Differential regulation of insulin resistance and hypertension by sex hormones in fructose-fed male rats

2005 ◽  
Vol 289 (4) ◽  
pp. H1335-H1342 ◽  
Author(s):  
Harish Vasudevan ◽  
Hong Xiang ◽  
John H. McNeill
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Insulin Sensitivity ◽  
Sex Hormones ◽  
Threshold Value ◽  
Relative Increase ◽  
Estrogen Treatment ◽  
Male Rats ◽  
Normal Chow

Differences in gender are in part responsible for the development of insulin resistance (IR) and associated hypertension. Currently, it is unclear whether these differences are dictated by gender itself or by the relative changes in plasma estrogen and/or testosterone. We investigated the interrelationships between testosterone and estrogen in the progression of IR and hypertension in vivo in intact and gonadectomized fructose-fed male rats. Treatment with estrogen significantly reduced the testosterone levels in both normal chow-fed and fructose-fed rats. Interestingly, fructose feeding induced a relative increase in estradiol levels, which did not affect IR in both intact and gonadectomized fructose-fed rats. However, increasing the estrogen levels improved insulin sensitivity in both intact and gonadectomized fructose-fed rats. In intact males, fructose feeding increased the blood pressure (140 ± 2 mmHg), which was prevented by estrogen treatment. However, the blood pressure in the fructose-fed estrogen rats (125 ± 1 mmHg) was significantly higher than that of normal chow-fed (113 ± 1 mmHg) and fructose-fed gonadectomized rats. Estrogen treatment did not affect the blood pressure in gonadectomized fructose-fed rats (105 ± 2 mmHg). These data suggest the existence of a threshold value for estrogen below which insulin sensitivity is unaffected. The development of hypertension in this model is dictated solely by the presence or absence of testosterone. In summary, the development of IR and hypertension is governed not by gender per se but by the interactions of specific sex hormones such as estrogen and testosterone.

Specific Deletion of CASK in Pancreatic β Cells Affects Glucose Homeostasis and Improves Insulin Sensitivity in Obese Mice by Reducing Hyperinsulinemia Running Title: β Cell CASK Deletion Reduces Hyperinsulinemia

2021 ◽  
Author(s):  
Xingjing Liu ◽  
Peng Sun ◽  
Qingzhao Yuan ◽  
Jinyang Xie ◽  
Ting Xiao ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Homeostasis ◽  
Chow Diet ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Calcium Calmodulin Dependent ◽  
Normal Chow

Calcium/calmodulin-dependent serine protein kinase (CASK) is involved in the secretion of insulin vesicles in pancreatic β-cells. The present study revealed a new <i>in vivo </i>role of CASK in glucose homeostasis during the progression of type 2 diabetes mellitus (T2DM). A Cre-loxP system was used to specifically delete the <i>Cask </i>gene in mouse β-cells (βCASKKO), and the glucose metabolism was evaluated in <a>βCASKKO</a> mice fed a normal chow diet (ND) or a high-fat diet (HFD). ND-fed mice exhibited impaired insulin secretion in response to glucose stimulation. Transmission electron microscopy showed significantly reduced numbers of insulin granules at or near the cell membrane in the islets of βCASKKO mice. By contrast, HFD-fed βCASKKO mice showed reduced blood glucose and a partial relief of hyperinsulinemia and insulin resistance when compared to HFD-fed wildtype mice. The IRS1/PI3K/AKT signaling pathway was upregulated in the adipose tissue of HFD-βCASKKO mice. These results indicated that knockout of the <i>Cask</i> gene in β cells had a diverse effect on glucose homeostasis: reduced insulin secretion in ND-fed mice, but improves insulin sensitivity in HFD-fed mice. Therefore, CASK appears to function in the insulin secretion and contributes to hyperinsulinemia and insulin resistance during the development of obesity-related T2DM.

