Adipocyte PU.1 knockout promotes insulin sensitivity in HFD-fed obese mice

Abstract Insulin resistance is a key feature of obesity and type 2 diabetes. PU.1 is a master transcription factor predominantly expressed in macrophages but after HFD feeding PU.1 expression is also significantly increased in adipocytes. We generated adipocyte specific PU.1 knockout mice using adiponectin cre to investigate the role of PU.1 in adipocyte biology, insulin and glucose homeostasis. In HFD-fed obese mice systemic glucose tolerance and insulin sensitivity were improved in PU.1 AKO mice and clamp studies indicated improvements in both adipose and liver insulin sensitivity. At the level of adipose tissue, macrophage infiltration and inflammation was decreased and glucose uptake was increased in PU.1 AKO mice compared with controls. While PU.1 deletion in adipocytes did not affect the gene expression of PPARg itself, we observed increased expression of PPARg target genes in eWAT from HFD fed PU.1 AKO mice compared with controls. Furthermore, we observed decreased phosphorylation at serine 273 in PU.1 AKO mice compared with fl/fl controls, indicating that PPARg is more active when PU.1 expression is reduced in adipocytes. Therefore, in obesity the increased expression of PU.1 in adipocytes modifies the adipocyte PPARg cistrome resulting in impaired glucose tolerance and insulin sensitivity.

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The Role of Diet on Insulin Sensitivity

Nutrients ◽

10.3390/nu12103042 ◽

2020 ◽

Vol 12 (10) ◽

pp. 3042

Author(s):

Maria Mirabelli ◽

Diego Russo ◽

Antonio Brunetti

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Insulin Sensitivity ◽

Dietary Composition ◽

Reproductive Disorders

Growing evidence shows that dietary composition has a marked impact on the risk of developing obesity, type 2 diabetes (T2D), cardiovascular disease (CVD), certain types of endocrine cancer and many other intertwined metabolic and reproductive disorders, all featured by insulin resistance (IR) [...]

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Reduced arterial stiffness after weight loss in obese type 2 diabetes and impaired glucose tolerance: The role of immune cell activation and insulin resistance

Diabetes and Vascular Disease Research ◽

10.1177/1479164112443375 ◽

2012 ◽

Vol 10 (1) ◽

pp. 40-48 ◽

Cited By ~ 18

Author(s):

Katherine Samaras ◽

Alexander Viardot ◽

Ping N Lee ◽

Alicia Jenkins ◽

Natalia K Botelho ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Weight Loss ◽

Arterial Stiffness ◽

Glucose Tolerance ◽

Cell Activation ◽

Immune Cell ◽

Immune Cell Activation

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In middle-aged siblings of patients with type 2 diabetes mellitus normal glucose tolerance is associated with insulin resistance and with increased insulin secretion. The SPIDER study

Acta Endocrinologica ◽

10.1530/eje.0.1430681 ◽

2000 ◽

pp. 681-686 ◽

Cited By ~ 7

Author(s):

AE Pontiroli ◽

LD Monti ◽

S Costa ◽

PE Sandoli ◽

A Pizzini ◽

...

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Normal Glucose Tolerance ◽

C Peptide ◽

Type 2 Dm ◽

Normal Glucose

OBJECTIVES: To evaluate the frequency of impaired glucose tolerance (IGT) and of Type 2 diabetes mellitus (Type 2 DM) in siblings of patients with Type 2 DM, and to assess insulin release and insulin sensitivity in siblings with normal glucose tolerance (NGT), compared with NGT spouses of probands without family history of Type 2 DM. DESIGN AND METHODS: We evaluated 87 families including 103 Type 2 DM patients (87 probands), and we carried out an oral glucose tolerance test (OGTT) in 130 siblings and in 60 spouses. Among NGT subjects, 12 siblings and 16 spouses underwent a low-dose insulin-glucose infusion test (LDIGIT) to evaluate C-peptide release and insulin sensitivity. RESULTS: After the OGTT, 24 siblings were classified as having Type 2 DM, 31 as IGT, and only 14 spouses as IGT (P=0.0012 vs siblings). NGT siblings (n=75) showed higher insulin levels at 120 min than NGT spouses (n=46) at OGTT, in spite of identical blood glucose levels; at LDIGIT, NGT siblings secreted more C-peptide and showed a lower insulin sensitivity than NGT spouses. CONCLUSIONS: These data indicate that middle-aged siblings of probands with Type 2 DM have a high frequency of IGT and Type 2 DM, and that NGT siblings have increased insulin resistance and increased insulin secretion when compared with adequate controls.

