scholarly journals Adipokine Protein Expression Pattern in Growth Hormone Deficiency Predisposes to the Increased Fat Cell Size and the Whole Body Metabolic Derangements

2008 ◽  
Vol 93 (6) ◽  
pp. 2255-2262 ◽  
Author(s):  
Jozef Ukropec ◽  
Adela Penesová ◽  
Martina Škopková ◽  
Mikuláš Pura ◽  
Miroslav Vlček ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Growth Factor ◽  
Glucose Tolerance ◽  
Protein Expression ◽  
Expression Pattern ◽  
Insulin Action ◽  
Whole Body ◽  
Protein Expression Pattern ◽  
Chemotactic Protein

Abstract Context: GH deficiency (GHD) in adults is associated with central adiposity, dyslipidemia, and insulin resistance. Objective: The objective of the study was to test the hypothesis that GHD might change the spectrum of adipokines and thus influence the adipose tissue and the whole-body metabolic and inflammatory status leading to development of insulin resistance. Design: This was a single-center observational study with a cross-sectional design. Participants and Methods: Protein arrays were used to characterize adipokines expressed in the sc adipose tissue obtained from young GHD adults and compared with age-, gender-, and body mass index (BMI)-matched group of healthy individuals. All subjects underwent an oral glucose tolerance test, euglycemic hyperinsulinemic clamp, and magnetic resonance imaging examination. Results: Presence of abdominal obesity, enlarged adipocytes, increased circulating high-sensitivity C-reactive protein, impaired glucose tolerance, and decreased insulin action were found in GHD. Changes in adipokine protein expression due to GHD were highly dependent on the obesity phenotype. Lean GHD individuals (BMI ∼23 kg/m2) had decreased protein levels for stem cell factor and epithelial growth factor, indicating a possible defect in adipocyte differentiation and proliferation. Decrease of vascular endothelial growth factor, stromal cell-derived factor, angiopoietin-2, and brain-derived neurotrophic factor advocated for attenuated angiogenesis and neurogenesis. Presence of obesity (BMI ∼31 kg/m2) eliminated these inhibitory effects. However, adipose tissue expansion in GHD individuals was paralleled by an elevation of adipose tissue proinflammatory cytokines (IL-1β, interferon-γ) and chemoattractants (interferon-inducible T cell α-chemoattractant, monocyte chemotactic protein-2, monocyte chemotactic protein-3, eotaxin). Conclusion: Our data demonstrate that GHD modulates adipokine and cytokine protein expression pattern, which might influence the adipose tissue growth and differentiation and predispose to tissue hypoxia, inflammation, and a defect in the whole-body insulin action.

scholarly journals Mechanisms of Insulin Action and Insulin Resistance

2018 ◽  
Vol 98 (4) ◽  
pp. 2133-2223 ◽  
Author(s):  
Max C. Petersen ◽  
Gerald I. Shulman
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Insulin Action ◽  
Big Bang ◽  
Whole Body ◽  
Detailed Knowledge ◽  
Bioactive Lipids ◽  
Mechanistic Investigation ◽  
The Impact

The 1921 discovery of insulin was a Big Bang from which a vast and expanding universe of research into insulin action and resistance has issued. In the intervening century, some discoveries have matured, coalescing into solid and fertile ground for clinical application; others remain incompletely investigated and scientifically controversial. Here, we attempt to synthesize this work to guide further mechanistic investigation and to inform the development of novel therapies for type 2 diabetes (T2D). The rational development of such therapies necessitates detailed knowledge of one of the key pathophysiological processes involved in T2D: insulin resistance. Understanding insulin resistance, in turn, requires knowledge of normal insulin action. In this review, both the physiology of insulin action and the pathophysiology of insulin resistance are described, focusing on three key insulin target tissues: skeletal muscle, liver, and white adipose tissue. We aim to develop an integrated physiological perspective, placing the intricate signaling effectors that carry out the cell-autonomous response to insulin in the context of the tissue-specific functions that generate the coordinated organismal response. First, in section II, the effectors and effects of direct, cell-autonomous insulin action in muscle, liver, and white adipose tissue are reviewed, beginning at the insulin receptor and working downstream. Section III considers the critical and underappreciated role of tissue crosstalk in whole body insulin action, especially the essential interaction between adipose lipolysis and hepatic gluconeogenesis. The pathophysiology of insulin resistance is then described in section IV. Special attention is given to which signaling pathways and functions become insulin resistant in the setting of chronic overnutrition, and an alternative explanation for the phenomenon of ‟selective hepatic insulin resistanceˮ is presented. Sections V, VI, and VII critically examine the evidence for and against several putative mediators of insulin resistance. Section V reviews work linking the bioactive lipids diacylglycerol, ceramide, and acylcarnitine to insulin resistance; section VI considers the impact of nutrient stresses in the endoplasmic reticulum and mitochondria on insulin resistance; and section VII discusses non-cell autonomous factors proposed to induce insulin resistance, including inflammatory mediators, branched-chain amino acids, adipokines, and hepatokines. Finally, in section VIII, we propose an integrated model of insulin resistance that links these mediators to final common pathways of metabolite-driven gluconeogenesis and ectopic lipid accumulation.

