Verapamil and beta cell function in adults with recent-onset type 1 diabetes

Ovalle, Fernando; Grimes, Tiffany; Xu, Guanlan; Patel, Anish J.; Grayson, Truman; Thielen, Lance; Liu, Mingchun; Shalev, Anath

doi:10.1038/s41591-018-0089-4

Cited by 165 publications

(121 citation statements)

References 32 publications

Supporting

Mentioning

111

Contrasting

Unclassified

Order By: Relevance

“…Approaches to improve beta-cell survival using agents such as Sitagliptin (DPP-IV inhibitor), Verapamil (calcium channel blocker) or agents neutralizing pro-inflammatory cytokines such as IL1beta (Canakinumab) have had some positive effects that will need further confirmation [34][35][36]. Nonetheless, such therapies do neither refrain the immune attack nor stimulate beta-cell regeneration.…”

Section: Immune Blocking and Beta-cell Replacement Therapiesmentioning

confidence: 99%

Time for a paradigm shift in treating type 1 diabetes mellitus: coupling inflammation to islet regeneration

Cobo-Vuilleumier

Gauthier

2020

Metabolism

View full text Add to dashboard Cite

Type 1 diabetes mellitus (T1DM) is an autoimmune disease that targets the destruction of islet beta-cells resulting in insulin deficiency, hyperglycemia and death if untreated. Despite advances in medical devices and longer-acting insulin, there is still no robust therapy to substitute and protect beta-cells that are lost in T1DM. Attempts to refrain from the autoimmune attack have failed to achieve glycemic control in patients highlighting the necessity for a paradigm shift in T1DM treatment. Paradoxically, beta-cells are present in T1DM patients indicating a disturbed equilibrium between the immune attack and beta-cell regeneration reminiscent of unresolved wound healing that under normal circumstances progression towards an anti-inflammatory milieu promotes regeneration. Thus, the ultimate T1DM therapy should concomitantly restore immune self-tolerance and replenish the beta-cell mass similar to wound healing. Recently the agonistic activation of the nuclear receptor LRH-1/ NR5A2 was shown to induce immune self-tolerance, increase beta-cell survival and promote regeneration through a mechanism of alpha-to-beta cell phenotypic switch. This trans-regeneration process appears to be facilitated by a pancreatic anti-inflammatory environment induced by LRH-1/NR5A2 activation. Herein, we review the literature on the role of LRH1/NR5A2 in immunity and islet physiology and propose that a cross-talk between these cellular compartments is mandatory to achieve therapeutic benefits.

show abstract

Section: Immune Blocking and Beta-cell Replacement Therapiesmentioning

confidence: 99%

Time for a paradigm shift in treating type 1 diabetes mellitus: coupling inflammation to islet regeneration

Cobo-Vuilleumier

Gauthier

2020

Metabolism

View full text Add to dashboard Cite

show abstract

“…Many current immunosuppressive regimes, including the use of rapamycin (sirolimus) [ 94 ], exert deleterious effects on beta cell function via effects on mitochondrial respiration and as such may not be optimal during islet transplantation. Furthermore, clinical trials are only beginning to demonstrate rescuing beta cell function as a therapeutic strategy (e.g., Verapamil [ 95 •]).…”

Section: Relevance Of Beta Cell Heterogeneity For T1d Pathogenesis Anmentioning

confidence: 99%

The Impact of Pancreatic Beta Cell Heterogeneity on Type 1 Diabetes Pathogenesis

et al. 2018

View full text Add to dashboard Cite

Purpose of ReviewTo discuss advances in our understanding of beta-cell heterogeneity and the ramifications of this for type 1 diabetes (T1D) and its therapy.Recent FindingsA number of studies have challenged the long-standing dogma that the majority of beta cells are eliminated in T1D. As many as 80% are present in some T1D subjects. Why don’t these cells function properly to release insulin in response to high glucose? Other findings deploying single-cell “omics” to study both healthy and diseased cells—from patients with both T1D and type 2 diabetes (T2D)—have revealed cell subpopulations and heterogeneity at the transcriptomic/protein level between individual cells. Finally, our own and others’ findings have demonstrated the importance of functional beta-cell subpopulations for insulin secretion.SummaryHeterogeneity may endow beta cells with molecular features that predispose them to failure/death during T1D.

show abstract

“…Tissues with high expression of L-type calcium channels, such as βcells, are therefore most likely to benefit from the resulting TXNIP inhibition. 45 In a study done on a wild-type male C57BL/6 mice rendered diabetic by streptozotocin to test if verapamil could reduce TXNIP levels, the results demonstrated that about 80% reduction in TXNIP levels in isolated islets of verapamil-treated animals compared with control mice. 46 In addition, several human studies reveal that verapamil can decrease TXNIP expression in diabetic patients as shown in Table 1 below.…”

Section: Verapamilmentioning

confidence: 99%

<p>Thioredoxin-Interacting Protein as a Novel Potential Therapeutic Target in Diabetes Mellitus and Its Underlying Complications</p>

Wondafrash¹,

Nire'a²,

Tafere³

et al. 2020

DMSO

View full text Add to dashboard Cite

Diabetes mellitus (DM) is a common metabolic disorder which is characterized by a persistent increment of blood glucose. Globally, DM affects millions of people and the prevalence is increasing alarmingly. The critical step in the pathophysiology of DM is the loss of βcells of the pancreas, which are responsible for the secretion of insulin. Thioredoxin-interacting protein (TXNIP) is among the factors that control the production and loss of the pancreatic βcells. TXNIP is an α-arrestin that can bind and inhibit thioredoxin (the antioxidant protein) which is produced in the pancreatic islet after glucose intake. Numerous studies illustrated that elevated TXNIP levels were found to induce β-cell apoptosis; whereas TXNIP deficiency protects against type I and type II diabetes by promoting β-cell survival. Nowadays, TXNIP depletion is becoming a key factor in pancreatic β-cell survival enhancement. In the present review, targeting TXNIP is found to be relevant as a unique therapeutic opportunity, not only to improve insulin secretion and sensitivity, but also ameliorating the long term microvascular and macrovascular complications of the disease. Thus, TXNIP inhibitors that could reduce the expression and/or activity of TXNIP to non-diabetic levels are promising agents to halt the alarming rate of diabetes and its related complications.

show abstract

Verapamil and beta cell function in adults with recent-onset type 1 diabetes

Cited by 165 publications

References 32 publications

Time for a paradigm shift in treating type 1 diabetes mellitus: coupling inflammation to islet regeneration

Time for a paradigm shift in treating type 1 diabetes mellitus: coupling inflammation to islet regeneration

The Impact of Pancreatic Beta Cell Heterogeneity on Type 1 Diabetes Pathogenesis

<p>Thioredoxin-Interacting Protein as a Novel Potential Therapeutic Target in Diabetes Mellitus and Its Underlying Complications</p>

Contact Info

Product

Resources

About