Prolonged insulin treatment sensitizes apoptosis pathways in pancreatic β cells

Bucris, Efrat; Beck, Avital; Boura‐Halfon, Sigalit; Isaac, Roi; Vinik, Yaron; Rosenzweig, Tovit; Sampson, Sanford R.; Zick, Yehiel

doi:10.1530/joe-15-0505

Cited by 22 publications

(19 citation statements)

References 81 publications

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“…However, the role of long-term exposure to high insulin (i.e., hyperinsulinemia) on β-cell function and mass is still unclear and very controversial. Studies, including ours, have suggested that prolonged exposure to hyperinsulinemia might induce common molecular defects in the insulin/IGF-1 signaling pathway leading to both peripheral and β-cell insulin resistance and therefore contribute to the development of T2DM [22][23][24].…”

Section: Insulin As a Foe: Negative Autocrine Actionsmentioning

confidence: 72%

“…The role of hyperinsulinemia and prolonged exposure to high insulin in β-cell insulin resistance and decompensation is still unclear and widely debated. Some researchers [22,23], including our group [24], have suggested that in conditions of insulin resistance and hyperinsulinemia, prolonged exposure to high concentrations of insulin may induce insulin resistance in β-cells and negatively impact their function and mass.…”

Section: Negative Actions Of Insulin On β-Cell Mass and Survivalmentioning

confidence: 99%

“…This reduction in β-cell mass was shown to be the result of increased β-cell apoptosis in these animals. In addition, prolonged exposure to high insulin primes apoptosis and ER-stress-inducing mechanisms and leads to a reduction in β-cell viability, due to increased oxidative stress in Min-6, RINm, INS-1 β-cell lines and isolated mouse and human islets [22,23]. These studies did not explore the effects of prolonged exposure to insulin on the insulin/IGF-1 signaling pathway in β-cells.…”

Section: Negative Actions Of Insulin On β-Cell Mass and Survivalmentioning

confidence: 99%

“…Although insulin signaling is known to be essential to β-cell growth and function [19][20][21], possible long term negative autocrine actions of insulin (i.e., hyperinsulinemia) on β-cell function and mass are still controversial. Work by our group and by others have reported such long term actions of insulin on β-cells [22][23][24]. The goal in undertaking this review was to summarize evidence that supports the principal idea of an autocrine action of insulin on β-cells.…”

Section: Introductionmentioning

confidence: 98%

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Insulin: The Friend and the Foe in the Development of Type 2 Diabetes Mellitus

Rachdaoui

2020

IJMS

106

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Insulin, a hormone produced by pancreatic β-cells, has a primary function of maintaining glucose homeostasis. Deficiencies in β-cell insulin secretion result in the development of type 1 and type 2 diabetes, metabolic disorders characterized by high levels of blood glucose. Type 2 diabetes mellitus (T2DM) is characterized by the presence of peripheral insulin resistance in tissues such as skeletal muscle, adipose tissue and liver and develops when β-cells fail to compensate for the peripheral insulin resistance. Insulin resistance triggers a rise in insulin demand and leads to β-cell compensation by increasing both β-cell mass and insulin secretion and leads to the development of hyperinsulinemia. In a vicious cycle, hyperinsulinemia exacerbates the metabolic dysregulations that lead to β-cell failure and the development of T2DM. Insulin and IGF-1 signaling pathways play critical roles in maintaining the differentiated phenotype of β-cells. The autocrine actions of secreted insulin on β-cells is still controversial; work by us and others has shown positive and negative actions by insulin on β-cells. We discuss findings that support the concept of an autocrine action of secreted insulin on β-cells. The hypothesis of whether, during the development of T2DM, secreted insulin initially acts as a friend and contributes to β-cell compensation and then, at a later stage, becomes a foe and contributes to β-cell decompensation will be discussed.

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Section: Insulin As a Foe: Negative Autocrine Actionsmentioning

confidence: 72%

Section: Negative Actions Of Insulin On β-Cell Mass and Survivalmentioning

confidence: 99%

Section: Negative Actions Of Insulin On β-Cell Mass and Survivalmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

See 2 more Smart Citations

Insulin: The Friend and the Foe in the Development of Type 2 Diabetes Mellitus

Rachdaoui

2020

IJMS

106

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“…Indeed, exposure to 0.5 nmol/l insulin has been found to cause DNA damage in a number of cell types, including human lymphocytes [ 42 , 54 ]. At the only concentration tested (100 nmol/l), insulin impairs oxygen radical defense and sensitizes apoptosis pathways in human islets [ 55 ]. In the brain of mice, hyperinsulinemia impairs electrophysiological functions of neurons and protein turnover, causing a transition to a senescent cell state and an accompanying cognitive decline [ 56 ].…”