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Assessment of Insulin Resistance in Subjects with Normal Glucose Tolerance, Hyperinsulinemia with Normal Blood Glucose Tolerance, Impaired Glucose Tolerance, and Newly Diagnosed Type 2 Diabetes (Prediabetes Insulin Resistance Research)

Journal of Diabetes Research ◽

10.1155/2016/9270768 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 9

Author(s):

Guang Yang ◽

Chunlin Li ◽

Yanping Gong ◽

Fusheng Fang ◽

Hui Tian ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Normal Glucose Tolerance ◽

Newly Diagnosed ◽

Factors Influencing ◽

Sensitivity Indices ◽

Normal Glucose

Aim.To evaluate the differences in insulin resistance (IR) among subjects with normal glucose tolerance (NGT), hyperinsulinemia with NGT (HINS), impaired glucose tolerance (IGT), and newly diagnosed type 2 diabetes mellitus (T2DM).Methods.5 NGT, 25 HINS, 25 IGT, and 25 T2DM subjects participated in this research. The hyperinsulinemic-euglycemic clamp technique (HECT) was performed in all of them to evaluate IR levels. The relative factors influencing IR were evaluated. The simple insulin sensitivity indices were calculated, and the correlation between each index and the M value was analyzed.Results.TheMvalues of NGT, HINS, IGT, and T2DM groups were 11.88 ± 2.93 mg·kg−1·min−1, 6.23 ± 1.73 mg·kg−1·min−1, 6.37 ± 2.12 mg·kg−1·min−1, and 6.19 ± 1.89 mg·kg−1·min−1, respectively.Mvalues in HINS, IGT, and T2DM groups were lower than those in the NGT group (P=0.005); however, the differences among the HINS, IGT, and T2DM groups were not statistically significant (P=0.835). The independent factors influencing theMvalue were waistline and fasting insulin level (FINS). The simple insulin sensitivity indices, especially Matsuda and Gutt index, were significantly associated with theMvalue (P<0.01).Conclusion.IR existed in the HINS, IGT, and T2DM groups, and IR levels were consistent in the three groups. The independent factors influencing IR were waistline and FINS.

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SAT-653 Exploring the Role of Brown Adipokines on Hepatic Insulin Resistance Using a Microfluidic Organ-On-Chip

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.570 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Nida Tanataweethum ◽

Chaeeun Lee ◽

Allyson Trang ◽

Franklin Zhong ◽

Kihwan Kim ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Glucose Production ◽

Conditioned Media ◽

Hepatic Insulin Resistance ◽

Brown Adipocyte ◽

On Chip

Abstract The development of insulin resistance (IR) in liver is a key of pathophysiologic response in type 2 diabetes. Although insulin resistance impairs its ability to suppress hepatic glucose production, insulin regulation of lipogenesis is maintained (1). Currently available insulin sensitizers are effective at lowering glucose levels, but have significant adverse effect on weight gain due to triglyceride accumulation, which highlights a need to develop new therapeutic treatment options for type 2 diabetes. Brown adipose tissue (BAT) has been studied as a new target for anti-obesity and type 2 diabetes as BAT stimulation increases energy expenditure, reduces adiposity, and improves insulin sensitivity (2). However, the underlying mechanisms are not completely understood. To identify the role of BAT adipokines on hepatic insulin resistance, we developed an insulin resistant liver organ-on-chip model and then perfused primary mouse brown adipocyte conditioned media through the hepatocytes. Our results demonstrate that IR hepatocytes treated with brown adipocyte - conditioned media restores insulin sensitivity and improves glucose metabolism. This was verified by significantly increased expression of Phospho-Akt (Ser473) and glucose production gene markers (G6pc and PEPCK), lowered glucose production, increased glucose uptake, and increased glycogen synthesis in treated hepatocytes over IR group (p < 0.05). Our results also indicate that brown adipocyte - conditioned media treatment has the potential to suppress lipogenesis in hepatic insulin resistance. This was confirmed by significantly reduced expression of a lipogenesis gene marker (SREPB1) and fatty acid uptake in treated hepatocytes over IR group (p < 0.05). Current efforts are focused towards identifying the BAT adipokine via mass spectrometry. We conclude that BAT-derived endocrine factors could be a potential target for new drug discovery for obesity and type 2 diabetes treatment. Reference: (1) Langlet et al. Cell. 2017 Nov;171(4):824-835. (2) Subhadraw et al. Am J Physiol Endocrinol Metlab. 2015 Jun;308(12):E1043-E1055. Nothing to Disclose: NT, CL, AT, FZ, KK, JM, RC, AB

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Role of Calpain-10 Gene Variants in Familial Type 2 Diabetes in Caucasians

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.87.2.8210 ◽

2002 ◽

Vol 87 (2) ◽

pp. 650-654 ◽

Cited By ~ 34

Author(s):

Steven C. Elbein ◽

Winston Chu ◽

Qianfang Ren ◽

Chris Hemphill ◽

John Schay ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Glucose Tolerance Test ◽

