| 1. |
- Avall, Karin, et al.
(författare)
-
Apolipoprotein CIII links islet insulin resistance to beta-cell failure in diabetes
- 2015
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 112:20, s. E2611-E2619
-
Tidskriftsartikel (refereegranskat)abstract
- Insulin resistance and beta-cell failure are the major defects in type 2 diabetes mellitus. However, the molecular mechanisms linking these two defects remain unknown. Elevated levels of apolipoprotein CIII (apoCIII) are associated not only with insulin resistance but also with cardiovascular disorders and inflammation. We now demonstrate that local apoCIII production is connected to pancreatic islet insulin resistance and beta-cell failure. An increase in islet apoCIII causes promotion of a local inflammatory milieu, increased mitochondrial metabolism, deranged regulation of beta-cell cytoplasmic free Ca2+ concentration ([Ca2+](i)) and apoptosis. Decreasing apoCIII in vivo results in improved glucose tolerance, and pancreatic apoCIII knockout islets transplanted into diabetic mice, with high systemic levels of the apolipoprotein, demonstrate a normal [Ca2+](i) response pattern and no hallmarks of inflammation. Hence, under conditions of islet insulin resistance, locally produced apoCIII is an important diabetogenic factor involved in impairment of beta-cell function and may thus constitute a novel target for the treatment of type 2 diabetes mellitus.
|
|
| 2. |
- Bränström, Robert, et al.
(författare)
-
Electrical short-circuit in β-cells from a patient with non-insulinoma pancreatogenous hypoglycemic syndrome (NIPHS) : a case report
- 2010
-
Ingår i: Journal of Medical Case Reports. - : Springer Science and Business Media LLC. - 1752-1947. ; 4:1, s. 315-
-
Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Non-insulinoma pancreatogenous hypoglycemic syndrome is a rare disorder among adults, and, to our knowledge, only about 40 cases have been reported in the literature. CASE PRESENTATION: The patient is a previously healthy 35-year-old Caucasian man. His symptoms began four years ago when he suddenly felt weakness in his legs and started sweating for unknown reasons. The symptoms worsened, and laboratory tests revealed hypoglycemia and hyperinsulinemia at the time of the symptoms. All diagnostics attempts using magnetic resonance imaging, computed tomography, and endoscopic ultrasound did not reveal any abnormalities. At this stage, surgical intervention was planned, and a distal 80% pancreatectomy was performed. The histopathologic and immunohistochemical investigations of the pancreas showed an increased number of islets of different sizes, more or less evenly distributed in the gland, but no insulinoma. Patch-clamp recordings from isolated pancreatic β-cells showed that, even at a low glucose concentration (3 mmol/L), the β-cell membrane was depolarized, and action potentials were seen. Surprisingly, in patch-clamp experiments, the addition of diazoxide had a marked effect on K-ATP channel activity and membrane potential, but no effect on insulin levels in vivo before surgery. CONCLUSION: This case report adds new information on the pathogenesis of non-insulinoma pancreatogenous hypoglycemic syndrome, as we performed an electrophysiologic characterization of isolated islet cells. We show, for the first time, that β-cells isolated from a non-insulinoma pancreatogenous hypoglycemic syndrome patient are constantly depolarized, even at low glucose levels, but display normal K-ATP channel physiology.
|
|
| 3. |
- Holmberg, Rebecka, et al.
(författare)
-
Antiviral treatments reduce severity of diabetes in Ljungan virus-infected CD-1 mice and delay onset in diabetes-prone BB rats
- 2009
-
Ingår i: Microbiology and immunology. - : Wiley. - 0385-5600 .- 1348-0421. ; 53:10, s. 567-572
-
Tidskriftsartikel (refereegranskat)abstract
- The effects of LV in two different species, CD-1 mice, without a genetic disposition for diabetes, and BB rats prone to T1D were examined. Male CD-1 mice that had been exposed to LV in utero developed a type 2-like diabetes with increased blood glucose, insulin levels and epididymal fat at the age of 10-15 weeks. Combination therapy including LV-antiserum and an antiviral drug, Pleconaril, significantly reduced the levels of blood glucose and insulin and the amount of abdominal fat. In BB rats, LV has been found in both prediabetic- and diabetic diabetes-prone rats, as well as in diabetes-resistant rats. To evaluate whether the presence of LV has any influence on the onset of T1D, prediabetic BB rats were treated with an antiserum against LV or a combination of the antiviral drugs Pleconaril and Ribavirin. In the group treated with antiviral drugs, the onset was significantly delayed. These results indicate that the presence of LV can be involved in the pathogenesis of diabetes in these animal models.
