IL-6 induced enhanced clearance of proANP and ANP by insulin-degrading enzyme in T1DM mouse

Cardiovascular disease (CVD) is the prevalent cause of morbidity and mortality in type I diabetes mellitus (T1DM) worldwide. However, the pathophysiological mechanisms underlying the relationship between CVD, CVD risk factors, and T1DM have not yet been sufficiently explored. Here we reported that insulin-degrading enzyme (IDE) effectively degrades the precursor of atrial natriuretic peptide (proANP) intracellular in HEK293T cells. Pro-inflammatory cytokine IL-6 elicited a significant dose-dependent increase in IDE protein expression. Inhibition of ERK/MAPK signaling pathway with selumetinib abolished IL-6-stimulated increase in IDE protein level and deceased in ANP secretion in H9C2 cells. Importantly, the T1DM mouse model displayed lower proANP in the heart and ANP in serum, due to increased IDE expression and activity. Our outcomes suggest a novel role of IL-6 on ANP metabolism via IDE and provide the possibilities for new potential therapeutic strategies for diabetes-related cardiovascular complications.

Download Full-text

Role of Hypoxia-Mediated Autophagy in Tumor Cell Death and Survival

Cancers ◽

10.3390/cancers13030533 ◽

2021 ◽

Vol 13 (3) ◽

pp. 533

Author(s):

Rania F. Zaarour ◽

Bilal Azakir ◽

Edries Y. Hajam ◽

Husam Nawafleh ◽

Nagwa A. Zeinelabdin ◽

...

Keyword(s):

Cell Death ◽

Type I ◽

Dependent Manner ◽

Destruction Process ◽

Tumor Cell Death ◽

Complex Regulation ◽

Cancer Immunotherapies ◽

The Relationship ◽

Shed Light

Programmed cell death or type I apoptosis has been extensively studied and its contribution to the pathogenesis of disease is well established. However, autophagy functions together with apoptosis to determine the overall fate of the cell. The cross talk between this active self-destruction process and apoptosis is quite complex and contradictory as well, but it is unquestionably decisive for cell survival or cell death. Autophagy can promote tumor suppression but also tumor growth by inducing cancer-cell development and proliferation. In this review, we will discuss how autophagy reprograms tumor cells in the context of tumor hypoxic stress. We will illustrate how autophagy acts as both a suppressor and a driver of tumorigenesis through tuning survival in a context dependent manner. We also shed light on the relationship between autophagy and immune response in this complex regulation. A better understanding of the autophagy mechanisms and pathways will undoubtedly ameliorate the design of therapeutics aimed at targeting autophagy for future cancer immunotherapies.

Download Full-text

Association of insulin-degrading enzyme with a 70 kDa cytosolic protein in hepatoma cells

Biochemical Journal ◽

10.1042/bj3190149 ◽

1996 ◽

Vol 319 (1) ◽

pp. 149-158 ◽

Cited By ~ 21

Author(s):

François AUTHIER ◽

Pamela H. CAMERON ◽

Véronique TAUPIN

Keyword(s):

Hepg2 Cells ◽

Chinese Hamster Ovary Cells ◽

Subcellular Location ◽

Hepatoma Cells ◽

Minor Amount ◽

Type I ◽

Insulin Degrading Enzyme ◽

Western Blots ◽

Degrading Enzyme ◽

Cell Lysates

We have investigated the biosynthesis, subcellular location and expression of insulin-degrading enzyme (IDE), a type-I peroxisomal protease, in semi-permeabilized hepatoma cells using pulse-chase experiments, non-denaturing immunoprecipitation protocols and Northern-blot analyses. In HepG2 cell lysates prepared from cells radiolabelled with Tran[35S]-label, immunoprecipitated IDE was observed immediately after a 5 min pulse and subsequently declined during chase with t½ of approx. 33 h. In addition to the 110 kDa IDE protein, a protein of 70 kDa (p70) was identified in radiolabelled immunoprecipitates when using a monoclonal anti-IDE antibody 9B12 under non-denaturing conditions. This same antibody did not recognize p70 on Western blots of whole-cell lysates nor in sequential immunoprecipitates of immunocomplex-bead eluates from anti-IDE immunoprecipitations. Likewise, cross-linking studies performed on intact HepG2 and H35 hepatoma cells in vivo revealed the existence of a hetero-oligomeric complex of 180 kDa in which IDE and p70 were physically associated. Digitonin-permeabilization studies in normal and 35S-labelled HepG2 cells have defined a predominant association of IDE and its associated protein p70 with cytosol (supernatant); only a minor amount of the protein IDE was detected in peroxisomes (cellular pellet). Immunoprecipitation of IDE from 35S-labelled cell lysates of normal and stably transfected Chinese hamster ovary cells overexpressing IDE failed to detect p70. Treatment of HepG2 cells with clofibrate, a peroxisome proliferator, resulted in a dose-dependent increase of the two human IDE transcripts of 3.6 and 3.2 kb. This effect was not accompanied by a similar change at the protein level, nor by a change in the subcellular location of the proteins IDE and p70. Based on these findings we propose that in hepatoma cells: (1) IDE mainly exists in a stable cytoplasmic pool that is unchanged in cells undergoing peroxisomal proliferation; and (2) p70 binding to IDE may serve to maintain the dual cytosolic and peroxisomal pools of IDE in a stable equilibrium. Receieved 11 March 1996/30 May 1996; accepted 25 June 1996

Download Full-text

The Role of Interferon-α in the Development of Type I Diabetes

Genetic Models of Immune and Inflammatory Diseases ◽

10.1007/978-1-4612-2376-4_16 ◽

1996 ◽

pp. 154-166

Author(s):

Xiaojian Huang ◽

Bruce Hultgren ◽

Sharon Pitts-Meek ◽

Jim Hully ◽

Jim Maclachlan ◽

...