Tolerance Test ◽

Diabetes Susceptibility ◽

Haplotype Combination ◽

Calpain 10

The calpain-10 gene (CAPN10) has been implicated in type 2 diabetes (T2DM) susceptibility by both linkage and association in a Hispanic population from Starr County Texas. Common intronic variants seem to alter CAPN10 mRNA levels and were associated with insulin resistance but not diabetes in Pima Indians. The role of these variants in Caucasian populations is less clear. We found some evidence for linkage of T2DM to chromosome 2q approximately 20 cM proximal to the NIDDM1/CAPN10 locus. To test the hypothesis that CAPN10 is a diabetes susceptibility locus in Caucasian families at high risk for T2DM, we examined the influence of the three previously implicated CAPN10 variants on both diabetes risk and measures of insulin sensitivity and glucose homeostasis. We genotyped approximately 700 members of 63 families for 3 variants (SNP-43, SNP-19, and SNP-63). We tested each variant separately and as haplotype combinations for altered transmission from parents to affected children (transmission disequilibrium test), and we tested for an effect of each variant individually on measures of glucose and insulin during a glucose tolerance test in nondiabetic family members. Finally, we looked for an effect of each variant on measures of insulin sensitivity (SI) and insulin secretion estimated by frequently sampled iv glucose tolerance test and Minimal Model analysis. We could not confirm an increase in risk for T2DM susceptibility for any variant or for any haplotype combination, although we found marginal evidence for an increased risk of the 111/221 haplotype combination (P = 0.036) after ascertainment correction. However, both SNP-19 and SNP-63 increased fasting and/or postchallenge insulin levels, consistent with reduced insulin sensitivity. Furthermore, SNP-19 had modest effects on insulin sensitivity measured by homeostatic model, and on postchallenge glucose. The reduction in insulin sensitivity was confirmed by analysis of the subset of individuals who underwent iv glucose tolerance tests, where SNP-19 significantly altered the insulin sensitivity index. CAPN10 cannot be considered a major diabetes susceptibility gene in our population and seems unlikely to explain the observed linkage findings. However, CAPN10 influences insulin sensitivity and glucose homeostasis in nondiabetic members of kindreds at high risk for T2DM.

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Reduced Muscle Strength Is Associated With Insulin Resistance in Type 2 Diabetes Patients With Osteoarthritis

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa912 ◽

2020 ◽

Author(s):

Oana Patricia Zaharia ◽

Dominik Hans Pesta ◽

Pavel Bobrov ◽

Yuliya Kupriyanova ◽

Christian Herder ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Quantitative Polymerase Chain Reaction ◽

Normal Glucose Tolerance ◽

Knee Extension ◽

Neural Function ◽

Intravenous Glucose

Abstract Context Type 2 diabetes is associated with a greater risk for musculoskeletal disorders, yet its impact on joint function remains unclear. Objective We hypothesized that patients with type 2 diabetes and osteoarthritis would exhibit musculoskeletal impairment, which would associate with insulin resistance and distinct microRNA profiles. Methods Participants of the German Diabetes Study with type 2 diabetes (T2D, n = 39) or normal glucose tolerance (CON, n = 27), both with (+OA) or without osteoarthritis (-OA) underwent intravenous glucose tolerance and hyperinsulinemic-euglycemic clamp tests. Musculoskeletal function was assessed by isometric knee extension strength (KES), grip strength, range of motion (ROM), and balance skills, while neural function was measured by nerve conductance velocity (NCV). Arthritis-related symptoms were quantified using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire, serum arthritis-related microRNA using quantitative polymerase chain reaction. Results Insulin sensitivity was lower in T2D+OA vs T2D-OA (4.4 ± 2.0 vs 5.7 ± 3.0 mg* kg–1*min–1) and in CON+OA vs CON-OA (8.1 ± 2.0 vs 12.0 ± 2.6 mg*kg–1,*min–1, both P < .05). In T2D+OA, KES and ROM were 60% and 22% lower than in CON+OA, respectively (both P < .05). Insulin sensitivity correlated positively with KES (r = 0.41, P < .05) among T2D, and negatively with symptom severity in CON and T2D (r = –0.60 and r = –0.46, respectively, P < .05). CON+OA and T2D+OA had inferior balance skills than CON-OA, whereas NCV was comparable in T2D+OA and T2D-OA. Expression of arthritis-related microRNAs was upregulated in T2D compared to CON, but downregulated in CON+OA compared to CON-OA (P < .05), and did not differ between T2D+OA and T2D-OA. Conclusion Musculoskeletal impairment and osteoarthritis-related symptoms are associated with insulin resistance. Type 2 diabetes can mask changes in arthritis-related microRNA profiles.

