Archives

  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2020-03
  • 2020-07
  • 2020-08
  • 2021-03
  • Midostaurin (PKC412) It is widely accepted that

    2019-07-08

    It is widely accepted that visceral obesity in subjects with metabolic syndrome predisposes to T2DM and other pathological components of the syndrome [25]. Contrasting this view, our findings show that only apoa1 mice developed Midostaurin (PKC412) intolerance and insulin resistance following feeding high-fat diet (Fig. 5). This discovery supports the notion that obesity does not always induce glucose metabolic abnormalities. It is worth mentioning that apoa1 mice displayed reduced glucose tolerance even on normal chow diet, before they were challenged with the western-type diet (Fig. 5A). This observation shows that the lack of Apoa1 predisposes even lean animals fed chow-diet to disturbed glucose homeostasis, a pathology which is exacerbated by feeding a high-fat diet (Fig. 5D). In agreement with these data, GSIS analysis in isolated pancreatic β-islets from apoa1 mice fed western-type diet for 24 weeks showed that insulin secretion in response to glucose stimulation is impaired in these mice compared to lcat and C57BL/6 mice. Depolarization of cell membrane in islets of Langerhans from apoa1 mice following treatment with KCl resulted in significant amount of secreted insulin that wαs comparable to those of C57BL/6 mice (Fig. 7B) indicating that the secretory machinery in the islets of apoa1 mice remains intact and functional, but unresponsive to glucose (Fig. 7A). The deposition of dietary cholesterol and triglycerides to the islets of apoa1 mice (Fig. 3A, B) appears not to be a confounding factor to the impairment of their secretory function given that similarly levels of dietary lipids were also measured in the islets from lcat mice. It is well-established that changes in plasma membrane cholesterol content may impact cell membrane fluidity [47,48], which in turn may affect the structure and responsiveness of ion-channels to natural stimuli [42]. Since insulin secretion involves substrate stimulated and voltage-gated channels, we next determined how Apoa1-deficiency may influence cell membrane fluidity in isolated islets, using Laurdan staining and two-photon microscopy. This analysis revealed a significant shift of cell-membrane fluidity towards a more rigid gel-like structure, a physicochemical property that is associated with reduced stimulation of ion-channels [42]. Our data raise the possibility that in the more rigid membrane microenvironment of apoa1 mice, ATP-dependent potassium channels and/or voltage-gated Ca+2 channels become less responsive to their natural stimuli. In addition to impaired insulin secretion, apoa1 mice display insulin resistant skeletal muscles (Figs. 5E, I and 6B) which further exacerbates their systemic glucose tolerance as shown in GTT (Fig. 5D). Conversely, islets of lcat mice were more responsive to glucose stimulation than those of apoa1 mice (Fig. 7A). Moreover, hexose uptake by the skeletal muscles of lcat mice remained responsive to insulin (Fig. 6) and lcat mice maintained similar glucose tolerance and insulin sensitivity comparable to C57BL/6 mice (Fig. 5D, H, E, I), despite their massive increase in visceral WAT accumulation at week 24 of the diet. When the HOMA index was determined, we found that all mouse strains had deteriorated insulin sensitivity in response to feeding high-fat diet, including lcat and C57BL/6 mice. Interestingly, lcat mice displayed the highest deterioration in insulin sensitivity based on their HOMA index, even though they displayed GTT and IST responses comparable to those of C57BL/6 mice. Apparently, when fed western-type diet for 24 weeks, lcat mice enter a hyperinsulinemic state that overcomes their insulin resistance and maintains their plasma glucose levels physiological. In contrast, apoa1 mice have plasma insulin levels comparable to those of C57BL/6 mice but obviously their skeletal muscles fail to respond to insulin (Fig. 6B), while their islets remain unresponsive to glucose and unable to boost plasma insulin to a level that could overcome peripheral insulin resistance (Fig. 7A). Of course, in this interpretation it is very important to keep in mind the significant limitations of HOMA index use in mice. Even though HOMA index is a measure of insulin resistance widely used in numerous human clinical studies [38,49], the HOMA model has not been validated for use in rodents or any other animals and such use may violate the assumptions of the model [49].