Relationship among hyperinsulinemia, insulin resistance, and hypertension is dependent on sex

2002 ◽  
Vol 283 (2) ◽  
pp. H562-H567 ◽  
Author(s):  
Denise M. Galipeau ◽  
Linfu Yao ◽  
John H. McNeill
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Insulin Sensitivity ◽  
Insulin Treatment ◽  
Tolerance Test ◽  
Female Rats ◽  
Male Rats ◽  
Oral Glucose ◽  
Male And Female ◽  
Male And Female Rats

Hyperinsulinemia and insulin resistance have been linked to hypertension; however, the influence of sex on this relationship has not been well studied. The purpose of this experiment was to compare the effects of chronic insulin treatment on insulin sensitivity and blood pressure in male and female rats. Male and female Wistar rats were treated with insulin (2 U/day) via subcutaneous sustained release implants for 5 wk. Systolic blood pressure was measured via the tail-cuff method before and after treatment, and insulin sensitivity was assessed with an oral glucose tolerance test. The insulin sensitivity of female rats was 4.5-fold greater than male rats. Chronic insulin treatment impaired insulin sensitivity in both sexes; however, this occurred to a greater degree in male rats. Blood pressure increased in male rats treated with insulin only. The results demonstrate that hyperinsulinemia and insulin resistance are associated with hypertension in male rats only. Therefore, the link between these conditions appears to depend on sex.

scholarly journals Specific Deletion of CASK in Pancreatic β Cells Affects Glucose Homeostasis and Improves Insulin Sensitivity in Obese Mice by Reducing Hyperinsulinemia Running Title: β Cell CASK Deletion Reduces Hyperinsulinemia

2021 ◽  
Author(s):  
Xingjing Liu ◽  
Peng Sun ◽  
Qingzhao Yuan ◽  
Jinyang Xie ◽  
Ting Xiao ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Homeostasis ◽  
Chow Diet ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Calcium Calmodulin Dependent ◽  
Normal Chow

Calcium/calmodulin-dependent serine protein kinase (CASK) is involved in the secretion of insulin vesicles in pancreatic β-cells. The present study revealed a new <i>in vivo </i>role of CASK in glucose homeostasis during the progression of type 2 diabetes mellitus (T2DM). A Cre-loxP system was used to specifically delete the <i>Cask </i>gene in mouse β-cells (βCASKKO), and the glucose metabolism was evaluated in <a>βCASKKO</a> mice fed a normal chow diet (ND) or a high-fat diet (HFD). ND-fed mice exhibited impaired insulin secretion in response to glucose stimulation. Transmission electron microscopy showed significantly reduced numbers of insulin granules at or near the cell membrane in the islets of βCASKKO mice. By contrast, HFD-fed βCASKKO mice showed reduced blood glucose and a partial relief of hyperinsulinemia and insulin resistance when compared to HFD-fed wildtype mice. The IRS1/PI3K/AKT signaling pathway was upregulated in the adipose tissue of HFD-βCASKKO mice. These results indicated that knockout of the <i>Cask</i> gene in β cells had a diverse effect on glucose homeostasis: reduced insulin secretion in ND-fed mice, but improves insulin sensitivity in HFD-fed mice. Therefore, CASK appears to function in the insulin secretion and contributes to hyperinsulinemia and insulin resistance during the development of obesity-related T2DM.

scholarly journals Growth hormone signaling and action in obese versus lean human subjects

2019 ◽  
Vol 316 (2) ◽  
pp. E333-E344 ◽  
Author(s):  
Morten Lyng Høgild ◽  
Ann Mosegaard Bak ◽  
Steen Bønløkke Pedersen ◽  
Jørgen Rungby ◽  
Jan Frystyk ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Growth Hormone ◽  
Human Subjects ◽  
Glucose Production ◽  
Relative Increase ◽  
Antagonistic Effect ◽  
Endogenous Glucose Production ◽  
Metabolic Adaptation ◽  
Igf I

