Diabetes, a road paved with unfolded proteins

Credit: www.chaval.es

Diabetes is a metabolic disorder characterized by an inefficiency to respond to the glucose requirements of the body, a process largely regulated by the popular hormone known as insulin. Insulin is produced and secreted in a specific type of cells in the pancreas called β-cells, which are able to detect and respond to high glucose levels in blood, in order to produce a secretion of insulin. As a result, glucose uptake increases at all tissue levels following an energetic need, and the blood vessels remain free from excessive glucose concentrations which in turn result harmful for the organism. When a genetic failure affects β-cells development or disrupts the molecular transducers of insulin signaling, we have the type I diabetes which is normally surpassed by an external, chronic administration of insulin.

However, it is known that diabetes can arise as a consequence of obesity, without the participation of the same genetic failures that give rise to type I diabetes. This type II diabetes is characterized by a lack of response of otherwise normal β-cells, which after a continuous and excessive exposure to high glucose levels in blood and the consequent overproduction of insulin, lose the capacity to regulate glucose intake. This situation is called insulin resistance and the mechanisms that it implies range from an increase in β-cell mass to an overproduction of insulin. However, the concrete processes that result in type II diabetes are being investigated and little is known about the molecular events that in a first instance trigger this misunderstanding of the insulin-regulated signals. It is intriguing the fact that some obese patients never develop diabetes whereas others do; but somehow the answer seems to lay in how particular β-cells are able to overcome the high insulin production required for maintaining glucose homeostasis without failing and dying in the process.

The genetically modified mice used in this study are defective in a signaling pathway controlled by the hormone leptin, which regulates apetite and metabolism in different ways, leading to an increased body weight among other symptoms. Readers are encouraged to guess which mouse in the picture is the genetically modified one | Credit: The Jackson Laboratory

The study presented by Chan and collaborators 1 puts forward a new and interesting point of view: the work is based in the comparison of two types of genetically modified mice, both of them suffering from obesity and insulin resistance (although each mouse strain is defective in different individual genes, both of them are related to the hormone leptin which regulates food intake and energetic metabolism). Interestingly, when bred in different conditions (after mating with mice with a slightly different genetic background), only one of the strains is able to overcome the progression to diabetes. The researchers reasoned that the differences of β-cells from the diabetes-prone strain, when compared to the diabetes-resistant one, may reflect what problems the β-cells from obese patients have to deal with, in order to avoid insulin resistance and diabetes.

The starting point for the study (scientists usually work following clues, like detectives) was the suggestion by other authors that one of the events that contribute to β-cell failure is the stress suffered by the endoplasmic reticulum (from now on, ER stress). When cells face adverse conditions, the endoplasmic reticulum (the place in the cell where proteins are assembled and processed, as in a factory) receives injuries that in turn promote a collection of badly formed proteins (proteins are constructed as linear chains that need to be properly folded to perform their functions). When these accumulate, the cell develops a response consisting in trying to properly fold and restructure these proteins, and when not possible, triggering their removal and even leading to a programmed cell death if everything fails. This chain of events is called unfolded protein response (UPR) and is a common contributor to many cell death processes with diverse origins.

Going back to our β-cells and their predisposition to diabetes, the authors selected a series of genes which have been reported to be activated or inhibited in certain cellular processes related to the object of the study (genes critical for β-cell function, genes involved in the UPR process and genes related to other significant mechanisms involved in cell death like inflammation or the response to oxidative stress). They compared the diabetes-prone strain and the diabetes-resistant one, and the comparison was performed at two different stages, 6 and 16 weeks of age in order to estimate the progression of the situation. Summarizing all the presented data, the diabetes-resistant cells showed a stronger capacity to maintain the response to unfolded proteins while kept inactivated the triggering of associated cell-death; they also maintained the expression of β-cell specific gene expression, and presented a markedly reduced expression of genes related to inflammation and oxidative stress responding genes. On the other hand, diabetes-prone β-cells progressively lost their particular β-cell phenotype (each set of cells in our body possesses a particular set of characteristics defined by their gene expression profile, this is called the phenotype) , presented a reduced response to unfolded proteins and an increased expression of inflammatory and oxidative stress genes.

Scheme depicting the chain of events hypothesized to link obesity with the development of diabetes, with ER stress as the key central process, as described by the authors | Credit: modified from Chan et al.

A question that arises is whether these particular molecular processes, and not others, are the only starting events that finally lead β-cells to death, or simply consequences of other yet unveiled failures of the cellular system. The authors addressed this matter treating cells with a substance that improves the folding of the proteins and minimizes the effects of the UPR process; what they observed was a recovery of the β-cell specific responses in diabetes-prone cells, although there were still several problems related to inflammation and oxidative stress.

What underlies this landscape of expression profiles is that the incapacity of cells to overcome a sustained exposure to unfolded proteins and ER stress is one of the first and main contributors to a loss of the β-cell phenotype. Since obesity is a condition that triggers the levels of reactive oxygen species (i.e. enhancing oxidative stress) and promotes an overproduction of insulin, β-cell populations which are unable to respond to this situation finally lose their specific genetic properties and fail in responding to other deleterious situations. The focus on particular mediators of the UPR and the expression of glucose homeostasis genes constitutes the final link that confirms a pivotal role for the ER stress as one of the most important processes that lead to the development of type II diabetes.

Unfolded protein response and oxidative stress are arising as otherwise normal cell processes which are severely altered in many disorders, in which they also play a feedback process that worsens the situation (oxidation of proteins contributes to improper folding). This chain of events is present in a vast majority of neurodegenerative pathologies, and now it seems to play an important role in the development of diabetes. May we know a future where the benefits of a correct and balanced diet and knowing the genetic profile of each patient’s β-cells will be enough to stop the progression to diabetes? Will discrete administration of drugs oriented to prevent unfolded proteins and ER stress become the final break on the progression to pathologies as different as neurological disorders or insulin resistance? It is too soon to tell, but it surely should be a research path to watch closely.


  1. Chan JY, Luzuriaga J, Bensellam M, Biden TJ, Laybutt DR (2012) Failure of the Adaptive Unfolded Protein Response in Islets of Obese Mice Is Linked With Abnormalities in β-Cell Gene Expression and Progression to Diabetes. Diabetes PMID: 23274897

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