Ongoing projects in clinical diabetes and metabolism

Pharmacology of human adipose tissue in metabolic disease

Researchers: Maria Joao Pereira, Cherno Sidibeh, Prasad Kamble, Gretha Boersma, Petros Katsogiannos,  Per Lundkvist, Xesus Abalo, Jan Eriksson

Many therapeutic agents affect glucose tolerance and can predispose to diabetes, especially when pre-existing factors are present.  These drugs may act by increasing insulin resistance, by affecting insulin secretion or both. Examples include glucocorticoids, immunosuppressive agents and antipsychotic drugs. Our group aims to identify novel mechanisms for insulin resistance induced by these drugs in insulin sensitive cells, in particular human adipocytes, by exploring pharmacologic manipulation, in vitro and in vivo, leading to insulin resistance.

Glucocorticoids and immunosuppressive agents

Glucocorticoids and immunosuppressive agents are used to prevent graft rejection after organ transplantation and to treat autoimmune and inflammatory diseases. In addition to suppression of the immune system, these drugs can increase the risk for dyslipidemia, diabetes, central adiposity and cardiovascular disease. Our previous work indicate that the immunosuppressive calcineurin inhibitors cyclosporin A and tacrolimus impair cellular glucose uptake in peripheral tissues by removing the major glucose transporter, GLUT4, from the cell surface, but without affecting the insulin signalling cascade. The project evaluates effects of calcineurin inhibitors on the expression of specific proteins involved in GLUT4 trafficking and glucose transport. Furthermore, our work has identified genes in adipose tissue that are highly regulated by glucocorticoids and that are associated with insulin resistance, and they include FKBP5, cannabinoid receptor type 1 and lipocalin-2. We perform mechanistic studies, using for example specific antagonists or agonists or gene editing (CRISPR/Cas9) to address their molecular pathways and causal role in metabolic disorders.

Antipsychotic agents

The underlying mechanisms by which antipsychotic drugs contribute to the development of insulin resistance, weight gain, dyslipidemia and type 2 diabetes are not clear. We will address the effects of antipsychotic drugs on whole-body and adipose tissue metabolism as well as on adipose tissue hormones, inflammatory markers and nerve activity that may be of importance for the development of type 2 diabetes and obesity.

These studies can provide novel mechanisms and biomarkers for drug-induced metabolic dysfunction of the adipose tissue. They can be used to identify therapeutic strategies to minimize or reverse such adverse effects. Importantly, these mechanisms can be of relevance for the development of future treatments for other forms of insulin resistance, including prediabetes and manifest type 2 diabetes.

Effects of gastric bypass surgery on glucose and lipid metabolism

Researchers: Niclas Abrahamsson, Anders Karlsson, Petros Katsogiannos, Gretha Boersma, Kristina Almby, Maria Joao Pereira, Jan Eriksson

The project is run in collaboration with the Dept of Surgery (Prof Magnus Sundbom), and it focuses on the profound changes seen in glucose and lipid metabolism following bariatric surgery. Obese patients undergoing gastric bypass (GBP) markedly improve their insulin sensitivity and glucose tolerance. According to most available data, these effects are much greater than what the weight loss itself can explain. Thus, it is believed that there are important factors induced by the rearrangement of intestinal anatomy that influence metabolism in various organs.

We investigate metabolic effects of GBP in comparison to similar weight loss achieved with very low-calorie diet on glucose and fatty acid turnover as well as insulin sensitivity in specific tissues. In addition, we perform functional assessments of the insulin-producing beta cells. Both type 2 diabetic and non-diabetic patients with obesity are enrolled, and a specific aim is to address mechanisms explaining the remission of diabetes that is often seen following GBP. We utilize a broad range of investigations such as glucose clamps, glucose challenge tests, imaging (PET and MRI), autonomic nerve activity and also in vitro assessments of tissue material obtained by biopsies.

The main purpose is to identify novel mechanisms following GBP that improve glucose and lipid metabolism. Such findings could potentially also lead to discovery of non-surgical treatment concepts, involving pharmaceuticals or life-style, to prevent or treat diabetes and obesity. In the long-term perspective, the results could also support bariatric/metabolic surgery as a treatment of choice for many type 2-diabetes patients.

Studies of clinical and metabolic effects of novel medicines

Researchers: Per Lundkvist, Maria Joao Pereira, Jan Eriksson, Maria Eriksson-Svensson

We currently perform several studies exploring possible novel indications for the antidiabetic drug class of SGLT2 inhibitors. They include exploratory clinical trials for proof-of-concept  as well as mechanistic human studies. They focus on energy balance and obesity, effects on fatty liver disease and endocrine effects relating to gut and pancreatic islets in particular. We plan to use PET/MRI investigations to performed detailed measurements of energy metabolism in specific organs. We are also involved in registry-based epidemiological studies addressing the clinical outcomes of such drugs in comparison to other diabetes treatments. Effects on cardiovascular and other organ complications and mortality as well as health economy are evaluated.

There are also collaborative studies on outcomes following treatment with new medicines, in particular biologicals, in dyslipidemia, osteoporosis and renal failure.