scholarly journals Adipocyte JAK2 Mediates Growth Hormone-Induced Hepatic Insulin Resistance

2016 ◽  
Author(s):  
Kevin C. Corbit ◽  
João Paulo G. Camporez ◽  
Jennifer L. Tran ◽  
Camella G. Wilson ◽  
Dylan Lowe ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Growth Hormone ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Homeostasis ◽  
Metabolic Stress ◽  
Hepatic Insulin Resistance ◽  
Whole Body ◽  
Insulin Signal Transduction ◽  
Conditional Deletion

ABSTRACTFor nearly 100 years, Growth Hormone (GH) has been known to impact insulin sensitivity and risk of diabetes. However, the tissue governing the effects of GH signaling on insulin and glucose homeostasis remains unknown. Excess GH reduces fat mass and insulin sensitivity. Conversely, GH insensitivity (GHI) is associated with increased adiposity, augmented insulin sensitivity, and protection from diabetes. Here we induce adipocyte-specific GHI through conditional deletion of Jak2 (JAK2A), an obligate transducer of GH signaling. Similar to whole-body GHI, JAK2A mice had increased adiposity and extreme insulin sensitivity. Loss of adipocyte Jak2 augmented hepatic insulin sensitivity and conferred resistance to diet-induced metabolic stress without overt changes in circulating fatty acids. While GH injections induced hepatic insulin resistance in control mice, the diabetogenic action was absent in JAK2A mice. Adipocyte GH signaling directly impinged on both adipose and hepatic insulin signal transduction. Collectively, our results show that adipose tissue governs the effects of GH on insulin and glucose homeostasis. Further, we show that JAK2 mediates liver insulin sensitivity via an extra-hepatic, adipose tissue-dependent mechanism.

Abdominal obesity in BTBR male mice is associated with peripheral but not hepatic insulin resistance

2007 ◽  
Vol 292 (3) ◽  
pp. E936-E945 ◽  
Author(s):  
Jessica B. Flowers ◽  
Angie T. Oler ◽  
Samuel T. Nadler ◽  
YounJeong Choi ◽  
Kathryn L. Schueler ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Genetic Difference ◽  
Inbred Mouse ◽  
Hepatic Insulin Resistance ◽  
Whole Body ◽  
Glucose Disposal ◽  
Mouse Strains ◽  
Chow Diet

Insulin resistance is a common feature of obesity. BTBR mice have more fat mass than most other inbred mouse strains. On a chow diet, BTBR mice have elevated insulin levels relative to the C57BL/6J (B6) strain. Male F1 progeny of a B6 × BTBR cross are insulin resistant. Previously, we reported insulin resistance in isolated muscle and in isolated adipocytes in this strain. Whereas the muscle insulin resistance was observed only in male F1 mice, adipocyte insulin resistance was also present in male BTBR mice. We examined in vivo mechanisms of insulin resistance with the hyperinsulinemic euglycemic clamp technique. At 10 wk of age, BTBR and F1 mice had a >30% reduction in whole body glucose disposal primarily due to insulin resistance in heart, soleus muscle, and adipose tissue. The increased adipose tissue mass and decreased muscle mass in BTBR and F1 mice were negatively and positively correlated with whole body glucose disposal, respectively. Genes involved in focal adhesion, actin cytoskeleton, and inflammation were more highly expressed in BTBR and F1 than in B6 adipose tissue. The BTBR and F1 mice have higher levels of testosterone, which may be related to the pathological changes in adipose tissue that lead to systemic insulin resistance. Despite profound peripheral insulin resistance, BTBR and F1 mice retained hepatic insulin sensitivity. These studies reveal a genetic difference in body composition that correlates with large differences in peripheral insulin sensitivity.

scholarly journals Role of patatin-like phospholipase domain-containing 3 gene for hepatic lipid content and insulin resistance in diabetes

2020 ◽  
Author(s):  
Oana P. Zaharia ◽  
Klaus Strassburger ◽  
Birgit Knebel ◽  
Yuliya Kupriyanova ◽  
Yanislava Karusheva ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Lipid Content ◽  
Whole Body ◽  
Hepatic Lipid ◽  
Insulin Resistant ◽  
Increased Risk ◽  
Glucose Tolerant ◽  
Hepatic Lipid Content

