scholarly journals Insulin Action, Glucose Homeostasis and Free Fatty Acid Metabolism: Insights From a Novel Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Darko Stefanovski ◽  
Naresh M. Punjabi ◽  
Raymond C. Boston ◽  
Richard M. Watanabe
Keyword(s):  
Insulin Sensitivity ◽  
Glucose Homeostasis ◽  
Insulin Action ◽  
Glucose Disposal ◽  
Parameter Estimates ◽  
Standardized Residuals ◽  
Standard Deviation Range ◽  
Free Fatty Acid Metabolism ◽  
Ffa Metabolism ◽  
Novel Model

Glucose and free fatty acids (FFA) are essential nutrients that are both partly regulated by insulin. Impaired insulin secretion and insulin resistance are hallmarks of aberrant glucose disposal, and type 2 diabetes (T2DM). In the current study, a novel model of FFA kinetics is proposed to estimate the role insulin action on FFA lipolysis and oxidation allowing estimation of adipose tissue insulin sensitivity (SIFFA). Twenty-five normal volunteers were recruited for the current study. To participate, volunteers had to be less than 40 years of age and have a body mass index (BMI) < 30 kg/m2, and be free of medical comorbidity. The proposed model of FFA kinetics was used to analyze the data derived from the insulin-modified FSIGT. Mean fractional standard deviations of the parameter estimates were all less than 20%. Standardized residuals of the fit of the model to the FFA temporal data were randomly distributed, with only one estimated point lying outside the 2-standard deviation range, suggesting an acceptable fit of the model to the FFA data. The current study describes a novel one-compartment non-linear model of FFA kinetics during an FSIGT that provides an FFA metabolism insulin sensitivity parameter (SIFFA). Furthermore, the models suggest a new role of glucose as the modulator of FFA disposal. Estimates of SIFFA confirmed previous findings that FFA metabolism is more sensitive to changes in insulin than glucose metabolism. Novel derived indices of insulin sensitivity of FFA (SIFFA) were correlated with minimal model indices. These associations suggest a cooperative rather than competitive interplay between the two primary nutrients (glucose and FFA) and allude to the FFA acting as the buffer, such that glucose homeostasis is maintained.

scholarly journals Glucocorticoids and Insulin Sensitivity: Dissociation of Insulin’s Metabolic and Vascular Actions

2003 ◽  
Vol 88 (12) ◽  
pp. 6008-6014 ◽  
Author(s):  
C. G. Perry ◽  
A. Spiers ◽  
S. J. Cleland ◽  
G. D. O. Lowe ◽  
J. R. Petrie ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Insulin Action ◽  
Random Order ◽  
Glucose Disposal ◽  
High Dose ◽  
Euglycemic Hyperinsulinemic Clamp ◽  
Double Blind ◽  
High Dose Dexamethasone ◽  
Short Term Exposure ◽  
Healthy Males

Abstract Insulin sensitivity in tissues such as a skeletal muscle and fat is closely correlated with insulin action in the vasculature, but the mechanism underlying this is unclear. We investigated the effect of dexamethasone on insulin-stimulated glucose disposal and vasodilation in healthy males to test the hypothesis that a reduction in glucose disposal would be accompanied by a reduction in insulin action in the vasculature. We performed a double-blind, placebo-controlled, cross-over trial comparing insulin sensitivity (measured by the euglycemic hyperinsulinemic clamp) and vascular insulin action (measured by small vessel wire myography) in young healthy males allocated to placebo or 1 mg dexamethasone twice daily for 6 d, each in random order. Six days of dexamethasone therapy was associated with a 30% (95% confidence interval, 19.1–40.0%) fall in insulin sensitivity. Despite this, there was no difference in insulin-mediated vasodilation between phases. Dexamethasone had no effect on circulating markers of endothelial function, such as d-dimer, von Willebrand factor, and tissue plasminogen activator. By short-term exposure to high dose dexamethasone we were able to differentially affect the metabolic and vascular actions of insulin. This implies that, using this model, there is physiological uncoupling of the effects of insulin in different tissues.

scholarly journals Loss of PDGF-B activity increases hepatic vascular permeability and enhances insulin sensitivity

2011 ◽  
Vol 301 (3) ◽  
pp. E517-E526 ◽  
Author(s):  
Summer M. Raines ◽  
Oliver C. Richards ◽  
Lindsay R. Schneider ◽  
Kathryn L. Schueler ◽  
Mary E. Rabaglia ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Insulin Signaling ◽  
Insulin Action ◽  
Basolateral Membrane ◽  
Tolerance Test ◽  
Whole Body ◽  
Glucose Disposal ◽  
Permeability Barrier ◽  
Loss Of Function ◽  
Transendothelial Transport

