Exploratory study reveals far reaching systemic and cellular effects of verapamil treatment in subjects with type 1 diabetes.

Currently, no oral medications are available for type 1 diabetes (T1D). While our recent randomized placebo-controlled T1D trial revealed that oral verapamil had short-term beneficial effects, their duration and underlying mechanisms remained elusive. Now, our global T1D serum proteomics analysis identified chromogranin A (CHGA), a T1D-autoantigen, as the top protein altered by verapamil and as a potential therapeutic marker and revealed that verapamil normalizes serum CHGA levels and reverses T1D-induced elevations in circulating proinflammatory T-follicular-helper cell markers. RNA-sequencing further confirmed that verapamil regulates the thioredoxin system and promotes an anti-oxidative, anti-apoptotic and immunomodulatory gene expression profile in human islets. Moreover, continuous use of oral verapamil delayed T1D progression, promoted endogenous beta-cell function and lowered insulin requirements and serum CHGA levels for at least 2 years and these benefits were lost upon discontinuation. Thus, the current studies provide crucial mechanistic and clinical insight into the beneficial effects of verapamil in T1D.

METFORMIN USE IS ASSOCIATED WITH REDUCED MORTALITY IN A DIVERSE POPULATION WITH COVID-19 AND DIABETES.

BACKGROUND: Coronavirus disease-2019 (COVID-19) is a growing pandemic with an increasing death toll that has been linked to various comorbidities as well as racial disparity. However, the specific characteristics of these at-risk populations are still not known and approaches to lower mortality are lacking. METHODS: We conducted a retrospective electronic health record data analysis of 25,326 subjects tested for COVID-19 between 2/25/20 and 6/22/20 at the University of Alabama at Birmingham Hospital, a tertiary health care center in the racially diverse Southern U.S. The primary outcome was mortality in COVID-19-positive subjects and the association with subject characteristics and comorbidities was analyzed using simple and multiple linear logistic regression. RESULTS: The odds ratio of contracting COVID-19 was disproportionately high in Blacks/African-Americans (OR 2.6; 95%CI 2.19-3.10; p<0.0001) and in subjects with obesity (OR 1.93; 95%CI 1.64-2.28; p<0.0001), hypertension (OR 2.46; 95%CI 2.07-2.93; p<0.0001), and diabetes (OR 2.11; 95%CI 1.78-2.48; p<0.0001). Diabetes was also associated with a dramatic increase in mortality (OR 3.62; 95%CI 2.11-6.2; p<0.0001) and emerged as an independent risk factor in this diverse population even after correcting for age, race, sex, obesity and hypertension. Interestingly, we found that metformin treatment was independently associated with a significant reduction in mortality in subjects with diabetes and COVID-19 (OR 0.33; 95%CI 0.13-0.84; p=0.0210). CONCLUSION: Thus, these results suggest that while diabetes is an independent risk factor for COVID-19-related mortality, this risk is dramatically reduced in subjects taking metformin, raising the possibility that metformin may provide a protective approach in this high risk population.

Metformin Use Is Associated With Reduced Mortality in a Diverse Population With COVID-19 and Diabetes.

Background: Coronavirus disease-2019 (COVID-19) is a growing pandemic with an increasing death toll that has been linked to various comorbidities as well as racial disparity. However, the specific characteristics of these at-risk populations are still not known and approaches to lower mortality are lacking. Methods: We conducted a retrospective electronic health record data analysis of 25,326 subjects tested for COVID-19 between 2/25/20 and 6/22/20 at the University of Alabama at Birmingham Hospital, a tertiary health care center in the racially diverse Southern U.S. The primary outcome was mortality in COVID-19-positive subjects and the association with subject characteristics and comorbidities was analyzed using simple and multiple linear logistic regression. Results: The odds ratio of contracting COVID-19 was disproportionately high in Blacks/African-Americans (OR 2.6; 95% CI 2.19-3.10; p<0.0001) and in subjects with obesity (OR 1.93; 95% CI 1.64-2.28; p<0.0001), hypertension (OR 2.46; 95% CI 2.07-2.93; p<0.0001), and diabetes (OR 2.11; 95% CI 1.78-2.48; p<0.0001). Diabetes was also associated with a dramatic increase in mortality (OR 3.62; 95% CI 2.11-6.2; p<0.0001) and emerged as an independent risk factor in this diverse population even after correcting for age, race, sex, obesity, and hypertension. Interestingly, we found that metformin treatment prior to diagnosis of COVID-19 was independently associated with a significant reduction in mortality in subjects with diabetes and COVID-19 (OR 0.33; 95% CI 0.13-0.84; p=0.0210). Conclusion: Thus, these results suggest that while diabetes is an independent risk factor for COVID-19-related mortality, this risk is dramatically reduced in subjects taking metformin prior to diagnosis of COVID-19, raising the possibility that metformin may provide a protective approach in this high risk population.

