Forkhead transcription factors of the FoxO family play a critical role in cellular differentiation, proliferation, apoptosis and stress resistance. FoxO1 regulates glucose and lipid production in ...liver; food intake in the hypothalamus and cell differentiation in preadipocytes, myoblasts and vascular endothelium. In this review, we summarize recent literature on the role of FoxO1 in pancreatic β cells. FoxO1 regulates β-cell proliferation and protects against β-cell failure induced by oxidative stress through NeuroD and MafA induction. In addition, FoxO1 nuclear exclusion is required for the proliferative effects of glucoincretin glucagon-like peptide-1 in islets. The data begin to outline an overarching role of FoxO1 in β-cell function.
Diabetes is caused by a combination of impaired responsiveness to insulin and reduced production of insulin by the pancreas. Until recently, the decline of insulin production had been ascribed to ...β‐cell death. But recent research has shown that β‐cells do not die in diabetes, but undergo a silencing process, termed “dedifferentiation.” The main implication of this discovery is that β‐cells can be revived by appropriate treatments. We have shown that mitochondrial abnormalities are a key step in the progression of β‐cell dysfunction towards dedifferentiation. In normal β‐cells, mitochondria generate energy required to sustain insulin production and its finely timed release in response to the body's nutritional status. A normal β‐cell can adapt its mitochondrial fuel source based on substrate availability, a concept known as “metabolic flexibility.” This capability is the first casualty in the progress of β‐cell failure. β‐Cells lose the ability to select the right fuel for mitochondrial energy production. Mitochondria become overloaded, and accumulate by‐products derived from incomplete fuel utilization. Energy production stalls, and insulin production drops, setting the stage for dedifferentiation. The ultimate goal of these investigations is to explore novel treatment paradigms that will benefit people with diabetes.
Adiponectin/Acrp30 is a hormone secreted by adipocytes, which acts as an antidiabetic and antiatherogenic adipokine. We reported
previously that AdipoR1 and -R2 serve as receptors for adiponectin and ...mediate increased fatty acid oxidation and glucose
uptake by adiponectin. In the present study, we examined the expression levels and roles of AdipoR1/R2 in several physiological
and pathophysiological states such as fasting/refeeding, obesity, and insulin resistance. Here we show that the expression
of AdipoR1/R2 in insulin target organs, such as skeletal muscle and liver, is significantly increased in fasted mice and decreased
in refed mice. Insulin deficiency induced by streptozotocin increased and insulin replenishment reduced the expression of
AdipoR1/R2 in vivo . Thus, the expression of AdipoR1/R2 appears to be inversely correlated with plasma insulin levels in vivo . Interestingly, the incubation of hepatocytes or myocytes with insulin reduced the expression of AdipoR1/R2 via the phosphoinositide
3-kinase/Foxo1-dependent pathway in vitro . Moreover, the expressions of AdipoR1/R2 in ob/ob mice were significantly decreased in skeletal muscle and adipose tissue,
which was correlated with decreased adiponectin binding to membrane fractions of skeletal muscle and decreased AMP kinase
activation by adiponectin. This adiponectin resistance in turn may play a role in worsening insulin resistance in ob/ob mice.
In conclusion, the expression of AdipoR1/R2 appears to be inversely regulated by insulin in physiological and pathophysiological
states such as fasting/refeeding, insulin deficiency, and hyper-insulinemia models via the insulin/phosphoinositide 3-kinase/Foxo1
pathway and is correlated with adiponectin sensitivity.
We review mechanisms of β-cell failure in type 2 diabetes. A wealth of information indicates that it is caused by impaired insulin secretion and decreased β-cell mass. Interestingly, there appears to ...be a link between these two mechanisms. The earliest reaction to peripheral insulin resistance is an increase in insulin production, owing primarily to increased secretion, and to a lesser extent to decreased clearance. Experimental animal models indicate that hyperinsulinaemia promotes an increase in β-cell mass, largely via increased β-cell replication. In contrast, following the onset of overt diabetes, there is a slowly progressive loss of β-cell function and mass, both in animal models and in diabetic humans. It is of great interest that most diabetes-associated genes identified in genome-wide association studies appear to be enriched in the β-cell and to have the potential to regulate mass and/or function. Here, we review evidence derived from experimental animal models to unravel the mechanisms underlying β-cell dysfunction. We focus primarily on signalling pathways, as opposed to nutrient sensing, and specifically on the notion that insulin and growth factor signalling via Foxo1 in pancreatic β-cells links insulin secretion with cellular proliferation and survival.
Type 2 diabetes arises from a combination of impaired insulin action and defective pancreatic beta-cell function. Classically, the two abnormalities have been viewed as distinct yet mutually ...detrimental processes. The combination of impaired insulin-dependent glucose metabolism in skeletal muscle and impaired beta-cell function causes an increase of hepatic glucose production, leading to a constellation of tissue abnormalities that has been referred to as the diabetes "ruling triumvirate." Targeted mutagenesis in mice has led to a critical reappraisal of the integrated physiology of insulin action. These studies indicate that insulin resistance in skeletal muscle and adipose tissue does not necessarily lead to hyperglycemia, so long as insulin sensitivity in other tissues is preserved. Additional data suggest a direct role of insulin signaling in beta-cell function and regulation of beta-cell mass, thus raising the possibility that insulin resistance may be the overarching feature of diabetes in all target tissues. I propose that we replace the original picture of a ruling triumvirate with that of a squabbling republic in which every tissue contributes to the onset of the disease.
The Islet and Metabolism Keep Time Thorens, B.; Accili, D.; Ahrén, B. ...
Diabetes, obesity & metabolism,
September 2015, Volume:
17, Issue:
S1
Journal Article
Abstract Background and aim We sought to identify mechanisms of beta cell failure in genetically obese mice. Little is known about the role of pancreatic innervation in the progression of beta cell ...failure. In this work we studied adrenergic innervation, in view of its potent inhibitory effect on insulin secretion. We analyzed genetically obese ob / ob and db / db mice at different ages (6- and 15-week-old), corresponding to different compensatory stages in the course of beta cell dysfunction. 15 week-old HFD mice were also studied. Methods and results All mice were characterized by measures of plasma glucose, insulin, and HOMA. After perfusion, pancreata were dissected and studied by light microscopy, electron microscopy, and morphometry. Insulin, Tyrosine Hydroxylase-positive fibers and cells and Neuropeptide Y-positive cells were scored by immunohistochemistry. Islets of obese mice showed increased noradrenergic fiber innervation, with significant increases of synaptoid structures contacting beta cells compared to controls. Noradrenergic innervation of the endocrine area in obese db / db mice tended to increase with age, as diabetes progressed. In ob / ob mice, we also detected an age-dependent trend toward increased noradrenergic innervation that, unlike in db / db mice, was unrelated to glucose levels. We also observed a progressive increase in Neuropeptide Y-immunoreactive elements localized to the islet core. Conclusions Our data show increased numbers of sympathetic nerve fibers with a potential to convey inhibitory signals on insulin secretion in pancreatic islets of genetically obese animals, regardless of their diabetic state. The findings suggest an alternative interpretation of the pathogenesis of beta cell failure, as well as novel strategies to reverse abnormalities in insulin secretion.
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