Adenosine kinase inhibition selectively promotes rodent and porcine islet β-cell replication

Annes, Justin P.; Ryu, Jennifer Hyoje; Lam, Kelvin; Carolan, Peter J.; Utz, Katrina; Hollister-Lock, Jennifer; Arvanites, Anthony C.; Rubin, Lee L.; Weir, Gordon C.; Melton, Douglas A.

doi:10.1073/pnas.1201149109

Cited by 128 publications

(137 citation statements)

References 60 publications

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“…In some patients, hyperinsulinism could be detected as the cause of recurrent hypoglycemia. Inhibitors of ADK and adenosine agonists were recently shown to specifically promote replication of primary β-cells of the pancreas in vitro and in vivo through the adenosine receptor A2aa and activation of the mTOR pathway (Annes et al 2012;Andersson et al 2012). Our finding of hyperinsulinism in patients with ADK deficiency suggests that adenosine signalling may influence insulin secretion in humans.…”

Section: Hypoglycemiamentioning

confidence: 71%

Adenosine kinase deficiency: expanding the clinical spectrum and evaluating therapeutic options

Staufner

Dionisi‐Vici

Freisinger

et al. 2015

J of Inher Metab Disea

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Background Adenosine kinase deficiency is a recently described defect affecting methionine metabolism with a severe clinical phenotype comprising mainly neurological and hepatic impairment and dysmorphism. Methods Clinical data of 11 additional patients from eight families with adenosine kinase deficiency were gathered through a retrospective questionnaire. Two liver biopsies of one patient were systematically evaluated. Results The main clinical symptoms are mild to severe liver dysfunction with neonatal onset, muscular hypotonia, global developmental retardation and dysmorphism (especially frontal bossing). Hepatic involvement is not a constant finding. Most patients have epilepsy and recurrent hypoglycemia due to hyperinsulinism. Major biochemical findings are intermittent hypermethioninemia, increased S-adenosylmethionine and Sadenosylhomocysteine in plasma and increased adenosine in urine. S-adenosylmethionine and S-adenosylhomocysteine are the most reliable biochemical markers. The major histological finding was pronounced microvesicular hepatic steatosis. Therapeutic trials with a methionine restricted diet indicate a potential beneficial effect on biochemical and clinical parameters in four patients and hyperinsulinism was responsive to diazoxide in two patients. Conclusion Adenosine kinase deficiency is a severe inborn error at the cross-road of methionine and adenosine metabolism that mainly causes dysmorphism, brain and liver symptoms, but also recurrent hypoglycemia.

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Section: Hypoglycemiamentioning

confidence: 71%

Adenosine kinase deficiency: expanding the clinical spectrum and evaluating therapeutic options

Staufner

Dionisi‐Vici

Freisinger

et al. 2015

J of Inher Metab Disea

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“…Additional molecular regulators of β-cell replication in rodents have been identified through high-throughput screening of reversibly immortalized β-cell lines or primary rodent islets. These regulators include phorbol esters, thiophene-pyrimidines, dihydropyridine derivatives and adenosine kinase inhibitors (Annes et al, 2012;Wang et al, 2009). Glucose or Glp1r agonists have an additive effect on the replication induced by most of these recently identified factors (Annes et al, 2012;Wang et al, 2009); however, it remains to be seen whether these small molecules will have an inductive effect on human islets.…”

Section: Screening For Small-molecule Effectors That Modulate Replicamentioning

confidence: 99%

“…These regulators include phorbol esters, thiophene-pyrimidines, dihydropyridine derivatives and adenosine kinase inhibitors (Annes et al, 2012;Wang et al, 2009). Glucose or Glp1r agonists have an additive effect on the replication induced by most of these recently identified factors (Annes et al, 2012;Wang et al, 2009); however, it remains to be seen whether these small molecules will have an inductive effect on human islets. More recently, Schultz and colleagues identified a novel small molecule, WS6, that increased both rat and human β-cell replication in vitro by sixfold in dispersed islets and by more than tenfold in intact islets (Shen et al, 2013).…”