<a><b>Objective</b></a>: The rs738409(G) single-nucleotide polymorphism (SNP) in the patatin-like phospholipase domain-containing 3 (<i>PNPLA3</i>) gene associates with increased risk and progression of nonalcoholic fatty liver disease (NAFLD). As the recently-described severe insulin-resistant diabetes (SIRD) cluster specifically relates to NAFLD, this study examined whether this SNP differently associates with hepatic lipid content (HCL) and insulin sensitivity in recent-onset diabetes mellitus. <p><b>Research Design and Methods</b>: A total of 917 participants of the German Diabetes Study underwent genotyping, hyperinsulinemic-euglycemic clamps with stable isotopic tracer dilution and magnetic resonance spectroscopy. </p> <p><b>Results:</b> The G allele associated positively with HCL (β=0.36, p<0.01), independent of age, sex and BMI across the whole cohort, but not in the individual clusters. SIRD exhibited lowest whole-body insulin sensitivity compared to severe insulin-deficient (SIDD), moderate obesity-related (MOD), moderate age-related (MARD) and severe autoimmune diabetes clusters (SAID; all p<0.001). Interestingly, SIRD presented with higher prevalence of the rs738409(G) SNP compared to other clusters and the glucose-tolerant control group (p<0.05). HCL was higher in SIRD [13.6 (5.8;19.1)%] compared to MOD [6.4 (2.1;12.4)%, p<0.05], MARD [3.0 (1.0;7.9)%, p<0.001], SAID [0.4 (0.0;1.5)%, p<0.001] and the glucose tolerant group [0.9 (0.4;4.9)%, p<0.001]. Although the <i>PNPLA3</i> polymorphism did not directly associate with whole-body insulin sensitivity in SIRD, the G allele carriers had higher circulating free fatty acid concentrations and greater adipose-tissue insulin resistance compared to non-carriers (both p<0.001).</p> <b>Conclusions:</b> Members of the severe insulin resistant diabetes cluster are more frequently carriers of the rs738409(G) variant. The SNP-associated adipose-tissue insulin resistance and excessive lipolysis may contribute to their NAFLD.

scholarly journals Growth hormone receptor antagonism with pegvisomant in insulin resistant non-diabetic men: A phase II pilot study

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 614 ◽  
Author(s):  
Ada P. Lee ◽  
Kathleen Mulligan ◽  
Morris Schambelan ◽  
Elizabeth J. Murphy ◽  
Ethan J. Weiss
Keyword(s):  
Insulin Resistance ◽  
Growth Hormone ◽  
Insulin Sensitivity ◽  
Pilot Study ◽  
Glucose Metabolism ◽  
Phase Ii ◽  
Whole Body ◽  
Sensitivity Index ◽  
Insulin Resistant ◽  
Gh Receptor

Background: Growth hormone (GH) is known to affect insulin and glucose metabolism.  Blocking its effects in acromegalic patients improves diabetes and glucose metabolism. We aimed to determine the effect of pegvisomant, a GH receptor antagonist, on insulin resistance, endogenous glucose production (EGP) and lipolysis in insulin resistant non-diabetic men.  Methods: Four men between the ages of 18-62 with a BMI of 18-35kg/m2, with insulin resistance as defined by a HOMA-IR > 2.77, were treated for four weeks with pegvisomant 20 mg daily.  Inpatient metabolic assessments were performed before and after treatment. The main outcome measurements were: change after pegvisomant therapy in insulin sensitivity as measured by hyperinsulinemic euglycemic clamp; and EGP and lipolysis assessed by stable isotope tracer techniques. Results: Insulin like growth factor-1 (IGF-1) concentrations decreased from 134.0 ± 41.5 (mean ± SD) to 72.0 ± 11.7 ng/mL (p = 0.04) after 4 weeks of therapy. Whole body insulin sensitivity index (M/I 3.2 ± 1.3 vs. 3.4 ± 2.4; P = 0.82), as well as suppression of EGP (89.7 ± 26.9 vs. 83.5 ± 21.6%; p = 0.10) and Ra glycerol (59.4 ± 22.1% vs. 61.2 ± 14.4%; p = 0.67) during the clamp were not changed significantly with pegvisomant treatment. Conclusions: Blockade of the GH receptor with pegvisomant for four weeks had no significant effect on insulin/glucose metabolism in a small phase II pilot study of non-diabetic insulin resistant participants without acromegaly.

