scholarly journals Characterization of the ZDSD Rat: A Translational Model for the Study of Metabolic Syndrome and Type 2 Diabetes

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Richard G. Peterson ◽  
Charles V. Jackson ◽  
Karen Zimmerman ◽  
Willem de Winter ◽  
Norman Huebert ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Metabolic Diseases ◽  
Oral Glucose ◽  
Glucose Levels ◽  
Zdf Rat ◽  
Obesity And Diabetes ◽  
Elevated Glucose ◽  
Polygenic Obesity

Metabolic syndrome and T2D produce significant health and economic issues. Many available animal models have monogenic leptin pathway mutations that are absent in the human population. Development of the ZDSD rat model was undertaken to produce a model that expresses polygenic obesity and diabetes with an intact leptin pathway. A lean ZDF rat with the propensity for beta-cell failure was crossed with a polygenetically obese Crl:CD (SD) rat. Offspring were selectively inbred for obesity and diabetes for >30 generations. In the current study, ZDSD rats were followed for 6 months; routine clinical metabolic endpoints were included throughout the study. In the prediabetic metabolic syndrome phase, ZDSD rats exhibited obesity with increased body fat, hyperglycemia, insulin resistance, dyslipidemia, glucose intolerance, and elevated HbA1c. As disease progressed to overt diabetes, ZDSD rats demonstrated elevated glucose levels, abnormal oral glucose tolerance, increases in HbA1c levels, reductions in body weight, increased insulin resistance with decreasing insulin levels, and dyslipidemia. The ZDSD rat develops prediabetic metabolic syndrome and T2D in a manner that mirrors the development of metabolic syndrome and T2D in humans. ZDSD rats will provide a novel, translational animal model for the study of human metabolic diseases and for the development of new therapies.

scholarly journals GPER Deficiency in Male Mice Results in Insulin Resistance, Dyslipidemia, and a Proinflammatory State

Endocrinology ◽  
2013 ◽  
Vol 154 (11) ◽  
pp. 4136-4145 ◽  
Author(s):  
Geetanjali Sharma ◽  
Chelin Hu ◽  
Jonathan L. Brigman ◽  
Gang Zhu ◽  
Helen J. Hathaway ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Glucose Intolerance ◽  
Fasting Blood Glucose ◽  
Interferon Γ ◽  
Male Mice ◽  
Glucose Levels ◽  
Obesity And Diabetes ◽  
Increased Risk ◽  
One Year

Estrogen is an important regulator of metabolic syndrome, a collection of abnormalities including obesity, insulin resistance/glucose intolerance, hypertension, dyslipidemia, and inflammation, which together lead to increased risk of cardiovascular disease and diabetes. The role of the G protein-coupled estrogen receptor (GPER/GPR30), particularly in males, in these pathologies remains unclear. We therefore sought to determine whether loss of GPER contributes to aspects of metabolic syndrome in male mice. Although 6-month-old male and female GPER knockout (KO) mice displayed increased body weight compared with wild-type littermates, only female GPER KO mice exhibited glucose intolerance at this age. Weight gain in male GPER KO mice was associated with increases in both visceral and sc fat. GPER KO mice, however, exhibited no differences in food intake or locomotor activity. One-year-old male GPER KO mice displayed an abnormal lipid profile with higher cholesterol and triglyceride levels. Fasting blood glucose levels remained normal, whereas insulin levels were elevated. Although insulin resistance was evident in GPER KO male mice from 6 months onward, glucose intolerance was pronounced only at 18 months of age. Furthermore, by 2 years of age, a proinflammatory phenotype was evident, with increases in the proinflammatory and immunomodulatory cytokines IL-1β, IL-6, IL-12, TNFα, monocyte chemotactic protein-1, interferon γ-induced protein 10, and monokine induced by interferon gamma and a concomitant decrease in the adipose-specific cytokine adiponectin. In conclusion, our study demonstrates for the first time that in male mice, GPER regulates metabolic parameters associated with obesity and diabetes.

scholarly journals Effects of 10-Week Concurrent Training on Insulin Resistance and the Serum Levels of Vaspin and Visfatin in Overweight Females

