miR-223-3p as a potential biomarker and player for adipose tissue dysfunction preceding type 2 diabetes onset

Acute inflammation in humans is associated with transient insulin resistance (IR) and dyslipidemia. Chronic low-grade inflammation is a pathogenic component of IR and adipose tissue dysfunction in obesity-induced type 2 diabetes. Because feline diabetes closely resembles human type 2 diabetes, we studied whether lipopolysaccharide (LPS)-induced subacute inflammation, in the absence of obesity, is the potential primary cause of IR and metabolic disorders. Cats received increasing iv doses (10–1000 ng/kg−1 · h−1) of LPS (n = 5) or saline (n = 5) for 10 d. Body temperature, proinflammatory and metabolic markers, and insulin sensitivity were measured daily. Tissue mRNA and protein expression were quantified on d 10. LPS infusion increased circulating and tissue markers of inflammation. Based on the homeostasis model assessment, endotoxemia induced transient IR and β-cell dysfunction. At the whole-body level, IR reverted after the 10-d treatment; however, tissue-specific indications of IR were observed, such as down-regulation of adipose glucose transporter 4, hepatic peroxisome proliferative activated receptor-γ1 and -2, and muscle insulin receptor substrate-1. In adipose tissue, increased hormone-sensitive lipase activity led to reduced adipocyte size, concomitant with increased plasma and hepatic triglyceride content and decreased total and high-density lipoprotein cholesterol levels. Prolonged LPS-induced inflammation caused acute IR, followed by long-lasting tissue-specific dysfunctions of lipid-, glucose-, and insulin metabolism-related targets; this ultimately resulted in dyslipidemia but not whole-body IR. Endotoxemia in cats may provide a promising model to study the cross talk between metabolic and inflammatory responses in the development of adipose tissue dysfunction and IR.

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Adipose tissue dysfunction and metabolic disorders: Is it possible to predict who will develop type 2 diabetes mellitus? Role of markErs in the progreSsion of dIabeteS in obese paTIeNts (The RESISTIN trial)

Cytokine ◽

10.1016/j.cyto.2019.154947 ◽

2020 ◽

Vol 127 ◽

pp. 154947 ◽

Cited By ~ 5

Author(s):

Giuseppe Derosa ◽

Gabriele Catena ◽

Giovanni Gaudio ◽

Angela D'Angelo ◽

Pamela Maffioli

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Adipose Tissue ◽

Metabolic Disorders ◽

Obese Patients ◽

Adipose Tissue Dysfunction ◽

Develop Type

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Administration of pioglitazone alone or with alogliptin delays diabetes onset in UCD-T2DM rats

Journal of Endocrinology ◽

10.1530/joe-13-0601 ◽

2014 ◽

Vol 221 (1) ◽

pp. 133-144 ◽

Cited By ~ 6

Author(s):

Bethany P Cummings ◽

Ahmed Bettaieb ◽

James L Graham ◽

Kimber Stanhope ◽

Fawaz G Haj ◽

...

Keyword(s):

Type 2 Diabetes ◽

Adipose Tissue ◽

Food Intake ◽

Glucose Tolerance ◽

Mitochondrial Biogenesis ◽

Treatment Groups ◽

Diabetes Onset ◽

Pioglitazone Treatment ◽

All Treatment

There is a need to identify strategies for type 2 diabetes prevention. Therefore, we investigated the efficacy of pioglitazone and alogliptin alone and in combination to prevent type 2 diabetes onset in UCD-T2DM rats, a model of polygenic obese type 2 diabetes. At 2 months of age, rats were divided into four groups: control, alogliptin (20 mg/kg per day), pioglitazone (2.5 mg/kg per day), and alogliptin+pioglitazone. Non-fasting blood glucose was measured weekly to determine diabetes onset. Pioglitazone alone and in combination with alogliptin lead to a 5-month delay in diabetes onset despite promoting increased food intake and body weight (BW). Alogliptin alone did not delay diabetes onset or affect food intake or BW relative to controls. Fasting plasma glucose, insulin, and lipid concentrations were lower and adiponectin concentrations were threefold higher in groups treated with pioglitazone. All treatment groups demonstrated improvements in glucose tolerance and insulin secretion during an oral glucose tolerance test with an additive improvement observed with alogliptin+pioglitazone. Islet histology revealed an improvement of islet morphology in all treatment groups compared with control. Pioglitazone treatment also resulted in increased expression of markers of mitochondrial biogenesis in brown adipose tissue and white adipose tissue, with mild elevations observed in animals treated with alogliptin alone. Pioglitazone markedly delays the onset of type 2 diabetes in UCD-T2DM rats through improvements of glucose tolerance, insulin sensitivity, islet function, and markers of adipose mitochondrial biogenesis; however, addition of alogliptin at a dose of 20 mg/kg per day to pioglitazone treatment does not enhance the prevention/delay of diabetes onset.

