Lowering apolipoprotein CIII delays onset of type 1 diabetes

Abstract

Serum levels of apolipoprotein CIII (apoCIII) are increased in type 1 diabetic patients, and when β cells are exposed to these diabetic sera, apoptosis occurs, an effect abolished by an antibody against apoCIII. We have investigated the BB rat, an animal model that develops a human-like type 1 diabetes, and found that apoCIII was also increased in sera from prediabetic rats. This increase in apoCIII promoted β-cell death. The endogenous levels of apoCIII were reduced by treating prediabetic animals with an antisense against this apolipoprotein, resulting in a significantly delayed onset of diabetes. ApoCIII thus serves as a diabetogenic factor, and intervention with this apolipoprotein in the prediabetic state can arrest disease progression. These findings suggest apoCIII as a target for the treatment of type 1 diabetes.W e have previously shown that there is a group of patients with type 1 diabetes (T1D) whose sera induce an increased activity of voltage-gated Ca 2+ channels in pancreatic β cells, resulting in increased cytoplasmic free Ca 2+ concentration ([Ca 2+ ] i ) and apoptosis (1). T1D serum was found to contain increased concentrations of apolipoprotein CIII (apoCIII), and we could later demonstrate that this serum factor was responsible for the [Ca 2+ ] i increase and β-cell death in vitro (2). Consequently, the effects of both T1D serum and apoCIII on [Ca 2+ ] i and β-cell death are abolished when β cells are coincubated with an antibody against apoCIII (2).To clarify the extent to which apoCIII is also involved in β-cell death in vivo, we have used the animal model diabetes-prone BB rat (DPBB), which spontaneously, at around the age of 60 d, develops T1D that resembles the human form of the disease (3, 4). Diabetes-resistant BB rats (DRBB) were developed from selective breeding from diabetes-prone (DP) forebears and were used as controls (5).This model gives an opportunity to study the impact of prediabetic interventions to prevent or delay onset of the disease. In this study, three prediabetic age groups (40, 50, and 60 d) were investigated both in vitro and in vivo, and we could demonstrate that lowering the endogenous levels of apoCIII by antisense treatment markedly delayed onset of diabetes. ResultsMorphological and Immunohistochemical Characterization. Qualitative morphological analysis showed that pancreas taken from prediabetic rats at the age of 40 d had a lower number of insulincontaining cells than the age-matched controls. The shape of the islets was round to oval with an intact thin layer of collagen around the islets. No inflammation was seen (Fig. 1A). At the age of 50 d, the number of insulin-containing cells did not differ compared with islets from control rats. Islet shape and border did not differ from control rats. No inflammation was seen (Fig. 1B). At 60 d of age, there was a clear decrease in the number of insulin-positive cells. The shape of the islet was irregular, and in some islets, exocrine cells were found. There was no distinct border between the islets and the surroun...

Antisense Oligonucleotide Inhibition of Apolipoprotein C-III Reduces Plasma Triglycerides in Rodents, Nonhuman Primates, and Humans

“…[32][33][34] Finally, apoC-III levels are increased in type 1 diabetic patients and are also thought to be a cofactor in pancreatic β cell death. 4,35 Taken together, these results support the concept that apoC-III is a multifunctional protein that not only regulates the metabolism of triglyceride-rich lipoproteins, but may also contribute to CHD and pathophysiological metabolic states.…”

Antisense-Mediated Lowering of Plasma Apolipoprotein C-III by Volanesorsen Improves Dyslipidemia and Insulin Sensitivity in Type 2 Diabetes

“…ApoC-III inhibition may also enhance the sensitivity to the normal insulin-mediated suppression of APOC3 gene expression (10), which is dysregulated in patients with type 2 diabetes. Finally, data also suggest that circulating apoC-III itself may act as a diabetogenic factor regulating the preservation of pancreatic b-cells by as yet undefined mechanisms (9).…”

“…Clinically, elevations in TRL levels have been shown to exacerbate the pathology of insulin resistance (9). It is thought that the inability of insulin resistant adipose tissue to store TG may be the initial step in the development of insulin resistance (1,31).…”

“…Clinically, elevations in TG-rich lipoprotein (TRL) levels have been shown to exacerbate the pathology of insulin resistance. Therefore, reducing TG and increasing HDL may not only reduce cardiovascular risk but also improve insulin sensitivity and delay b-cell failure (1,9).…”

Antisense Oligonucleotides and Therapeutical Monoclonal Antibodies as a Basement for Novel Biological Lipidlowering Drugs

“…Одной из наиболее очевидных мишеней является апоСIII, из-за связи данного апобелка с развитием триглице-ридемии, атеросклероза, ССЗ и других метаболиче-ских нарушений [28,29]. Генетические исследования свидетельствуют о положительном влиянии пони-женного уровня апоСIII на уровень ТГ и атерогенных апоВ100-содержащих липопротеидов, а также на про-должительность жизни [30].…”