  
Nor Azmi Kamaruddin ◽  
Molham AL-Habori ◽  
Sami A Al-Dubai ◽  
Wan Zurinah Wan Ngah
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Metabolic Syndrome ◽  
Blood Glucose ◽  
Glycemic Control ◽  
Diabetic Patients ◽  
C Peptide ◽  
The Metabolic Syndrome ◽  
Cardiovascular Morbidity And Mortality

Abstract Background Chronic complication of Type 2 Diabetes (T2D) such as macrovascular disease is amplified with the increase in the number of the metabolic syndrome (MetS) risk factors. Specific criteria for diagnosis of MetS are essential to help in glycemic control and reduce cardiovascular morbidity and mortality in diabetic patients with metabolic syndrome.Methods The study is cross-sectional observational study which involved 485 T2D patients who are receiving treatment at the University Kebangsaan Malaysia Medical Center (UKMMC), Kuala Lumpur, Malaysia. Metabolic syndrome among the T2D patients was diagnosed based on IDF and NCEP-R criteria. C-peptide and glycated hemoglobin (HbA1c) levels were determined by an automated quantitative immunoassay analyzer and high-performance liquid chromatography, respectively. The metabolic syndrome factors, glucose, triglyceride and HDL cholesterol were measured by spectrophotometer Results Application of IDF and NCEP-R criteria respectively resulted in 73% and 85% of T2D subjects being diagnosed with MetS. The concordance of these criteria in diagnosing MetS among T2D was low (κ =0.33, P<0.001). Both IDF and NCEP-R criteria indicated that T2D with five criteria of MetS had higher insulin resistance (P=2.1×10-13, P=1.4×10-11), C-peptide (P=1.21×10-13; 4.1×10-11), blood glucose (P=0.01; 0.021) and HbA1c (P=0.039; 0.018) than those T2D without MetS respectively. Conclusion Although, there is a low concordance between IDF and NCEP-R criteria in the diagnosis of MetS among T2D, both criteria showed that T2D with five criteria of MetS had higher insulin resistance, blood glucose and HbA1c.

scholarly journals Scutellaria baicalensis Alleviates Insulin Resistance in Diet-Induced Obese Mice by Modulating Inflammation

2019 ◽  
Vol 20 (3) ◽  
pp. 727 ◽  
Author(s):  
Hyun-Young Na ◽  
Byung-Cheol Lee
Keyword(s):  
Insulin Resistance ◽  
Inflammatory Responses ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Postprandial Glucose ◽  
Scutellaria Baicalensis ◽  
Necrosis Factor Alpha ◽  
Insulin Resistant ◽  
The Metabolic Syndrome ◽  
Epididymal Fat

Insulin resistance is strongly associated with the metabolic syndrome, and chronic inflammation is known to be a major mechanism of insulin resistance and is a therapeutic target. This study was designed to evaluate the effect of Scutellaria baicalensis (SB) in high-fat diet (HFD)-induced insulin-resistant mice and to investigate its mechanism based on inflammatory responses. Mice were fed a HFD to induce insulin resistance and then administered SB for nine weeks. Body weight, glucose, lipid, insulin, epididymal fat pad and liver weights, and histologic characteristics were evaluated to determine the effect on insulin resistance. In order to evaluate the effects on the inflammatory process, we analyzed the proportions of macrophages in liver and epididymal fat and measured inflammatory gene expression. Fasting and postprandial glucose, fasting insulin, HOMA-IR, triglycerides, and low density lipoprotein cholesterol levels were significantly decreased by SB administration. The epididymal fat and liver showed significant weight decreases and histological improvements. Total adipose tissue macrophages (ATMs) decreased (27.71 ± 3.47% vs. 45.26 ± 7.26%, p < 0.05), M2 ATMs increased (47.02 ± 6.63% vs. 24.28 ± 8.00%, p < 0.05), and CD11b+ Kupffer cells decreased. The expression levels of tumor necrosis factor alpha and F4/80 in the liver were significantly decreased (12.03 ± 1.47% vs. 25.88 ± 4.57%, p < 0.05) compared to HFD group. These results suggest that SB improved insulin resistance through inhibition of macrophage-mediated inflammation.

