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Year : 2016  |  Volume : 29  |  Issue : 2  |  Page : 181-186

β-Cell plasticity

1 Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Internal Medicine, Health Insurance Organization (HIO), Menoufia, Egypt

Date of Submission15-May-2014
Date of Acceptance16-Aug-2014
Date of Web Publication18-Oct-2016

Correspondence Address:
Mohammed A Farahat
Shebin El-Kom, Menoufia, 32511
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1110-2098.192413

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The aim of this study was to present the current trends and methodologies in the preservation of the β-cell function by targeting the β-cell mass.
Data sources:
Medical text books and also the ScienceDirect database were searched from the start date of the database and a search was performed on January 2014 with no language restrictions.
Data selection:
The selected articles are systematic reviews and experimental studies that address the β-cell plasticity and the β-cell mass and plasticity.
Data extraction:
Extraction was performed according to the quality, validity, and originality of the selected reviews and studies that fulfilled the previous criteria; in addition, the main focus was on studies that presented the latest or the most updated findings on the prevention and treatment of the β-cell failure.
Data synthesis:
Each review and study were reviewed independently without intercomparisons. The layout was selected to present a wide range of data including the most recent findings on the subject.
Recent findings:
Most recent studies concluded that the successful management of the growing epidemic of type-2 diabetes involves stopping the progressive loss of the β-cell mass and/or function before diabetes develops.
The main conclusion of the studies and reviews that were presented in the current research paper is that the preservation of a functional β-cell mass is the means to prevent diabetes. β-Cell plasticity is the ability of β-cells to adjust to the body's demand for insulin. Preservation of β-cell plasticity will preserve a functional β-cell mass. Once there is a functional β-cell mass diabetes cannot develop; in addition, a proper diet alone might be able to restore a good environment for the β-cell to function properly and preserve its mass, and many new strategies and approaches are being investigated for this purpose.

Keywords: β-cell mass, diabetes, diet, insulin resistance, plasticity

How to cite this article:
El-Kafrawy NA, Shoaib AA, Farahat MA. β-Cell plasticity. Menoufia Med J 2016;29:181-6

How to cite this URL:
El-Kafrawy NA, Shoaib AA, Farahat MA. β-Cell plasticity. Menoufia Med J [serial online] 2016 [cited 2024 Feb 29];29:181-6. Available from: http://www.mmj.eg.net/text.asp?2016/29/2/181/192413

  Introduction Top

β-Cell plasticity encompasses both expansion and involution of β-cells in response to changes in insulin demands for the maintenance of glucose homeostasis throughout the life span [1].

β-Cell mass is determined and maintained by the balance of islet neogenesis (formation of islets from islet precursor cells), hyperplasia (replication of pre-existing β-cell), hypertrophy (increase in the size of individual β-cells), and apoptosis (programmed cell death) [2].

During growth and development, islet neogenesis and β-cell replication are key mechanisms in β-cell mass expansion. Changes in insulin sensitivity induce changes in insulin secretion to maintain glucose concentrations within a narrow range [3].

Adaptation of β-cell mass can contribute toward this altered demand for insulin secretory capacity. Glucose is an attractive candidate because it plays a central role in the feedback loop between β-cell and the insulin-sensitive tissues responsible for glucose uptake. Incretins are also involved in the maintenance of β-cell mass and participate in glucose intracellular signaling pathway mechanisms. Other nonglucose mediators that are related to insulin resistance such as fatty acids (FAs), other humoral factors, and autonomic neurons might also be involved [3].

The current study discusses the factors that influence β-cell mass and the potential strategies for a therapeutic intervention in the preservation of β-cell mass.

  β-Cell Plasticity Top

Endocrine pancreas plasticity may be defined as the ability of the organ to adapt the cell mass to variations in insulin demand to ensure optimal control of glucose homeostasis. This property is essential and can be considered to enable long-term regulation of insulin secretion [4].

Net changes in β-cell mass are reflective of the amount of growth (i.e. the sum of β-cell replication, neogenesis, and size) minus the degree of β-cell death (i.e. the sum of β-cell apoptosis, necrosis, and autophagic cell death) [5].

