Apolipoprotein CIII links islet insulin resistance to β-cell failure in diabetes

Åvall, Karin; Ali, Yusuf; Leibiger, Ingo B.; Leibiger, Barbara; Moede, Tilo; Paschen, Meike; Dicker, Andrea; Daré, Elisabetta; Köhler, Martin; Ilegems, Erwin; Abdulreda, Midhat H.; Graham, Mark; Crooke, Rosanne M.; Tay, Vanessa Shi Yun; Refai, Essam; Nilsson, Stefan K.; Jacob, Stefan; Selander, Lars; Berggren, Per‐Olof; Juntti‐Berggren, Lisa

doi:10.1073/pnas.1423849112

Cited by 71 publications

(109 citation statements)

References 42 publications

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“…Our studies are at variance with Avall et al (51), who reported that adenovirus-mediated ectopic ApoC3 production resulted in beta cell apoptosis and dysfunction in MIN6 cells and islets. However, the physiological significance of this study is uncertain, as islet cells are not the cell type responsible for endogenous ApoC3 production.…”

Section: Discussioncontrasting

confidence: 99%

Effect of Hypertriglyceridemia on Beta Cell Mass and Function in ApoC3 Transgenic Mice

Liu

Cheng

Zhang

et al. 2016

Journal of Biological Chemistry

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Hypertriglyceridemia results from increased production and decreased clearance of triglyceride-rich very low-density lipoproteins, a pathological condition that accounts for heightened risk of ischemic vascular diseases in obesity and type 2 diabetes. Despite its intimate association with insulin resistance, whether hypertriglyceridemia constitutes an independent risk for beta cell dysfunction in diabetes is unknown. Answering this fundamental question is stymied by the fact that hypertriglyceridemia is intertwined with hyperglycemia and insulin resistance in obese and diabetic subjects. To circumvent this limitation, we took advantage of apolipoprotein C3 (ApoC3)-transgenic mice, a model with genetic predisposition to hypertriglyceridemia. We showed that ApoC3-transgenic mice, as opposed to age/sexmatched wild-type littermates, develop hypertriglyceridemia with concomitant elevations in plasma cholesterol and non-esterified fatty acid levels. Anti-insulin and anti-glucagon dual immunohistochemistry in combination with morphometric analysis revealed that ApoC3-transgenic and wild-type littermates had similar beta cell and alpha cell masses as well as islet size and architecture. These effects correlated with similar amplitudes of glucosestimulated insulin secretion and similar degrees of postprandial glucose excursion in ApoC3-transgenic versus wild-type littermates. Oil Red O histology did not visualize lipid infiltration into islets, correlating with the lack of ectopic triglyceride and cholesterol depositions in the pancreata of ApoC3-transgenic versus wild-type littermates. ApoC3-transgenic mice, despite persistent hypertriglyceridemia, maintained euglycemia under both fed and fasting conditions without manifestation of insulin resistance and fasting hyperinsulinemia. Thus, hypertriglyceridemia per se is not an independent risk factor for beta cell dysfunction in ApoC3 transgenic mice.Hypertriglyceridemia, characterized by elevated plasma triglyceride (TG) 5 levels, results from increased production and/or decreased clearance of TG-rich very low-density lipoproteins (VLDL-TG) (1, 2). Preclinical and clinical studies characterize hypertriglyceridemia as a major risk factor for ischemic vascular diseases (3-8). Hypertriglyceridemia is a hallmark of diabetic dyslipidemia in insulin-resistant subjects with visceral obesity or type 2 diabetes (7, 9 -11). To date, it remains unknown whether hypertriglyceridemia constitutes an independent risk for beta cell dysfunction in obesity and type 2 diabetes.Critical for plasma TG metabolism is ApoC3, an apolipoprotein (79 amino acids in length) that is produced mainly in the liver and to a lesser extent in the intestine (12). Plasma ApoC3 proteins are present predominantly in TG-rich lipoproteins such as VLDL and chylomicrons (13). ApoC3 exerts its impact on TG metabolism by three distinct mechanisms. First, ApoC3 functions as an inhibitor of hepatic and lipoprotein lipases, key enzymes that catalyze the hydrolysis of TG in VLDL and chylomicrons (14 -16). Second, ApoC3 act...

