Scientists at City of Hope®, one of the largest and most advanced cancer research and treatment organizations in the U.S. and a leading research center for diabetes and other life-threatening diseases, have discovered a gene called SMOC1 that plays a surprising role in the development of type 2 diabetes (T2D) by converting pancreatic cells that normally produce insulin into ones that raise blood sugar.
The findings, published in Nature Communications , identify an important new therapeutic target for type 2 diabetes and explain why the number of insulin-producing cells in the pancreas often decreases over the course of the disease.
Pancreatic islets are clusters of cells that produce and release hormones into the bloodstream. Beta cells produce insulin, which lowers blood sugar, and alpha cells produce glucagon, which raises blood sugar. Maintaining this hormonal balance is critical for regulating normal blood sugar levels. In type 2 diabetes, some beta cells malfunction, forget their assigned task and lose their unique properties. They begin to act more like alpha cells and produce glucagon instead of insulin, leading to dysregulation of blood sugar levels.
To decipher why beta cells suffer an identity crisis in type 2 diabetes, City of Hope scientists used advanced RNA sequencing techniques to analyze individual islet cells from 26 people — half with type 2 diabetes and half without. The researchers sorted the cells into precise subgroups and mapped how one cell type transformed into another over time.
The team discovered five distinct types of islet cells, each with its own trajectory and genetic signature.
“In healthy people, islet cells can mature in different directions — some develop more toward alpha cells, others toward beta cells,” said the study’s lead author, Dr. Adolfo Garcia-Ocaña , the Ruth B. and Robert K. Lanman Professor of Gene Regulation and Drug Discovery at City of Hope and chair of the? Department of Molecular and Cellular Endocrinology . “However, in type 2 diabetes, there is only one direction: beta cells start to mimic alpha cells. This development could explain why insulin levels decrease and glucagon levels increase in people with this disease.”
In healthy islet cells, some cells follow branched pathways that can lead to maturation as alpha or beta cells, suggesting a flexibility of cell identity. However, in diabetic islet cells, this flexibility was lost; beta cells only converted into alpha cells.
The researchers also identified so-called AB cells that produce both insulin and glucagon. This unusual discovery suggests that these cells can develop into either alpha or beta cells.
Among the ten genes that showed consistent activity in cells transforming from beta to alpha identity, SMOC1 stood out as a central player. However, the protein it produced did not stay where it belonged.
“Normally, SMOC1 is active in the alpha cells of healthy people,” explained co-author Geming Lu, MD, Assistant Research Professor. “But we found that it also appears in the beta cells of diabetic people. It shouldn’t have been there.”
SMOC1 activity in the wrong place led to unwanted consequences: insulin production decreased, the activity of genes determining beta cell identity came to a standstill, and the beta cells showed typical markers of immature or alpha cells. Taken together, these findings suggest that SMOC1 expression in beta cells lowers insulin levels, leading to higher blood sugar levels, and provides scientists with a better understanding of the progression of type 2 diabetes.
“Our findings suggest that SMOC1 causes beta cell dysfunction and the shift of cells to an alpha-cell-like state,” said Dr. Garcia-Ocaña. “This helps explain why, in people with type 2 diabetes, insulin levels decrease and glucagon levels increase.”
