University of Oxford

Academic Institute

OFHR26040202OXF

This study aims to understand why some people are naturally protected against type 2 diabetes. Recent research has shown that individuals with rare variants in the genes ACVR1C and INHBE have a lower risk of developing the condition. These genes are active in key metabolic tissues, including the liver, fat tissue, and pancreas, which plays a central role in insulin secretion. We hypothesise that these genes influence communication between these organs to regulate fat storage and insulin release. To test this, we will assess insulin secretion and glucose metabolism in response to both oral (drink) and intravenous glucose administration in individuals carrying these variants, compared with carefully matched non-carriers. The primary research question is whether people with these genetic variants release insulin differently in response to sugar. Secondary questions include whether these variants affect how the body processes nutrients and how different tissues respond to sugar. By improving our understanding of this protective effect, the study may help identify new ways to prevent and treat type 2 diabetes. Type 2 diabetes is a common condition that develops when the body cannot produce enough insulin or use it effectively. While lifestyle factors are important, genetics also plays a key role in determining an individual’s risk. Recent studies have identified rare genetic changes in two genes, ACVR1C and INHBE, that appear to protect against type 2 diabetes, but the reasons for this protection are not yet well understood. These genes are active in key metabolic organs, including the liver, fat tissue, and pancreas, suggesting they may influence how these organs work together to control blood sugar and insulin levels. Most research, including our own, has focused on their role in fat tissue, particularly in regulating fat distribution and the breakdown of fat. However, ACVR1C (also known as ALK7) is also expressed in the insulin-producing cells of the pancreas, and animal studies suggest that reduced function of ACVR1C and INHBE increases insulin secretion. There is currently a gap in knowledge about how these genetic changes affect insulin production and the body’s response to glucose in humans. This study will address this gap by examining how individuals with these genetic changes respond to glucose, compared with people without them. Understanding these mechanisms could provide new insights into how type 2 diabetes develops and help identify new targets for treatment, with the potential to improve prevention and therapy in the future.

Type 2 diabetes is a major public health problem that can lead to serious complications, including kidney failure, blindness, heart attacks, strokes, and limb amputation. Although treatments are available, they are not always fully effective in preventing or managing the condition, and many people remain at risk of long-term complications. Type 2 diabetes is also a leading cause of preventable illness and early death worldwide. This study aims to understand why some people are naturally protected against type 2 diabetes. By studying individuals with rare protective genetic changes in the ACVR1C and INHBE genes, we hope to identify biological pathways that help maintain healthy blood sugar levels and fat metabolism. The findings could have several public benefits. First, they may support the development of new treatments that mimic this natural protection. Early studies targeting INHBE have already shown reductions in body fat and liver fat, suggesting wider benefits for metabolic health. Second, because the protein made by the INHBE gene can be measured in the blood, this research may help develop new ways to identify people at higher risk or to monitor how well treatments are working. Type 2 diabetes disproportionately affects people from disadvantaged backgrounds and certain ethnic groups. By improving prevention and treatment strategies, this research has the potential to reduce health inequalities and improve long-term outcomes.

Public Health Research

22/05/2026

Release