Apolipoprotein ciii is an important piece in the type-1 diabetes jigsaw puzzle

It is well known that type-2 diabetes mellitus (T2D) is increasing worldwide, but also the autoimmune form, type-1 diabetes (T1D), is affecting more people. The latest estimation from the International Diabetes Federation (IDF) is that 1.1 million children and adolescents below 20 years of age have T1D. At present, we have no primary, secondary or tertiary prevention or treatment available, although many efforts testing different strategies have been made. This review is based on the findings that apolipoprotein CIII (apoCIII) is increased in T1D and that in vitro studies revealed that healthy beta-cells exposed to apoCIII became apoptotic, together with the observation that humans with higher levels of the apolipoprotein, due to mutations in the gene, are more susceptible to developing T1D. We have summarized what is known about apoCIII in relation to inflammation and autoimmunity in in vitro and in vivo studies of T1D. The aim is to highlight the need for exploring this field as we still are only seeing the top of the iceberg

Apolipoprotein CIII Reduction Protects White Adipose Tissues against Obesity-Induced Inflammation and Insulin Resistance in Mice

Apolipoprotein CIII (apoCIII) is proinflammatory and increases in high-fat diet (HFD)-induced obesity and insulin resistance. We have previously shown that reducing apoCIII improves insulin sensitivity in vivo by complex mechanisms involving liver and brown adipose tissue. In this study the focus was on subcutaneous (SAT) and visceral (VAT) white adipose tissue (WAT). Mice were either given HFD for 14 weeks and directly from start also treated with antisense oligonucleotide (ASO) against apoCIII or given HFD for 10 weeks and HFD+ASO for an additional 14 weeks. Both groups had animals treated with inactive (Scr) ASO as controls and in parallel chow-fed mice were injected with saline. Preventing an increase or lowering apoCIII in the HFD-fed mice decreased adipocytes’ size, reduced expression of inflammatory cytokines and increased expression of genes related to thermogenesis and beiging. Isolated adipocytes from both VAT and SAT from the ASO-treated mice had normal insulin-induced inhibition of lipolysis compared to cells from Scr-treated mice. In conclusion, the HFD-induced metabolic derangements in WATs can be prevented and reversed by lowering apoCIII

Proton-Induced and Electron-Induced X-Ray Microanalysis of Insulin-Secreting Cells

Elemental redistribution induced by insulin secretion, was investigated by electron and proton probe X-ray microanalysis. In particular, ion fluxes following immediately upon stimulation were studied. As the sensitivity of the electron probe was insufficient, the proton microprobe was employed. In order to see whether the cell is asymmetric with respect to Ca2+ influx, the cells were stimulated in the presence of Sr2+ (as a Ca2+ analog). Insulin-secreting cells (RINm5F cells and isolated mouse β-cells) were cultured on grids and shock-frozen at 2-30 seconds after stimulation. In a large number of cells, the major elements and and large fluxes were analyzed by the electron microprobe. In the proton microprobe, selected cells were analyzed and elemental maps were compared with electron micrographs of the same cells. The proton microprobe, but not the electron microprobe, could detect an influx of Sr in response to K+-stimulation for 2 seconds, in RINm5F-cells. No polarization of Sr2+ uptake in RINm5F-cells could be detected, and the β-cells did not respond to high K+ by uptake of Sr. Momentary stimulation of β-cells also resulted in a significant increase in Na, detected by the electron probe. Spreading of the β-cells on the substrate appears to influence the subcellular elemental distribution. Thus, the proton probe has potential to detect small changes in elements such as those occurring after short-time stimulation

Islet Transplantation to the Anterior Chamber of the Eye—A Future Treatment Option for Insulin-Deficient Type-2 Diabetics? A Case Report from a Nonhuman Type-2 Diabetic Primate

10.1177/0963689720913256Cell Transplantation2

Apolipoprotein CIII is a new player in diabetes

Purpose of review Type-1 and type-2 diabetes are diseases with an increasing number of patients and a complex, multifactorial pathogenesis. Apolipoprotein (apo) CIII is increased in both types of diabetes and interventions preventing the increase have effects on the development of diabetes. Recent findings ApoCIII affects intracellular Ca2+-handling by activating voltage-gated Ca2+-channels. ApoCIII is produced within the pancreatic islets and it increases in parallel with the development of insulin resistance and type-2 diabetes. Preventing the increase maintains a normal glucose tolerance as well as Ca2+-handling and no signs of inflammation can be seen in islets wherein the augmented local production of the apolipoprotein is absent. Summary ApoCIII has been found to interfere with both function and survival of the beta-cell and thereby promote the development of diabetes. Increased levels of this apolipoprotein affects intracellular Ca2+-handling and insulin sensitivity, which finally results in impaired glucose homeostasis and diabetes. Interestingly, in a type-1 diabetes rat model lowering of apoCIII delays onset of diabetes. In type-2 diabetes insulin resistance within the pancreatic islets leads to a local increase in apoCIII that promotes inflammation and beta-cell dysfunction. Hence, targeting apoCIII may constitute a novel pharmacological strategy to treat both type-1 and type-2 diabetes

Neither polyphenol-rich red wine nor fenofibrate affects the onset of type-1 diabetes mellitus in the BB rat

Serum levels of the pro-inflammatory apolipoprotein CIII (apoCIII) are increased in type-1 diabetic (T1D) patients and when β-cells are exposed to apoCIII they undergo apoptosis, which can be prevented by an antibody against apoCIII. We have previously investigated the BB rat, an animal model that develops a human-like T1D at the age of around 60 days, and found that apoCIII was also increased in sera from pre-diabetic rats and this promoted β-cell death. Lowering apoCIII with an oligonucleotide antisense during a phase of the pre-diabetic period prolonged the time to onset of T1D. In order to find other ways to lower apoCIII we in this study tested non-alcoholic red wine with medium and high concentrations of polyphenols and the lipid-lowering drug, fenofibrate, both reported to decrease the expression of apoCIII by activating peroxisome proliferator-activated receptors. Pre-diabetic BB-rats were treated orally for one month prior to the expected onset of diabetes with the two different wines or fenofibrate. None of the treatments prevented or prolonged the time to onset of diabetes and the expression of apoCIII was unaffected in this animal model for T1D. However, it must be emphasized that this does not exclude that other species can show a response to these substances

Proton microprobe analysis of 15 elements in pancreatic B cells and exocrine pancreas in diabetic Chinese hamsters

Diabetes mellitus spontaneously develops in certain sublines of non-obese Chinese hamsters, and the diabetic L-subline is known for subnormal pancreatic insulin release in vitro. The cause of the secretory defect is unknown. Freeze-dried pancreas sections from genetically diabetic Chinese hamsters and normal controls were subjected to proton bombardment and the concentration of 15 elements in B cells and acini was calculated from the X-rays emitted. Diabetic B cells contained significantly less Al (−61%) and significantly more Cu (+92 %), Mg (+6 %) and Rb (+13 %) than their normal counterparts. The diabetic acini showed similar, significant changes. The molar ratio between K and Na was about 10 in endocrine as well as exocrine pancreas from both groups of animals, implying that neither sample preparation nor irradiation had induced significant diffusive changes. In conclusion, the high K/Na ratio suggests that the diabetic B cell has a well-functioning Na+/K+ pump. However, significant and parallel changes in Al-, Cu-, Mg- and Rb-levels were found in both the B cells and acinar portion of the diabetic pancreas. It is not clear whether these elemental changes cause the islet secretory defect or result from it