Investigation of insulin resistance through a multiorgan microfluidic organ-on-chip

2021 ◽  
Author(s):  
Nida Tanataweethum ◽  
Allyson Trang ◽  
Chaeeun Lee ◽  
Jhalak Mehta ◽  
Neha Patel ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Lipid Synthesis ◽  
Hepatic Insulin Resistance ◽  
Insulin Resistant ◽  
Brown Adipose ◽  
Hepatic Glucose ◽  
On Chip ◽  
Adipose Organ

Abstract The development of hepatic insulin resistance (IR) is a critical factor in developing type 2 diabetes (T2D), where insulin fails to inhibit hepatic glucose production but retains its capacity to promote hepatic lipogenesis. Improving insulin sensitivity can be effective in preventing and treating T2D. However, selective control of glucose and lipid synthesis has been difficult. It is known that excess white adipose tissue is detrimental to insulin sensitivity, whereas brown adipose tissue transplantation can restore it in diabetic mice. However, challenges remain in our understanding of liver-adipose communication because the confounding effects of hypothalamic regulation of metabolic function cannot be ruled out in previous studies. There is a lack of in vitro models that use primary cells to study cellular-crosstalk under insulin resistant conditions. Building upon our previous work on the microfluidic primary liver and adipose organ-on-chips, we report for the first time the development of integrated insulin resistant liver-adipose (white and brown) organ-on-chip. The design of the microfluidic device was carried out using computational fluid dynamics; the experimental studies were conducted by carrying out detailed biochemical analysis RNA-seq analysis on both cell types. Further, we tested the hypothesis that brown adipocytes regulated both hepatic insulin sensitivity and lipogenesis. Our results show effective co-modulation of hepatic glucose and lipid synthesis through a platform for identifying potential therapeutics for IR and diabetes.

scholarly journals Early postnatal oestradiol exposure causes insulin resistance and signs of inflammation in circulation and skeletal muscle

2009 ◽  
Vol 201 (1) ◽  
pp. 49-58 ◽  
Author(s):  
Camilla Alexanderson ◽  
Elias Eriksson ◽  
Elisabet Stener-Victorin ◽  
Malin Lönn ◽  
Agneta Holmäng
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Uncoupling Protein ◽  
Female Rats ◽  
Whole Body ◽  
Low Grade ◽  
Expression Of Genes ◽  
Genes Encoding

Early postnatal events can predispose to metabolic and endocrine disease in adulthood. In this study, we evaluated the programming effects of a single early postnatal oestradiol injection on insulin sensitivity in adult female rats. We also assessed the expression of genes involved in inflammation and glucose metabolism in skeletal muscle and adipose tissue and analysed circulating inflammation markers as possible mediators of insulin resistance. Neonatal oestradiol exposure reduced insulin sensitivity and increased plasma levels of monocyte chemoattractant protein-1 (MCP-1) and soluble intercellular adhesion molecule-1. In skeletal muscle, oestradiol increased the expression of genes encoding complement component 3 (C3), Mcp-1, retinol binding protein-4 (Rbp4) and transforming growth factor β1 (Tgfβ1). C3 and MCP-1 are both related to insulin resistance, and C3, MCP-1 and TGFβ1 are also involved in inflammation. Expression of genes encoding glucose transporter-4 (Glut 4), carnitine-palmitoyl transferase 1b (Cpt1b), peroxisome proliferator-activated receptor δ (Ppard) and uncoupling protein 3 (Ucp3), which are connected to glucose uptake, lipid oxidation, and energy uncoupling, was down regulated. Expression of several inflammatory genes in skeletal muscle correlated negatively with whole-body insulin sensitivity. In s.c. inguinal adipose tissue, expression of Tgfβ1, Ppard and C3 was decreased, while expression of Rbp4 and Cpt1b was increased. Inguinal adipose tissue weight was increased but adipocyte size was unaltered, suggesting an increased number of adipocytes. We suggest that early neonatal oestrogen exposure may reduce insulin sensitivity by inducing chronic, low-grade systemic and skeletal muscle inflammation and disturbances of glucose and lipid metabolism in skeletal muscle in adulthood.