2019 ◽  
Vol 25 (3) ◽  
pp. 146-157
Author(s):  
Abdolreza Kazemi ◽  
◽  
Sareh Mahalati ◽  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Diseases ◽  
Intervention Group ◽  
Serum Levels ◽  
Analysis Of Covariance ◽  
Concurrent Training ◽  
Improve Insulin Sensitivity ◽  
Glucose Levels ◽  
Kerman City ◽  
Training Protocol

Aims: The present study investigated the effects of a 10-week concurrent training on the serum levels of vaspin and visfatin in overweight females. Methods & Materials: Twenty-four over-weight females from Kerman City, Iran (Mean±SD age: 11.23±0.62 years; Mean±SD weight: 64.83±2.70kg; Mean±SD BMI: 27.97±0.47 kg/m2) were randomly assigned into the control and concurrent training groups. The intervention group performed the training protocol as follows: endurance training: 65-85% of Vo2 max for 20 minutes per session, and resistance training: 50-60% of One Repetition Maximum (1RM) for 30 minutes per session and 3 days a week for 10 weeks. Fasting plasma vaspin, visfatin, and insulin levels were measured by ELISA method. To analyze the data, Analysis of Covariance (ANCOVA) was used. Findings: Performing 10 weeks of concurrent training significantly decreased vaspin and visfatin plasma levels, and insulin resistance resting levels (P≤0.05); however, there was no significant decrease in glucose levels. Conclusion: Concurrent training can decrease insulin resistance, probably by reducing vaspin and visfatin in overweight females. Therefore, it is suggested that overweight females use concurrent training to improve insulin sensitivity and prevent metabolic diseases.

scholarly journals Parameters of Glucose Homeostasis in the Recognition of the Metabolic Syndrome in Young Adults with Prader–Willi Syndrome

2021 ◽  
Vol 10 (23) ◽  
pp. 5635
Author(s):  
Graziano Grugni ◽  
Antonio Fanolla ◽  
Fiorenzo Lupi ◽  
Silvia Longhi ◽  
Antonella Saezza ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Glucose Homeostasis ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Prader Willi Syndrome ◽  
Insulinogenic Index ◽  
Glucose Levels ◽  
The Metabolic Syndrome ◽  
Diagnostic Threshold ◽  
Age Related

To verify the accuracy of different indices of glucose homeostasis in recognizing the metabolic syndrome in a group of adult patients with Prader–Willi syndrome (PWS), 102 PWS patients (53 females/49 males), age ±SD 26.9 ± 7.6 yrs, Body Mass Index (BMI) 35.7 ± 10.7, were studied. The following indices were assessed in each subject during an oral glucose tolerance test (OGTT): 1 h (>155 mg/dL) and 2 h (140–199 mg/dL) glucose levels, the oral disposition index (ODI), the insulinogenic index (IGI), the insulin resistance (HOMA-IR) were evaluated at baseline, 1 h and 2 h. Although minor differences among indices were found, according to the ROC analysis, no index performed better in recognizing MetS. Furthermore, the diagnostic threshold levels changed over the years and therefore the age-related thresholds were calculated. The easily calculated HOMA-IR at baseline may be used to accurately diagnose MetS, thus avoiding more complicated procedures.

Plasma Glucagon and Free Fatty Acid Responses to a Glucose Load in the Obese Spontaneous Hypertensive Rat (SHROB) Model of Metabolic Syndrome X

2002 ◽  
Vol 227 (3) ◽  
pp. 164-170 ◽  
Author(s):  
Rodney A. Velliquette ◽  
Richard J. Koletsky ◽  
Paul Ernsberger
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Metabolic Syndrome X ◽  
Molar Ratio ◽  
Syndrome X ◽  
Oral Glucose ◽  
Plasma Glucagon ◽  
Glucose Load ◽  
Spontaneous Hypertensive Rat ◽  
Hypertensive Rat

