Insulin and glucagon regulate pancreatic α-cell proliferation.
TL;DR: It is demonstrated that pancreatic α-cell proliferation increases as diabetes develops, resulting in elevated plasma glucagon levels, and both insulin and glucagon are trophic factors to α-cells.
Abstract: Type 2 diabetes mellitus (T2DM) results from insulin resistance and β-cell dysfunction, in the setting of hyperglucagonemia. Glucagon is a 29 amino acid peptide hormone, which is secreted from pancreatic α cells: excessively high circulating levels of glucagon lead to excessive hepatic glucose output. We investigated if α-cell numbers increase in T2DM and what factor (s) regulate α-cell turnover. Lepr(db)/Lepr(db) (db/db) mice were used as a T2DM model and αTC1 cells were used to study potential α-cell trophic factors. Here, we demonstrate that in db/db mice α-cell number and plasma glucagon levels increased as diabetes progressed. Insulin treatment (EC50 = 2 nM) of α cells significantly increased α-cell proliferation in a concentration-dependent manner compared to non-insulin-treated α cells. Insulin up-regulated α-cell proliferation through the IR/IRS2/AKT/mTOR signaling pathway, and increased insulin-mediated proliferation was prevented by pretreatment with rapamycin, a specific mTOR inhibitor. GcgR antagonism resulted in reduced rates of cell proliferation in αTC1 cells. In addition, blockade of GcgRs in db/db mice improved glucose homeostasis, lessened α-cell proliferation, and increased intra-islet insulin content in β cells in db/db mice. These studies illustrate that pancreatic α-cell proliferation increases as diabetes develops, resulting in elevated plasma glucagon levels, and both insulin and glucagon are trophic factors to α-cells. Our current findings suggest that new therapeutic strategies for the treatment of T2DM may include targeting α cells and glucagon.
Citations
More filters
TL;DR: Results suggest that a circulating factor generated after disruption of hepatic Gcgr signaling can increase α-cell proliferation independent of direct pancreatic input, which may facilitate the generation and expansion of α-cells for transdifferentiation into β-cells and the treatment of diabetes.
Abstract: Glucagon is a critical regulator of glucose homeostasis; however, mechanisms regulating glucagon action and α-cell function and number are incompletely understood. To elucidate the role of the hepatic glucagon receptor (Gcgr) in glucagon action, we generated mice with hepatocyte-specific deletion of the glucagon receptor. GcgrHep−/− mice exhibited reductions in fasting blood glucose and improvements in insulin sensitivity and glucose tolerance compared with wild-type controls, similar in magnitude to changes observed in Gcgr−/− mice. Despite preservation of islet Gcgr signaling, GcgrHep−/− mice developed hyperglucagonemia and α-cell hyperplasia. To investigate mechanisms by which signaling through the Gcgr regulates α-cell mass, wild-type islets were transplanted into Gcgr−/− or GcgrHep−/− mice. Wild-type islets beneath the renal capsule of Gcgr−/− or GcgrHep−/− mice exhibited an increased rate of α-cell proliferation and expansion of α-cell area, consistent with changes exhibited by endogenous α-cells in Gcgr−/− and GcgrHep−/− pancreata. These results suggest that a circulating factor generated after disruption of hepatic Gcgr signaling can increase α-cell proliferation independent of direct pancreatic input. Identification of novel factors regulating α-cell proliferation and mass may facilitate the generation and expansion of α-cells for transdifferentiation into β-cells and the treatment of diabetes.
166 citations
Cites background from "Insulin and glucagon regulate pancr..."
...Furthermore, direct attenuation of GCGR signaling in a-cells does not result in increased rates of cell proliferation (35)....
[...]
TL;DR: Blockade of miR-338-3p in β cells using specific anti-miR molecules mimicked gene expression changes occurring during β cell mass expansion and resulted in increased proliferation and improved survival both in vitro and in vivo.