Hepatic vasculature is not thought to pose a permeability barrier for diffusion of macromolecules from the bloodstream to hepatocytes. In contrast, in extrahepatic tissues, the microvasculature is critically important for insulin action, because transport of insulin across the endothelial cell layer is rate limiting for insulin-stimulated glucose disposal. However, very little is known concerning the role in this process of pericytes, the mural cells lining the basolateral membrane of endothelial cells. PDGF-B is a growth factor involved in the recruitment and function of pericytes. We studied insulin action in mice expressing PDGF-B lacking the proteoglycan binding domain, producing a protein with a partial loss of function (PDGF-B ret/ ret). Insulin action was assessed through measurements of insulin signaling and insulin and glucose tolerance tests. PDGF-B deficiency enhanced hepatic vascular transendothelial transport. One outcome of this change was an increase in hepatic insulin signaling. This correlated with enhanced whole body glucose homeostasis and increased insulin clearance from the circulation during an insulin tolerance test. In obese mice, PDGF-B deficiency was associated with an 80% reduction in fasting insulin and drastically reduced insulin secretion. These mice did not have significantly higher glucose levels, reflecting a dramatic increase in insulin action. Our findings show that, despite already having a high permeability, hepatic transendothelial transport can be further enhanced. To the best of our knowledge, this is the first study to connect PDGF-B-induced changes in hepatic sinusoidal transport to changes in insulin action, demonstrating a link between PDGF-B signaling and insulin sensitivity.

scholarly journals Novel Indices of Glucose Homeostasis Derived from Principal Component Analysis: Application for Metabolic Assessment in Pregnancy

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Tina Stopp ◽  
Michael Feichtinger ◽  
Ingo Rosicky ◽  
Gülen Yerlikaya-Schatten ◽  
Johannes Ott ◽  
...  
Keyword(s):  
Principal Component Analysis ◽  
Insulin Sensitivity ◽  
Glucose Homeostasis ◽  
Insulin Action ◽  
Cell Function ◽  
Principal Component ◽  
Component Analysis ◽  
Oral Glucose ◽  
Prospective Longitudinal Study ◽  
Prospective Longitudinal

Aims. This study is aimed at assessing the association of previously developed indices of glucose homeostasis derived from principal component analysis (PCA) with parameters of insulin action, secretion, and beta cell function during pregnancy. Methods. In this prospective longitudinal study, an oral glucose tolerance test was performed in sixty-seven pregnant women at two prepartum (12+0 to 22+6 and 24+0 to 28+6) and one postpartum (2 to 11 months) visits. Three principal component scores (PCS) were calculated based on measurements of glucose, insulin, C-peptide, age, and BMI to assess their association with fasting and dynamic indices of insulin action, secretion, and β-cell function. Results. PCS1 was positively associated with fasting and dynamic parameters of insulin sensitivity (Matsuda index: r=0.93, p<0.001), whereas a strong negative association was observed for early, late, and total insulin response. PCS2 was associated with higher mean glucose but negatively related to parameters of insulin secretion. PCS3 was significantly associated with fasting indices of insulin sensitivity. PCS1 to 3 assessed at early pregnancy were also associated with development of GDM, whereby random forest analysis revealed the highest variable importance for PCS1. PCS1 to 3 were significantly related to the oral disposition index explaining 49.0% of its variance. Conclusions. PCS1 to 3 behaved similarly as compared to previous observations in nonpregnant women and were furthermore associated with the development of GDM. These findings support our hypothesis that PCS1 to 3 could be used as novel indices of glucose disposal during pregnancy.

Glucose disposal by insulin, but not IGF-1, is dependent on the hepatic parasympathetic nerves

2000 ◽  
Vol 78 (10) ◽  
pp. 807-812 ◽  
Author(s):  
Parissa Sadri ◽  
W Wayne Lautt
Keyword(s):  
Skeletal Muscle ◽  
Liver Disease ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Insulin Action ◽  
Glucose Disposal ◽  
Surgical Ablation ◽  
Insulin Resistant ◽  
Parasympathetic Nerves ◽  
Stimulation Of

Insulin-like growth factor-1 (IGF-1) has many insulin-like activities, including stimulation of glucose uptake in skeletal muscle. However, those with diabetes or chronic liver disease are insulin resistant but show a normal hypoglycemic response to IGF-1. We have previously shown that insulin sensitivity depends on a hepatic parasympathetic reflex release of a hormone from the liver. The hypothesis was tested that insulin action, but not IGF-1 action, is dependent on the hepatic parasympathetic reflex. Glucose disposal in response to three doses of IGF-1 (25, 100, 200 µg/kg) was determined in rats. IGF-1 at 200 µg/kg had similar effect on glucose disposal as did 50 mU/kg of insulin. Interruption of the hepatic parasympathetic reflex either by surgical ablation of the anterior nerve plexus or by atropine (1.0 mg/kg) resulted in insulin, but not IGF-1, resistance. Sixteen hours of fasting resulted in insulin, but not IGF-1, resistance. In conclusion, insulin, but not IGF-1, triggers the hepatic parasympathetic dependent release of a putative hepatic insulin sensitizing substance (HISS) that stimulates glucose uptake in skeletal muscle.Key words: HISS, RIST, atropine, insulin sensitivity, fasting.