Metabolic Syndrome X is a cluster of abnormalities including insulin resistance, hyperlipidemia, hypertension, and obesity. We sought to determine if excess plasma glucagon and free fatty acids (FFA) might contribute to the insulin resistance in the obese spontaneous hypertensive rat (SHROB), a unique animal model of leptin resistance and metabolic Syndrome X. SHROB were extremely hyperinsulinemic and mildly glucose intolerant compared with lean SHR. SHROB had elevated fasting plasma glucagon and FFA, and showed paradoxical responses to an oral glucose challenge, with increased glucagon at 30 and 60 min postchallenge (200% ± 45% and 91% ± 13%, respectively; n = 9). In lean SHR, glucagon was nearly unchanged by glucose loading (<30% increase, P > 0.05; n = 5). Plasma FFA were not affected by a glucose load in SHROB, whereas SHR showed a decrease of 40% ± 6% (n = 5–9). The I/G molar ratio changed in opposite directions in the two genotypes, with a decrease in SHROB at 30 and 60 min, in contrast to the appropriate increase at 30 and 60 min postchallenge in the lean SHR (P < 0.01; n = 5–9). Administration of 500 ng/kg exogenous glucagon to SHR raised glucagon 56% ± 5% to a level that was similar to fasting SHROB. This level of circulating glucagon was sufficient to elevate glucose and insulin during the 7 hr of observation (n = 9). Based on these results, we suggest that fasting hyperglucagonemia and impaired suppression of glucagon secretion and FFA in response to an oral glucose load may contribute to insulin resistance and glucose intolerance in the SHROB model of metabolic Syndrome X.

scholarly journals Elevated Circulating Fetuin-B Levels Are Associated with Insulin Resistance and Reduced by GLP-1RA in Newly Diagnosed PCOS Women

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Mani Mokou ◽  
Shan Yang ◽  
Bin Zhan ◽  
Shan Geng ◽  
Kejia Li ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Glucose ◽  
Glucose Tolerance ◽  
Metabolic Diseases ◽  
Polycystic Ovary ◽  
Fasting Blood Glucose ◽  
Resistance Index ◽  
Oral Glucose ◽  
Healthy Women ◽  
Tnf Α

Background. Previous studies have suggested that Fetuin-B seems to be a secreted adipokine related to metabolic diseases. However, the results have been inconsistent. Here, our objective is to investigate the changes in circulating Fetuin-B levels in women with polycystic ovary syndrome (PCOS) and analyze the association of Fetuin-B and insulin resistance (IR). Methods. The current study is comprised of a cross-sectional study and a series of interventional studies. Oral glucose tolerance test (OGTT) and euglycemic-hyperinsulinemic clamp (EHC) were engaged to assess glucose tolerance and insulin sensitivity. Serum Fetuin-B levels were determined by ELISA. Results. Serum Fetuin-B and TNF-α levels were markedly increased in women with PCOS compared to healthy women. Circulating Fetuin-B was positively associated with body mass index, waist-to-hip ratio, the percentage of body fat (FAT%), systolic blood pressure, triglyceride, low-density lipoprotein cholesterol, fasting blood glucose, 2 h blood glucose after glucose overload, fasting insulin, 2 h insulin after glucose overload, HOMA-insulin resistance index (HOMA-IR), the area under the curve for insulin (AUCi), AUCg, and TNF-α, while negatively associated with M value and follicular stimulating hormone (FSH). During the EHC, Fetuin-B levels were found to be significantly increased in PCOS women. After a glucose challenge, serum Fetuin-B levels in healthy women were significantly increased. Lipid infusion reduced serum Fetuin-B levels in 30 healthy subjects. After six months of glucagon-like peptide-1 receptor agonist (GLP-1RA) intervention, serum Fetuin-B concentrations in PCOS women markedly decreased following ameliorated IR. Conclusion. Our results indicate that Fetuin-B may be a biomarker of IR in individuals with PCOS. This trial is registered with ChiCTR-IIR-16007901.

scholarly journals The Role of Insulin-Like Growth Factor (IGF) Binding Protein-2 in the Insulin-Mediated Decrease in IGF-I Bioactivity