scholarly journals Chronic renin inhibition with aliskiren improves glucose tolerance, insulin sensitivity, and skeletal muscle glucose transport activity in obese Zucker rats

2012 ◽  
Vol 302 (1) ◽  
pp. R137-R142 ◽  
Author(s):  
Elizabeth M. Marchionne ◽  
Maggie K. Diamond-Stanic ◽  
Mujalin Prasonnarong ◽  
Erik J. Henriksen
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Glucose Transport ◽  
Insulin Action ◽  
Whole Body ◽  
Zucker Rats ◽  
Obese Zucker Rats ◽  
Renin Inhibition

We have demonstrated previously that overactivity of the renin-angiotensin system (RAS) is associated with whole body and skeletal muscle insulin resistance in obese Zucker ( fa/fa) rats. Moreover, this obesity-associated insulin resistance is reduced by treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor (type 1) blockers. However, it is currently unknown whether specific inhibition of renin itself, the rate-limiting step in RAS functionality, improves insulin action in obesity-associated insulin resistance. Therefore, the present study assessed the effect of chronic, selective renin inhibition using aliskiren on glucose tolerance, whole body insulin sensitivity, and insulin action on the glucose transport system in skeletal muscle of obese Zucker rats. Obese Zucker rats were treated for 21 days with either vehicle or aliskiren (50 mg/kg body wt ip). Renin inhibition was associated with a significant lowering (10%, P < 0.05) of resting systolic blood pressure and induced reductions in fasting plasma glucose (11%) and free fatty acids (46%) and homeostatic model assessment for insulin resistance (13%). Glucose tolerance (glucose area under the curve) and whole body insulin sensitivity (inverse of the glucose-insulin index) during an oral glucose tolerance test were improved by 15% and 16%, respectively, following chronic renin inhibition. Moreover, insulin-stimulated glucose transport activity in isolated soleus muscle of renin inhibitor-treated animals was increased by 36% and was associated with a 2.2-fold greater Akt Ser473 phosphorylation. These data provide evidence that chronic selective inhibition of renin activity leads to improvements in glucose tolerance and whole body insulin sensitivity in the insulin-resistant obese Zucker rat. Importantly, chronic renin inhibition is associated with upregulation of insulin action on skeletal muscle glucose transport, and it may involve improved Akt signaling. These data support the strategy of targeting the RAS to improve both blood pressure regulation and insulin action in conditions of insulin resistance.

scholarly journals Central insulin‐like growth factor‐1 ( IGF ‐1) restores whole‐body insulin action in a model of age‐related insulin resistance and IGF ‐1 decline

Aging Cell ◽  
2015 ◽  
Vol 15 (1) ◽  
pp. 181-186 ◽  
Author(s):  
Derek M. Huffman ◽  
Gabriela Farias Quipildor ◽  
Kai Mao ◽  
Xueying Zhang ◽  
Junxiang Wan ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Growth Factor ◽  
Insulin Action ◽  
Whole Body ◽  
Insulin Like Growth Factor ◽  
Age Related

Abstract T P114: Insulin Resistance in Skeletal Muscle of Chronic Stroke

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Alice S Ryan ◽  
Heidi Ortmeyer ◽  
Frederick Ivey ◽  
Charlene Hafer-Macko
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Insulin Action ◽  
Glycogen Synthase ◽  
Chronic Stroke ◽  
Whole Body ◽  
Wide Range