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Adipose Tissue Insulin Resistance Is Longitudinally Associated With Adipose Tissue Dysfunction, Circulating Lipids, and Dysglycemia: The PROMISE Cohort

10.2337/figshare.14368298.v1 ◽

2021 ◽

Author(s):

Zhila Semnani-Azad ◽

Philip W. Connelly ◽

Richard P. Bazinet ◽

Ravi Retnakaran ◽

David J. A. Jenkins ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Adipose Tissue ◽

Total Cholesterol ◽

Estimating Equation ◽

Adipose Tissue Dysfunction ◽

Increased Risk ◽

Tnf Α ◽

Design And Methods

Aim: Our objective was to determine the association of adipose tissue insulin resistance with longitudinal changes in biomarkers of adipose tissue function, circulating lipids, and dysglycemia. <div>Research design and methods: Adults at-risk for type 2 diabetes in the Prospective Metabolism and Islet Cell Evaluation (PROMISE) cohort had up to four assessments over 9 years (n=468). Adipose tissue insulin resistance was determined using a novel validated index, Adipo-IR, calculated as the product of fasting insulin and non-esterified fatty acids measured at baseline. Fasting serum was used to measure biomarkers of adipose tissue function (adiponectin and sCD163), circulating lipids (total cholesterol, HDL, LDL, TG), and systemic inflammation (Il-6 and TNF-α). Incident dysglycemia was defined as the onset of impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes at follow-up. Generalized estimating equation (GEE) models were used to assess the relationship of Adipo-IR with longitudinal outcomes. Results: GEE analyses showed that elevated Adipo-IR was longitudinally associated with adipose tissue dysfunction (adiponectin: -4.20% (95%CI, -6.40 to –1.95); sCD163: 4.36% (95%CI, 1.73 – 7.06), HDL (-3.87% (95%CI, -5.15 to -2.57)) and TG (9.26% (95%CI, 5.01 to 13.69)). Adipo-IR was associated with increased risk of incident dysglycemia (OR=1.59; 95%CI, 1.09 to 2.31, per SD increase). Associations remained significant after adjustment for waist circumference, and surrogate indices for insulin resistance. There were no significant longitudinal associations of Adipo-IR with Il-6, TNF-α, total cholesterol, or LDL. Conclusion: Our findings demonstrate that adipose tissue insulin resistance is prospectively associated with adipose tissue function, HDL, TG, and incident dysglycemia. </div>

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Evaluation of cyclooxygenase oxylipins as potential biomarker for obesity-associated adipose tissue inflammation and type 2 diabetes using targeted multiple reaction monitoring mass spectrometry

Prostaglandins Leukotrienes and Essential Fatty Acids ◽

10.1016/j.plefa.2020.102157 ◽

2020 ◽

Vol 160 ◽

pp. 102157

Author(s):

Roel Tans ◽

Rieke Bande ◽

Arno van Rooij ◽

Billy J. Molloy ◽

Rinke Stienstra ◽

...

Keyword(s):

Mass Spectrometry ◽

Type 2 Diabetes ◽

Adipose Tissue ◽

Multiple Reaction Monitoring ◽

Reaction Monitoring ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

Potential Biomarker

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Adipose Tissue Insulin Resistance Is Longitudinally Associated With Adipose Tissue Dysfunction, Circulating Lipids, and Dysglycemia: The PROMISE Cohort

10.2337/figshare.14368298 ◽

2021 ◽

Author(s):

Zhila Semnani-Azad ◽

Philip W. Connelly ◽

Richard P. Bazinet ◽

Ravi Retnakaran ◽

David J. A. Jenkins ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Adipose Tissue ◽

Total Cholesterol ◽

Estimating Equation ◽

Adipose Tissue Dysfunction ◽

Increased Risk ◽

Tnf Α ◽

Design And Methods

Aim: Our objective was to determine the association of adipose tissue insulin resistance with longitudinal changes in biomarkers of adipose tissue function, circulating lipids, and dysglycemia. <div>Research design and methods: Adults at-risk for type 2 diabetes in the Prospective Metabolism and Islet Cell Evaluation (PROMISE) cohort had up to four assessments over 9 years (n=468). Adipose tissue insulin resistance was determined using a novel validated index, Adipo-IR, calculated as the product of fasting insulin and non-esterified fatty acids measured at baseline. Fasting serum was used to measure biomarkers of adipose tissue function (adiponectin and sCD163), circulating lipids (total cholesterol, HDL, LDL, TG), and systemic inflammation (Il-6 and TNF-α). Incident dysglycemia was defined as the onset of impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes at follow-up. Generalized estimating equation (GEE) models were used to assess the relationship of Adipo-IR with longitudinal outcomes. Results: GEE analyses showed that elevated Adipo-IR was longitudinally associated with adipose tissue dysfunction (adiponectin: -4.20% (95%CI, -6.40 to –1.95); sCD163: 4.36% (95%CI, 1.73 – 7.06), HDL (-3.87% (95%CI, -5.15 to -2.57)) and TG (9.26% (95%CI, 5.01 to 13.69)). Adipo-IR was associated with increased risk of incident dysglycemia (OR=1.59; 95%CI, 1.09 to 2.31, per SD increase). Associations remained significant after adjustment for waist circumference, and surrogate indices for insulin resistance. There were no significant longitudinal associations of Adipo-IR with Il-6, TNF-α, total cholesterol, or LDL. Conclusion: Our findings demonstrate that adipose tissue insulin resistance is prospectively associated with adipose tissue function, HDL, TG, and incident dysglycemia. </div>

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