3rd BBDC-Joslin-UCPH symposium

3rd BBDC-Joslin-UCPH symposium

On November 10-12, 2016 the Banting and Best Diabetes Centre (BBDC), Joslin Diabetes Center (Joslin) and University of Copenhagen (UCPH), is hosting their third joint symposium on diabetes with the title Cellular Mechanisms and Cell-Based Therapies of DiabetesTo continue the collaboration with these three oldest and largest diabetes centers in the world, the Danish Diabetes Academy has supported 11 trainees from Denmark to attend the 3rd BBDC-Joslin-UPCH symposium at Harvard Medical School in Boston. 

  1. Amarnadh Nalla (poster)
  2. Elahu Gosney Sustarsic (oral presentation)
  3. Elias Sundelin (poster)
  4. Honggang Huang (poster)
  5. Julian Geiger (oral presentation)
  6. Kristine Williams (poster)
  7. Morten Lundh (poster)
  8. Naja Z. Jespersen (poster)
  9. Line Hjort (oral presentation)
  10. Theresia Schnurr (poster)
  11. Tina Fløyel (poster)

Below you can read short descriptions of the above listed 11 selected trainees' resesarch - their abstracts have been accepted for poster presentation and three have also been accepted for oral presentation at the symposium.

 

AMARNADH NALLA

Identification of circulating factors in serum from pregnant, non-diabetic obese and post-gastric bypass 

Pancreatic beta cell mass and function is known to increase in conditions such as obesity, pregnancy and after the gastric bypass. At any given time, beta cell mass is regulated by cell differentiation, neogenesis, cell death and proliferation of existing betacells.

Destruction of beta cells results in the development of type 1 diabetes due to autoimmunity early in life or with late onset. The reduced beta cell growth in type 2 diabetes may be related to impaired the fetal development of the endocrine pancreas combined with postnatal obesity and/or loss of beta cells due to gluco-lipoxicity.

We hypothesize that factors circulating in blood are involved in increased beta cell mass in various known physiological conditions such as pregnancy, non-diabetic obese and betacell function after gastric bypass. Therefore, the main objective of our project is to the identification of circulating factors in serum from pregnant, non-diabetic obese and post-gastric bypass that promote beta cell proliferation, neogenesis and function in human beta cells and duct cells.

We are also interested in studying not only factors that are promoting beta cell regeneration and function but also involved in survival and apoptosis inducers on beta cell in serum from diabetic subjects such as gestational diabetes and insulin resistance which will serve as controls.

Identification of circulating factors will be performed by proteomic screening approach governed by bioassays on human beta cells and human pancreatic duct cells.

ELAHU GOSNEY SUSTARSIC  

Our goal is to use fat to burn energy and improve blood sugar levels

We are focused on the global obesity and diabetes pandemic. Although fat is a big part of the problem, we think it may also be part of the solution. Our goal is to use fat to burn energy and improve blood sugar levels.

Fat is generally understood as an energy storage tissue, but there is a special type of fat, brown or beige fat, which can actually consume energy to generate heat. Human infants have large amounts of brown fat in order to keep warm. Recently, the existence of brown fat has been “rediscovered” in adult humans, which has spurred intense interest in the potential of this tissue to be exploited to help treat obesity and diabetes. 

Through our research, we hope to better understand how these specialized fat cells function with the hope that we can find new ways to activate them to burn energy.  

ELIAS SUNDELIN

Hope to lay the first bricks on the pathway towards personalized medicine in the treatment of type 2 diabetes 

Metformin is the first line treatment of type 2 diabetes and is prescribed to over 100 million patients around the world. It is known to lower the blood glucose and lower the risk of cardiovascular disease.

However, some patients do not have the desirable effect of metformin in lowering blood sugar levels and others develop side effects that lead to discontinuation of metformin treatment. Organic cation transporters are proteins that are involved in distribution of metformin into target organs in the body.

We believe that mutations in genes that encode these proteins and the number of transporters may predict effects and side effects of metformin treatment. With our study, we hope to lay the first bricks on the pathway towards personalized medicine in the treatment of type 2 diabetes.

HONGGANG HUANG

Some anti-diabetic treatment strategies can also be helpful for patients with atherosclerosis 

In his postdoc project, Honggang Huang firstly synthesized a novel chemical tag and developed an efficient method for simultaneous enrichment and characterization of multiple PTMs including phosphorylation, Cys PTMs and glycosylation. A US patent (EFS ID 25173836) was filed for this method. The paper was published in Molecular Cellular Proteomics (MCP) which is the prestigious No.1 journal in proteomics area.