Risk of glucose intolerance and diabetes increases in chronic stroke. The purpose of this study was to assess insulin sensitivity and glycogen synthase (GS), a known benchmark index of insulin action in skeletal muscle, and to compare the activity of this important regulatory enzyme between paretic (P) and non-paretic (NP) skeletal muscle in chronic stroke. We measured insulin sensitivity (M) and bilateral GS fractional activity (ratio of independent to total activity), in lyophilized microdissected muscle samples obtained after an overnight fast and 2 hrs into a 3-hr 80 mU . m -2. min -1 hyperinsulinemic-euglycemic clamp in 21 stroke survivors (n=15 men, n=6 women) (age: 59±2 yrs, BMI: 31±2 kg/m 2 , X±SEM). All had hemiparetic gait after ischemic stroke (>6 months), low aerobic capacity (VO 2 peak, 19.7±1.3 ml/kg/min), and wide range of %body fat (11-48%). Leg lean mass was lower in P than NP (9.3±0.5 vs. 10.0±0.5 kg, P<0.001). Subjects had either normal glucose tolerance (n=7), impaired glucose tolerance (n=7), or diabetes (n=7) and insulin resistance (M: 38.5±2.6 umol/kgFFM/min). Insulin robustly increased GS fractional activity (basal vs. insulin) in P (2.8±0.4 vs.7.5±0.8%, P<0.00001) and NP (2.7±0.4 vs. 9.1±1.1%, P<0.00001) muscle. The %change was greater in NP than P (213±32 vs. 296±36%, P=0.04). The effect of in vivo insulin to increase GS fractional activity was associated with M in P and NP muscle (r=0.59 and r=0.49, P<0.05). In conclusion, muscle atrophy and a reduction in insulin action in paretic muscle likely contribute to whole body insulin resistance in chronic stroke.

Retinol-binding protein 4 is associated with impaired glucose tolerance but not with whole body or hepatic insulin resistance in Mexican Americans

2009 ◽  
Vol 296 (4) ◽  
pp. E758-E764 ◽  
Author(s):  
Alberto O. Chavez ◽  
Dawn K. Coletta ◽  
Subhash Kamath ◽  
Douglas T. Cromack ◽  
Adriana Monroy ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Mexican Americans ◽  
Hepatic Glucose Production ◽  
Retinol Binding Protein ◽  
Hepatic Insulin Resistance ◽  
Whole Body

Retinol-binding protein-4 (RBP4), a novel protein secreted mainly by adipose tissue, has been associated with insulin resistance in obese subjects and in individuals with type 2 diabetes mellitus (T2DM). We examined the relationship between plasma RBP4 levels, expression of RBP4 in skeletal muscle and adipose tissue, and insulin sensitivity in Mexican Americans with varying degrees of obesity and glucose tolerance. Seventy-two subjects [16 lean normal-glucose-tolerant (NGT), 17 obese NGT, and 39 subjects with impaired fasting glucose/impaired glucose tolerance/T2DM] received an oral glucose tolerance test (OGTT) and euglycemic-hyperinsulinemic clamp. Insulin secretion was measured as insulinogenic index during OGTT. In a subset of subjects, hepatic glucose production was measured by 3-[3H]glucose infusion, biopsies of the vastus lateralis muscle and subcutaneous adipose tissue were obtained under basal conditions, and quantitative RT-PCR was performed to measure the RBP4 mRNA gene expression. Plasma RBP4 was significantly elevated in impaired glucose tolerance/T2DM compared with NGT lean or obese subjects. Plasma RBP4 levels correlated with 2-h glucose, triglycerides, and hemoglobin A1c. There was no association between RBP4 levels and whole body insulin sensitivity measured with either the euglycemic insulin clamp or OGTT, basal hepatic glucose production rates, and the hepatic insulin resistance index. There was no correlation between plasma RBP4 levels and indexes of insulin secretion. RBP4 mRNA expression in skeletal muscle was similar in lean NGT subjects, obese NGT subjects, and T2DM subjects. There was no difference in RBP4 mRNA expression in adipose tissue between lean and obese NGT subjects or between NGT and T2DM individuals. Plasma RBP4 levels are elevated in T2DM and associated with impaired glucose tolerance, but not associated with obesity or insulin resistance or impaired insulin secretion in Mexican Americans.