Antisense oligonucleotides against the lipid phosphatase SHIP2 improve muscle insulin sensitivity in a dietary rat model of the metabolic syndrome

2007 ◽  
Vol 292 (6) ◽  
pp. E1871-E1878 ◽  
Author(s):  
Roland Buettner ◽  
Iris Ottinger ◽  
Christiane Gerhardt-Salbert ◽  
Christian E. Wrede ◽  
Jürgen Schölmerich ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Insulin Sensitivity ◽  
Protein Content ◽  
Insulin Action ◽  
Whole Body ◽  
Glucose Disposal ◽  
Standard Diet ◽  
The Metabolic Syndrome ◽  
Lipid Phosphatase

The lipid phosphatase SH2 domain-containing lipid phosphatase (SHIP2) has been implicated in the regulation of insulin sensitivity, but its role in the therapy of insulin-resistant states remains to be defined. Here, we examined the effects of an antisense oligonucleotide (AS) therapy directed against SHIP2 on whole body insulin sensitivity and insulin action in liver and muscle tissue in a dietary rodent model of the metabolic syndrome, the high-fat-fed (HF) rat. Whole body insulin sensitivity was examined in vivo by insulin tolerance tests before and after the intraperitoneal application of an AS directed against SHIP2 (HF-SHIP2-AS) or a control AS (HF-Con-AS) in HF rats. Insulin action in liver and muscle was assayed by measuring the activation of protein kinase B (Akt) and insulin receptor substrate (IRS)-1/2 after a portal venous insulin bolus. SHIP2 mRNA and protein content were quantified in these tissues by real-time PCR and immunoblotting, respectively. In HF-SHIP2-AS, whole body glucose disposal after an insulin bolus was markedly elevated compared with HF-Con-AS. In liver, insulin activated Akt similarly in both groups. In muscle, insulin did not clearly activate Akt in HF-Con-AS animals, whereas insulin-induced Akt phosphorylation was sustained in SHIP2-AS-treated rats. IRS-1/2 activation did not differ between the experimental groups. SHIP2 mRNA and protein content were markedly reduced only in muscle. In standard diet-fed controls, SHIP2-AS reduced SHIP2 protein levels in liver and muscle, but it had no significant effect on insulin sensitivity. We conclude that treatment with SHIP2-AS can rapidly improve muscle insulin sensitivity in dietary insulin resistance. The long-term feasability of such a strategy should be examined further.

scholarly journals Delivery of adiponectin gene to skeletal muscle using ultrasound targeted microbubbles improves insulin sensitivity and whole body glucose homeostasis

2013 ◽  
Vol 304 (2) ◽  
pp. E168-E175 ◽  
Author(s):  
Vivian Vu ◽  
Ying Liu ◽  
Sanjana Sen ◽  
Aimin Xu ◽  
Gary Sweeney
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Homeostasis ◽  
Fluorescent Protein ◽  
Systemic Circulation ◽  
Tolerance Test ◽  
Whole Body ◽  
Glucose Disposal ◽  
Adiponectin Gene ◽  
Green Fluorescent

Numerous studies have shown that adiponectin confers antidiabetic effects via both insulin-like and insulin-sensitizing actions. The majority of adiponectin in circulation is derived from adipocytes; however, other tissues such as skeletal muscle can produce adiponectin. This study was designed to investigate the functional significance of adiponectin produced by skeletal muscle. We encapsulated the adiponectin gene in lipid-coated microspheres filled with octafluoropropane gas that were injected into the systemic circulation and destroyed within the microvasculature of skeletal muscle using ultrasound. We first demonstrated safe and successful targeting of luciferase and green fluorescent protein reporter genes to skeletal muscle using this approach and then confirmed efficient overexpression of adiponectin mRNA and oligomeric protein forms. Glucose tolerance test indicated that overexpression of adiponectin in skeletal muscle was able to improve glucose intolerance induced by feeding mice a high-fat diet (HFD), and this correlated with improved skeletal muscle insulin signaling. We then performed hyperinsulinemic-euglycemic clamp studies and demonstrated that adiponectin overexpression attenuated the decreases in glucose infusion rate, glucose disposal, and increase in glucose appearance induced by HFD. Ultrasound-targeted microbubble destruction (UTMD) delivery of adiponectin to skeletal muscle also enhanced serum adiponectin levels and improved hepatic insulin sensitivity. In conclusion, our data show that UTMD efficiently delivers adiponectin to skeletal muscle and that this improves insulin sensitivity and glucose homeostasis.