Section: Screening For Small-molecule Effectors That Modulate Replicamentioning

confidence: 99%

How to make a functional β-cell

2013

Self Cite

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SummaryInsulin-secreting pancreatic β-cells are essential regulators of mammalian metabolism. The absence of functional β-cells leads to hyperglycemia and diabetes, making patients dependent on exogenously supplied insulin. Recent insights into β-cell development, combined with the discovery of pluripotent stem cells, have led to an unprecedented opportunity to generate new β-cells for transplantation therapy and drug screening. Progress has also been made in converting terminally differentiated cell types into β-cells using transcriptional regulators identified as key players in normal development, and in identifying conditions that induce β-cell replication in vivo and in vitro. Here, we summarize what is currently known about how these strategies could be utilized to generate new β-cells and highlight how further study into the mechanisms governing later stages of differentiation and the acquisition of functional capabilities could inform this effort. Key words: β cell, Diabetes mellitus, Mammalian metabolism IntroductionDiabetes mellitus is a metabolic disease that results from a failure in glucose regulation, causing severe hyperglycemia, tissue/organ damage and increased morbidity and mortality. Pancreatic β-cells respond to high blood glucose levels by secreting the peptide hormone insulin, which acts on other tissues to promote glucose uptake from the blood, for example in the liver where it promotes energy storage by glycogen synthesis (Powers and D'Alessio, 2011). The Centers of Disease Control (CDC) estimated that 25.8 million Americans had diabetes in 2010, and more than 300 million people are affected worldwide according to the International Diabetes Federation, thus making diabetes a major worldwide healthcare challenge.Diabetes is classified into two related but distinct diseases with different causes. Type 1 diabetes results from autoimmune destruction of insulin-producing β-cells in the pancreas. Type 2 diabetes, which is commonly associated with obesity, occurs when insulin demand due to persistently high blood sugar overwhelms the capacity of β-cells to produce sufficient insulin to prevent hyperglycemia. In Type 2 diabetes, peripheral tissues, such as fat and muscle, also become resistant to the effects of insulin. This high demand on β-cells frequently leads to β-cell malfunction, dedifferentiation and death (Ashcroft and Rorsman, 2012;Talchai et al., 2012). The number of β-cells lost in Type 2 diabetes is unclear but can approach 60% (Butler et al., 2003;Rahier et al., 2008), and the remaining β-cells are likely to be in some way dysfunctional.In diabetes, the persistent misregulation of glucose homeostasis also leads to a variety of secondary complications including cardiovascular disease, retinopathy and associated blindness, neuropathy that can result in amputations, and kidney disease leading to renal failure (Powers and D'Alessio, 2011). According to the CDC, diabetes is the leading cause of kidney failure, blindness and amputations in American adults. Cardiovascular complications, whi...

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“…Intracellular signaling pathways regulating β cell replication. Many groups have used high-throughput screening methods to discover novel molecules and pathways that could stimulate β cell mass expansion (129)(130)(131)(132)(133)(134)(135)(136)(137)(138). Some of these screens have led to the discovery of novel compounds with therapeutic potential.…”

Section: Introductionmentioning

confidence: 99%

Advances in β cell replacement and regeneration strategies for treating diabetes

Benthuysen¹,

Carrano²,

Sander³

2016

Journal of Clinical Investigation

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Adenosine kinase inhibition selectively promotes rodent and porcine islet β-cell replication

Cited by 128 publications

References 60 publications

Adenosine kinase deficiency: expanding the clinical spectrum and evaluating therapeutic options

Adenosine kinase deficiency: expanding the clinical spectrum and evaluating therapeutic options

How to make a functional β-cell

Advances in β cell replacement and regeneration strategies for treating diabetes

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