Keyword(s):

Type I Diabetes ◽

Interferon Α ◽

Type I

Download Full-text

The Role of Type I Diabetes in Intervertebral Disc Degeneration

Spine ◽

10.1097/brs.0000000000003054 ◽

2019 ◽

Vol 44 (17) ◽

pp. 1177-1185 ◽

Cited By ~ 5

Author(s):

Fabrizio Russo ◽

Luca Ambrosio ◽

Kevin Ngo ◽

Gianluca Vadalà ◽

Vincenzo Denaro ◽

...

Keyword(s):

Intervertebral Disc ◽

Disc Degeneration ◽

Intervertebral Disc Degeneration ◽

Type I Diabetes ◽

Type I

Download Full-text

Glucagon enhances the direct suppressive effect of insulin on hepatic glucose production in humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1997.272.3.e371 ◽

1997 ◽

Vol 272 (3) ◽

pp. E371-E378 ◽

Cited By ~ 4

Author(s):

G. F. Lewis ◽

M. Vranic ◽

A. Giacca

Keyword(s):

Type I Diabetes ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Insulin Delivery ◽

Suppressive Effect ◽

Type I ◽

Constant Rate ◽

Hepatic Glucose ◽

Infusion Method

The present study examines the role of glucagon in modulating the hepatic and extrahepatic effects of insulin on hepatic glucose production (HGP). We infused glucagon at a constant rate (0.65 ng x kg(-1) x min(-1)) during equimolar portal and peripheral insulin delivery in seven healthy males by our previously published tolbutamide infusion method. In contrast to our previous study, in which glucagon fell by approximately 30% during hyperinsulinemia and suppression of HGP was significantly greater with equimolar peripheral than with portal insulin delivery, HGP was actually suppressed to a lesser extent with peripheral insulin delivery (69 +/- 10%) than when insulin was delivered portally (76 +/- 5%, P < 0.05). To further examine whether glucagon was enhancing the effect of portal insulin, in four additional individuals HGP was suppressed to a greater extent during a tolbutamide infusion when glucagon was administered continuously throughout the basal and hyperinsulinemic periods than when glucagon was infused during the basal period only; HGP suppressed by 63 +/- 3 vs. 52 +/- 3%, respectively, P = 0.02). Tolbutamide had no effect on HGP when infused into three C-peptide-negative individuals with type I diabetes during a low-dose insulin and glucagon infusion. These data suggest that glucagon levels are an important determinant of the balance between insulin's direct and indirect effects on HGP, with glucagon likely potentiating the direct hepatic effect of insulin.

Download Full-text

The relationship of the renin-angiotensin system in type I diabetes to microvascular disease.

Hypertension ◽

10.1161/01.hyp.7.6_pt_2.ii84 ◽

1985 ◽

Vol 7 (6_pt_2) ◽

Cited By ~ 5

Author(s):

P L Drury ◽

H J Bodansky

Keyword(s):

Type I Diabetes ◽

Microvascular Disease ◽

Renin Angiotensin System ◽

Type I ◽

Angiotensin System ◽

Renin Angiotensin ◽

Relationship Of ◽

The Relationship

Download Full-text

Cancer Biology and Prevention in Diabetes

Cells ◽

10.3390/cells9061380 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1380 ◽

Cited By ~ 1

Author(s):

Swayam Prakash Srivastava ◽

Julie E. Goodwin

Keyword(s):

Type Ii Diabetes ◽

Cancer Biology ◽

Cancer Metastasis ◽

Type I Diabetes ◽

Type I ◽

Type Ii ◽

Mesenchymal Transition ◽

Wide Range ◽

Risk Of Cancer

The available evidence suggests a complex relationship between diabetes and cancer. Epidemiological data suggest a positive correlation, however, in certain types of cancer, a more complex picture emerges, such as in some site-specific cancers being specific to type I diabetes but not to type II diabetes. Reports share common and differential mechanisms which affect the relationship between diabetes and cancer. We discuss the use of antidiabetic drugs in a wide range of cancer therapy and cancer therapeutics in the development of hyperglycemia, especially antineoplastic drugs which often induce hyperglycemia by targeting insulin/IGF-1 signaling. Similarly, dipeptidyl peptidase 4 (DPP-4), a well-known target in type II diabetes mellitus, has differential effects on cancer types. Past studies suggest a protective role of DPP-4 inhibitors, but recent studies show that DPP-4 inhibition induces cancer metastasis. Moreover, molecular pathological mechanisms of cancer in diabetes are currently largely unclear. The cancer-causing mechanisms in diabetes have been shown to be complex, including excessive ROS-formation, destruction of essential biomolecules, chronic inflammation, and impaired healing phenomena, collectively leading to carcinogenesis in diabetic conditions. Diabetes-associated epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndMT) contribute to cancer-associated fibroblast (CAF) formation in tumors, allowing the epithelium and endothelium to enable tumor cell extravasation. In this review, we discuss the risk of cancer associated with anti-diabetic therapies, including DPP-4 inhibitors and SGLT2 inhibitors, and the role of catechol-o-methyltransferase (COMT), AMPK, and cell-specific glucocorticoid receptors in cancer biology. We explore possible mechanistic links between diabetes and cancer biology and discuss new therapeutic approaches.

Download Full-text