Insulin and Ferritin
Insulin

Author: Gianpiero Pescarmona
Date: 09/12/2008

Description

Is Deferoxamine a suitable therapy for Diabetes in patients with over 500 ng/mL Ferritin?

Deferoxamine therapy in high-ferritin diabetes. 1989 FullText

Who is the expert?

Papers Fargion Silvia

Interactions between Iron load and Insulin sensitivity

Also, Fargion et al. (8) studied a cohort of 40 patients with hyperferritinemia and found IR in
69%. Several hypotheses have been postulated to explain this association. Iron overload is believed to lead to IR, as suggested by the fact that iron depletion can improve insulin sensitivity (9–11).
Also, a recent study showed a decrease in the development of diabetes mellitus in blood donors,
which correlated with a reduction in iron deposits and an increase in insulin sensitivity (12). Besides, iron overload can interfere with insulin signaling through the induction of reactive oxygen species, the latter impairing insulin uptake through a direct effect on insulin receptor function, by
inhibiting the translocation of GLUT4 to the plasma membrane (13, 14) and iron can also induce IR of glucose transport in adipocytes (15).
Nash, insulin resistance and iron 2006

A relationship between serum ferritin and the insulin resistance syndrome is present in non-diabetic women but not in non-diabetic men 2002

Iron and Insulin, Medscape 2002

Endocytosis mechanism

Endocytosis cartoon

Insulin endocytosis Reactome;

Na+/H+ antiporter is the primary proton transport system used by osteoclasts during bone resorption.Hall TJ, Chambers TJ.J Cell Physiol. 1990

This redistribution of transferrin receptors between cellular membrane fractions in response to insulin is remarkably similar to the regulation by insulin of glucose transporters and type II insulin-like growth factor receptors. We conclude that insulin stimulates fat cell iron uptake by a mechanism that may involve the redistribution of transferrin receptors from an internal membrane compartment (low density microsomes) to the cell surface (plasma membrane).
Insulin stimulates cellular iron uptake and causes the redistribution of intracellular transferrin receptors to the plasma membrane 1986

Arrest of endosome acidification by bafilomycin A1 mimics insulin action on GLUT4 translocation in 3T3-L1 adipocytes. 1999

Insulin-induced redistribution of GLUT4 glucose carriers in the muscle fiber. In search of GLUT4 trafficking pathways. 1996

Differential expression of a subunit isoforms of the vacuolar-type proton pump ATPase in mouse endocrine tissues. 2007

The V-type H+ ATPase: molecular structure and function, physiological roles and regulation. 2006

Bafilomycin A(1), a diagnostically specific inhibitor of V-ATPase, inhibited insulin- and nigericin-stimulated 2-DG uptake.
Involvement of vesicular H+-ATPase in insulin-stimulated glucose transport in 3T3-F442A adipocytes. 2007

Role of furin in granular acidification in the endocrine pancreas: identification of the V-ATPase subunit Ac45 as a candidate substrate. 2008

Association with hyperparathyroidism

In contrast to the novel work with PTHrP, parathyroid hormone (PTH) has a longstanding clinical link with CPPD deposition disease. Hyperparathyroidism is a well-established risk factor for chondrocalcinosis [25]. This year, Pawlotsky et al. [26•] demonstrated how this connection might be broadened to apply to hemochromatosis, another metabolic disorder associated with chondrocalcinosis. In this study, the authors hypothesized that the arthritis associated with hemochromatosis might be related to increased levels of PTH in these patients. They found that of the 210 patients with hemochromatosis tested, one third had elevated PTH 44-68 levels, and that levels of this PTH fragment correlated with serum ferritin and the number of affected joints. They postulated that this PTH fragment might affect mineralization of bone and cartilage. The authors propose that elevated levels of this PTH fragment may result from iron deposition in the parathyroid gland itself. Certainly, further studies are necessary to establish the connection between iron overload and increased serum PTH fragments. However, this work suggests at least one common thread between the seemingly heterogeneous group of metabolic abnormalities associated with CPPD deposition. It will be interesting to see if these PTH fragments have direct effects on articular cartilage, and whether these PTH fragments are elevated in patients with idiopathic CPPD deposition disease. FullText

Coexisting hyperparathyroidism, renal osteodystrophy and psoriatic arthritis 1997 FullText

....hyperparathyroidism (4), di-. abetes mellitus. (5),. acromegaly (6), Wilson’s. disease. (7). and hemochromatosis (8-18). In re- ..
The Arthropathy of Hemochromatosis Without Hemochromatosis 1972

more information ....

Insulin stimulates glucose transport via nitric oxide/cyclic GMP pathway in human vascular smooth muscle cells. 2003

Large amount of (apo)ferritin in the pancreatic insulin cell and ... 1994

Ultrastructural localization of insulin receptors on adipocytes

Nef from HIV

HIV-1 Nef protects human-monocyte-derived macrophages from HIV-1-induced apoptosis 2006

Intracellular free iron and acidic pathways mediate TNF-induced death of rat hepatoma cells. 2005

Cutting Edge: SIV Nef Protein Utilizes Both Leucine- and Tyrosine-Based Protein Sorting Pathways for Down-Regulation of CD41 1999

There is a significant difference (p=0.004) between control and SIV Nef-treated cells
for Glut4 translocation upon stimulation with Insulin

Nef-mediated down-modulation of transferrin trafficking.

Modulation of Cellular Protein Trafficking by Human Immunodeficiency Virus Type 1 Nef: Role of the Acidic Residue in the ExxxLL Motif 2006 of Cellular Protein Trafficking by Human Immunodeficiency Virus Type 1 Nef: Role of the Acidic Residue in the ExxxLL Motif

Leucine-based motifs mediate the sorting of membrane proteins at such cellular sites as the trans-Golgi network, endosomes and plasma membrane.

A family of leucine-based motifs: distinct reading of different structural determinants modulates the dileucine-mediated transport steps of the lysosomal membrane protein LIMPII and the insulin-sensitive glucose transporter GLUT4 2000

Loss of Hmga1 expression, induced in mice by disrupting the Hmga1 gene, considerably decreased insulin receptor expression in the major targets of insulin action, largely impaired insulin signaling and severely reduced insulin secretion, causing a phenotype characteristic of human type 2 diabetes.
Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in humans and mice 2005

Alternative therapies

Use of alternative medicines in diabetes mellitus 2001

Viceversa: Insulin induces ferritin?

Hyperinsulinemia may boost both hematocrit and iron absorption by up-regulating activity of hypoxia-inducible factor-1alpha. 2003

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