Lipotoxicity in the Pancreatic Beta Cell: Not Just Survival and Function, but Proliferation as Well?

Sharma, Rohit; Alonso, Laura

doi:10.1007/s11892-014-0492-2

Cited by 116 publications

(95 citation statements)

References 110 publications

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“…Nonalcoholic fatty pancreas (NAFP) may be diagnosed by imaging techniques[102], and it is common in the general population[99]. The role of NAFP as a pathogenic mediator for the association between NAFLD and T2D risk has recently been reviewed[103-105]. …”

Section: Nafldmentioning

confidence: 99%

Fatty liver is associated with an increased risk of diabetes and cardiovascular disease - Evidence from three different disease models: NAFLD, HCV and HIV

Lonardo¹,

Ballestri²,

Guaraldi³

et al. 2016

WJG

101

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Fatty liver, which frequently coexists with necro-inflammatory and fibrotic changes, may occur in the setting of nonalcoholic fatty liver disease (NAFLD) and chronic infections due to either hepatitis C virus (HCV) or human immunodeficiency virus (HIV). These three pathologic conditions are associated with an increased prevalence and incidence of cardiovascular disease (CVD) and type 2 diabetes (T2D). In this multidisciplinary clinical review, we aim to discuss the ever-expanding wealth of clinical and epidemiological evidence supporting a key role of fatty liver in the development of T2D and CVD in patients with NAFLD and in those with HCV or HIV infections. For each of these three common diseases, the epidemiological features, pathophysiologic mechanisms and clinical implications of the presence of fatty liver in predicting the risk of incident T2D and CVD are examined in depth. Collectively, the data discussed in this updated review, which follows an innovative comparative approach, further reinforce the conclusion that the presence of fatty/inflamed/fibrotic liver might be a shared important determinant for the development of T2D and CVD in patients with NAFLD, HCV or HIV. This review may also open new avenues in the clinical and research arenas and paves the way for the planning of future, well-designed prospective and intervention studies.

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Section: Nafldmentioning

confidence: 99%

Fatty liver is associated with an increased risk of diabetes and cardiovascular disease - Evidence from three different disease models: NAFLD, HCV and HIV

Lonardo¹,

Ballestri²,

Guaraldi³

et al. 2016

WJG

101

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“…The impact of lipid excess on beta cell proliferation remains controversial [123, 157, 158]. In vivo or ex vivo exposure to glucolipotoxicity reduced proliferation and induced islet p16 INK4A expression in young mice [123].…”

Section: Evidence That Cdkn2a/b Influences Type 2 Diabetes Risk Via Bmentioning

confidence: 99%

“…The intriguing relationship between CDKN2A/B genotype and response to thiazolidinedione in the DPP cohort suggests activity in adipose tissue; as lipids negatively impact pancreatic beta cell proliferation and function this may represent an adipocyte–beta cell axis [123, 157, 215]. In a Japanese population, CDKN2A/B was not related to visceral fat accumulation [219], but in an Indian sibling-pair study, CDKN2A/B polymorphisms impacted fasting insulin and HOMA-IR but not HOMA-B, suggesting a primary effect on insulin sensitivity [220].…”

Section: Evidence That Cdkn2a/b Influences Type 2 Diabetes Risk Via Nmentioning

confidence: 99%

Islet biology, the CDKN2A/B locus and type 2 diabetes risk

et al. 2016

Self Cite

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Type 2 diabetes, fuelled by the obesity epidemic, is an escalating worldwide cause of personal hardship and public cost. Diabetes incidence increases with age, and many studies link the classic senescence and ageing protein p16INK4A to diabetes pathophysiology via pancreatic islet biology. Genome-wide association studies (GWASs) have unequivocally linked the CDKN2A/B locus, which encodes p16 inhibitor of cyclin-dependent kinase (p16INK4A) and three other gene products, p14 alternate reading frame (p14ARF), p15INK4B and antisense non-coding RNA in the INK4 locus (ANRIL), with human diabetes risk. However, the mechanism by which the CDKN2A/B locus influences diabetes risk remains uncertain. Here, we weigh the evidence that CDKN2A/B polymorphisms impact metabolic health via islet biology vs effects in other tissues. Structured in a bedside-to-bench-to-bedside approach, we begin with a summary of the evidence that the CDKN2A/B locus impacts diabetes risk and a brief review of the basic biology of CDKN2A/B gene products. The main emphasis of this work is an in-depth look at the nuanced roles that CDKN2A/B gene products and related proteins play in the regulation of beta cell mass, proliferation and insulin secretory function, as well as roles in other metabolic tissues. We finish with a synthesis of basic biology and clinical observations, incorporating human physiology data. We conclude that it is likely that the CDKN2A/B locus influences diabetes risk through both islet and non-islet mechanisms.