Abstract: Pregnancy and obesity are frequently associated with diminished insulin sensitivity, which is normally compensated for by an expansion of the functional β cell mass that prevents chronic hyperglycemia and development of diabetes mellitus. The molecular basis underlying compensatory β cell mass expansion is largely unknown. We found in rodents that β cell mass expansion during pregnancy and obesity is associated with changes in the expression of several islet microRNAs, including miR-338-3p. In isolated pancreatic islets, we recapitulated the decreased miR-338-3p level observed in gestation and obesity by activating the G protein-coupled estrogen receptor GPR30 and the glucagon-like peptide 1 (GLP1) receptor. Blockade of miR-338-3p in β cells using specific anti-miR molecules mimicked gene expression changes occurring during β cell mass expansion and resulted in increased proliferation and improved survival both in vitro and in vivo. These findings point to a major role for miR-338-3p in compensatory β cell mass expansion occurring under different insulin resistance states.
156 citations
Cites background from "Insulin and glucagon regulate pancr..."
...miR-338-3p on β cells was mediated through induction of Igf1r, a receptor that seems to not be involved in α cell proliferation (53)....
[...]
TL;DR: An in‐depth analysis of glucose metabolism in SMA is initiated to establish a cause-and-effect relationship between glucose metabolism and spinal muscular atrophy.
Abstract: Spinal muscular atrophy (SMA) is a neuromuscular disorder affecting 1 in 6,000 to 10,000 live births. SMA is a leading inherited cause of death in children 95% of cases of this devastating autosomal recessive disease.1,3 Pathological and clinical manifestations of SMA are largely due to loss of motor neurons in the spinal cord and brainstem, resulting in generalized muscular atrophy, weakness, respiratory insufficiency, and in >50% of cases, death in infancy or early childhood.2
The SMN gene is essential for survival, and a complete depletion of the protein results in early developmental lethality.4 In humans, the loss of the telomeric SMN1 gene is compensated for by the presence of the duplicated centromeric SMN2 gene.3 Although the 2 genes differ by several nucleotides, the functional difference lies within a C to T substitution at position 6 of exon 7 in SMN2.5 This silent mutation causes aberrant splicing of the SMN2 gene and the production of an unstable protein, termed SMNΔ7, due to the excision and loss of exon 7.3,5 This alteration in splicing most likely results from the loss of an exon splice enhancer and/or the gain of an exon splice silencer.3,6,7 Although the major product of the SMN2 gene is the SMNΔ7 protein, the full-length SMN protein is still produced in small quantities (~10%).3 As such, SMA severity is heavily modulated by the number of SMN2 copies present in patients.3,8
Although the pathological hallmark of SMA is motor neuron loss, recent reports have identified additional defects in the muscle,9 at the neuromuscular junction,10 and in the heart.11–13 In the present work, we report for the first time glucose metabolism and pancreatic developmental defects in an SMA mouse model and human SMA patients. Our results demonstrate a progressive loss of the insulin-producing β cells and a corresponding increase in the number of the glucagon-producing α cells in pancreatic islets. This altered cell fate is accompanied by glucose clearance defects in the SMA mice during fasting and following an acute glucose tolerance test. In addition, pathology specimens from human SMA type I infants demonstrate similar abnormalities in pancreatic islet cell morphology and distribution. These observations in the SMA mouse model, and the corresponding parallels in human tissues, indicate that these findings may indeed be relevant to the human condition.
These novel findings have 2 major implications. First, the observed defects in glucose metabolism and pancreatic development may contribute additional stressors, which impact motor neuron loss, muscle function, and survival in SMA. Second, as SMA patients are living longer due to improved assistive technology, further studies to assess the metabolic consequences of impaired glucose metabolism and its potential impact on their clinical course will be of utmost importance.
143 citations
TL;DR: A nutrient-sensing circuit between liver and pancreas in which glucagon-dependent control of hepatic amino acid metabolism regulates α-cell mass is proposed, which reveals that amino acids act as sensors of glucagon signaling and can function as growth factors that increase α- cell proliferation.
141 citations
Cites background from "Insulin and glucagon regulate pancr..."
..., 2011); rapamycin was found to inhibit alphaTC1 cell proliferation in vitro (Liu et al., 2011); and Everolimus, an mTOR inhibitor, was recently approved for the treatment of human pancreatic neuroendocrine tumors, including glucagonomas....
[...]
...…in the mTOR pathway have been found in human glucagonomas (Jiao et al., 2011); rapamycin was found to inhibit alphaTC1 cell proliferation in vitro (Liu et al., 2011); and Everolimus, an mTOR inhibitor, was recently approved for the treatment of human pancreatic neuroendocrine tumors, including…...