Short-term hyperglycemia and hyperinsulinemia improve insulin action but do not alter glucose action in normal humans

1992 ◽  
Vol 262 (4) ◽  
pp. E518-E523 ◽  
Author(s):  
S. E. Kahn ◽  
R. N. Bergman ◽  
M. W. Schwartz ◽  
G. J. Taborsky ◽  
D. Porte
Keyword(s):  
Insulin Sensitivity ◽  
Basal Insulin ◽  
Insulin Action ◽  
Insulin Response ◽  
Glucose Infusion ◽  
Glucose Disposal ◽  
Second Phase ◽  
Insulin Effect ◽  
Glucose Effectiveness ◽  
Mild Hyperglycemia

Tissue glucose uptake occurs by insulin-dependent and insulin-independent mechanisms. To evaluate the effect of mild hyperglycemia and hyperinsulinemia on the parameters responsible for glucose disposal, glucose (1.17 mmol/min) or saline was infused into six healthy male subjects (age 25-38 yr, body mass index 22.1-26.3 kg/m2) for 24 h. Thereafter, while the infusion continued, indexes of insulin sensitivity (SI), glucose effectiveness at basal insulin (SG), basal insulin effect (BIE = SI x basal insulin), and glucose effectiveness at zero insulin (GEZI = SG - BIE) were measured using Bergman's minimal model of insulin action. GEZI provides a measure of the efficiency of glucose to accelerate its own disposal independent of insulin. Twenty-four hours of glucose infusion increased the basal plasma glucose (5.1 +/- 0.1 to 6.4 +/- 0.2 mM, P = 0.001) and insulin (79 +/- 8 to 174 +/- 31 pM, P less than 0.05) levels. Hyperglycemia was also associated with an increase in the insulin response, predominantly in the second-phase component (138 +/- 31 to 258 +/- 66 pM, P less than 0.05). SI (4.8 +/- 1.0 to 8.2 +/- 1.6 x 10(-5) min-1.pM-1, P less than 0.05) and SG (1.7 +/- 0.1 to 2.5 +/- 0.3 x 10(-2) min-1, P less than 0.05) both increased after glucose infusion. The increase in SG was entirely due to the combined increase in basal insulin and insulin sensitivity (BIE 0.4 +/- 0.1 to 1.2 +/- 0.1 x 10(-2) min-1, P = 0.001) since GEZI did not change at all (1.3 +/- 0.1 vs. 1.3 +/- 0.3 x 10(-2) min-1, P = not significant). From these data we conclude that, in normal subjects, the mild hyperglycemia and hyperinsulinemia occurring during a prolonged glucose infusion improves glucose disposal in the basal state by increasing insulin secretion and insulin sensitivity but does not enhance glucose effectiveness independent of insulin. Both of these changes thus tend to minimize the development of hyperglycemia.

Pattern of insulin delivery affects hepatic insulin sensitizing substance (HISS) action and insulin resistance

2004 ◽  
Vol 82 (12) ◽  
pp. 1068-1074 ◽  
Author(s):  
Maria A. G Reid ◽  
W Wayne Lautt
Keyword(s):  
Insulin Sensitivity ◽  
Insulin Action ◽  
Insulin Infusion ◽  
Insulin Delivery ◽  
Glucose Disposal ◽  
Sprague Dawley ◽  
Fed State ◽  
Significant Difference ◽  
Bolus Insulin ◽  
Continuous Insulin Infusion

Hepatic insulin sensitizing substance (HISS) action accounts for 55% of the glucose disposal effect of a bolus of insulin in the fed state. To determine the effect of continuous versus pulsatile insulin delivery on HISS action in male Sprague–Dawley rats, insulin sensitivity was assessed using the rapid insulin sensitivity test (RIST) before and after a continuous, pulsatile, or bolus insulin (60 mU/kg i.v.) delivery. There was a significant difference in the RIST index after a continuous insulin infusion (247.9 mg/kg before, 73.2 mg/kg after) but not after 3 pulses where insulin action returned to baseline between pulses (211.6 mg/kg before, 191.0 mg/kg after) or single bolus (205.8 mg/kg before, 189.9 mg/kg after) insulin infusion. If a 3-pulse infusion was timed so that insulin action did not return to baseline between pulses, HISS action was suppressed. Continuous insulin infusion (10–30 min) showed progressive postinfusion blockade of HISS action. To maintain HISS-dependent insulin action, continuous insulin infusions should be avoided.Key words: pulsatile, glucose uptake, RIST, euglycemic clamp, insulin sensitivity.

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