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“…Átmeneti FFA-szint-emelkedés akár az inzulintermelés fiziológiás stimulusának is tekinthető, amennyiben a tápanyagkínálat jelzéseként pozitívan befolyásolja a β-sejtek működését (glükóz által kiváltott inzulinszekré-cióját), és még a β-sejt-tömeget is inkább növeli [30]. Ezeket az előnyös hatásokat elsősorban sejtfelszíni (szabadzsírsav-receptor-1 -FFAR-1 -, más néven G-fehérjé-hez kapcsolt receptor-40 -GPR-40) és sejten belüli (peroxiszómaproliferátor-receptor -PPAR-α és -γ) receptorokon keresztül fejti ki.…”

Section: Zsírsavtúltengés éS β-Sejt-károsodásunclassified

“…Ezeket az előnyös hatásokat elsősorban sejtfelszíni (szabadzsírsav-receptor-1 -FFAR-1 -, más néven G-fehérjé-hez kapcsolt receptor-40 -GPR-40) és sejten belüli (peroxiszómaproliferátor-receptor -PPAR-α és -γ) receptorokon keresztül fejti ki. Tartós zsírsavtúltengés azonban akadályozza a β-sejt-funkciót és csökkenti a β-sejt-tömeget [30]. Ilyenkor ugyanis dominánssá válnak a negatív hatások, amelyek a már részletezett oxidatív és ER-stressz közvetítésével érvényesülnek.…”

Section: Zsírsavtúltengés éS β-Sejt-károsodásunclassified

Zsírsavtúltengés – inzulinrezisztencia és β-sejt-halál

Csala

2016

Orvosi Hetilap

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A 2-es típusú diabetes terjedése összefügg az elhízás gyakoriságának és mértékének növekedésével. A tápanyagfelesleg raktározása megviseli a zsírsejteket, ami lokális gyulladás révén felgyorsítja a triglicerid-anyagcsere körforgását és megemeli a szabad zsírsavak plazmaszintjét. A tartós zsírsavtúltengés károsítja a sejtek működését (lipotoxicitás), sőt akár programozott sejthalált is okozhat. Az aktiválódó stresszkinázok akadályozzák az inzulin-jelátvitelt, és gyakran elősegítik az apoptózist. A zsírsavtúltengés tehát az inzulinrezisztencia és a β-sejt-károsodás révén összekapcsolja az elhízást a cukorbetegséggel. A lipotoxicitással kapcsolatos kutatások -és ezen belül a telített, telítetlen, illetve transzzsírsavak hatásainak összehasonlítása -magyarázattal szolgálnak számos korábban is ismert jelenségre. Az e téren bővülő ismeretek pedig a metabolikus szindróma és a diabetes megelőzésének, illetve gyógyításának új stratégiáit kínálják. Orv. Hetil., 2016, 157(19), 733-739. Kulcsszavak: elhízás, szabad zsírsav, lipotoxicitás, lipoapoptózis, inzulinrezisztencia Hyper-free fatty acidemia -insulin resistance and β-cell deathThe increasing prevalence of type 2 diabetes correlates with the rapid spread of obesity worldwide. Adipocytes are strained by the demand of excessive storage, and the local inflammation accelerates triglyceride turnover, which elevates the plasma levels of free fatty acids. Sustained hyper-free fatty acidemia leads to disturbances in cellular functions (lipotoxicity) or even to programmed cell death. Activated stress kinases interfere with insulin signaling, and often facilitate apoptosis. Hyper-free fatty acidemia, therefore, links obesity to diabetes through insulin resistance and β-cell damage. Lipotoxicity research -including the comparison of the effects exerted by saturated, unsaturated and trans fatty acids -provides explanations for long-known phenomena. Our widening knowledge in the field offers new strategies for prevention and treatment of the metabolic syndrome and diabetes.Keywords: obesity, free fatty acid, lipotoxicity, lipoapoptosis, insulin resistance Csala, M. [Hyper-free fatty acidemia -insulin resistance and β-cell death]. Orv. Hetil., 2016, 157(19), 733-739. Rövidítések ATF-6 = aktiváló transzkripciós faktor-6; ER = endoplazmás reticulum; FAT/CD-36 = zsírsav/transzlokáz receptor; FFA = szabad zsírsav; FFAR-1/GPR-40 = szabadzsírsav-receptor-1 -más néven G-fehérjéhez kapcsolt receptor-40; IGF-1 = inzulinszerű növekedési faktor-1; IKK = inhibitor-κB-kináz; IL-1β = interleukin-1β; IL-1R = interleukin-1-receptor; IL-6 = interleukin-6; IRE-1α = inozitolfüggő enzim-1α; IRS = inzulinreceptor-szubsztrát; JNK = c-Jun aminoterminális kináz; KoA = koenzim-A; MCP-1 = monocyta kemotaktikus fehérje-1; NEFA = szabad (nem észteresített) zsírsav; NF-κB = nukleáris faktor-κB; p38 MAPK = p38 mitogénaktivált proteinkináz; PERK = PKR-szerű ER-beli kináz; PKC = proteinkináz C; PLC = foszfolipáz C; PPAR = peroxiszómaproliferátor-aktivált receptor; ROS = reaktív oxigénszármazék(ok); SFA = telített...

show abstract

Lipotoxicity in the Pancreatic Beta Cell: Not Just Survival and Function, but Proliferation as Well?

Cited by 116 publications

References 110 publications

Fatty liver is associated with an increased risk of diabetes and cardiovascular disease - Evidence from three different disease models: NAFLD, HCV and HIV

Fatty liver is associated with an increased risk of diabetes and cardiovascular disease - Evidence from three different disease models: NAFLD, HCV and HIV

Islet biology, the CDKN2A/B locus and type 2 diabetes risk

Zsírsavtúltengés – inzulinrezisztencia és β-sejt-halál

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