Serum miR-204 is an early biomarker of type 1 diabetes-associated pancreatic beta-cell loss.

Pancreatic beta-cell death is a major factor in the pathogenesis of type 1 diabetes (T1D), but straightforward methods to measure beta-cell loss in humans are lacking, underlining the need for novel biomarkers. Using studies in INS-1 cells, human islets, diabetic mice, and serum samples of subjects with T1D at different stages, we have identified serum miR-204 as an early biomarker of T1D-associated beta-cell loss in humans. MiR-204 is a highly enriched microRNA in human beta-cells, and we found that it is released from dying beta-cells and detectable in human serum. We further discovered that serum miR-204 was elevated in children and adults with T1D and in autoantibody-positive at-risk subjects but not in type 2 diabetes or other autoimmune diseases and was inversely correlated with remaining beta-cell function in recent-onset T1D. Thus, serum miR-204 may provide a much needed novel approach to assess early T1D-associated human beta-cell loss even before onset of overt disease.

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

Pancreatic beta cell loss is a key factor in the pathogenesis of type 1 diabetes (T1D), but therapies to halt this process are lacking. We previously reported that the approved antihypertensive calcium-channel blocker verapamil, by decreasing the expression of thioredoxin-interacting protein, promotes the survival of insulin-producing beta cells and reverses diabetes in mouse models1. To translate these findings into humans, we conducted a randomized double-blind placebo-controlled phase 2 clinical trial ( NCT02372253 ) to assess the efficacy and safety of oral verapamil added for 12 months to a standard insulin regimen in adult subjects with recent-onset T1D. Verapamil treatment, compared with placebo was well tolerated and associated with an improved mixed-meal-stimulated C-peptide area under the curve, a measure of endogenous beta cell function, at 3 and 12 months (prespecified primary endpoint), as well as with a lower increase in insulin requirements, fewer hypoglycemic events and on-target glycemic control (secondary endpoints). Thus, addition of once-daily oral verapamil may be a safe and effective novel approach to promote endogenous beta cell function and reduce insulin requirements and hypoglycemic episodes in adult individuals with recent-onset T1D.

"In our stories": The perspectives of women living with HIV on an evidence-based group intervention.

A qualitative study among women living with HIV assessed the aspects of an evidence-based intervention targeting HIV transmission risk reduction (Women Involved in Life Learning from Other Women [WiLLOW]) that women valued and how their lives were impacted. Thirty-one women (80.6% African American) completed interviews. Women valued the personal stories and positive group dynamics (i.e. safety, trust, openness, getting feedback, bonding, and socializing). As a result of WiLLOW, women embraced a strong woman image, joined groups, changed behaviors, accepted their HIV status, became optimistic, and spoke up/advocated in their relationships and communities. Interventions for HIV-positive women may benefit from incorporating the sharing of stories in their curricula and factors that build positive group dynamics.

The moderating role of sexual identity in group teletherapy for adults aging with HIV.

Older adults living with HIV/AIDS experience high rates of depression and suicidal ideation but are less likely than their younger counterparts to seek psychological services. HIV continues to disproportionately impact older men who have sex with men (MSM), many of whom were infected in their 20s and 30s. This study examined whether therapy attendance rates and the efficacies of two group-format teletherapies for the treatment of depression (coping effectiveness group training and supportive-expressive group therapy) were comparable for older MSM and older heterosexuals living with HIV. Intervention-outcome analyses found that older MSM and older heterosexuals living with HIV attended comparable numbers of teletherapy sessions. Older heterosexuals living with HIV who received telephone-administered supportive-expressive group therapy reported significantly greater reductions in depressive symptoms than SOC controls. A similar pattern was not found in older MSM. More research is needed to personalize and tailor group teletherapies for older MSM living with HIV.