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Preventing ?-cell loss and diabetes with calcium channel blockers.

ABSTRACT: Although loss of functional ?-cell mass is a hallmark of diabetes, no treatment approaches that halt this process are currently available. We recently identified thioredoxin-interacting protein (TXNIP) as an attractive target in this regard. Glucose and diabetes upregulate ?-cell TXNIP expression, and TXNIP overexpression induces ?-cell apoptosis. In contrast, genetic ablation of TXNIP promotes endogenous ?-cell survival and prevents streptozotocin (STZ)- and obesity-induced diabetes. Finding an oral medication that could inhibit ?-cell TXNIP expression would therefore represent a major breakthrough. We were surprised to discover that calcium channel blockers inhibited TXNIP expression in INS-1 cells and human islets and that orally administered verapamil reduced TXNIP expression and ?-cell apoptosis, enhanced endogenous insulin levels, and rescued mice from STZ-induced diabetes. Verapamil also promoted ?-cell survival and improved glucose homeostasis and insulin sensitivity in BTBR ob/ob mice. Our data further suggest that this verapamil-mediated TXNIP repression is conferred by reduction of intracellular calcium, inhibition of calcineurin signaling, and nuclear exclusion and decreased binding of carbohydrate response element-binding protein to the E-box repeat in the TXNIP promoter. Thus, for the first time, we have identified an oral medication that can inhibit proapoptotic ?-cell TXNIP expression, enhance ?-cell survival and function, and prevent and even improve overt diabetes.

SUBMITTER: Xu G

PROVIDER: S-EPMC3314354 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Preventing β-cell loss and diabetes with calcium channel blockers.

Xu Guanlan G Chen Junqin J Jing Gu G Shalev Anath A

Diabetes 20120401 4

Although loss of functional β-cell mass is a hallmark of diabetes, no treatment approaches that halt this process are currently available. We recently identified thioredoxin-interacting protein (TXNIP) as an attractive target in this regard. Glucose and diabetes upregulate β-cell TXNIP expression, and TXNIP overexpression induces β-cell apoptosis. In contrast, genetic ablation of TXNIP promotes endogenous β-cell survival and prevents streptozotocin (STZ)- and obesity-induced diabetes. Finding an ...[more]

PMID: 22442301

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Project description:IntroductionUse of certain antihypertensive medications has been an area of interest during the COVID-19 pandemic, and several hypotheses have been developed regarding the effects of renin-angiotensin system blockers as well as calcium channel blockers in those infected with COVID-19. We seek to determine the association between exposure to ACEI, ARB, and CCB and outcomes in those admitted to the hospital with COVID-19 infection.MethodsThis retrospective cohort study included 841 adult patients hospitalized with COVID-19 infection at the University of Chicago Medical Center between March 25 and June 22, 2020. Out of these 841, 453 patients had a personal history of hypertension. For the first part, we evaluated primary outcomes of in-hospital mortality and ICU admission in hospitalized COVID-19 patients based on their exposure to particular medications regardless of a personal history of hypertension and compared them with those who were not on these medications. For the second part, we evaluated the aforementioned outcomes in 453 patients with a personal history of hypertension based on their medication exposure. Secondary outcomes of length of stay, readmission rate, and new-onset dialysis requirement were also compared across the study groups.ResultsOut of 841 patients, 111 (13.19%) were on ACEI/ARB (median age: 66.1, SD 15.4; 52.25% females) and 730 (86.80%) were not on them (median age: 56.6, SD 20.3; 50.14% females), while 277 (32.93%) used CCB (median age: 64.6, SD 15.2; 57.04% females) and 564 (67.06%) did not use CCB (median age: 54.6, SD 21.2; 47.16% females). After adjusting for demographics and covariates, neither ACEI/ARB nor CCB exposure was associated with any effect on mortality, but ACEI/ARB exposure was associated with 42% reduction in risk of ICU admissions (OR 0.58, 95% CI [0.35, 0.95], p value 0.03). In addition, combined use of ACEI/ARB and CCB was associated with statistically significant (45%) reduction in ICU admission (OR 0.55, 95% CI [0.32, 0.94], p value 0.029). Out of 453 patients with a personal history of hypertension, 85 (18.76%) were taking ACEI/ARB (median age 65, SD 15.6; 56.47% females) and 368 (81.24%) were not on ACEI/ARB (median age 62.8, SD 16.4; 54.89% females), while 208 (45.92%) out of 453 were on CCB (median age 65; SD 14.8; 60.1% females) and 245 (54.08%) were not on CCB (median age 61.7, SD 17.3; 51.02% females). In the fully adjusted model in this group, ACEI use was associated with 71% reduction in in-house mortality (OR 0.29, 95% CI [0.09, 0.93], p value 0.03).Discussion/conclusionAmong all hospitalized patients with COVID-19 infection, exposure to ACEI/ARB, as well as combined exposure to ACEI/ARB and CCB, were associated with reduced incidence of ICU admissions. In those admitted patients who had a personal history of hypertension, there was a trend towards reduced in-hospital mortality in those exposed to ACEI.

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Preventing ?-cell loss and diabetes with calcium channel blockers.

Publications

Preventing β-cell loss and diabetes with calcium channel blockers.

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