Glucose stimulates human beta cell replication in vivo in islets transplanted into NOD–severe combined immunodeficiency (SCID) mice

Levitt, Helena; Cyphert, Travis J.; Pascoe, Jordan L.; Hollern, Douglas A.; Abraham, Nader G.; Lundell, R. J.; Rosa, Taylor C.; Romano, Lia C.; Zou, Baobo; O’Donnell, Christopher P.; Stewart, Andrew F.; Garcı́a-Ocaña, Adolfo; Alonso, Laura

doi:10.1007/s00125-010-1919-1

Cited by 103 publications

(93 citation statements)

References 45 publications

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“…However, human islets exhibit a reduced and transient increase in islet mass in response to hyperglycemia. This is consistent with the low regenerative potential reported for human b-cells under comparable conditions (36,37), and could be related to species or age differences in mouse and human donor islets (38). The observed functional b-cell recovery is likely to be the underlying mechanism of the so-called honeymoon phase of partial or complete transient T1D remission observed in patients after initial therapy (39).…”

Section: Discussionsupporting

confidence: 82%

Distinct Roles of β-Cell Mass and Function During Type 1 Diabetes Onset and Remission

et al. 2015

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Cure of type 1 diabetes (T1D) by immune intervention at disease onset depends on the restoration of insulin secretion by endogenous b-cells. However, little is known about the potential of b-cell mass and function to recover after autoimmune attack ablation. Using a longitudinal in vivo imaging approach, we show how functional status and mass of b-cells adapt in response to the onset and remission of T1D. We demonstrate that infiltration reduces b-cell mass prior to onset and, together with emerging hyperglycemia, affects b-cell function. After immune intervention, persisting hyperglycemia prevents functional recovery but promotes b-cell mass increase in mouse islets. When blood glucose levels return to normoglycemia b-cell mass expansion stops, and subsequently glucose tolerance recovers in combination with b-cell function. Similar to mouse islets, human islets exhibit cell exhaustion and recovery in response to transient hyperglycemia. However, the effect of hyperglycemia on human islet mass increase is minor and transient. Our data demonstrate a major role of functional exhaustion and recovery of b-cells during T1D onset and remission. Therefore, these findings support early intervention therapy for individuals with T1D.Successful therapy at the onset of type 1 diabetes (T1D) not only requires an effective block of the pathological autoimmune process, but also the restoration of adequate insulin levels. Most promising for optimal glucose control is endogenous b-cell activity, which even at low levels reduces the risk for complications and hypoglycemic events (1). Therefore, preserved b-cell function and mass at diagnosis and their potential to recover after immune intervention are a crucial aspect of T1D therapy. Initially, b-cell mass was suggested to be almost completely destroyed at T1D onset (2,3), which questioned the justification of immune intervention at this late time point (4). However, more recent data demonstrate preserved b-cell mass and function in patients with newly diagnosed (5-7) and long-standing T1D (8,9). These observations raise the question of whether immune intervention at T1D onset will allow functional and morphological recovery of the residual b-cells. Indications of a potential recovery are the so-called "honeymoon phase" observed after initial insulin treatment (10), as well as the reported detection of b-cell proliferation in patients with T1D (11). However, it is unclear if b-cell mass and function have the capability to recover after immune intervention, and their distinct roles in the remission process have not been shown.Here we take advantage of a noninvasive in vivo imaging platform (12,13), and the possibility of successful immune intervention in mouse models of T1D (14), to study functional and morphological changes of b-cells and islets during the onset and remission of T1D. Our results demonstrate substantial morphological and functional b-cell plasticity before and after immune intervention. We furthermore show that b-cell mass and function differentially progress duri...

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Section: Discussionsupporting

confidence: 82%

Distinct Roles of β-Cell Mass and Function During Type 1 Diabetes Onset and Remission

et al. 2015

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“…However, the ratio of a-cells per graft was not significantly changed. In untreated mice, the rate of human b-cell proliferation was 0.4 6 0.07%, consistent with previous findings under similar conditions (4,5). Administration of GABA significantly increased the rate of b-cell proliferation by approximately fivefold, revealing a potent stimulatory effect.…”