In humans – immediately after birth, there is a transient burst of β- cell replication, followed by a transitory increase in neogenesis. In this phase, the rate of apoptosis is low and the net effect is a marked increase in β-cell growth early in life. Then, during childhood and adolescence, the rates of β-cell replication, neogenesis, and apoptosis adjust to reach a balance that ensures adequate β-cell mass through adulthood. With age, β-cell mass may decrease as apoptosis slightly outweighs replication and neogenesis. In rodents, β-cells have an estimated half-life of 50–60 days. Under normal conditions, 0.5% of adult β-cell undergo apoptosis, but this is balanced by the formation of new β-cells [4].

Pancreatic autopsy samples from obese patients with diabetes or with impaired fasting glucose or without diabetes as well as from lean patients were examined [6].

Relative β-cell volume was found to increase in obese versus lean nondiabetic individuals by increased neogenesis [7]. Compared with individuals with no diabetes, obese individuals with impaired fasting glucose and type-2 diabetes showed a 50 and 63% reduction in β-cell mass, respectively, whereas lean diabetics had a 41% deficit. In all cases, low rates of cell replication were observed, with no difference between diabetic and nondiabetic individuals. In contrast, the frequency of β-cell apoptosis was 10-fold greater in lean individuals and three-fold greater in obese individuals [8].

  β -Cell in Type-2 Diabetes Top

In type-2 diabetic patients, both increased apoptosis and decreased proliferation may contribute toward β-cell loss and reduced β-cell mass, although the precise mechanisms are yet to be fully elucidated. According to the glucolipotoxicity hypothesis, the deleterious effects of FAs on β-cells (impairment of insulin secretion, impairment of insulin gene expression, and induction of β-cell death) [9] may only occur in the presence of elevated glucose levels [0].

β-Cells exposed to chronic hyperglycemia generate excess levels of reactive oxygen species, leading to oxidative stress and β-cell dysfunction [1].

In the presence of excess glucose and FA levels, FA oxidation is inhibited and the esterification pathway is activated, leading to cytosolic accumulation of lipid-derived signals such as ceramides and triglycerides, all of which are deleterious to β-cells [2].

A variety of proapoptotic mechanisms, including endoplasmic reticulum (ER) stress, are also associated with the disease. In patients with type-2 diabetes, insulin resistance leads to prolonged stimulation of insulin biosynthesis. This means that such constant stimulation of the β-cell may cause the physiological process of 'the biosynthesis of insulin' to change into a pathophysiological process. The demand exceeds the folding capacity of the ER and results in stress, caused by ER accumulation of misfolded or unfolded proteins, finally leading to β-cell loss [3].

Under physiological conditions, ER stress can be caused by the adaptive unfolded protein response, but when ER stress is excessive or a defect is present in the unfolded protein response, the cells cannot maintain ER homeostasis and undergo cell death. For these reasons, chronic ER stress in β-cells can lead to β-cell dysfunction and death [4].

  Prevention of β -Cell Failure Top

Diet and lifestyle prevention

There is compelling clinical trial evidence that diabetes can be prevented or its onset can be delayed by lifestyle interventions; thus, it is critical to delineate the best dietary strategies. The importance of diet in the context of diabetes medical nutrition therapy has been the topic of several reviews, but few have focused on diabetes prevention [5].

A diet that might serve the purpose of both preventing diabetes in healthy individuals and contribute toward glycemic control in patients with established disease should contain abundant fiber from whole-grain foods, fruits, and vegetables, including pulses and nuts, and avoid simple sugars, especially those found in soda and fruit juices, as well as animal sources of saturated fatty acids (meat and meat products) and commercial sources of trans fatty acids (hydrogenated oils and margarines). Low-fat dairy products, moderate consumption of alcoholic beverages, and reasonable amounts of coffee or tea may be included in the daily diet, with some benefit [5].

Pharmacological intervention in the prevention of β-cell failure

Diabetes prevention with metformin

The Diabetes Prevention Program included a metformin arm, in which the incidence of diabetes was reduced by 31% [6]. The Center for Outcomes Research (CORE) diabetes model predicted that the interventions used in the Diabetes Prevention Program (metformin or lifestyle modification) would lead to an increase in diabetes-free years of life, improvements in life expectancy, and either cost savings or minor increases in costs compared with standard lifestyle advice in a population with impaired glucose tolerance (IGT) [7].