|
|
| 4. |
- Holmberg, Rebecka, et al.
(författare)
-
Lowering apolipoprotein CIII delays onset of type 1 diabetes
- 2011
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 108:26, s. 10685-10689
-
Tidskriftsartikel (refereegranskat)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.
|
|
| 5. |
- Juntti-Berggren, Lisa, et al.
(författare)
-
Dihydroxyacetone-induced oscillations in cytoplasmic free Ca2+ and the ATP/ADP ratio in pancreatic beta-cells at substimulatory glucose.
- 2003
-
Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 278:42, s. 40710-40716
-
Tidskriftsartikel (refereegranskat)abstract
- Glucose stimulation of pancreatic beta-cells causes oscillatory influx of Ca2+, leading to pulsatile insulin secretion. We have proposed that this is due to oscillations of glycolysis and the ATP/ADP ratio, which modulate the activity of ATP-sensitive K+ channels. We show here that dihydroxyacetone, a secretagogue that feeds into glycolysis below the putative oscillator phosphofructokinase, could cause a single initial peak in cytoplasmic free Ca2+ ([Ca2+]i) but did not by itself cause repeated oscillations in [Ca2+]i in mouse pancreatic beta-cells. However, in the presence of a substimulatory concentration of glucose (4 mm), dihydroxyacetone induced [Ca2+]i oscillations. Furthermore, these oscillations correlated with oscillations in the ATP/ADP ratio, as seen previously with glucose stimulation. Insulin secretion in response to dihydroxyacetone was transient in the absence of glucose but was considerably enhanced and somewhat prolonged in the presence of a substimulatory concentration of glucose, in accordance with the enhanced [Ca2+]i response. These results are consistent with the hypothesized role of phosphofructokinase as the generator of the oscillations. Dihydroxyacetone may affect phosphofructokinase by raising the free concentration of fructose 1,6-bisphosphate to a critical level at which it activates the enzyme autocatalytically, thereby inducing the pulses of phosphofructokinase activity that cause the metabolic oscillations.
|
|
| 6. |
- Niklasson, Bo, et al.
(författare)
-
Diabetes Prevention Through Antiviral Treatment in Biobreeding Rats
- 2016
-
Ingår i: Viral immunology. - : Mary Ann Liebert Inc. - 0882-8245 .- 1557-8976. ; 29:8, s. 452-458
-
Tidskriftsartikel (refereegranskat)abstract
- A picornavirus (Ljungan virus) has been associated with diabetes in its wild rodent reservoir and in diabetesprone biobreeding (DP-BB) rats. We attempted to alter the development of diabetes in DP-BB rats using two anti-picornavirus compounds (pleconaril and APO-N039), singly or in combination. Antiviral therapy was initiated 2 weeks before expected onset of diabetes. Pleconaril or APO-N039 alone did not affect the debut of diabetes. However, animals receiving a combination of both compounds were protected for at least the entire period of treatment (4 weeks after expected time of diabetes onset). Immunohistochemistry demonstrated that the presence and distribution of virus antigen in the pancreatic islets coincided with the clinical status of the animal. Data indicate that a treatable picornavirus can be involved in the cellular assault resulting in diabetes and in these cases the disease mechanism appears to involve a virus present in the pancreatic beta cell mass itself.
|
|
| 7. |
- Pålsgård, Eva, et al.