Endocrinology ◽  
2009 ◽  
Vol 150 (11) ◽  
pp. 5192-5192
Author(s):  
Ayman M. Arafat ◽  
Martin O. Weickert ◽  
Jan Frystyk ◽  
Joachim Spranger ◽  
Christof Schöfl ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Glucose Tolerance ◽  
Glucose Tolerance Test ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Oral Glucose Tolerance ◽  
Igf System ◽  
Igf I ◽  
Igf Binding

ABSTRACT Context: Insulin interacts with the GH-IGF system by a reciprocal regulation of IGF-binding proteins (IGFBP) and GH, which in turn regulate insulin sensitivity via bioactive IGF-I. This network is linked to metabolic syndrome and cardiovascular diseases. Objective: We evaluated the effect of glucose and insulin on IGFBP-1-4, particularly IGFBP-2, in the regulation of bioactive IGF-I and its relation to insulin resistance. Setting: The study was conducted at an endocrinology center. Research Design and Methods: Twenty-four healthy subjects (12 men; aged 21–72 yr; body mass index 25.9 ± 0.9 kg/m2) and 19 subjects with impaired glucose tolerance (IGT; eight men; aged 26–71 yr; body mass index 28.9 ± 1.2 kg/m2 ) were prospectively studied using oral glucose tolerance test and hyperinsulinemic euglycemic clamp. Results: During the clamp, insulin decreased IGF-I bioactivity in both IGT subjects and controls (−16.2 ± 2.8 and −13.9 ± 3.3%, respectively; P &lt; 0.01). In addition, insulin increased IGFBP-2 and GH and decreased IGFBP-1 and -4 but did not alter total IGF-I, IGF-II, or IGFBP-3 levels. During the oral glucose tolerance test, GH and IGFBP-1 were markedly suppressed. Subjects with IGT showed more pronounced insulin resistance and lower GH, IGFBP-1, and IGFBP-2 levels (P &lt; 0.05). In multiple regression analysis, IGFBP-2 was an independent predictor of insulin sensitivity (β = 0.36, P &lt; 0.05) and IGF-I bioactivity (β = −0.5, P &lt; 0.05). Conclusions: Our data indicate that insulin acutely decreases IGF-I bioactivity through differential modulation of IGFBPs. Furthermore, IGFBP-2 plays a central role in the insulin-IGF system cross talk and is closely linked to insulin resistance, thereby providing a further explanation for its association with the metabolic syndrome.

scholarly journals Insulin Resistance, the Metabolic Syndrome, and Nonalcoholic Fatty Liver Disease

2005 ◽  
Vol 90 (3) ◽  
pp. 1578-1582 ◽  
Author(s):  
F. Angelico ◽  
M. Del Ben ◽  
R. Conti ◽  
S. Francioso ◽  
K. Feole ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Oral Glucose ◽  
Nonalcoholic Fatty Liver ◽  
Insulin Resistant ◽  
The Metabolic Syndrome

Background/Aims: An association of nonalcoholic fatty liver disease with the insulin-resistant metabolic syndrome has been suggested. The aim of the study was to assess the association of fatty liver to different degrees of insulin resistance and secretion. Methods and Results: The study was performed in 308 alcohol- and virus-negative consecutive patients attending a metabolic clinic, who underwent a complete clinical and biochemical work-up including oral glucose tolerance test and routine liver ultrasonography. Steatosis was graded as absent/mild, moderate, and severe. In nondiabetic subjects, a progressive (P &lt; 0.05) increase in mean homeostasis model of insulin resistance was recorded from the group without steatosis to the groups with mild/moderate and severe steatosis. Severe steatosis was associated with the clustering of the five clinical and biochemical features proposed for the clinical diagnosis of the metabolic syndrome. Subjects with the metabolic syndrome with a more pronounced insulin resistance had a higher prevalence of severe steatosis (P &lt; 0.01) compared with those with homeostasis model of insulin resistance below the median. Conclusions: The findings stress the heterogeneous presentation of patients with the metabolic syndrome when the diagnosis is based on the broad Adult Treatment Panel III clinical criteria and demonstrate that those who are more insulin resistant have a higher prevalence of severe steatosis.