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Section: Discussioncontrasting

confidence: 99%

Effect of Hypertriglyceridemia on Beta Cell Mass and Function in ApoC3 Transgenic Mice

Liu

Cheng

Zhang

et al. 2016

Journal of Biological Chemistry

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“…This study also reported that apoC-III related to coronary artery calcification in a triglyceride dependent manner Thus, decreasing plasma apoC-III concentrations is able to improve glucose tolerance and help slow disease progression to a certain extent, providing new thinking for treating diabetes besides hypoglycemic drugs (49,50). …”

Section: Accepted Manuscriptmentioning

confidence: 75%

“…Previous data indicated that therapeutic measures, including the use of antisense toward apoC-III mRNA, attenuated its apoptosis effect. Type 2 diabetic insulin resistance, partly attributed to hypertriglyceridemia, could be caused by high levels of apoC-III, which further accelerates the intra-islet apoptosis process (50). In a study conducted by Omar's group, they found that plasma apoC-III levels were correlated positively with fasting glucose and hemoglobin A1c (HbA1c) in type 2 diabetic patients (51).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Apoprotein C-III: A review of its clinical implications

Jin

Guo

2016

Clinica Chimica Acta

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“…Furthermore, insulin resistance can also increase the production of other proteins such as apoCIII which affect or influence the circulating levels of lipoprotein. ApoCIII is a small apoprotein that may increase VLDL and LDL-C by preventing the action of lipoprotein lipase (LpL) and inhibiting lipoprotein uptake via the LDL receptor-related protein [16]. Another possible factor for the pathogenesis of diabetic dyslipidemia is the hepatic lipase deficiency which results from insulin resistance or relative insulin deficiency.…”

Section: Introductionmentioning

confidence: 99%

Effect of Raw and Cooked Ginger (<i>Zingiber officinale</i> Roscoe) Extracts on Serum Cholesterol and Triglyceride in Normal and Diabetic Rats

Paulina¹,

Rasaki²,

Veronica³

2018

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Dyslipidemia is a risk factor of concern in public health even in a state of anomaly in blood glucose level. The effect of different ginger extracts on body lipids has been reported, few scientific studies have documented the effect of raw ginger extracts while the effect of cooked ginger extract (the form in which the spice is commonly consumed) is yet to be explored. This experimental study was therefore designed to determine the effect of raw and cooked ginger extracts on serum triglycerides and total cholesterol in diabetic rats and compare this with that of non-diabetic rats. Fresh ginger rhizomes were washed peeled, washed, wet-milled (without addition of water) and sieved to give the raw extract. A portion of of the extract was boiled for one hour and cooled to give cooked ginger extract. Seventy male albino rats of weight range 155g-195g were divided into 7 groups (n=10) with 3 groups kept as normal or non-diabetic while the remaining 4 groups were rendered diabetic by intraperitoneal administration of 60mg/kg body weight of streptozocin (STZ) to mimic Type 1 diabetes mellitus. These were repeated with another set of seventy rats but diabetes was induced in the 4 diabetic groups here with a 12 week consumption of high-fat diet (HFD) to mimic Type 2 diabetes mellitus. Serum total cholesterol and triglyceride were determined before and after diabetes induction as well as at the 2 nd and 4 th weeks of extracts and diabetic drugs administration using standard methods. Mean data were compared using Least Significant Difference at p≤0.05.Raw and cooked ginger extracts significantly reduced serum total cholesterol and triglyceride in both medium (2 weeks) and long (4 weeks) terms administration in non diabetic rats. In STZ-induced diabetic rats only raw ginger extract lowered these parameters significantly while the cooked extracts and glybenclamide increased these significantly. However, in HFD-induced diabetic rats, raw, cooked ginger extracts and Metformin reduced both serum total cholesterol and triglyceride significantly. Ginger in both raw and cooked forms may therefore be useful in ameliorating hyperlipidemia which commonly associates diabetic state. Human trial is hereby recommended.

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Apolipoprotein CIII links islet insulin resistance to β-cell failure in diabetes

Cited by 71 publications

References 42 publications

Effect of Hypertriglyceridemia on Beta Cell Mass and Function in ApoC3 Transgenic Mice

Effect of Hypertriglyceridemia on Beta Cell Mass and Function in ApoC3 Transgenic Mice

Apoprotein C-III: A review of its clinical implications

Effect of Raw and Cooked Ginger (<i>Zingiber officinale</i> Roscoe) Extracts on Serum Cholesterol and Triglyceride in Normal and Diabetic Rats

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