[...]
TL;DR: UCP2 does not behave as a classical metabolic uncoupler in the β-cell, but has a more prominent role in the regulation of intracellular ROS levels that contribute to GSIS amplification.
Abstract: OBJECTIVE-The role of uncoupling protein 2 (UCP2) in pancreatic beta-cells is highly debated, partly because of the broad tissue distribution of UCP2 and thus limitations of whole-body UCP2 knockou ...
122 citations
Cites background from "Insulin and glucagon regulate pancr..."
...Interestingly, increasing concentrations of insulin (one consequence of UCP2 deficiency in b-cells) can also increase a-cell proliferation through the insulin-receptor signaling pathway (42)....
[...]
References
More filters
TL;DR: The physiological consequences of mammalianTORC1 dysregulation suggest that inhibitors of mammalian TOR may be useful in the treatment of cancer, cardiovascular disease, autoimmunity, and metabolic disorders.
5,553 citations
"Insulin and glucagon regulate pancr..." refers background in this paper
...mTOR, an evolutionarily conserved serine-threonine kinase, interacts with AKT and promotes protein translation and cell growth in response to growth factors [28,29]....
[...]
TL;DR: Both the upstream components of the signaling pathway(s) that activates mammalian TOR (mTOR) and the downstream targets that affect protein synthesis are described.
Abstract: The evolutionarily conserved checkpoint protein kinase, TOR (target of rapamycin), has emerged as a major effector of cell growth and proliferation via the regulation of protein synthesis. Work in the last decade clearly demonstrates that TOR controls protein synthesis through a stunning number of downstream targets. Some of the targets are phosphorylated directly by TOR, but many are phosphorylated indirectly. In this review, we summarize some recent developments in this fast-evolving field. We describe both the upstream components of the signaling pathway(s) that activates mammalian TOR (mTOR) and the downstream targets that affect protein synthesis. We also summarize the roles of mTOR in the control of cell growth and proliferation, as well as its relevance to cancer and synaptic plasticity.
4,074 citations
"Insulin and glucagon regulate pancr..." refers background in this paper
...mTOR, an evolutionarily conserved serine-threonine kinase, interacts with AKT and promotes protein translation and cell growth in response to growth factors [28,29]....
[...]
TL;DR: It is reported that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age.
Abstract: Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruitflies; however, whether inhibition of mTOR signalling can extend lifespan in a mammalian species was unknown. Here we report that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age. On the basis of age at 90% mortality, rapamycin led to an increase of 14% for females and 9% for males. The effect was seen at three independent test sites in genetically heterogeneous mice, chosen to avoid genotype-specific effects on disease susceptibility. Disease patterns of rapamycin-treated mice did not differ from those of control mice. In a separate study, rapamycin fed to mice beginning at 270 days of age also increased survival in both males and females, based on an interim analysis conducted near the median survival point. Rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of ageing, or both. To our knowledge, these are the first results to demonstrate a role for mTOR signalling in the regulation of mammalian lifespan, as well as pharmacological extension of lifespan in both genders. These findings have implications for further development of interventions targeting mTOR for the treatment and prevention of age-related diseases.
3,216 citations
"Insulin and glucagon regulate pancr..." refers background in this paper
...Very interestingly, rapamycin just recently was shown to increase life-span in mice even when given late in life [43] and mTOR inhibitors (or rapalogs that do not have the immunosuppressant effects of rapamycin), are now being explored by companies to extend human life [44]....
[...]
TL;DR: Most cellular reduction of MTT occurs extramitochondrially and probably involves the pyridine nucleotide cofactors NADH and NADPH-dependent mechanisms that are insensitive to respiratory chain inhibitors.
1,331 citations
"Insulin and glucagon regulate pancr..." refers background in this paper
...the number of viable cells in proliferation [22]....
[...]
TL;DR: The results suggest that the PI3K/Akt/TOR pathway regulates protein and lipid biosynthesis in an orchestrated manner and that both processes are required for cell growth.
1,143 citations
"Insulin and glucagon regulate pancr..." refers background in this paper
...It has been reported that mTOR is required for AKT-dependent cell growth in human retinal cells [31] and our data show that insulin activates mTOR in a cells....
[...]