Mystery of important blood pressure drugs solved
Diuretic drugs from the thiazide group have been used for 60 years to treat high blood pressure. But they also increase the risk of developing diabetes. Researchers at the University of Bern and Inselspital have now pinpointed the cause of this side effect and in the process also gained new insights into the development of diabetes.
High blood pressure is a global health problem. In Switzerland, one in two people over the age of 65 has high blood pressure. This has been shown to increase the risk of serious secondary diseases such as dementia, stroke, cerebral hemorrhage, heart attack, and kidney failure. According to estimates by the World Health Organization, for example, around 54 percent of strokes are a direct result of high blood pressure. "Accordingly, there is a great need for effective, and also inexpensive and widely available antihypertensive drugs - particularly in light of our aging society," explains Prof. Daniel Fuster, M.D., from the Department for BioMedical Research at the University of Bern (DBMR) and Head Physician at the Department of Nephrology and Hypertension at Inselspital, Bern University Hospital.
Tried and true antihypertensives increase risk of diabetes
Diuretics from the group of thiazides were the first blood pressure medications to be effective. That was around six decades ago. Today, they are still among the most frequently prescribed drugs and are an integral part of the treatment of high blood pressure. They are also frequently used to treat water retention in the body, known as edema.
Thiazides are available worldwide and are extremely inexpensive. They are often used in combination with other active ingredients and are effective at lowering blood pressure - and thus the risk of dangerous secondary diseases. But thiazides have a serious side effect. "Patients taking thiazides have a 20 to 50 percent increased risk of developing diabetes, depending on the study. For a long time, this has been known, but the reason has been unclear," Fuster says. A team of researchers led by Fuster from the University of Bern, the Department of Nephrology and Hypertension at Inselspital, and the Department of Pediatric Endocrinology at the Children's Hospital in Zurich, has now investigated the cause of thiazides' diabetes risk. In experiments with cell cultures and mice, they were able to show that thiazides inhibit insulin secretion in specific cells of the pancreas. These are the cells in the body that produce insulin. Insulin is a hormone that is very important for metabolism: it makes sure that sugar from the blood gets into the body's cells as "fuel". It is also the only hormone that keeps blood sugar levels in balance so that they do not get too high. Now, by inhibiting the insulin-producing cells in the pancreas, thiazides interfere with insulin secretion, which leads to elevated blood sugar and can thus trigger diabetes.
Mechanism described for the first time
First, the researchers demonstrated that thiazides significantly increase blood glucose in mice. In subsequent experiments, they were able to describe the mechanism behind this: Thiazides inhibit a specific enzyme, called carbonic anhydrase 5b, that plays an important role in the secretion of insulin. Enzymes are complex proteins that accelerate biochemical reactions in the body's cells. If this enzyme is inhibited, the metabolism in the insulin-producing cells of the pancreas is disturbed, resulting in less insulin in the blood and thus increased blood sugar levels.
The researchers were able to confirm this relationship discovered in cell cultures in mice. Animals that were genetically modified so that they could not produce carbonic anhydrase 5b also had significantly reduced insulin secretion. Moreover, thiazides showed no side effects in them, which further indicates that the mechanism which was discovered is indeed influenced by these drugs.
New insight into the development of diabetes
Normally, each cell in the body has various carbonic anhydrases that support different metabolic processes. The study by Fuster and colleagues, now published in the Journal of the American Society of Nephrology, has shown for the first time that the insulin-producing cells of the pancreas are a major exception in this respect. They possess only one carbonic anhydrase, type 5b. This enzyme appears to be crucial for the normal secretion of insulin.
The research team has thus not only solved the long-known and unsolved mystery of the diabetes-promoting effect of thiazides, but at the same time provided new insights into how insulin is secreted. Study leader Fuster is already thinking ahead, "now we need even more to investigate the function and regulation of carbonic anhydrase 5b in the insulin-producing cells of the pancreas in order to gain a better understanding of the development of diabetes in humans and to lay the foundations for new treatments. Because just like hypertension, diabetes is a serious global health problem."
This study was funded by the Swiss National Science Foundation (SNSF), the Swiss National Centres of Competence in Research (NCCR TransCure and NCCR Kidney.CH), the Novartis Foundation and the Professor Max Cloëtta M.D. Foundation.
Kucharczyk P, Albano G, Deisl C, Ho TM, Bargagli M, Anderegg M, Wueest S, Konrad D, Fuster DG. Thiazides attenuate insulin secretion through inhibition of mitochondrial carbonic anhydrase 5b in β-islet cells in mice. Journal of the Amercian Society of Nephroogy. 2023 Mar 1, publication ahead of print. https://doi.org/10.1681/ASN.0000000000000122
Department for BioMedical Research (DBMR)
The Department for BioMedical Research (DBMR) of the Faculty of Medicine at the University of Bern was established in 1994 by the University of Bern and Inselspital, Bern University Hospital. The DBMR is comprised of 13 research programs with approximately 100 participating individual labs and several independent research labs whose research spans all biomedical fields. To bridge the gap between bench and bedside, the DBMR promotes an integrative perspective to clinical research with a strong emphasis on the development of translational approaches, the use of omics and other cutting-edge technologies, as well as extensive interaction and collaboration between laboratory-based and patient-oriented clinical research. The DBMR is also committed to fostering the careers of young academics.