Evidence of betacell dedifferentiation in human type 2 diabetes. Astwood award lecture by recipient domenico accili, md, on the dedifferentiation, rather than the death, of pancreatic. Intriguingly, fgf1 levels are elevated in newly diagnosed cases of type 2 diabetes as compared to normal glucose tolerance controls. Thorens from the center for integrative genomics, university of lausanne, lausanne, switzerland.
Cell failure in type 2 diabetes type 2 diabetes t2d, which accounts for the vast majority of diabetes cases, is one of the greatest global health problems. We arbitrarily defined a dedifferentiated cell as a synpositive ie, endocrine cell that failed to react with antibodies to the 5 pancreatic hormones. Alterations in beta cell identity in type 1 and type 2 diabetes. Beta cell dedifferentiation in type 2 diabetes jdrf npod.
Here, we examined the sensitivity of key isletenriched transcription factors to oxidative stress, a condition associated with. Targeting betacell preservation in the management of type. The objective of the study was to establish the potential impact of. A decrease in the number of functional insulinproducing. Normal betacell function the main role of betacell is to synthesize and secrete insulin in order to maintain circulating glucose levels within physiological range. Currently it affects 9% of world population, and its prevalence is increasing in epidemic proportions 1. Cell dedifferentiation in human type 2 diabetes article pdf available in the journal of clinical endocrinology and metabolism 1014.
Type 1, type 2, lada or since onfusion abounds, isnt it time for a new classification schema for the diagnosis and treatment of diabetes mellitus dm get us ready for preision mediine. The conference featured prominent discussions surrounding beta cells in type 2 diabetes, notably the michaela diamant memorial symposium on beta cell failure in type 2 diabetes, chaired by kenneth polonsky, md, and the edwin b. Type 2 diabetes is associated with defective insulin secretion, reduced. The role of glucagon on type 2 diabetes at a glance. Although several studies have highlighted evidence from rodent models, 75 cell dedifferentiation is also proposed to be a feature in the pathophysiology of human type 2 diabetes. The opposite effects of insulin and glucagon in fuel homeostasis, the paracrineendocrine inhibitory effects of insulin on glucagon secretion and the hyperglucagonemia in the pathogenesis of type 2 diabetes t2d have long been recognized.
We thus hypothesize that an excess pancreatic fgf can contribute to. Inappropriately increased alphacell function importantly contributes to hyperglycemia and reflects the loss of tonic restraint normally exerted by high. Type 2 diabetes mellitus t2dm is believed to be associated with lowgrade chronic inflammation. For patients with type 1 diabetes, it is accepted among the scientific community that there is a marked reduction in. The reversible nature of early type 2 diabetes has been demonstrated in in vivo human studies. New data provide support for betacell dedifferentiation as a cause of reduced insulin secretion. Cell lineagetracing in rodents and human autopsy surveys support the notion of. Genetic predisposition for beta cell fragility underlies.
Beta cells and the future of diabetes care feature. Modeling human pancreatic beta cell dedifferentiation. Type 2 diabetes results from a combination of insulin resistance and dysfunction of insulin producing pancreatic beta cells. Calorie restriction for longterm remission of type 2 diabetes. Pancreatic beta cell dedifferentiation as a mechanism of. Betacell failure in type 2diabetes type 2 diabetes t2d, which accounts for the vast majority of diabetes cases, is one of the greatest global health problems. Moreover, type 2 diabetes is a heterogeneous disease, and it is plausible that there are other groups of patients perhaps lean patients, as opposed to the obese patients reported here in which. Betacell failure in type 2 diabetes t2d was recently proposed to involve dedifferentiation of betacells and ectopic expression of other islet hormones, including somatostatin and glucagon. Stein 2 1 division of endocrinology, diabetes and metabolism, comprehensive diabetes center and department of medicine, university of alabama at birmingham, birmingham, al, usa. Gradual accumulation of fat in the liver and pancreas leads eventually to beta cell dedifferentiation and loss of specialised function. We scored dedifferentiation using markers of endocrine lineage. The current study aims to investigate the involvement of leptin and tnf.