Growth hormone (GH) levels are blunted in obesity, but it is not known whether this relates to altered GH sensitivity and whether this influences the metabolic adaptation to fasting. Therefore, we investigated the effect of obesity on GH signal transduction and fasting-induced changes in GH action. Nine obese (BMI 35.7 kg/m2) and nine lean (BMI 21.5 kg/m2) men were studied in a randomized crossover design with 1) an intravenous GH bolus, 2) an intravenous saline bolus, and 3) 72 h of fasting. Insulin sensitivity (hyperinsulinemic, euglycemic clamp) and substrate metabolism (glucose tracer and indirect calorimetry) were measured in studies 1 and 2. In vivo GH signaling was assessed in muscle and fat biopsies. GH pharmacokinetics did not differ between obese and lean subjects, but endogenous GH levels were reduced in obesity. GH signaling (STAT5b phosphorylation and CISH mRNA transcription), and GH action (induction of lipolysis and peripheral insulin resistance) were similar in the two groups, but a GH-induced insulin antagonistic effect on endogenous glucose production only occurred in the obese. Fasting-induced IGF-I reduction was completely abrogated in obese subjects despite a comparable relative increase in GH levels (ΔIGF-I: lean, −66 ± 10 vs. obese, 27 ± 16 µg/l; P < 0.01; ΔGH: lean, 647 ± 280 vs. obese, 544 ± 220%; P = 0.76]. We conclude that 1) GH signaling is normal in obesity, 2) in the obese state, the preservation of IGF-I with fasting and the augmented GH-induced central insulin resistance indicate increased hepatic GH sensitivity, 3) blunted GH levels in obesity may protect against insulin resistance without compromising IGF-I status.

scholarly journals Pioglitazone improves insulin resistance and decreases blood pressure in adult patients with congenital adrenal hyperplasia

2009 ◽  
Vol 161 (6) ◽  
pp. 887-894 ◽  
Author(s):  
Jeanne Margot Kroese ◽  
Christiaan F Mooij ◽  
Marinette van der Graaf ◽  
Ad R M M Hermus ◽  
Cees J Tack
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Insulin Sensitivity ◽  
Body Fat ◽  
Matched Control ◽  
Fat Distribution ◽  
Body Fat Distribution ◽  
Adrenal Hyperplasia ◽  
Insulin Resistant ◽  
Steroid Profiles

ContextPatients with congenital adrenal hyperplasia (CAH) are chronically treated with supraphysiological doses of glucocorticoids, which are known to induce insulin resistance. Thiazolidinediones might reverse this effect and improve insulin sensitivity.ObjectivesTo assess insulin sensitivity in CAH patients and the effect of pioglitazone treatment on insulin sensitivity in CAH patients. Secondary objectives were the effects of treatment with pioglitazone on blood pressure, body fat distribution, lipid, and steroid profiles.DesignRandomized placebo controlled crossover trial.ParticipantsTwelve CAH patients and 12 body mass and age-matched control subjects.InterventionSixteen-week treatment with pioglitazone (45 mg/day) or placebo.Main outcome measureInsulin sensitivity measured by euglycemic clamp and oral glucose tolerance test. Further measures were 24-h blood pressure profiles, body fat distribution measured by magnetic resonance imaging, dual energy x-ray absorptiometry (DEXA) and bioimpedance procedures, liver fat by magnetic resonance spectroscopy, lipid, and steroid profiles.ResultsCAH patients were insulin resistant compared with healthy controls. Treatment with pioglitazone significantly improved insulin sensitivity in CAH patients (glucose infusion rate (GIR) from 28.5±11.6 to 38.9±11.0 μmol/kg per min, P=0.000, GIR in controls 46.2±23.4 μmol/kg per min, P<0.05 versus CAH). Treatment with pioglitazone decreased blood pressure (systolic: 124.0±13.6 vs 127.0±14.9 mmHg, P<0.001, diastolic: 72.8±11.5 vs 77.4±12.6 mmHg, P<0.001). No changes in body fat distribution, lipid, and steroid profiles were observed.ConclusionsCAH patients are insulin resistant compared with matched control subjects. Treatment with pioglitazone improves insulin sensitivity and decreases blood pressure in CAH patients.

