The pancreatic β-cell in deadly encounter with apolipoprotein CIII

Destruction or dysfunction of the insulin secreting pancreatic β-cell is central to the pathogenesis of diabetes mellitus. Increased levels of apolipoprotein CIII (apoCIII) in sera from patients with type-1 diabetes mellitus (T1DM) have been shown to promote Ca²⁺-induced β-cell apoptosis ^1,2 Not only is apoCIII of interest in T1DM it has also been shown to be increased in patients with type-2 diabetes (T2DM) and it is known that insulin resistance, as well as deficiency of insulin, up-regulates the apoCIII gene.

Blood glucose levels are under healthy conditions kept within a very narrow range and in T2DM the 2 most important components for deteriorating a normal glucose control are reduced insulin sensitivity and impaired secretion of insulin from the pancreatic β-cells. So far no mechanism linking these 2 defects has been identified. This is highly important, since it can lead to the development of novel therapies for diabetes and its complications.

T2DM occurs when there is an imbalance between the secreted insulin and the increased need caused by the resistance in the peripheral insulin target tissues, like the liver. There are insulin receptors on the pancreatic β-cell and therefore also these cells are dependent on a functioning insulin induced signal-transduction³ Interestingly, we now show that during the development of T2DM insulin resistance occurs also within the pancreatic islets. This results in a progressive change in FoxO1-regulated gene expression and compromised insulin signaling at the islet level. Consequently, there is an insulin resistance induced increase in apoCIII not only in serum, but also locally within the pancreatic islet.

To test whether apoCIII indeed is of interest for the development of diabetes in a T2DM mouse model, we treated mice with an antisense against apoCIII, that lowered the levels to about 50%, and this prevented the development of obesity and diabetes ⁴

Figure 1.

Effects of apoCIII within the islet. Upper: An ob/ob mouse with ob/ob islets transplanted to the right eye and apoCIII knock out islets transplanted to the left eye. Lower left: a confocal microscopic image of an islet within the eye of the living mouse, vascularization pattern seen in red. Lower right: Schematic overview of the negative effects of apoCIII in the β-cell.

To prove that local in vivo islet production of apoCIII is of importance for the function of the β-cell, on top of the already high systemic levels produced by the liver, we combined the advantages of a global apoCIII^−/− mouse and the anterior chamber of the eye as an in vivo experimental platform⁵ We used 2 models for insulin resistance and T2DM namely the ob/ob mice and B57Bl/6 (B6) mice fed a high fat diet (HFD). The ob/ob mice were transplanted with ob/ob islets to one eye and apoCIII^−/− islets to the other eye and the B6 mice got B6 respectively apoCIII^−/− islets to their eyes. This created a situation where the same animal served both as a control and a β-cell specific apoCIII−/−. All transplanted islets were exposed to high levels of apoCIII in the circulating blood, but the apoCIII^−/− islets could not increase their production of the apolipoprotein within the islets, despite being in a diabetic milieu. This lack of ability to locally increase apoCIII resulted in a protection of the islets. Ob/ob and B6 islets demonstrated, compared with apoCIII^−/− islets, unphysiological increases in [Ca²⁺]i and apoptosis, higher in vivo proliferative activity, paralleled by an increase in vessel density, islet macrophages and NAD(P)H/FAD ratio, as a marker of β-cell metabolism⁴ All these changes are characteristic for an inflammatory milieu and caused by locally released apoCIII within the islet, as a consequence of islet insulin resistance^6,7

Moreover, we found an increased number of apoCIII positive cells in islets from a patient with T2DM compared with islets from healthy individuals, which strengthens our data and suggest that this is also of importance in human T2DM.

In conclusion, we demonstrate that preventing insulin resistance at the islet level is crucial to maintain β-cell function and survival in diabetes. To target the local islet production of apoCIII can thus form the basis for a novel treatment strategy for diabetes and its complications. In this context, it is of interest to note that there are humans with a genetic mutation in the apoCIII gene and thereby life-long reduced levels of apoCIII. These persons are overall healthier, live longer and have increased insulin sensitivity.