Abstract 594: Macrophage Proteomics Identifies Mechanistic Links Between Type 2 Diabetes and Atherosclerosis

Obesity and Type 2 Diabetes (T2Ds) are associated with increased risk of atherosclerosis and CHD. However, the mechanism(s) linking these diseases are incompletely understood. Macrophages play essential roles in the pathogenesis of both disorders, suggesting that changes in macrophage biology link obesity/T2D and atherosclerosis. We previously showed that the atherogenic actions of cholesterol-loaded macrophages (foam cells) are an emergent property of a dysregulated sterol responsive protein network secreted by macrophages (MSRN). Thus, we hypothesized that obesity/T2Ds may impact atherogenesis by similarly disrupting the MSRN. To test this hypothesis, we isolated peritoneal macrophages (PMΦ) from C57BL/6 mice fed a chow or obesogenic diet and interrogated their secreted proteomes using mass spectrometry. Based on stringent statistical analysis (FDR<5%), we identified 36 proteins that were differentially expressed in media conditioned by macrophages from obese relative to lean mice. Unsupervised gene set enrichment analysis demonstrated that obesity-induced changes to the PMΦ proteome significantly targeted the MSRN. Importantly, this phenomenon could not be explained by cholesterol accumulation or inflammation, since PMΦ’s from obese mice did not accumulate cholesterol and pro-inflammatory cytokine expression was not induced in PMΦ’s from obese or atherogenic mice. Our previous studies showed that treating hypercholesterolemic Ldlr -/- mice with TZD (insulin sensitizer) could normalize MSRN protein expression in vivo , suggesting that insulin resistance is a key regulator of the network. To test this hypothesis, we placed C57BL/6 mice on an obesogenic diet for 7 weeks and treated the mice with TZD for 2 weeks. TZD therapy had no effect on body weight, but normalized fasting glucose levels. Moreover, PMΦ’s isolated from TZD-treated mice, demonstrated normalized protein expression patterns. Collectively, our studies suggest that insulin resistance in T2Ds reproduces macrophage protein dysfunction observed in atherogenic models, and provides a plausible mechanism by which T2Ds may act to increase risk of atherosclerosis.

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Is Vitamin D Deficiency Related to Increased Cancer Risk in Patients with Type 2 Diabetes Mellitus?

International Journal of Molecular Sciences ◽

10.3390/ijms22126444 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6444

Author(s):

Anna Gabryanczyk ◽

Sylwia Klimczak ◽

Izabela Szymczak-Pajor ◽

Agnieszka Śliwińska

Keyword(s):

Diabetes Mellitus ◽

Risk Factors ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Vitamin D ◽

Cancer Risk ◽

Vitamin D Deficiency ◽

Cancer Development ◽

Increased Risk

There is mounting evidence that type 2 diabetes mellitus (T2DM) is related with increased risk for the development of cancer. Apart from shared common risk factors typical for both diseases, diabetes driven factors including hyperinsulinemia, insulin resistance, hyperglycemia and low grade chronic inflammation are of great importance. Recently, vitamin D deficiency was reported to be associated with the pathogenesis of numerous diseases, including T2DM and cancer. However, little is known whether vitamin D deficiency may be responsible for elevated cancer risk development in T2DM patients. Therefore, the aim of the current review is to identify the molecular mechanisms by which vitamin D deficiency may contribute to cancer development in T2DM patients. Vitamin D via alleviation of insulin resistance, hyperglycemia, oxidative stress and inflammation reduces diabetes driven cancer risk factors. Moreover, vitamin D strengthens the DNA repair process, and regulates apoptosis and autophagy of cancer cells as well as signaling pathways involved in tumorigenesis i.e., tumor growth factor β (TGFβ), insulin-like growth factor (IGF) and Wnt-β-Cathenin. It should also be underlined that many types of cancer cells present alterations in vitamin D metabolism and action as a result of Vitamin D Receptor (VDR) and CYP27B1 expression dysregulation. Although, numerous studies revealed that adequate vitamin D concentration prevents or delays T2DM and cancer development, little is known how the vitamin affects cancer risk among T2DM patients. There is a pressing need for randomized clinical trials to clarify whether vitamin D deficiency may be a factor responsible for increased risk of cancer in T2DM patients, and whether the use of the vitamin by patients with diabetes and cancer may improve cancer prognosis and metabolic control of diabetes.