Abstract 610: Ineffective Suppression of Adipocyte Lipolysis in Metabolic Syndrome: An in vivo Test for Adipocyte Insulin Resistance

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Jennifer L Ford ◽  
Raymond C Boston ◽  
Rachel E Walker ◽  
Gregory C Shearer
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Insulin Sensitivity ◽  
Lipid Droplet ◽  
Minimal Model ◽  
Initial Rate ◽  
Intravenous Glucose Tolerance Test ◽  
Intravenous Glucose ◽  
In Vivo Test

Background: Insulin resistance is a major contributor to metabolic syndrome, disrupting both glucose and non-esterified fatty acid (NEFA) dynamics through ineffective glucose clearance and decreased suppression of lipid droplet lipolysis. The minimal model of glucose dynamics is used for glycemic insulin sensitivity however it does not measure adipocyte insulin sensitivity, the primary determinant of plasma NEFA. An in-vivo approach to measuring adipocyte insulin sensitivity using NEFA is employed, comparing healthy and metabolic syndrome subjects. Both the models are employed to estimate insulin sensitivity and validate the NEFA approach. Objective: To test the use of NEFA kinetics to measure adipocyte insulin sensitivity compared to the glucose minimal model. Approach and results: Metabolic syndrome (n=56) and optimally healthy (n=14) subjects underwent a frequently sampled intravenous glucose tolerance test, and plasma analyzed for insulin, glucose, and NEFA. Insulin sensitivity ( S I ) and glucose effectiveness ( S G ) were calculated from the glucose minimal model. S I was 1.7 (mU/L) -1 min -1 and 0.40 (mU/L) -1 /min -1 and S G was 0.027 min -1 and 0.017 min -1 for the healthy and metabolic syndrome groups, respectively, indicating substantial glycemic insulin resistance in the latter. A model using glucose as the driver for NEFA kinetics was then applied. We found the initial rate of NEFA utilization by tissues (NU) was less, but the threshold glucose (tG) and glucose concentration required for a unit change in lipolysis inhibition ( G i ) were greater in metabolic syndrome verses healthy (NU: 0.050[0.045, 0.057] vs. 0.068[0.054, 0.086] p=0.03; tG: 6.7[6.2, 7.2] vs. 5.0[4.3, 5.9] p=0.001; G i : 0.30[0.25, 0.35] vs. 0.17[0.07, 0.27] p=0.02). No differences were found in initial rate of NEFA production or glucose utilization. Conclusion: Our results indicate that suppression of lipid-droplet lipolysis requires greater stimulus in metabolic syndrome compared to insulin sensitive adipocytes. Further, the rate of NEFA removal is less in metabolic syndrome. These results reveal components of insulin sensitivity not demonstrated by the glucose model. The NEFA model provides a measurement of adipocyte insulin sensitivity not captured by glycemic indices.

scholarly journals Cross-Sectional Association between Blood Pressure, in vivo Insulin Sensitivity and Adiponectin in Overweight Adolescents

2011 ◽  
Vol 76 (6) ◽  
pp. 379-385 ◽  
Author(s):  
Javier De Las Heras ◽  
Sojung Lee ◽  
Fida Bacha ◽  
Hala Tfayli ◽  
Silva Arslanian
Keyword(s):  
Blood Pressure ◽  
Insulin Sensitivity ◽  
Cross Sectional ◽  
Overweight Adolescents

scholarly journals PGRN Induces Impaired Insulin Sensitivity and Defective Autophagy in Hepatic Insulin Resistance

2015 ◽  
Vol 29 (4) ◽  
pp. 528-541 ◽  
Author(s):  
Jiali Liu ◽  
Huixia Li ◽  
Bo Zhou ◽  
Lin Xu ◽  
Xiaomin Kang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Insulin Signaling ◽  
Nuclear Factor Κb ◽  
Hepatic Insulin Resistance ◽  
Causative Role ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Impaired Insulin