scholarly journals Growth Hormone Treatment in Adolescent Males with Idiopathic Short Stature: Changes in Body Composition, Protein, Fat, and Glucose Metabolism

2007 ◽  
Vol 92 (8) ◽  
pp. 3033-3039 ◽  
Author(s):  
Tamara S. Hannon ◽  
Kapriel Danadian ◽  
Chittiwat Suprasongsin ◽  
Silva A. Arslanian
Keyword(s):  
Insulin Resistance ◽  
Body Composition ◽  
Insulin Sensitivity ◽  
Short Stature ◽  
Academic Medical Center ◽  
Idiopathic Short Stature ◽  
Adolescent Males ◽  
Hepatic Insulin Resistance ◽  
Whole Body ◽  
Insulin Levels

Abstract Context: Cross-sectional observations show an inverse relationship between pubertal increase in GH and insulin sensitivity, suggesting that pubertal insulin resistance may be mediated by GH. Objective: Our objective was to assess longitudinally the effects of short-term GH supplementation in adolescent males with non-GH-deficient idiopathic short stature (ISS) on body composition, substrate metabolism, and insulin sensitivity. Children with ISS were studied to simulate the pubertal increase in GH secretion. Participants and Setting: Eight males with ISS (10.8–16.5 yr) were recruited from pediatric endocrinology clinics at an academic medical center. Study Design: Participants were evaluated in the General Clinical Research Center before and after 4 months of GH supplementation (0.3 mg/kg·wk). Body composition was assessed with dual-energy x-ray absorptiometry. Whole-body glucose, protein, and fat turnover were measured using stable isotopes. In vivo insulin action was assessed during a 3-h hyperinsulinemic (40 mU/m2·min) euglycemic clamp. Results: GH supplementation led to 1) increase in hepatic glucose production and fasting insulin levels, 2) increase in lean body mass and decrease in fat mass, and 3) improvement in cardiovascular lipid risk profile. Plasma IGF-I levels correlated positively with insulin levels. Conclusions: Four months of GH supplementation in adolescent males with ISS is associated with significant body composition changes and hepatic insulin resistance.

scholarly journals Brown Adipose Tissue Improves Whole-Body Glucose Homeostasis and Insulin Sensitivity in Humans

Diabetes ◽  
2014 ◽  
Vol 63 (12) ◽  
pp. 4089-4099 ◽  
Author(s):  
M. Chondronikola ◽  
E. Volpi ◽  
E. Borsheim ◽  
C. Porter ◽  
P. Annamalai ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Brown Adipose Tissue ◽  
Glucose Homeostasis ◽  
Whole Body ◽  
Brown Adipose

scholarly journals Four‑Stage Evolution of Diabetes or Whole Body Insulin Resistance (WBIR): Debunking of the Lipid‑Induced Insulin Resistance (LIIR) and Proposing of the Glycation‑Induced Insulin Resistance (GIIR)

2019 ◽  
Author(s):  
Song Jae Lee ◽  
Sang Won Shin
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Glucose Uptake ◽  
Hepatic Insulin Resistance ◽  
Whole Body ◽  
Rapid Weight Loss ◽  
Global Parameter ◽  
Tissue Specific ◽  
Visceral Adipose ◽  
Subcutaneous Adipose