Strikingly, we identify the same sequence of events as a feature of different models of murine diabetes. Cell dedifferentiation, however, is a broad and loosely defined term that generally refers to an alteration in. Themetabolicstressof chronic nutrient oversupply can lead to reduced expression or nuclear activity ofkey bcell tran. Effect of the sodiumglucose cotransporter 2 inhibitor. Preventing beta cell dedifferentiation in type 1 diabetes. Betacell dedifferentiation and type 2 diabetes new england. As betacell function progressively declines over time, blood glucose rises. This is a pdf file of an unedited manuscript that has been. Betacell dedifferentiation and type 2 diabetes request pdf.
Beta cell failure is a central feature of type 2 diabetes t2d, but the molecular underpinnings of the process remain only partly understood. Type 2 diabetes mellitus t2dm, which constitutes more than 90 % of the diabetes patients, is generally linked with insulin resistance of peripheral tissue, reduction of beta cell mass and compromised insulin secretion ability of beta cells 1, 2. This includes the loss of transcriptional regulators of beta cell function as well as other critical components of beta cell function. Recent evidence suggests that beta cell dedifferentiation is a key early mechanism that underlies the pathogenesis of type 2 diabetes t2d 1. Type 2 diabetes is caused by enhanced insulin resistance and reduced insulin secretion. Evidence for loss in identity, dedifferentiation, and transdifferentiation of islet. Beta cell formation in vivo through cellular networking. It has been suggested that beta cell failure in t2d involves massive cell death. Type 2 diabetes t2d is caused by an inherited predisposition to pancreatic. Although it is well established that type 2 diabetes t2d is generally due to the progressive loss of.
Both classic forms of diabetes mellitus are characterized by the inability of pancreatic. Betacell dedifferentiation and type 2 diabetes nejm. Targeting betacell preservation in the management of type 2 diabetes type 2 diabetes t2d is widely considered a chronic and progressive disease without cure. This concept is termed dedifferentiation and has been proposed, besides cell death, as a contributing factor to the loss of functional. Starting with a hypothesis which postulated a simple explanation arising from the basic cause of type 2 diabetes, a series of studies has introduced a paradigm shift in our understanding of the condition. Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure. Request pdf on feb 7, 20, yuval dor and others published betacell dedifferentiation and type 2 diabetes find, read and cite all the research you need. In type 2 diabetes, the body becomes resistant to its insulin and attempts to compensate by producing a higher quantity of insulin. Type 2 diabetes t2d, which accounts for the vast majority of diabetes cases, is one of the greatest global health problems. By these criteria, dedifferentiated cells accounted for 31. This process is reversible, such that the same cell can regain an insulinpositive. They find that the changes in the molecular pathways identified as contributing to beta cell loss are paralleled in human islets from patients with type 2 diabetes. Although a few fdaapproved therapies for type 2 diabetes meglitinides, sulfonylureas, incretinbased drugs directly enhance betacell function, no therapies for any form of diabetes. We propose that dedifferentiation trumps endocrine cell death in the natural history of.
Cell maturation and identity in health and disease mdpi. Other studies ascribe beta cell failure to cell exhaustion, due to chronic oxidative or endoplasmic reticulum stress leading to cellular dysfunction. Betacell dedifferentiation in type 2 diabetes stem. Type 2 diabetes mellitus t2d is characterized by insulin resistance in tissues including the liver, skeletal muscle and adipose tissue, and by impaired pancreatic beta cell function 1. We assessed dedifferentiation in pancreata from organ donors with and without diabetes.
Disclosure forms provided by the authors are available with the full text of this article at nejm. Beta cell mass is a simple concept, it is just the weight of all of the. Opinions diverge regarding the relative contribution of a decrease in. Instead, we observed similar numbers of red cells in the two genotypes. Research has shown that chronically elevated blood glucose levels chronic hyperglycemia over a long period of time can lead to beta cells wearing out, referred to as beta cell. Metabolic stress and compromised identity of pancreatic. Research design and methods a group of experts participated in a conference on 1416 october 20 cosponsored by the endocrine society and the american diabetes. We intend to investigate whether humans with type 1 and 2 diabetes develop the same abnormalities observed in foxo1. In a similar study using insulinresistant rodents, betatrophin was found to. Betacell dedifferentiation and type 2 diabetes article in new england journal of medicine 3686. Alterations in beta cell identity in type 1 and type 2.