(författare)
-
Effects of K+-induced depolarization and purinergic receptor activation on elemental content in insulin-producing RINm5F-cells
- 1995
-
Ingår i: Cell Biology International. - : Wiley. - 1065-6995 .- 1095-8355. ; 19:1, s. 25-34
-
Tidskriftsartikel (refereegranskat)abstract
- X-ray microanalysis was used to detect elemental changes in the insulin-producing tumor cell-lineRINm5F. To improve discrimination between mobile ions and ions bound to macromolecules a new approach was employed, consisting of multivariate statistical analysis of correlations between the concentrations of Na, Mg, P, S, CI, K, and Ca. RINm5F cells, cultured an Formvar-coated titanium grids, were stimulated with high K+ or ATP, that are both known to stimulate insulin release. The buffers used contained Ca2+ or one of the Ca2+-analogues Sr2+ and Ba2+, to represent Ca2+ uptake inresponse to stimulation. After stimulation the cells were shock-frozen and freeze-dried overnight. Incubation for 10-20 seconds in a Ca2+-containing buffer did not significantly affect elementalcomposition, whereas cellular Mg, P and K decreased in a Sr2+-containing buffer. Depolarization with high K+ concentration caused an increase in the cellular Na content, both in Ca2+- and Sr2+-containing buffers, but not in the buffer where Ca2+ had been replaced by Ba2+. X-ray microanalysis is useful for detection of elemental changes subsequent to stimulation of cultured cells. Moreover, multivariate statistical analysis strengthens the idea that stimulation of RINm5F cells causes redistribution of ions possibly due to changes in the state of binding of some elements to cellular proteins.
|
|
| 8. |
- Pålsgård, Eva, et al.
(författare)
-
Proton-induced and electron-induced X-ray microanalysis of insulin-secreting cells
- 1994
-
Ingår i: Scanning Microscopy Suppl.. ; 8, s. 325-333
-
Tidskriftsartikel (refereegranskat)abstract
- 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 beta-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 beta-cells did not respond to high K+ by uptake of Sr. Momentary stimulation of beta-cells also resulted in a significant increase in Na, detected by the electron probe. Spreading of the beta-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.
|
|
| 9. |
|
|
| 10. |
- Størling, Joachim, et al.
(författare)
-
Apolipoprotein CIII reduces proinflammatory cytokine-induced apoptosis in rat pancreatic islets via the Akt prosurvival pathway
- 2011
-
Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 152:8, s. 3040-3048
-
Tidskriftsartikel (refereegranskat)abstract
- Apolipoprotein CIII (ApoCIII) is mainly synthesized in the liver and is important for triglyceride metabolism. The plasma concentration of ApoCIII is elevated in patients with type 1 diabetes (T1D), and in vitro ApoCIII causes apoptosis in pancreatic β-cells in the absence of inflammatory stress. Here, we investigated the effects of ApoCIII on function, signaling, and viability in intact rat pancreatic islets exposed to proinflammatory cytokines to model the intraislet inflammatory milieu in T1D. In contrast to earlier observations in mouse β-cells, exposure of rat islets to ApoCIII alone (50 μg/ml) did not cause apoptosis. In the presence of the islet-cytotoxic cytokines IL-1β + interferon-γ, ApoCIII reduced cytokine-mediated islet cell death and impairment of β-cell function. ApoCIII had no effects on mitogen-activated protein kinases (c-Jun N-terminal kinase, p38, and ERK) and had no impact on IL-1β-induced c-Jun N-terminal kinase activation. However, ApoCIII augmented cytokine-mediated nitric oxide (NO) production and inducible NO synthase expression. Further, ApoCIII caused degradation of the nuclear factor κB-inhibitor inhibitor of κB and stimulated Ser473-phosphorylation of the survival serine-threonine kinase Akt. Inhibition of the Akt signaling pathway by the phosphatidylinositol 3 kinase inhibitor LY294002 counteracted the antiapoptotic effect of ApoCIII on cytokine-induced apoptosis. We conclude that ApoCIII in the presence of T1D-relevant proinflammatory cytokines reduces rat pancreatic islet cell apoptosis via Akt.
|
|
