scholarly journals An integrative transcriptional logic model of hepatic insulin resistance

2021 ◽  
Author(s):  
TAKUMI KITAMOTO ◽  
Taiyi Kuo ◽  
Atsushi Okabe ◽  
Atsushi Kaneda ◽  
Domenico Accili
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Regulatory Elements ◽  
Hepatic Insulin Resistance ◽  
Dependent Manner ◽  
Metabolic Genes ◽  
Target Sites ◽  
Common Pathogenesis ◽  
Glucose Abnormalities

Abnormalities of lipid/lipoprotein and glucose metabolism are hallmarks of hepatic insulin resistance in type 2 diabetes. The former antedate the latter, but the latter become progressively refractory to treatment and contribute to therapeutic failures. It's unclear whether the two processes share a common pathogenesis and what underlies their progressive nature. In this study, we investigated the hypothesis that genes in the lipid/lipoprotein pathway and those in the glucose metabolic pathway are governed by different transcriptional logics that affect their response to physiologic (fasting/refeeding) as well as pathophysiologic cues (insulin resistance and hyperglycemia). To this end, we obtained genomic and transcriptomic maps of the key insulin-regulated transcription factor, FoxO1, and integrated them with those of CREB, PPARα, and glucocorticoid receptor. We found an enrichment of glucose metabolic genes among those regulated by intergenic and promoter enhancers in a fasting-dependent manner, while lipid genes were enriched among fasting-dependent intron enhancers and fasting-independent enhancer-less introns. Glucose genes also showed a remarkable transcriptional resiliency, i.e., an enrichment of active marks at shared PPARα/FoxO1 regulatory elements when FoxO1 was inactivated. Surprisingly, the main features associated with insulin resistance and hyperglycemia were a ″spreading″ of FoxO1 binding to enhancers, and the emergence of target sites unique to this condition. We surmise that this unusual pattern correlates with the progressively intractable nature of hepatic insulin resistance. This transcriptional logic provides an integrated model to interpret the combined lipid and glucose abnormalities of type 2 diabetes.

scholarly journals An integrative transcriptional logic model of hepatic insulin resistance

2021 ◽  
Vol 118 (45) ◽  
pp. e2102222118
Author(s):  
Takumi Kitamoto ◽  
Taiyi Kuo ◽  
Atsushi Okabe ◽  
Atsushi Kaneda ◽  
Domenico Accili
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Regulatory Elements ◽  
Hepatic Insulin Resistance ◽  
Dependent Manner ◽  
Metabolic Genes ◽  
Transcriptional Regulatory ◽  
Common Pathogenesis ◽  
Glucose Abnormalities

Abnormalities of lipid/lipoprotein and glucose metabolism are hallmarks of hepatic insulin resistance in type 2 diabetes. The former antedate the latter, but the latter become progressively refractory to treatment and contribute to therapeutic failures. It’s unclear whether the two processes share a common pathogenesis and what underlies their progressive nature. In this study, we investigated the hypothesis that genes in the lipid/lipoprotein pathway and those in the glucose metabolic pathway are governed by different transcriptional regulatory logics that affect their response to physiologic (fasting/refeeding) as well as pathophysiologic cues (insulin resistance and hyperglycemia). To this end, we obtained genomic and transcriptomic maps of the key insulin-regulated transcription factor, FoxO1, and integrated them with those of CREB, PPAR-α, and glucocorticoid receptor. We found that glucose metabolic genes are primarily regulated by promoter and intergenic enhancers in a fasting-dependent manner, while lipid genes are regulated through fasting-dependent intron enhancers and fasting-independent enhancerless introns. Glucose genes also showed a remarkable transcriptional resiliency (i.e., the ability to compensate following constitutive FoxO1 ablation through an enrichment of active marks at shared PPAR-α/FoxO1 regulatory elements). Unexpectedly, insulin resistance and hyperglycemia were associated with a “spreading” of FoxO1 binding to enhancers and the emergence of unique target sites. We surmise that this unusual pattern correlates with the progressively intractable nature of hepatic insulin resistance. This transcriptional logic provides an integrated model to interpret the combined lipid and glucose abnormalities of type 2 diabetes.

1746-P: Obese Youth with Type 1 Diabetes (T1D) Have Worse Hepatic Insulin Resistance (IR) Than Youth with Type 2 Diabetes (T2D)

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 1746-P
Author(s):  
PATTARA WIROMRAT ◽  
MELANIE CREE-GREEN ◽  
BRYAN C. BERGMAN ◽  
KALIE L. TOMMERDAHL ◽  
AMY BAUMGARTNER ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 1 Diabetes ◽  
Hepatic Insulin Resistance ◽  
Obese Youth

Association between new markers of cardiovascular risk and hepatic insulin resistance in those at high risk of developing type 2 diabetes

Endocrine ◽  
2021 ◽  
Author(s):  
Lucilla D. Monti ◽  
Camillo Bechi Genzano ◽  
Barbara Fontana ◽  
Elena Galluccio ◽  
Serena Spadoni ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Cardiovascular Risk ◽  
High Risk ◽  
Hepatic Insulin Resistance