Even though it has long been known that diabetes develops in distinctive stages over a long span of time, no comprehensive diabetes development model has been developed yet. Insulin resistance (IR) plays a major role in development of diabetes. A widespread belief regarding IR is that it is a global parameter affecting the whole body simultaneously by merely impairing glucose uptake in tissues. However, investigation by a new methodology that we have named integrated approach suggests that IR not merely impairs glucose uptake in tissues but also produces tissue‑specific metabolic disruptions varying widely from tissue to tissue, and that IR would not necessarily develop simultaneously over the whole body but instead develop first preferentially in the muscle tissue with a relatively low cell turnover and then progresses in sequence to the subcutaneous adipose tissue to the visceral adipose tissue to the liver with higher cell turnovers. This is the most important rationale for subdividing IR into the four distinct tissue‑specific IRs: muscle insulin resistance (MIR), subcutaneous adipose insulin resistance (s‑AIR), visceral adipose insulin resistance (v‑AIR), and hepatic insulin resistance (HIR). Sequential development of tissue‑specific IRs, in the order of MIR, s‑AIR, v‑AIR, and HIR, producing tissue‑specific metabolic disruptions is nothing but the whole body insulin resistance (WBIR) evolving in four distinctively insulin‑resistant stages. Four‑stage evolution from rapid weight gain to visceral obesity to rapid weight loss to full‑blown diabetic state not only complies well with the natural development history of diabetes, but also resolves most of controversies on diabetes or obesity. Development of the four‑stage WBIR evolution model, which also refutes the entrenched notion of the lipid‑induced insulin resistance (LIIR) but instead supports the glycation‑induced insulin resistance (GIIR) proposed in this study, may possibly be considered a breakthrough in study of diabetes or obesity.

scholarly journals The PERSonalized Glucose Optimization Through Nutritional Intervention (PERSON) Study: Rationale, Design and Preliminary Screening Results

2021 ◽  
Vol 8 ◽  
Author(s):  
Anouk Gijbels ◽  
Inez Trouwborst ◽  
Kelly M. Jardon ◽  
Gabby B. Hul ◽  
Els Siebelink ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Metabolism ◽  
Dietary Intervention ◽  
Hepatic Insulin Resistance ◽  
Whole Body ◽  
Primary Study ◽  
Sensitivity Index ◽  
Tissue Specific

Background: It is well-established that the etiology of type 2 diabetes differs between individuals. Insulin resistance (IR) may develop in different tissues, but the severity of IR may differ in key metabolic organs such as the liver and skeletal muscle. Recent evidence suggests that these distinct tissue-specific IR phenotypes may also respond differentially to dietary macronutrient composition with respect to improvements in glucose metabolism.Objective: The main objective of the PERSON study is to investigate the effects of an optimal vs. suboptimal dietary macronutrient intervention according to tissue-specific IR phenotype on glucose metabolism and other health outcomes.Methods: In total, 240 overweight/obese (BMI 25 – 40 kg/m2) men and women (age 40 – 75 years) with either skeletal muscle insulin resistance (MIR) or liver insulin resistance (LIR) will participate in a two-center, randomized, double-blind, parallel, 12-week dietary intervention study. At screening, participants undergo a 7-point oral glucose tolerance test (OGTT) to determine the hepatic insulin resistance index (HIRI) and muscle insulin sensitivity index (MISI), classifying each participant as either “No MIR/LIR,” “MIR,” “LIR,” or “combined MIR/LIR.” Individuals with MIR or LIR are randomized to follow one of two isocaloric diets varying in macronutrient content and quality, that is hypothesized to be either an optimal or suboptimal diet, depending on their tissue-specific IR phenotype (MIR/LIR). Extensive measurements in a controlled laboratory setting as well as phenotyping in daily life are performed before and after the intervention. The primary study outcome is the difference in change in disposition index, which is the product of insulin sensitivity and first-phase insulin secretion, between participants who received their hypothesized optimal or suboptimal diet.Discussion: The PERSON study is one of the first randomized clinical trials in the field of precision nutrition to test effects of a more personalized dietary intervention based on IR phenotype. The results of the PERSON study will contribute knowledge on the effectiveness of targeted nutritional strategies to the emerging field of precision nutrition, and improve our understanding of the complex pathophysiology of whole body and tissue-specific IR.Clinical Trial Registration:https://clinicaltrials.gov/ct2/show/NCT03708419, clinicaltrials.gov as NCT03708419.

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