Prediction and prevention of Type 1 diabetes mellitus. J

Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado 80045, USA.
Journal of Diabetes (Impact Factor: 1.93). 11/2010; 3(1):48-57. DOI: 10.1111/j.1753-0407.2010.00102.x
Source: PubMed


Type 1A diabetes mellitus (T1DM) is caused by autoimmune islet β-cell destruction with consequent severe insulin deficiency. We can now predict the development of T1DM by determining four biochemically characterized islet autoantibodies, namely those antibodies against insulin, glutamic acid decarboxylase 65, insulinoma antigen (IA)-2 (ICA512) and the zinc transporter ZnT8. We can also prevent T1DM in animal models, but the final goal is the prevention of T1DM in humans. Multiple clinical trials are underway investigating methods to prevent β-cell destruction.

Download full-text


Available from: Li Zhang, May 20, 2014
  • Source
    • "T1D has a strong genetic component. Relatives of diabetic patients have a high risk of developing the disease; siblings have a greater risk than offspring, and there is a high concordance rate among identical twins [27] [28]. This genetic predisposition (or lack thereof) is determined by the balance between susceptibility and resistance alleles. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We review type 1 diabetes and host genetic components, as well as epigenetics and viruses associated with type 1 diabetes, with added emphasis on the enteroviruses, which are often associated with triggering the disease. Genus Enterovirus is classified into twelve species of which seven (Enterovirus A, Enterovirus B, Enterovirus C, and Enterovirus D and Rhinovirus A, Rhinovirus B, and Rhinovirus C) are human pathogens. These viruses are transmitted mainly by the fecal-oral route; they may also spread via the nasopharyngeal route. Enterovirus infections are highly prevalent, but these infections are usually subclinical or cause a mild flu-like illness. However, infections caused by enteroviruses can sometimes be serious, with manifestations of meningoencephalitis, paralysis, myocarditis, and in neonates a fulminant sepsis-like syndrome. These viruses are often implicated in chronic (inflammatory) diseases as chronic myocarditis, chronic pancreatitis, and type 1 diabetes. In this review we discuss the currently suggested mechanisms involved in the viral induction of type 1 diabetes. We recapitulate current basic knowledge and definitions.
    Full-text · Article · Dec 2014
  • Source
    • "An insufficient zinc level inside the insulin manufacturing organelles such as endoplasmic reticulum (ER) or vesicles may result in hypoinsulinemia. Recently, several research groups offered that ZnT transporters (from Slc30a genes) transporting zinc out of the cells or organelles particularly ZnT8 as a culprit responsible for gestational diabetes [6], type 1 diabetes [7] and type 2 diabetes [8]. On the other hand, studies on the Slc39a8 gene for ZIP8 transporter in relation to diabetes are rare. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Without zinc, pancreatic beta cells cannot either assemble insulin molecules or precipitate insulin crystals; thus, a lack of zinc concentration in the beta cells would result in a decreased insulin production. ZIP8 is one of the zinc uptake transporters involved in zinc influx into the cytosol of beta cells. Thus, if ZIP8 is down-regulated, a decreased insulin production would result. We assumed that intermittent hypoxic exposure to the beta cells may result in a decreased production of insulin due to a lack of zinc. To test this hypothesis we harvested pancreatic islets from the rats conditioned under intermittent hypoxia (IH) (fluctuating between 20.5% and 10% every 4 min for 1 h) and compared the results with those from control animals and islets. We also compared their insulin and glucose homeostasis using glucose tolerance tests (GTT) after 3 weeks. GTT results show a significant delay (P<0.05) in recovery of the blood glucose level in IH treated pups. ZIP8 expression in the beta cell membrane was down-regulated. The zinc concentration in the cell as well as insulin production was significantly decreased in the islets harvested from IH animals. However, mRNA for insulin and C-peptide/insulin protein levels in the total cell lysates remained the same as those of controls. When we treated the beta cells using siRNA mediated ZIP8, we observed the commensurate results from the IH-treated islets. We conclude that a transient IH exposure could knockdown ZIP8 transporters at mRNA as well as protein levels in the beta cells, which would decrease the level of blood insulin. However, the transcriptional activity of insulin remains the same. We conclude that the precipitation process of insulin crystal may be disturbed by a lack of zinc in the cytosol that is modulated by mainly ZIP8 after IH exposure.
    Full-text · Article · Feb 2014 · PLoS ONE
  • Source
    • "This genetic association implies an increased risk for T1DM in those carrying the mutation, but because T1DM is a multifactorial disease, mutations in TCF19 alone are clearly not causal in isolation. A genetic predisposition to autoimmunity is already a clear factor in the development of T1DM, but only a small percentage of individuals with at-risk human leukocyte antigen alleles go on to develop disease (54). In addition, islet autoantibodies can be present in individuals who do not have T1DM or go on to develop it much later in life (54). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recently, a novel type 1 diabetes association locus was identified at human chromosome 6p31.3, and TCF19 is a likely causal gene. Little is known about Tcf19, and we now show that it plays a role in both proliferation and apoptosis in insulinoma cells. Tcf19 is expressed in mouse and human islets, with increasing mRNA expression in non-diabetic obesity. The expression of Tcf19 is correlated with β-cell mass expansion, suggesting that it may be a transcriptional regulator of β-cell mass. Increasing proliferation and decreasing apoptotic cell death are two strategies to increase pancreatic β-cell mass and prevent or delay diabetes. siRNA-mediated knockdown of Tcf19 in the INS-1 insulinoma cell line, a β-cell model, results in a decrease in proliferation and an increase in apoptosis. There was a significant reduction in the expression of numerous cell cycle genes from late G1 phase through M phase and cells were arrested at the G1/S checkpoint. We also observed increased apoptosis and susceptibility to endoplasmic reticulum (ER)-stress after Tcf19 knockdown. There was a reduction in expression of genes important in maintenance of ER homeostasis (Bip, p58(IPK), Edem1, and Calreticulin) and an increase in pro-apoptotic genes (Bim, Bid, Nix, Gadd34, and Pdia2). Therefore, Tcf19 is necessary for both proliferation and survival and is a novel regulator of these pathways.
    Full-text · Article · Jul 2013 · AJP Endocrinology and Metabolism
Show more