A small study in 70 Chinese patients with IGT compared the onset of diabetes over 1 year in those receiving either metformin or placebo. For a period of 1 year, the conversion rate to diabetes was significantly lower in the metformin group (3 vs. 16% in the placebo group) [7].

Diabetes prevention with thiazolidinediones

The Diabetes Prevention Program initially included a troglitazone intervention arm, which was discontinued after only 10 months (and substituted with a modified lifestyle intervention) because of the drug's withdrawal from the market [6]. The effect of troglitazone was attributed to improved insulin sensitivity along with maintenance of insulin secretion. However, because of the short duration of this arm of the study, the conclusions remain tentative and ongoing studies with thiazolidinediones (TZDs) will hopefully provide more definitive results. The landmark Troglitazone in Prevention of Diabetes (TRIPOD) study reported by Buchanan and colleagues investigated the development of diabetes in 266 high-risk Hispanic women with previous gestational diabetes treated with either troglitazone or placebo. During blinded treatment, after a median follow-up of 30 months, the average annual diabetes incidence rates in women who returned for follow-up were 12.1 and 5.4% in the placebo and the troglitazone groups, respectively, which represents a 55% reduction. Troglitazone treatment significantly improved insulin sensitivity, along with an unchanged acute insulin response, resulting in a significant improvement in the disposition index from baseline and versus placebo, suggesting improved β-cell compensation for insulin resistance [17],[18].

The cumulative incidence of diabetes decreased to zero in patients treated with troglitazone for more than 3 years, suggesting true diabetes prevention in a subset of the cohort. Participants in the TRIPOD study were also tested 8 months after they had stopped placebo or troglitazone [8]. The group that had been diabetes free by the treatment of troglitazone showed continued protection from diabetes, with stable glucose levels and β-cell function that had lasted for 4.5 years from the beginning of the study. However, those who had been on placebo continued to develop diabetes, as expected [7].

The Pioglitazone in Prevention of Diabetes (PIPOD) study tests whether the stability of glycemia and β-cell function observed during TRIPOD can be maintained with pioglitazone. All women who completed 8-month post-trial testing in the TRIPOD study were offered participation in the PIPOD study for a planned 3 years of open-label pioglitazone treatment and 6 months of postdrug washout. Among the 89 women without diabetes at completion of TRIPOD who enrolled in PIPOD, the annual diabetes incidence rate was 4.6%, almost identical to that in the initial troglitazone arm of the TRIPOD study [7].

Furthermore, β-cell function (as measured by disposition index) did not change significantly during PIPOD even in women originally on placebo who had shown a 33% decrease in function over a median of 4.6 years in the TRIPOD study. Thus, the protection from diabetes observed during the TRIPOD study remained during the 3 years of pioglitazone treatment in the PIPOD study. A recent single-center study that used a nonconventional (low-key) randomization approach lent support to the primary findings of the TRIPOD and PIPOD studies [9]. Over an average of 3 years, patients with IGT and insulin resistance (n = 172) received either a TZD (troglitazone was switched to pioglitazone or rosiglitazone after 10 months because of its withdrawal from the market) or a placebo. After 2 years, none of the patients receiving TZD therapy progressed to diabetes, and only three patients progressed to diabetes by the study end date. This translated into an 89% lower risk of diabetes in the TZD group compared with the control group after 3 years [7].

Other promising therapies

Studies with other non-insulin-sensitizing glucose-lowering therapies have also shown some promise for preventing diabetes. A study aimed at preventing non-insulin-dependent diabetes mellitus (STOP-NIDDM trial) showed a 25% reduction in diabetes rates over 3.3 years with the α-glucosidase inhibitor acarbose[20].

Furthermore, in the subgroup (37%) of patients with IGT in the EDIT study, the relative risk of diabetes was reduced significantly with acarbose (but not metformin or combination therapy). As acarbose is not absorbed systemically, it should not have any pharmacologic effect beyond its action to reduce glucose absorption in the gut; thus, any β-cell preserving effect is likely to be indirect [7].

In animal models, glucagon-like peptide-1 (GLP-1) (an incretin hormone), GLP-1 agonists (e.g. exendin-4), or inhibitors of dipeptidyl peptidase-4 (DPP-4, the enzyme that inactivates GLP-1) stimulate β-cell proliferation and neogenesis and reduce susceptibility to apoptotic injury [1].

