
Peter C. Butler, MD
There are more questions than answers about beta cell function in type 2 diabetes.
The mechanisms that cause beta cells to decrease or cease insulin secretion in response to glucose are not clear. It’s not even clear what a physiologically normal complement of beta cells might be.
“Some people end up with two grams of beta cells by early adulthood and some people have one-tenth of that,” said Peter C. Butler, MD, Professor and Director of the Larry L. Hillblom Islet Research Center at the University of California, Los Angeles, David Geffen School of Medicine. “And that’s in people who do not have diabetes. Imagine if some of us were one foot tall and some of us were 10 feet tall. That’s the range of beta cells we see in people even without diabetes.”
Dr. Butler will kick off a two-hour symposium Saturday afternoon titled Beta-Cell Dedifferentiation—True or False? The session begins at 1:45 p.m. in room W312.
When a pancreas becomes available at autopsy or surgery from a type 2 diabetes patient, typically their pancreas contains fewer beta cells than matched controls. It’s not known if the relative lack of beta cells is a result of diabetes, or if that individual had fewer beta cells to begin with and is more susceptible to the increased demands and effects of insulin resistance and metabolic conditions associated with type 2 diabetes.
“One cause of type 2 diabetes may well be that an individual had fewer beta cells, then gained weight, became less active, and somewhat insulin resistant,” Dr. Butler said. “The amount of insulin they could make compared to what they needed crossed over, and they developed diabetes. Whereas, if they had 10-fold more beta cells to begin with, they might be fine.”
Hereditary factors likely play a role in the failure of beta cells to secrete sufficient insulin. Similar to men with male pattern baldness gradually losing hair follicles in a hereditary manner, some families with a strong history of diabetes presumably have beta cells that are more vulnerable.
Another potential factor is beta cells that survive but stop making insulin altogether, a condition often referred to as beta-cell dedifferentiation.
“Beta cells in the pancreas are remarkably resistant to dying,” Dr. Butler said. “People live with type 2 diabetes for 15, 20, 30 years and still have as much as half of their beta cells present despite a hostile environment. We have identified a widely used injury repair response that’s activated in beta cells in type 2 diabetes. Other groups have reported the same injury response pathway active in Alzheimer’s disease. Activating this defense repair pathway keeps cells alive longer but at the expense of them not working.”
Beta cell failure is not forever. Type 2 diabetes remission is seen in about half of patients following bariatric surgery or following dramatic dietary changes, such as those documented in the Diabetes Remission Clinical Trial (DiRECT).
“We are identifying a trajectory of beta cell dysfunction to corroborate in vivo findings from bariatric surgery or severe dietary changes where about 50 percent of patients experience normalization of their blood glucose in the absence of any pharmacological treatment,” said Piero Marchetti, MD, PhD, Professor of Endocrinology and Metabolism of Organ and Cellular Transplantation at the University of Pisa, Italy.
“When we take islets from donors with diabetes and put them in medium with normal glucose levels, there is spontaneous recovery of beta cell function in about half of the preparations,” he continued. “Beta cell damage, even when type 2 diabetes is already present, can be rescued.”
It appears that beta cells from patients with more recent onset of type 2 diabetes are more likely to recover, Dr. Marchetti said. But it’s not clear why some beta cells restart insulin secretion or the mechanisms involved.
“We are comparing the transcriptomes of islets that recover versus islets that do not recover,” he said. “We are confident that we will see some mechanisms that differentiate these populations.”
Other researchers are following similar evidence but focused on transcription factors. In the earlier stages of type 2 diabetes, beta cells lose their identity characteristics rather than die.

Avital Swisa, PhD
“There are a number of transcription factors that define the identify of beta cells,” said Avital Swisa, PhD, a Postdoctoral Research Fellow at the University of Pennsylvania. “In some cases during the early stages of the disease, beta cells lose the expression of these transcription factors and begin expressing markers of other endocrine cells.”
Dr. Swisa and other researchers have shown that beta cells transdifferentiate toward ghrelin- or gastrin-producing endocrine cells, hormones normally secreted in the gastrointestinal tract.
“Beta cell identity is fragile,” she said. “Chronic metabolic changes like high glucose levels and oxidative stress can lead to changes in transcription programming and lead to a different identity. This dedifferentiation and redifferentiation is not unique to mice. We see similar changes in human beta cells.”
Genetic factors also can affect the incremental steps leading to beta cell dysfunction.
“Everybody talks about beta cell dysfunction and beta cell stress, but nobody can quite put their finger on the sequential effects and how stress can contribute to loss of function,” said Mark A. Magnuson, MD, Professor of Molecular Physiology and Biophysics, and the Louise B. McGavlock Chair of Cell and Developmental Biology at Vanderbilt University School of Medicine. “We are studying how the thousands of genes active in beta cells change in response to different metabolic stresses and whether there’s a single or multiple pathways to beta cell failure.”

Mark A. Magnuson, MD
Dr. Magnuson is exploring male gender, excitotoxicity, obesity, pseudo pregnancy, and glucose toxicity in mouse models.
“Pancreatic beta cell failure is the heart of type 2 diabetes,” he said. “We won’t understand type 2 diabetes, and maybe even type 1, without understanding the mechanisms of beta cell stress and failure.”