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Relationship between Serum Lipoprotein Ratios and Insulin Resistance in Obesity

Clinical Chemistry ◽

10.1373/clinchem.2004.037556 ◽

2004 ◽

Vol 50 (12) ◽

pp. 2316-2322 ◽

Cited By ~ 63

Author(s):

Attila Brehm ◽

Georg Pfeiler ◽

Giovanni Pacini ◽

Heinrich Vierhapper ◽

Michael Roden

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Impaired Glucose Tolerance ◽

Serum Lipid ◽

Fasting Serum ◽

Lipid Ratios ◽

Glucose Tolerant

Abstract Background: The fasting serum lipid profile [triglycerides (TGs), total cholesterol (TC), and LDL- and HDL-cholesterol (LDL-C and HDL-C)] is used to calculate lipid ratios (TC/HDL-C, LDL-C/HDL-C, TG/HDL-C) that allow identification of individuals at increased risk for cardiovascular disease. Because these individuals are also frequently insulin resistant, this study analyzed the relationships between lipid ratios and insulin sensitivity. Methods: In 132 obese [mean (SE) body mass index, 37.5 (0.6) kg/m2] outpatients without known diabetes mellitus, fasting serum lipid profiles and 75-g oral glucose tolerance tests were performed. Insulin sensitivity was assessed from surrogate estimates for fasting (QUICKI) and dynamic (OGIS) conditions. Results: After exclusion of other endocrine diseases (n = 35), the remaining patients were classified as glucose tolerant (n = 56), glucose intolerant (n = 22), or as having type 2 diabetes (n = 19). QUICKI and OGIS indicated severe insulin resistance in all individuals with type 2 diabetes and impaired glucose tolerance compared with glucose-tolerant individuals: QUICKI, glucose tolerant, 0.302 (0.002); glucose intolerant, 0.290 (0.002); type 2 diabetes, 0.281 (0.005); P <0.001; OGIS (mL · m−2 · min−1), glucose tolerant, 343 (7), glucose intolerant, 293 (9); type 2 diabetes, 256 (12); P <0.001. Serum TG (P <0.005) and TG/HDL-C ratios (P <0.05) were increased in individuals with impaired glucose tolerance. TG/HDL-C ratios negatively correlated with QUICKI (r = −0.370; P < 0.001) and OGIS (r = −0.333; P < 0.005) in nondiabetic individuals (glucose tolerant plus glucose intolerant), but not in patients with type 2 diabetes (not significant). Conclusions: This study demonstrates that the TG/HDL-C ratio positively correlates with insulin resistance in severely obese nondiabetic individuals.

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Impact of tissue macrophage proliferation on peripheral and systemic insulin resistance in obese mice with diabetes

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001578 ◽

2020 ◽

Vol 8 (1) ◽

pp. e001578

Author(s):

Yutaro Morita ◽

Takafumi Senokuchi ◽

Sarie Yamada ◽

Toshiaki Wada ◽

Tatsuya Furusho ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Skeletal Muscle ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Liver Steatosis ◽

Histological Changes ◽

Tissue Macrophage ◽

Systemic Insulin Resistance

IntroductionObesity-related insulin resistance is a widely accepted pathophysiological feature in type 2 diabetes. Systemic metabolism and immunity are closely related, and obesity represents impaired immune function that predisposes individuals to systemic chronic inflammation. Increased macrophage infiltration and activation in peripheral insulin target tissues in obese subjects are strongly related to insulin resistance. Using a macrophage-specific proliferation inhibition mouse model (mac-p27Tg), we previously reported that suppressed plaque inflammation reduced atherosclerosis and improved plaque stabilization. However, the direct evidence that proliferating macrophages are responsible for inducing insulin resistance was not provided.Research design and methodsThe mac-p27Tg mice were fed a high-fat diet, and glucose metabolism, histological changes, macrophage polarization, and tissue functions were investigated to reveal the significance of tissue macrophage proliferation in insulin resistance and obesity.ResultsThe mac-p27Tg mice showed improved glucose tolerance and insulin sensitivity, along with a decrease in the number and ratio of inflammatory macrophages. Obesity-induced inflammation and oxidative stress was attenuated in white adipose tissue, liver, and gastrocnemius. Histological changes related to insulin resistance, such as liver steatosis/fibrosis, adipocyte enlargement, and skeletal muscle fiber transformation to fast type, were ameliorated in mac-p27Tg mice. Serum tumor necrosis factor alpha and free fatty acid were decreased, which might partially impact improved insulin sensitivity and histological changes.ConclusionsMacrophage proliferation in adipose tissue, liver, and skeletal muscle was involved in promoting the development of systemic insulin resistance. Controlling the number of tissue macrophages by inhibiting macrophage proliferation could be a therapeutic target for insulin resistance and type 2 diabetes.

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