Myopia and Early Onset Type 2 Diabetes: A Nationwide Cohort Study

2021 ◽  
Author(s):  
Alon Peled ◽  
Itamar Raz ◽  
Inbar Zucker ◽  
Estela Derazne ◽  
Jacob Megreli ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Cohort Study ◽  
Young Adulthood ◽  
Military Service ◽  
High Myopia ◽  
Continuous Variable ◽  
Dependent Manner ◽  
Increased Risk

Abstract Objective A correlation between myopia and insulin-resistance has been suggested. We investigated the association between myopia in adolescence and type 2 diabetes (T2D) incidence in young adulthood. Design Population-based, retrospective, cohort study. Methods 1,329,705 adolescents (579,543 women, 43.6%) aged 16-19 years, medically examined before mandatory military service during 1993-2012; and whose data were linked to the Israel National Diabetes Registry. Myopia was defined based on right eye refractive data. Cox proportional models were applied, separately for women and men, to estimate hazard ratios (HRs) for T2D incidence per person-years of follow-up. Results There was an interaction between myopia and sex with T2D (P<0.001). For women, T2D incidence rates (per 100,000 person-years) were 16.6, 19.2, and 25.1 for those without myopia, and with mild-to-moderate and high myopia, respectively. These corresponded to HRs of 1.29 (95%CI 1.14-1.45) and 1.63 (1.21-2.18) for women with mild-to-moderate and high myopia, respectively, compared to those without myopia, after adjustment for age at study entry, birth year, adolescent BMI, cognitive performance, socioeconomic status, and immigration status. Results persisted in extensive sensitivity and subgroup analyses. When managed as a continuous variable, every 1 diopter lower spherical equivalent yielded a 6.5% higher adjusted HR for T2D incidence (P= 0.003). There was no significant association among men. Conclusions For women, myopia in adolescence was associated with a significantly increased risk for incident T2D in young adulthood, in a severity-dependent manner. This finding may support the role of insulin resistance in myopia pathogenesis.

scholarly journals Increased hypothalamic-pituitary-adrenal axis activity and hepatic insulin resistance in low-birth-weight rats

2007 ◽  
Vol 293 (5) ◽  
pp. E1451-E1458 ◽  
Author(s):  
Esben S. Buhl ◽  
Susanne Neschen ◽  
Shin Yonemitsu ◽  
Joerg Rossbacher ◽  
Dongyan Zhang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Birth Weight ◽  
Insulin Sensitivity ◽  
Low Birth Weight ◽  
Hepatic Insulin Resistance ◽  
Hypothalamic Pituitary Adrenal ◽  
Adrenal Axis ◽  
Pituitary Adrenal Axis

Individuals born with a low birth weight (LBW) have an increased prevalence of type 2 diabetes, but the mechanisms responsible for this association are unknown. Given the important role of insulin resistance in the pathogenesis of type 2 diabetes, we examined insulin sensitivity in a rat model of LBW due to intrauterine fetal stress. During the last 7 days of gestation, rat dams were treated with dexamethasone and insulin sensitivity was assessed in the LBW offspring by a hyperinsulinemic euglycemic clamp. The LBW group had liver-specific insulin resistance associated with increased levels of PEPCK expression. These changes were associated with pituitary hyperplasia of the ACTH-secreting cells, increased morning plasma ACTH concentrations, elevated corticosterone secretion during restraint stress, and an ∼70% increase in 24-h urine corticosterone excretion. These data support the hypothesis that prenatal stress can result in chronic hyperactivity of the hypothalamic-pituitary-adrenal axis, resulting in increased plasma corticosterone concentrations, upregulation of hepatic gluconeogenesis, and hepatic insulin resistance.

scholarly journals Combined Effects of Insulin Resistance and Inflammation on Comorbidities of Type 2 Diabetes

2021 ◽  
Vol 22 (3) ◽  
pp. 207-219
Author(s):  
Eun Jung Kim ◽  
Eun Young Lee ◽  
Yong-Ho Lee ◽  
Young Ju Choi ◽  
Seok Won Park ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Synergistic Effects ◽  
High Sensitivity ◽  
Tolerance Test ◽  
Metabolic Parameters ◽  
Dependent Manner ◽  
Insulin Tolerance ◽  
Hs Crp

Background: Insulin resistance (IR) and inflammation are closely related to each other and share common pathophysiological and metabolic mechanisms. We aimed to investigate the combined effect of IR and inflammation on comorbidities of type 2 diabetes mellitus (T2DM). Methods: A total 3,758 patients with T2DM were recruited through Huh’s Diabetes Center from January 2003 to June 2009. Insulin sensitivity was measured by a rate constant for plasma glucose disappearance (Kitt , %/min) using short insulin tolerance test. High sensitivity C-reactive protein (hs-CRP) was used as a surrogate for inflammation.Results: Patients with the lowest tertile of Kitt (IR group) showed worse cardio-metabolic parameters while those with the highest tertile of hs-CRP levels had worse cardio-metabolic parameters. The prevalence of metabolic syndrome, fatty liver, albuminuria, and carotid atherosclerosis decreased with Kitt tertile, but increased with hs-CRP tertile. In multiple regression analysis, both Kitt and hs-CRP were independent risk factors for comorbidities of T2DM. In addition, they showed synergistic effects on these comorbidities. Conclusion: Both IR and inflammation were significantly associated with comorbidities of T2DM in a dose dependent manner. In addition, the coexistence of IR and inflammation may synergistically contribute to increased comorbidities of T2DM.

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