More recently, the DPP-4 inhibitor sitagliptin has been shown to preserve β-cell mass and function in a rodent model of diabetes [2].

In human studies, the DPP-4 inhibitor vildagliptin has been shown to improve meal-related β-cell function. GLP-1 and the TZDs have different mechanisms of action, and combination treatment with pioglitazone and GLP-1 resulted in additive glucose-lowering effects. Similarly, exendin-4 improved glycemic control in patients who could not achieve goals with TZDs [3]. It is therefore also possible that the combination of the two classes of agents may also exert a synergistic effect on β-cell function [7].

  Treatment of β-Cell Failure Top

Actual treatments of type-2 diabetes aim to control hyperglycemia through lifestyle interventions (dietary management and development of physical activity), and antidiabetic drugs that increase insulin levels (insulin, sulfonylureas, incretin-mimetics, DPP-4 inhibitors), decrease insulin resistance (TZDs, biguanides), and/or slow postprandial glucose absorption (glucosidase inhibitors, amylin). Besides alleviating hyperglycemia, emerging experimental and clinical evidences indicate that some pharmacological therapies — but not all — exert a direct beneficial effect on β-cell [7].

Although the classical treatments such as metformin (biguanide), insulin, and sulfonylureas cannot prevent the progressive decrease of β-cell function in already diabetic patients, the synthetic ligands of peroxisome proliferator-activated receptor c (TZDs) used primarily as insulin sensitizers as well as the incretin-mimetics and DPP-4 inhibitors have been shown to exert important beneficial effects on β-cell function and survival both in vitro and in vivo, at least in rodents. They are actually used in the treatment of type-2 diabetes, mainly in combination with other drugs; however, the maintenance of their beneficial effect is not certain. Besides, recent observations in humans suggest that they may represent a major risk for the development of pancreatitis, several cancers, and myocardial infarction. Other potentially interesting therapeutic agents in clinical development include the sodium-glucose cotransporter type-2 (SGLT2) inhibitors that prevent glucotoxicity through the inhibition of renal glucose reabsorption [4] ([Figure 1],[Figure 2],[Figure 3],[Figure 4],[Figure 5]).
Figure 1:  Islets of Langerhans More Details – highly vascularized miniorgans

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Figure 2: Endocrine pancreas plasticity: capacity to modulate functional β-cell mass to adapt insulin production to insulin demand

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Figure 3: The β-cell mass is constantly renewed through a balance between mechanisms of expansion and involution

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Figure 4: Regulatory mechanisms of the pancreatic β-cell mass

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Figure 5: Effects of nutrients on pathways to development of diabetes. MUFA, monounsaturated fats; PUFA, polyunsaturated fats; SFA, saturated fatty acids; TFA, trans fatty acids; IGT, impaired glucose tolerance; SU, sulfonylureas

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  Conclusion Top

The main conclusions derived from the presented reviews and studies are as follows:

  1. Preservation of a functional β-cell mass is the means to prevent diabetes.
  2. β-Cell plasticity is a physiological mechanism by which the β-cell increases or decreases its mass to cope with the body's demand for insulin.
  3. Failure or disturbance of β-cell plasticity is the main cause for development of type-2 diabetes mellitus.
  4. Better understanding of this physiological mechanism and how it turns into a pathological mechanism would enable us to develop new approaches to deal with individuals at high risk of developing diabetes by many years.
  5. Many new strategies and approaches are being investigated for this purpose, but safety data on long-term use are still awaited.


The following recommendations can be drawn from the preceding discussion:

  1. Prolonged Sulfonylureas (SU) treatment resulted in decreased glycemic control because of a reduction in β-cell function, whereas it should be noted that the second-generation and third-generation SU are less associated with increased apoptosis rates in vitro; more studies should investigate whether SU treatment may preserve the β-cell mass.
  2. Further studies are recommended to investigate the long-term effects of incretin on β-cells and other parts of the body.
  3. Studies should be carried out on the safety of the use of new treatments for diabetes such as K channel openers as a means of inducing β-cell rest, agents that modulate Akt signaling, as it may have beneficial effects on β-cell mass and secretory capacity, the NF-κB inhibitor sodium salicylate, β-cell growth factors and 11-b-hydroxysteroid-dehydrogenase-1 inhibitors, and free fatty acid receptor 1 as all these may represent new additional therapies for preserving functional β-cell mass.
  4. Further studies to study the manner of β-cell in diabetic patient using the new imaging techniques.

