Phospho-BAD BH3 Mimicry Protects β Cells and Restores Functional β Cell Mass in Diabetes

Abstract

SUMMARY Strategies that simultaneously enhance the survival and glucose responsiveness of insulin-producing β cells will greatly augment β cell replacement therapies in type 1 diabetes (T1D). We show that genetic and pharmacologic mimetics of the phosphorylated BCL-2 homology 3 (BH3) domain of BAD impart β cell autonomous protective effects in the face of stress stimuli relevant to β cell demise in T1D. Importantly, these benefits translate into improved engraftment of donor islets in transplanted diabetic mice, increased β cell viability in islet grafts, restoration of insulin release, and diabetes reversal. Survival of β cells in this setting is not merely due to the inability of phospho-BAD to suppress pro-survival BCL-2 proteins but requires its activation of the glucose-metabolizing enzyme glucokinase. Thus, BAD phospho-BH3 mimetics may prove useful in restoration of functional β cell mass in diabetes.

Regulation of mitochondrial nutrient and energy metabolism by BCL-2 family proteins

“…GK activity in β-cells is tightly linked to their capacity to oxidize glucose and release insulin in a glucose dose responsive manner (glucose sensing) [28]. Studies in islets derived from Bad −/− and Bad S155A knockin mice, and in human donor islets indicate that the phospho-BAD BH3 helix is necessary and sufficient for proper mitochondrial oxidation of glucose and the attendant increase in insulin secretion, but does not affect insulin release in response to amino acids or other secretagogues that donate carbons to the tricarboxylic acid (TCA) cycle independent of GK activity [25, 27, 32]. This selective defect in glucose-stimulated insulin secretion rather than a broad deficiency in insulin release is in agreement with GK as the metabolic target of BAD phosphorylation, and is further in line with the observation that mutations in BAD do not produce global defects in mitochondrial substrate metabolism and oxidative phosphorylation (OXPHOS), which would otherwise lead to a general defect in insulin secretion in response to glucose and non-glucose secretagogues.…”

“…Glucose metabolism in β-cells not only triggers insulin secretion but can also affect β-cell mass by promoting β-cell proliferation and survival as well as preventing their de-differentiation [32-36]. Recent findings indicate that genetic and pharmacologic approaches to mimic BAD phosphorylation within its BH3 helix augment functional β-cell mass through β-cell autonomous protective effects [32].…”

“…Recent findings indicate that genetic and pharmacologic approaches to mimic BAD phosphorylation within its BH3 helix augment functional β-cell mass through β-cell autonomous protective effects [32]. The benefits of phospho-BAD in β-cells include protection from apoptosis induced by inflammatory, oxidative and ER stress stimuli, as well as increased glucose handling and insulin secretory capacities (Figure 3).…”

HK2 Recruitment to Phospho-BAD Prevents Its Degradation, Promoting Warburg Glycolysis by Theileria-Transformed Leukocytes

“…The Bcl-2 family member BAD plays an important regulatory role in glycolysis, where its activity is regulated by phosphorylation in response to growth factors and survival. 29,30 We have previously described that in Theileria -transformed B cells, PKA is constitutively active and BAD is permanently phosphorylated at S155. 21 …”

“…In nontransformed hepatocytes, cell-penetrating phosphomimic peptides that disrupt the BAD/GK complex counteract gluconeogenesis and improve glycemia in models of diabetes and insulin resistance, and it has been proposed that phospho-BAD mimetics may restore functional β cell mass in diabetes. 30 We propose that ablating HK2 recruitment to BAD could negatively affect the proliferation of any cell that preferentially uses Warburg glycolysis, as proteasomal degradation of HK2 would render them reliant of HK1-mediated oxidative glycolysis for growth. On the basis of these findings, disruption of BAD S155 phosphorylation may serve as a useful strategy for the treatment not only of tropical theileriosis but also of cancer due to tumor dependence on Warburg glycolysis.…”