Abstract Progranulin (PGRN) has recently emerged as an important regulator for glucose metabolism and insulin sensitivity. However, the underlying mechanisms of PGRN in the regulation of insulin sensitivity and autophagy remain elusive. In this study, we aimed to address the direct effects of PGRN in vivo and to evaluate the potential interaction of impaired insulin sensitivity and autophagic disorders in hepatic insulin resistance. We found that mice treated with PGRN for 21 days exhibited the impaired glucose tolerance and insulin tolerance and hepatic autophagy imbalance as well as defective insulin signaling. Furthermore, treatment of mice with TNF receptor (TNFR)-1 blocking peptide-Fc, a TNFR1 blocking peptide-Fc fusion protein to competitively block the interaction of PGRN and TNFR1, resulted in the restoration of systemic insulin sensitivity and the recovery of autophagy and insulin signaling in liver. Consistent with these findings in vivo, we also observed that PGRN treatment induced defective autophagy and impaired insulin signaling in hepatocytes, with such effects being drastically nullified by the addition of TNFR1 blocking peptide -Fc or TNFR1-small interference RNA via the TNFR1-nuclear factor-κB-dependent manner, indicating the causative role of PGRN in hepatic insulin resistance. In conclusion, our findings supported the notion that PGRN is a key regulator of hepatic insulin resistance and that PGRN may mediate its effects, at least in part, by inducing defective autophagy via TNFR1/nuclear factor-κB.

scholarly journals The tumor suppressor TMEM127 regulates insulin sensitivity in a tissue-specific manner

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Subramanya Srikantan ◽  
Yilun Deng ◽  
Zi-Ming Cheng ◽  
Anqi Luo ◽  
Yuejuan Qin ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Tumor Suppressor ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Suppressor Gene ◽  
Nutrient Sensing ◽  
Whole Body ◽  
Insulin Sensitizer

Abstract Understanding the molecular components of insulin signaling is relevant to effectively manage insulin resistance. We investigated the phenotype of the TMEM127 tumor suppressor gene deficiency in vivo. Whole-body Tmem127 knockout mice have decreased adiposity and maintain insulin sensitivity, low hepatic fat deposition and peripheral glucose clearance after a high-fat diet. Liver-specific and adipose-specific Tmem127 deletion partially overlap global Tmem127 loss: liver Tmem127 promotes hepatic gluconeogenesis and inhibits peripheral glucose uptake, while adipose Tmem127 downregulates adipogenesis and hepatic glucose production. mTORC2 is activated in TMEM127-deficient hepatocytes suggesting that it interacts with TMEM127 to control insulin sensitivity. Murine hepatic Tmem127 expression is increased in insulin-resistant states and is reversed by diet or the insulin sensitizer pioglitazone. Importantly, human liver TMEM127 expression correlates with steatohepatitis and insulin resistance. Our results suggest that besides tumor suppression activities, TMEM127 is a nutrient-sensing component of glucose/lipid homeostasis and may be a target in insulin resistance.

Insulin sensitivity and big ET-1 conversion to ET-1 after ETA- or ETB-receptor blockade in humans

2002 ◽  
Vol 93 (6) ◽  
pp. 2112-2121 ◽  
Author(s):  
Gunvor Ahlborg ◽  
Jonas Lindström
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Healthy Subjects ◽  
Receptor Blockade ◽  
Receptor Stimulation ◽  
Renal Vasoconstriction ◽  
Arterial Blood ◽  
Etb Receptor

Cardiovascular diseases are characterized by insulin resistance and elevated endothelin (ET)-1 levels. Furthermore, ET-1 induces insulin resistance. To elucidate this mechanism, six healthy subjects were studied during a hyperinsulinemic euglycemic clamp during infusion of (the ET-1 precursor) big ET-1 alone or after ETA- or ETB-receptor blockade. Insulin levels rose after big ET-1 with or without the ETB antagonist BQ-788 ( P < 0.05) but were unchanged after the ETA antagonist BQ-123 + big ET-1. Infused glucose divided by insulin fell after big ET-1 with or without BQ-788 ( P < 0.05). Insulin and infused glucose divided by insulin values were normalized by ETA blockade. Mean arterial blood pressure rose during big ET-1 with or without BQ-788 ( P < 0.001) but was unchanged after BQ-123. Skeletal muscle, splanchnic, and renal blood flow responses to big ET-1 were abolished by BQ-123. ET-1 levels rose after big ET-1 ( P< 0.01) in a similar way after BQ-123 or BQ-788, despite higher elimination capacity after ETA blockade. In conclusion, ET-1-induced reduction in insulin sensitivity and clearance as well as splanchnic and renal vasoconstriction are ETA mediated. ETA-receptor stimulation seems to inhibit the conversion of big ET-1 to ET-1.

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