Section: Gaba Enhanced Human B-cell Mass and Elevated Human Insulin Lsupporting

confidence: 90%

“…In vivo, the proliferation of adult human b-cells is very low, but an increase has been detected in a patient with recent-onset type 1 diabetes (T1D) (3), suggesting a regenerative capacity. This is supported by recent studies showing that mild hyperglycemia can increase human b-cell proliferation in vivo (4,5). These observations suggest that it may be possible to use stimuli to induce the b-cell regeneration and promote b-cell mass in the diabetic condition.…”

supporting

confidence: 65%

“…The clinical data of donors used for islet transplantation experiments are shown (Supplementary Table 1 , NSG) (denoted NOD-scid-g or NSG) mice (five animals per group) were rendered diabetic with streptozotocin (STZ) injections (125 mg/kg for two consecutive days; Sigma). Mice with blood glucose (BG) $18 mmol/L for .2 days were selected for experiments and transplanted with a suboptimal dose of human islets (1,500 islet equivalents [IEQ]) under the kidney capsule as previously described (4,5). This leaves a margin to observe whether GABA treatment improves hyperglycemia in these diabetic mice.…”

Section: Human Islet Isolationmentioning

confidence: 99%

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GABA Promotes Human β-Cell Proliferation and Modulates Glucose Homeostasis

et al. 2014

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γ-Aminobutyric acid (GABA) exerts protective and regenerative effects on mouse islet β-cells. However, in humans it is unknown whether it can increase β-cell mass and improve glucose homeostasis. To address this question, we transplanted a suboptimal mass of human islets into immunodeficient NOD-scid-γ mice with streptozotocin-induced diabetes. GABA treatment increased grafted β-cell proliferation, while decreasing apoptosis, leading to enhanced β-cell mass. This was associated with increased circulating human insulin and reduced glucagon levels. Importantly, GABA administration lowered blood glucose levels and improved glucose excursion rates. We investigated GABA receptor expression and signaling mechanisms. In human islets, GABA activated a calcium-dependent signaling pathway through both GABA A receptor and GABA B receptor. This activated the phosphatidylinositol 3-kinase–Akt and CREB–IRS-2 signaling pathways that convey GABA signals responsible for β-cell proliferation and survival. Our findings suggest that GABA regulates human β-cell mass and may be beneficial for the treatment of diabetes or improvement of islet transplantation.

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“…Thus, understanding how β-cells proliferate and elucidating the molecular mechanisms that natural mitogens stimulate the expansion of functional β-cells is beneficial for diabetes therapy. Glucose is a well-known potent β-cell mitogen in mice, rats, and humans, and plays a dominant role in the β-cell compensation of insulin demands (Chick 1973, Bonner-Weir et al 1989, Alonso et al 2007, Terauchi et al 2007, Weir & Bonner-Weir 2007, Levitt et al 2011. However, the mechanisms underlying its mitogenic activity remain unclear.…”

Section: :2mentioning

confidence: 99%

Sfrp5 mediates glucose-induced proliferation in rat pancreatic β-cells

Guan¹,

Li²,

Li³

et al. 2016

Journal of Endocrinology

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The cellular and molecular mechanisms of glucose-stimulated β-cell proliferation are poorly understood. Recently, secreted frizzled-related protein 5 (encoded by Sfrp5; a Wnt signaling inhibitor) has been demonstrated to be involved in β-cell proliferation in obesity. A previous study demonstrated that glucose enhanced Wnt signaling to promote cell proliferation. We hypothesized that inhibition of SFRP5 contributes to glucose-stimulated β-cell proliferation. In this study, we found that the Sfrp5 level was significantly reduced in high glucose-treated INS-1 cells, primary rat β-cells, and islets isolated from glucose-infused rats. Overexpression of SFRP5 diminished glucosestimulated proliferation in both INS-1 cells and primary β-cells, with a concomitant inhibition of the Wnt signaling pathway and decreased cyclin D2 expression. In addition, we showed that glucose-induced Sfrp5 suppression was modulated by the PI3K/AKT pathway. Therefore, we conclude that glucose inhibits Sfrp5 expression via the PI3K/AKT pathway and hence promotes rat pancreatic β-cell proliferation. Sfrp5 mediates β-cells proliferation

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Glucose stimulates human beta cell replication in vivo in islets transplanted into NOD–severe combined immunodeficiency (SCID) mice

Cited by 103 publications

References 45 publications

Distinct Roles of β-Cell Mass and Function During Type 1 Diabetes Onset and Remission

Distinct Roles of β-Cell Mass and Function During Type 1 Diabetes Onset and Remission

GABA Promotes Human β-Cell Proliferation and Modulates Glucose Homeostasis

Sfrp5 mediates glucose-induced proliferation in rat pancreatic β-cells

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