Metabolic Endocrine Regulators of Hematopoietic Stem Cell Formation and Function.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1496-1496
Author(s):  
James Harris ◽  
Claire C Cutting ◽  
Michael Dovey ◽  
Wolfram Goessling ◽  
Trista North
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Energy Production ◽  
Functional Redundancy ◽  
Hematopoietic Stem ◽  
Glucose Levels ◽  
Obesity And Diabetes ◽  
Elevated Glucose ◽  
Glucose Treatment

Abstract Abstract 1496 Poster Board I-519 Obesity and subsequent diabetes have emerged as major health problems in the U.S. While the consequences of elevated blood glucose levels on the cardiovascular system and other organs are well known, the direct effects on the hematopoietic system are more elusive. Similarly, the impact of gestational diabetes on embryonic hematopoiesis has not been examined in detail. The zebrafish has emerged as an important model system to study conserved regulators of organ development and homeostasis. In order to evaluate the role of elevated glucose levels on hematopoietic stem cell (HSC) production, zebrafish embryos were exposed to increasing doses of D-glucose from 5 somites to 36 hours post fertilization (hpf); HSC number, as indicated by in situ hybridization for the conserved markers runx1 and cmyb in the Aorta-Gonad-Mesonephros (AGM) region, was increased at 0.5, 1% and 2% glucose; results were confirmed by in analysis of CD41 expression. Quantification using FACS analysis of fluorescent HSC reporter embryos and qPCR revealed a 2-3-fold enhancement following 1% glucose treatment. Other mono, di-, and trisaccharide sugars had similar effects, causing increased numbers of HSCs, however, L-glucose had no impact. BrdU incorporation in the AGM region was elevated after 1% glucose treatment, while acridine orange staining revealed an inhibitory effect on apoptosis. To evaluate potential mediators of these glucose-responsive effects, embryos were injected with antisense morpholino oligonucleotides (MO) against both the insulin (insr), and insulin-like growth factor receptors (igfr); insr and igfr receptors can each bind insulin, released following elevations in blood sugar levels. MO knockdown of insra or igfrb, but not igfra, influenceded runx1+ HSCs substantially, indicating an important role of these endocrine regulatory signaling pathways in HSC formation. However, D-glucose completely reversed these effects, implying either functional redundancy, or a multi-step, multi-effector process of HSC regulation by endocrine factors. To further clarify when insr- and/or igfr-mediated activity was influencing HSC formation and to correlate that effect with elevated glucose exposure, embryos were treated for defined periods with either 1% glucose, insulin, or IGF; exposure from 10 somites to 24 hpf influences the formation and arterial/venous specification of dorsal aorta, the conserved site of initial definitive HSC production, while exposure from 24 to 36 hpf regulates HSC induction. IGF exerted a positive effect on HSCs only after the establishment of the hematopoietic niche (>24hpf). Glucose treatment, however, positively influenced HSC formation at all time points examined, suggesting it works not only in the HSC niche to induce HSCs, but also prior to HSC formation. MO knockdown of the glucose transporter glut1 resulted in diminished HSC production, confirming a direct role of glucose in this process. To determine whether the effect of glucose elevation was mediated by changes in cellular energy production, embryos were exposed to chemical inhibitors of oxidative phosphorylation. Cyanide and oxaloacetate reversed the beneficial effects of D-glucose, indicating that energy production can modulate HSC formation. Investigation into the functional redundancy and cross-regulation of insulin and IGF on HSC self-renewal and the evolutionary conservation of the effects of energy metabolism on HSC production are ongoing; further studies will be needed to determine if glucose maintains an influential role on HSC homeostasis or bone marrow recovery following injury. These results could have an impact on methods for HSC modulation for therapeutic purposes, and may further unveil specific risks of obesity and diabetes for hematopoiesis and HSC homeostasis during gestation and in the adult. Disclosures: Goessling: Fate Therapeutics: Consultancy, Patents & Royalties. North: Fate Therapeutics: Consultancy, Patents & Royalties.

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