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Cardiovascular events in patients with type 2 diabetes

The British Journal of Diabetes ◽

10.1177/1474651402002001s0201 ◽

2002 ◽

Vol 2 (1_suppl) ◽

pp. S4-S8

Author(s):

Erland Erdmann

Keyword(s):

Risk Factors ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Risk Factor ◽

Adverse Effects ◽

Cardiovascular Events ◽

Left Ventricular ◽

Diabetic Patients ◽

Increased Risk

Diabetes is a common risk factor for cardiovascular disease. Coronary heart disease and left ventricular dysfunction are more common in diabetic patients than in non-diabetic patients, and diabetic patients benefit less from revascularisation procedures. This increased risk can only partly be explained by the adverse effects of diabetes on established risk factors; hence, a substantial part of the excess risk must be attributable to direct effects of hyperglycaemia and diabetes. In type 2 diabetes, hyperinsulinaemia, insulin resistance and hyperglycaemia have a number of potential adverse effects, including effects on endothelial function and coagulation. Risk factor modification has been shown to reduce the occurrence of cardiovascular events in patients with diabetes; indeed, diabetic patients appear to benefit more in absolute terms than non-diabetic patients. There is thus a strong case for intensive treatment of risk factors, including insulin resistance and hyperglycaemia, in patients with type 2 diabetes.

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Elevated circulating follistatin associates with an increased risk of type 2 diabetes

Nature Communications ◽

10.1038/s41467-021-26536-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Chuanyan Wu ◽

Yan Borné ◽

Rui Gao ◽

Maykel López Rodriguez ◽

William C. Roell ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Adipose Tissue ◽

Genome Wide Association Study ◽

Regulatory Protein ◽

Alcoholic Fatty Liver ◽

Increased Risk

AbstractThe hepatokine follistatin is elevated in patients with type 2 diabetes (T2D) and promotes hyperglycemia in mice. Here we explore the relationship of plasma follistatin levels with incident T2D and mechanisms involved. Adjusted hazard ratio (HR) per standard deviation (SD) increase in follistatin levels for T2D is 1.24 (CI: 1.04–1.47, p < 0.05) during 19-year follow-up (n = 4060, Sweden); and 1.31 (CI: 1.09–1.58, p < 0.01) during 4-year follow-up (n = 883, Finland). High circulating follistatin associates with adipose tissue insulin resistance and non-alcoholic fatty liver disease (n = 210, Germany). In human adipocytes, follistatin dose-dependently increases free fatty acid release. In genome-wide association study (GWAS), variation in the glucokinase regulatory protein gene (GCKR) associates with plasma follistatin levels (n = 4239, Sweden; n = 885, UK, Italy and Sweden) and GCKR regulates follistatin secretion in hepatocytes in vitro. Our findings suggest that GCKR regulates follistatin secretion and that elevated circulating follistatin associates with an increased risk of T2D by inducing adipose tissue insulin resistance.

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

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab669 ◽

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.

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Abstract 424: An IFNg-regulated Macrophage Protein Network Links Type 2 Diabetes to Atherosclerosis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.424 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Catherine A Reardon ◽

Amulya Lingaraju ◽

Kelly Q Schoenfelt ◽

Guolin Zhou ◽

Ning-Chun Liu ◽

...

Keyword(s):

Type 2 Diabetes ◽

Foam Cell ◽

Cell Formation ◽

Foam Cell Formation ◽

Increased Risk ◽

Macrophage Dysfunction ◽

Macrophage Protein

Type 2 diabetics have a higher risk for atherosclerosis, but the mechanisms underlying the increased risk are poorly understood. Macrophages, which are activated in type 2 diabetes (T2D) and have a role in all stages of atherogenesis, are an attractive link. Our hypothesis is that T2D promotes macrophage dysfunction to promote atherosclerosis. To investigate the relationship between T2D and macrophage dysfunction, we used a proteomics approach to identify dysregulated proteins secreted from peritoneal macrophages in a diet induced mouse model of obesity and insulin resistance in the absence of hypercholesterolemia. Twenty-seven T2D responsive proteins were identified that predict defects in many of the critical functions of macrophages in atherosclerosis (e.g. decreased apoE- cholesterol efflux; decreased MFGE8 – efferocytosis, increased MMP12- matrix degradation). The macrophages from lean and obese mice were not lipid loaded, but the obese macrophages accumulated significantly more cholesterol when exposed to high levels of atherogenic lipoproteins in vitro suggesting that dysregulation of the T2D responsive proteins in diabetic mice render macrophages more susceptible to cholesterol loading. Importantly, many of these same protein changes, which were present in atherosclerotic Ldlr-/- mice with T2D, were normalized when these mice were fed non-diabetogenic hypercholesterolemic diets. Thus, foam cell formation in the presence and absence of T2D produces distinct effects on macrophage protein levels, and hence function. Further, we identify IFNγ as a mediator of the T2D responsive protein dysfunction. IFNγ, but not other cytokines, insulin or glucose, promote the T2D responsive protein dysregulation and increased susceptibility to cholesterol accumulation in vitro and the dysregulation is not observed in macrophage foam cells obtained from obese, diabetic IFNγ receptor 1 knockout animals. We also demonstrate that IFNγ can target these proteins in arterial wall macrophages in vivo . These studies suggest that IFNγ is an important mediator of macrophage dysfunction in T2D that may contribute to the enhanced cardiovascular risk in these patients.

