two years after diagnosis
Benefits of the blood pressure medication verapamil include delayed
disease progression, lowered insulin requirements and preservation of some beta cell function.

Date:
March 3, 2022
Source:
University of Alabama at Birmingham
Summary:
Use of the drug verapamil to treat Type 1 diabetes continues to show
benefits lasting at least two years, researchers report. Patients
taking the oral blood pressure medication not only required less
daily insulin two years after first diagnosis of the disease,
but also showed evidence of surprising immunomodulatory benefits.



FULL STORY ==========================================================================
Use of the drug verapamil to treat Type 1 diabetes continues to show
benefits lasting at least two years, researchers report in the journal
Nature Communications. Patients taking the oral blood pressure medication
not only required less daily insulin two years after first diagnosis
of the disease, but also showed evidence of surprising immunomodulatory benefits.


========================================================================== Continuing medication was necessary. In the two-year study, subjects who stopped daily doses of verapamil at one year saw their disease at two
years worsen at rates similar to those of the control group of diabetes patients who did not use verapamil at all.

Type 1 diabetes is an autoimmune disease that causes loss of pancreatic
beta cells, which produce endogenous insulin. To replace that, patients
must take exogenous insulin by shots or pump and are at risk of dangerous
low blood sugar events. There is no current oral treatment for this
disease.

The suggestion that verapamil might serve as a potential Type 1 diabetes
drug was the serendipitous discovery of study leader Anath Shalev,
M.D., director of the Comprehensive Diabetes Center at the University
of Alabama at Birmingham.

This finding stemmed from more than two decades of her basic research
into a gene in pancreatic islets called TXNIP. In 2014, Shalev's UAB
research lab reported that verapamil completely reversed diabetes in
animal models, and she announced plans to test the effects of the drug
in a human clinical trial. The United States Food and Drug Administration approved verapamil for the treatment of high blood pressure in 1981.

In 2018, Shalev and colleagues reported the benefits of verapamil in a
one-year clinical study of Type 1 diabetes patients, finding that regular
oral administration of verapamil enabled patients to produce higher levels
of their own insulin, thus limiting their need for injected insulin to
regulate blood sugar levels.

The current study extends on that finding and provides crucial mechanistic
and clinical insights into the beneficial effects of verapamil in Type
1 diabetes, using proteomics analysis and RNA sequencing.



==========================================================================
To examine changes in circulating proteins in response to verapamil
treatment, the researchers used liquid chromatography-tandem mass
spectrometry of blood serum samples from subjects diagnosed with
Type 1 diabetes within three months of diagnosis and at one year of
follow-up. Fifty-three proteins showed significantly altered relative
abundance over time in response to verapamil.

These included proteins known to be involved in immune modulation and autoimmunity of Type 1 diabetes.

The top serum protein altered by verapamil treatment was chromogranin
A, or CHGA, which was downregulated with treatment. CHGA is localized
in secretory granules, including those of pancreatic beta cells,
suggesting that changed CHGA levels might reflect alterations in beta cell integrity. In contrast, the elevated levels of CHGA at Type 1 diabetes
onset did not change in control subjects who did not take verapamil.

CHGA levels were also easily measured directly in serum using a simple
ELISA assay after a blood draw, and lower levels in verapamil-treated
subjects correlated with better endogenous insulin production as measured
by mixed-meal- stimulated C-peptide, a standard test of Type 1 diabetes progression. Also, serum CHGA levels in healthy, non-diabetic volunteers
were about twofold lower compared to subjects with Type 1 diabetes, and
after one year of verapamil treatment, verapamil-treated Type 1 diabetes subjects had similar CHGA levels compared with healthy individuals. In
the second year, CHGA levels continued to drop in verapamil-treated
subjects, but they rose in Type 1 diabetes subjects who discontinued
verapamil during year two.

"Thus, serum CHGA seems to reflect changes in beta cell function in
response to verapamil treatment or Type 1 diabetes progression and
therefore may provide a longitudinal marker of treatment success or
disease worsening," Shalev said.

"This would address a critical need, as the lack of a simple longitudinal marker has been a major challenge in the Type 1 diabetes field."
Other labs have identified CHGA as an autoantigen in Type 1 diabetes that provokes immune T cells involved in the autoimmune disease. Thus, Shalev
and colleagues asked whether verapamil affected T cells. They found that several proinflammatory markers of T follicular helper cells, including
CXCR5 and interleukin 21, were significantly elevated in monocytes from subjects with Type 1 diabetes, as compared to healthy controls, and they
found that these changes were reversed by verapamil treatment.

"Now our results reveal for the first time that verapamil treatment may
also affect the immune system and reverse these Type 1 diabetes-induced changes," Shalev said. "This suggests that verapamil, and/or the Type
1 diabetes improvements achieved by it, can modulate some circulating proinflammatory cytokines and T helper cell subsets, which in turn
may contribute to the overall beneficial effects observed clinically."
To assess changes in gene expression, RNA sequencing of human pancreatic
islet samples exposed to glucose, with or without verapamil was performed
and revealed a large number of genes that were either upregulated or downregulated.

Analysis of these genes showed that verapamil regulates the thioredoxin
system, including TXNIP, and promotes an anti-oxidative, anti-apoptotic
and immunomodulatory gene expression profile in human islets. Such
protective changes in the pancreatic islets might further explain the
sustained improvements in pancreatic beta cell function observed with continuous verapamil use.

Shalev and colleagues caution that their study, with its small number
of subjects, needs to be confirmed by larger clinical studies, such as
a current verapamil-Type 1 diabetes study ongoing in Europe.

But the preservation of some beta cell function is promising. "In
humans with Type 1 diabetes, even a small amount of preserved
endogenous insulin production -- as opposed to higher exogenous
insulin requirements -- has been shown to be associated with improved
outcomes and could help improve quality of life and lower the high
costs associated with insulin use," Shalev said. "The fact that these beneficial verapamil effects seemed to persist for two years, whereas discontinuation of verapamil led to disease progression, provides some additional support for its potential usefulness for long-term treatment." ========================================================================== Story Source: Materials provided by
University_of_Alabama_at_Birmingham. Original written by Jeff
Hansen. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Guanlan Xu, Tiffany D. Grimes, Truman B. Grayson, Junqin Chen,
Lance A.

Thielen, Hubert M. Tse, Peng Li, Matt Kanke, Tai-Tu Lin, Athena A.

Schepmoes, Adam C. Swensen, Vladislav A. Petyuk, Fernando Ovalle,
Praveen Sethupathy, Wei-Jun Qian, Anath Shalev. Exploratory study
reveals far reaching systemic and cellular effects of verapamil
treatment in subjects with type 1 diabetes. Nature Communications,
2022; 13 (1) DOI: 10.1038/ s41467-022-28826-3 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220303095705.htm

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