Prevalence and features of impaired glucose tolerance in young underweight Japanese women

2021 ◽  
Author(s):  
Motonori Sato ◽  
Yoshifumi Tamura ◽  
Takashi Nakagata ◽  
Yuki Someya ◽  
Hideyoshi Kaga ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Japanese Women ◽  
Normal Weight ◽  
Whole Body ◽  
Insulinogenic Index ◽  
Matsuda Index ◽  
Young Japanese Women

Abstract Objective In Japan, while it is known that underweight women over the age 40 years have a high risk for type 2 diabetes, there is a lack of clarity on the association between glucose tolerance and underweight in younger women. Accordingly, we aimed to investigate the prevalence and features of impaired glucose tolerance (IGT) in young Japanese underweight women. Designs and Methods In this cross-sectional study, we recruited 56 normal weight and 98 underweight young Japanese women and evaluated their glucose tolerance levels using an oral glucose tolerance test. Then, we compared the clinical characteristics associated with normal glucose tolerance (NGT) and IGT in the underweight women. Insulin secretion, whole-body insulin sensitivity, and adipose tissue insulin resistance values were measured using the insulinogenic index, whole-body insulin sensitivity index (Matsuda index), and adipose insulin resistance index (Adipo-IR), respectively. Fitness level (peak VO2) was measured using an ergometer. Results The prevalence of IGT was higher in the underweight women than the normal weight women (13.3% vs 1.8%). The underweight women with IGT showed a lower insulinogenic index, lower peak VO2 and Matsuda index, and a higher fasting free fatty acid level and Adipo-IR than those with NGT. The whole-body composition was comparable between the NGT and IGT groups. Conclusions The prevalence of IGT was higher in young Japanese women with underweight than those with a normal weight. The underweight women with IGT showed impaired early-phase insulin secretion, low fitness levels, and reduced whole-body and adipose tissue insulin sensitivity levels.

Tissue-specific expression and regulation of GSK-3 in human skeletal muscle and adipose tissue

2006 ◽  
Vol 291 (5) ◽  
pp. E891-E898 ◽  
Author(s):  
Theodore P. Ciaraldi ◽  
Deborah K. Oh ◽  
Louis Christiansen ◽  
Svetlana E. Nikoulina ◽  
Alice P. S. Kong ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Protein Expression ◽  
Insulin Action ◽  
Glycogen Synthase ◽  
Serine Phosphorylation ◽  
Whole Body ◽  
Glucose Disposal ◽  
Specific Expression ◽  
Gsk 3Β

Glycogen synthase kinase-3 (GSK-3) is a ubiquitous kinase implicated in both insulin action and adipogenesis. To determine how these multiple roles may relate to insulin resistance, we studied the regulation of GSK-3 protein expression and phosphorylation in skeletal muscle and isolated adipocytes from nonobese healthy control (HC), obese control (OC), and obese type 2 diabetic (OT2D) subjects. At baseline there were no differences in the GSK-3 protein expression in adipocytes. OC subjects underwent a 6-mo caloric restriction resulting in a 7% decrease in body mass index (BMI) and a 21% improvement in insulin-stimulated whole body glucose disposal rate (GDR). GSK-3α and GSK-3β expression decreased in adipocytes ( P < 0.05), whereas GSK-3α protein expression increased in skeletal muscle ( P < 0.05). OT2D subjects were treated with troglitazone or metformin for 3–4 mo. After troglitazone treatment GDR improved ( P < 0.05) despite an increase in BMI ( P < 0.05), whereas metformin had no significant effect on GDR. There was no significant change in GSK-3 expression in adipocytes following troglitazone, whereas both GSK-3α and -β were decreased in skeletal muscle ( P < 0.05). Metformin treatment had no significant impact on GSK-3 protein expression in either adipocytes or skeletal muscle. Neither treatment influenced GSK-3 serine phosphorylation in skeletal muscle or adipocytes. These results suggest that there is tissue specificity for the regulation of GSK-3 in humans. In skeletal muscle GSK-3 plays a role in control of metabolism and insulin action, whereas the function in adipose tissue is less clear.

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