Metabolic Regulation and Disease
New Role for BAD Yields Novel Diabetes Therapy
Ever since she was a postdoctoral fellow in the laboratory of
the late Stanley Korsmeyer, Nika Danial, PhD, has been intrigued
with BAD (BCL-2 associated death promoter), a member of the BCL-2
family of proteins known to regulate apoptosis, a process that many
cancer cells escape. Like an alert sentinel, BAD senses cellular
damage and communicates this information to the mitochondria, which
in turn, release apoptogenic factors leading to destruction of the
damaged cell. But, Danial was curious about the biology of BAD and
whether the protein might play a nonapoptotic role in healthy
cells.
She and colleagues embarked upon a series of biochemical studies
of the proteins to which BAD binds at mitochondria, she says, and
"literally stumbled" upon glucokinase (GK, an enzyme that
facilitates phosphorylation of glucose), suggesting a new role for
BAD in the metabolism of glucose. Moreover, genetic experiments
showed that mice lacking the BAD protein had fasting hyperglycemia
and impaired glucose tolerance, features characteristic of type 2
diabetes.
This startling discovery led to a series of experiments to
figure out how BAD toggles between its two functions. To their
surprise, the BH3 domain of BAD controls both apoptosis and glucose
metabolism, says Danial, now assistant professor in the Department
of Cancer Biology. Like a master switch, the phosphorylation status
of the BH3 domain regulates the ligands to which BAD can bind and,
thereby, determines whether the cell signals through the apoptotic
or the metabolic pathway. When investigators created a genetic
mutant of BAD whose BH3 domain could not be phosphorylated, the
mutant could bind only to its pro-apoptotic partners and proved
incompetent for metabolic function, explains Danial. Conversely, a
genetic mutant whose BH3 domain was constitutively phosphorylated
could bind only to GK, required for glucose metabolism, and could
not induce apoptosis.
These unusual findings sparked a new idea. "If we could mimic
the phosphorylated BH3 domain through genetic or pharmacologic
maneuvers," explains Danial, "we could stimulate BAD's metabolic
function without sensitizing cells to apoptosis." To test this
hypothesis, Danial's laboratory collaborated with Loren Walensky, MD, PhD, of the Department of Pediatric Oncology, who turned the amino acid sequence of the
constitutively phosphorylated BH3 domain of BAD into a
peptidemimetic compound. Danial's lab then tested the compound in
defective beta cells of the pancreas, which in type 2 diabetes
become incapable of secreting insulin in response to glucose.
Strikingly, the compound restored glucose metabolism and insulin
secretion in the faulty cells. "This demonstrates that the BH3
domain is not only required, but also sufficient for BAD's function
in glucose homeostasis," Danial emphasizes. "And, remarkably, it
opens up a whole new therapeutic strategy for diabetes based on
mimicking the function of a domain that nature has already designed
to activate GK."
Ongoing animal model studies using both genetic and
pharmacologic manipulations of BAD's metabolic function are
beginning to show promise as well. The mimetic compounds that
emerged from this collaboration between biologists and chemists
have the potential to serve a dual therapeutic purpose, observes
Danial. "They may help control blood glucose while preventing
apoptosis in the cell," thus eliminating some toxicity problems.
"We hope this novel therapeutic strategy will have significant
implications for type 2 diabetes."