Conflicts of interest

There are no conflicts of interest.[24]

  References Top

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Bonner-Weir S. Perspective: postnatal pancreatic beta-cell growth. Endocrinology 2000; 141:1926–1929.  Back to cited text no. 2
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Rhodes CJ. Type 2 diabetes – a matter of beta-cell life and death. Science 2005; 307:380–384.  Back to cited text no. 4
Rhodes CJ. Regulation of beta-cell growth and death. In: Susumu J, Bell JI, editors. Pancreatic beta-cell in health and disease. Japan: Springer; 2008. 215.  Back to cited text no. 5
Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003; 52:102–110.  Back to cited text no. 6
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Butler AE, Janson J, Soeller WC, Butler PC. Increased beta-cell apoptosis prevents adaptive increase in beta-cell mass in mouse model of type 2 diabetes: evidence for role of islet amyloid formation rather than direct action of amyloid. Diabetes 2003; 52:2304–2314.  Back to cited text no. 8
Poitout V, Robertson RP. Glucolipotoxicity: fuel excess and beta-cell dysfunction. Endocr Rev 2008; 29:351–366.  Back to cited text no. 9
10Prentki M, Joly E, El-Assaad W, Roduit R. Malonyl-CoA signaling, lipid partitioning, and glucolipotoxicity: role in beta-cell adaptation and failure in the etiology of diabetes. Diabetes 2002; 51:405–413.  Back to cited text no. 10
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12Robertson RP. Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta-cells in diabetes. J Biol Chem 2004; 279:42351–42354.  Back to cited text no. 12
13Lipson KL, Fonseca SG, Ishigaki S, Nguyen LX, Foss E, Bortell R, et al. Regulation of insulin biosynthesis in pancreatic beta-cells by an endoplasmic reticulum-resident protein kinase IRE1. Cell Metab 2006; 4:245–254.  Back to cited text no. 13
14Lipson KL, Fonseca SG, Urano F. Endoplasmic reticulum stress-induced apoptosis and auto-immunity in diabetes. Curr Mol Med 2006; 6:71–77.  Back to cited text no. 14
15Salas-Salvado J, Martinez-González MA, Bullo M, Ros E. The role of diet in the prevention of type 2 diabetes. Nutr Metab Cardiovasc Dis 2011; 21:32–48.  Back to cited text no. 15
16Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 364:393–403.  Back to cited text no. 16
17Campbell IW, Mariz S. Beta-cell preservation with thiazolidinediones. Diabetes Res Clin Pract 2007; 76:163–176.  Back to cited text no. 17
18Buchanan TA, Xiang RH, Peters RK, et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes 2002; 51:2796–2803.  Back to cited text no. 18
19Durbin RJ. Thiazolidinedione therapy in the prevention/delay of type 2 diabetes in patients with impaired glucose tolerance and insulin resistance. Diabetes Obes Metab 2004; 6:280–285.  Back to cited text no. 19
20Chiasson RG, Josse R, Gomis R, Hanefeld M, Karasik A, Laakso M, et al. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 2002; 359:2072–2077.  Back to cited text no. 20
21Tourrel C, Bailbe D, Lacorne M, et al. Persistent improvement of type 2 diabetes in the Goto-Kakizaki rat model by expansion of the b-cell mass during the prediabetic period with glucagon-like peptide-1 or exendin-4. Diabetes 2002; 51:1443–1452.  Back to cited text no. 21
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23Zinman B, Hoogwerf B, Duran Garcia S, et al. Safety and efficacy of exenatide in patients with type 2 diabetes mellitus using thiazolidinediones with or without metformin. Ann Intern Med 2007; 146:477–485.  Back to cited text no. 23
24DeFronzo RA, Davidson JA, Del Prato S. The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia. Diabetes Obes Metab 2012; 14:5–14.  Back to cited text no. 24


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]


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