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Insulin therapy in patients with type 2 diabetes and high insulin resistance is associated with increased risk of complications and mortality

Postgraduate Medicine ◽

10.1080/00325481.2019.1643635 ◽

2019 ◽

Vol 131 (6) ◽

pp. 376-382 ◽

Cited By ~ 2

Author(s):

Carlos E. Mendez ◽

Rebekah J. Walker ◽

Christian R. Eiler ◽

Basem M. Mishriky ◽

Leonard E. Egede

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Therapy ◽

Increased Risk ◽

High Insulin ◽

Complications And Mortality

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MECHANISMS IN ENDOCRINOLOGY: Skeletal muscle lipotoxicity in insulin resistance and type 2 diabetes: a causal mechanism or an innocent bystander?

Acta Endocrinologica ◽

10.1530/eje-16-0488 ◽

2017 ◽

Vol 176 (2) ◽

pp. R67-R78 ◽

Cited By ~ 37

Author(s):

Charlotte Brøns ◽

Louise Groth Grunnet

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Skeletal Muscle ◽

Adipose Tissue ◽

Cellular Localization ◽

Future Research ◽

Causal Mechanism ◽

Increased Risk ◽

Adipose Tissue Expandability

Dysfunctional adipose tissue is associated with an increased risk of developing type 2 diabetes (T2D). One characteristic of a dysfunctional adipose tissue is the reduced expandability of the subcutaneous adipose tissue leading to ectopic storage of fat in organs and/or tissues involved in the pathogenesis of T2D that can cause lipotoxicity. Accumulation of lipids in the skeletal muscle is associated with insulin resistance, but the majority of previous studies do not prove any causality. Most studies agree that it is not the intramuscular lipids per se that causes insulin resistance, but rather lipid intermediates such as diacylglycerols, fatty acyl-CoAs and ceramides and that it is the localization, composition and turnover of these intermediates that play an important role in the development of insulin resistance and T2D. Adipose tissue is a more active tissue than previously thought, and future research should thus aim at examining the exact role of lipid composition, cellular localization and the dynamics of lipid turnover on the development of insulin resistance. In addition, ectopic storage of fat has differential impact on various organs in different phenotypes at risk of developing T2D; thus, understanding how adipogenesis is regulated, the interference with metabolic outcomes and what determines the capacity of adipose tissue expandability in distinct population groups is necessary. This study is a review of the current literature on the adipose tissue expandability hypothesis and how the following ectopic lipid accumulation as a consequence of a limited adipose tissue expandability may be associated with insulin resistance in muscle and liver.

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Metabolic signature of obesity-associated insulin resistance and type 2 diabetes

Journal of Translational Medicine ◽

10.1186/s12967-019-2096-8 ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 4

Author(s):

Haya Al-Sulaiti ◽

Ilhame Diboun ◽

Maha V. Agha ◽

Fatima F. S. Mohamed ◽

Stephen Atkin ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Serum Samples ◽

Metabolic Markers ◽

Insulin Resistant ◽

Increased Risk ◽

Novel Biomarkers ◽

Prospective Cohorts

Abstract Background Obesity is associated with an increased risk of insulin resistance and type 2 diabetes mellitus (T2DM). However, some obese individuals maintain their insulin sensitivity and exhibit a lower risk of associated comorbidities. The underlying metabolic pathways differentiating obese insulin sensitive (OIS) and obese insulin resistant (OIR) individuals remain unclear. Methods In this study, 107 subjects underwent untargeted metabolomics of serum samples using the Metabolon platform. Thirty-two subjects were lean controls whilst 75 subjects were obese including 20 OIS, 41 OIR, and 14 T2DM individuals. Results Our results showed that phospholipid metabolites including choline, glycerophosphoethanolamine and glycerophosphorylcholine were significantly altered from OIS when compared with OIR and T2DM individuals. Furthermore, our data confirmed changes in metabolic markers of liver disease, vascular disease and T2DM, such as 3-hydroxymyristate, dimethylarginine and 1,5-anhydroglucitol, respectively. Conclusion This pilot data has identified phospholipid metabolites as potential novel biomarkers of obesity-associated insulin sensitivity and confirmed the association of known metabolites with increased risk of obesity-associated insulin resistance, with possible diagnostic and therapeutic applications. Further studies are warranted to confirm these associations in prospective cohorts and to investigate their functionality.

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