Section: Main Textmentioning

confidence: 99%

Insulin: too much of a good thing is bad

Kolb

Kempf

Röhling

et al. 2020

BMC Med

124

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Background: Insulin shares a limited physiological concentration range with other endocrine hormones. Not only too low, but also too high systemic insulin levels are detrimental for body functions. Main body: The physiological function and clinical relevance of insulin are usually seen in association with its role in maintaining glucose homeostasis. However, insulin is an anabolic hormone which stimulates a large number of cellular responses. Not only too low, but also excess insulin concentrations are detrimental to the physiological balance. Although the glucoregulatory activity of insulin is mitigated during hyperinsulinemia by dampening the efficiency of insulin signaling ("insulin resistance"), this is not the case for most other hormonal actions of insulin, including the promotion of protein synthesis, de novo lipogenesis, and cell proliferation; the inhibition of lipolysis, of autophagy-dependent cellular turnover, and of nuclear factor E2-related factor-2 (Nrf2)-dependent antioxidative; and other defense mechanisms. Hence, there is no general insulin resistance but selective impairment of insulin signaling which causes less glucose uptake from the blood and reduced activation of endothelial NO synthase (eNOS). Because of the largely unrestricted insulin signaling, hyperinsulinemia increases the risk of obesity, type 2 diabetes, and cardiovascular disease and decreases health span and life expectancy. In epidemiological studies, high-dose insulin therapy is associated with an increased risk of cardiovascular disease. Randomized controlled trials of insulin treatment did not observe any effect on disease risk, but these trials only studied low insulin doses up to 40 IU/day. Proof for a causal link between elevated insulin levels and cardiovascular disease risk comes from Mendelian randomization studies comparing individuals with genetically controlled low or high insulin production. Conclusions: The detrimental actions of prolonged high insulin concentrations, seen also in cell culture, argue in favor of a lifestyle that limits circadian insulin levels. The health risks associated with hyperinsulinemia may have implications for treatment regimens used in type 2 diabetes.

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Chronic administration of delta9‐tetrahydrocannabinol protects hyperinsulinemic gastric tissue in rats

Colak,

Coskun Yazici,

Bolkent

2023

Cell Biochemistry & Function

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Hyperinsulinemia (HI) can result from some reasons such as an increase in basal/fasting circulating insulin and/or potentiation of postprandial insulin production. Diabetes mellitus (DM) is indirectly related to HI since it both causes and results from insulin resistance. Understanding the causes of HI and treating this is crucial for preventing DM. Previous research has shown that delta9‐tetrahydrocannabinol (THC) has medicinal benefits. In light of this, the relationship between THC and oxidative stress, DNA repair mechanism, apoptosis, and its regulatory impact on appetite hormones in the gastric tissue of hyperinsulinemic rats has been investigated for the first time. Male rats (Spraque−Dawley, total = 32) were used, and they were randomly divided into the following groups (n = 8 in each group): control (CTRL), HI, THC administered control (THC, 1.5 mg/kg/day, during 4 weeks), and THC administered HI (HI + THC) groups. The number of poly (ADP‐ribose) polymerase‐1 and proliferating cell nuclear antigen (PCNA) and caspase‐3 immunopositive cells in the HI group was significantly reduced compared to the CTRL group. The number of PCNA and caspase‐9 immunopositive cells was significantly increased in the HI + THC group compared to the HI group. Obestatin immunopositive cell numbers in the HI + THC group were higher than in the HI and CTRL groups. The results show that THC administration may affect the regulation of appetite hormones and regeneration in the fundus of rats with HI. Glutathione (GSH) levels were higher in the HI + THC group than in the HI group. Both immunohistochemical and biochemical analyses revealed that THC promotes regeneration and regulates appetite hormones in hyperinsulinemic gastric tissues.

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Prolonged insulin treatment sensitizes apoptosis pathways in pancreatic β cells

Cited by 22 publications

References 81 publications

Insulin: The Friend and the Foe in the Development of Type 2 Diabetes Mellitus

Insulin: The Friend and the Foe in the Development of Type 2 Diabetes Mellitus

Insulin: too much of a good thing is bad

Chronic administration of delta9‐tetrahydrocannabinol protects hyperinsulinemic gastric tissue in rats

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