Impact of Glucose Metabolism Disorders on IGF-1 Levels in Patients with Acromegaly

2018 ◽  
Vol 50 (05) ◽  
pp. 408-413 ◽  
Author(s):  
Sema Dogansen ◽  
Gulsah Yalin ◽  
Seher Tanrikulu ◽  
Sema Yarman
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Glucose Metabolism ◽  
Glucose Tolerance ◽  
Normal Glucose Tolerance ◽  
Glucose Metabolism Disorders ◽  
Insulin Resistant ◽  
Normal Glucose ◽  
Resistant Group ◽  
The Impact

AbstractIn this study, we aimed to evaluate the presence of glucose metabolism abnormalities and their impact on IGF-1 levels in patients with acromegaly. Ninety-three patients with acromegaly (n=93; 52 males/41 females) were included in this study. Patients were separated into three groups such as; normal glucose tolerance (n=23, 25%), prediabetes (n=38, 41%), and diabetes mellitus (n=32, 34%). Insulin resistance was calculated with homeostasis model assessment (HOMA). HOMA-IR > 2.5 or ≤2.5 were defined as insulin resistant or noninsulin resistant groups, respectively. Groups were compared in terms of factors that may be associated with glucose metabolism abnormalities. IGF-1% ULN (upper limit of normal)/GH ratios were used to evaluate the impact of glucose metabolism abnormalities on IGF-1 levels. Patients with diabetes mellitus were significantly older with an increased frequency of hypertension (p<0.001, p=0.01, respectively). IGF-1% ULN/GH ratio was significantly lower in prediabetes group than in normal glucose tolerance group (p=0.04). Similarly IGF-1% ULN/GH ratio was significantly lower in insulin resistant group than in noninsulin resistant group (p=0.04). Baseline and suppressed GH levels were significantly higher in insulin resistant group than in noninsulin resistant group (p=0.024, p<0.001, respectively). IGF-1% ULN/GH ratio is a useful marker indicating glucose metabolism disorders and IGF-1 levels might be inappropriately lower in acromegalic patients with insulin resistance or prediabetes. We suggest that IGF-1 levels should be re-evaluated after the improvement of insulin resistance or glycemic regulation for the successful management of patients with acromegaly.

scholarly journals Exercise, heat shock proteins and insulin resistance

2017 ◽  
Vol 373 (1738) ◽  
pp. 20160529 ◽  
Author(s):  
Ashley E. Archer ◽  
Alex T. Von Schulze ◽  
Paige C. Geiger
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Heat Shock ◽  
Heat Shock Proteins ◽  
Metabolic Effects ◽  
Diabetic Patients ◽  
Alcoholic Fatty Liver ◽  
Insulin Resistant ◽  
Exercise Induced ◽  
Shock Proteins

Best known as chaperones, heat shock proteins (HSPs) also have roles in cell signalling and regulation of metabolism. Rodent studies demonstrate that heat treatment, transgenic overexpression and pharmacological induction of HSP72 prevent high-fat diet-induced glucose intolerance and skeletal muscle insulin resistance. Overexpression of skeletal muscle HSP72 in mice has been shown to increase endurance running capacity nearly twofold and increase mitochondrial content by 50%. A positive correlation between HSP72 mRNA expression and mitochondrial enzyme activity has been observed in human skeletal muscle, and HSP72 expression is markedly decreased in skeletal muscle of insulin resistant and type 2 diabetic patients. In addition, decreased levels of HSP72 correlate with insulin resistance and non-alcoholic fatty liver disease progression in livers from obese patients. These data suggest the targeted induction of HSPs could be a therapeutic approach for preventing metabolic disease by maintaining the body's natural stress response. Exercise elicits a number of metabolic adaptations and is a powerful tool in the prevention and treatment of insulin resistance. Exercise training is also a stimulus for increased HSP expression. Although the underlying mechanism(s) for exercise-induced HSP expression are currently unknown, the HSP response may be critical for the beneficial metabolic effects of exercise. Exercise-induced extracellular HSP release may also contribute to metabolic homeostasis by actively restoring HSP72 content in insulin resistant tissues containing low endogenous levels of HSPs. This article is part of the theme issue ‘Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective’.

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