ROS is known to have fundamental detrimental effects on the development of diabetes and atherosclerosis. Therefore, he used the novel tools he developed to investigate the effects of ROS on proteins and PTMs during the development of diabetes and atherosclerosis. He and medical doctor Prof. Lars Melholt Rasmussen at Odense University Hospital identified some novel proteins and PTM sites, which can be candidate biomarkers or therapeutical targets for diabetes and atherosclerosis.

Interestingly, his study also revealed that anti-diabetic treatment for patients with both diabetes and atherosclerosis can also have beneficial improvement for anti-atherosclerosis, compared to atherosclerosis patients receiving only anti- atherosclerosis treatment. They confirmed this finding at protein level, suggesting that some anti-diabetic treatment strategies can also be helpful for patients with atherosclerosis.

JULIAN GEIGER

Investigates how microRNAs readjust mitochondrial function in diabetes 

One out of five Danes suffers from diabetes or is on the way of getting it. The costs caused by this disease are more than 80 mio kr per day in Denmark alone.

But what happens that gives rise to the high blood sugar levels and puts a diabetic fate on so many people? Blood sugar levels are tightly regulated by the hormone insulin, which is produced in the beta-cells of the pancreas. For running properly, the sugar-sensor machinery of beta-cells requires energy, which is provided by the in-house power suppliers called mitochondria. However, in a lot of diabetic patients the mitochondria are not functioning well, which consequently disturbs glucose sensing and insulin release.

With our research, we investigate how novel regulators called microRNAs readjust mitochondrial function in diabetes. MicroRNAs participate in a lot of processes and they are deregulated in numerous diseases. In addition, microRNAs have recently been shown to affect mitochondria.

KRISTINE WILLIAMS

Generates maps of enhancer activity in skeletal muscle cells in various insulin resistance states 

Insulin resistance is a clinical state preceding Type II diabetes where insulin action is impaired in metabolic tissues, notably skeletal muscle. Genome-wide association studies (GWAS) have identified hundreds of genetic variants, such as small nucleotide polymorphisms (SNPs), associated with insulin resistance or Type II diabetes. 

However, the majority of these SNPs are located outside coding regions making it difficult to predict their molecular function. We hypothesize that most disease-associated SNPs are located within regulatory DNA elements like enhancers. Enhancers are transcriptional regulating elements that are often located far away from the genes that they regulate. 

The aim of this study is to generate maps of enhancer activity in skeletal muscle cells in various insulin resistance states, and to determine if these enhancer-regions overlaps with previously identified disease-associated SNPs. Finally, we are studying the 3D conformation of DNA to understand the complex connections between enhancers and promoters in order to predict the transcriptional consequences of genetic variations within enhancers. 

MORTEN LUNDH

Develops novel strategies to increase the activity of Afadin and brown fat 

Obesity and obesity-related disorders such as type 2 diabetes are increasing worldwide. Novel therapeutics are needed to fight this escalation. Brown adipose tissue, also known as brown fat, possesses the ability to “burn” calories by uncoupling the oxidative phosphorylation pathway in the mitochondria. The net result of this reaction is an increased metabolic rate, which is why approaches to generate and/or activate brown adipose tissue hold great promise for the treatment of obesity and Type 2 Diabetes.

Intriguingly, within recent years it has been shown that human adults also possess brown fat. We have identified a novel protein called Afadin, which is regulated by insulin. We found that Afadin is involved in the development and function of brown fat. Using advanced molecular tools we are addressing how Afadin does so.

We hope that through a deeper understanding of the molecular signaling pathways in brown fat, novel strategies to increase the activity of this tissue can be developed with the aim of treating obesity and obesity-related disorders.

NAJA Z. JESPERSEN

Brown Adipose Tissue in adult humans - implications for glucose homeostasis

Brown Adipose tissue (BAT) has recently been identified in adult humans and holds the ability to combust large amounts of glucose and lipids, while dissipating the energy as pure heat. Due to this unique function, BAT is interesting to investigate as a potential target for anti-obesity and anti-diabetic treatments. 

However, still not much is known about the characteristics, regulation and metabolic potential of the different human BAT depots. 

Thus, the aim of my Ph.d-project is to characterize human brown fat from various depots including the supraclavicular and the perirenal depot. This is done by obtaining fat biopsies from these depots from different subject groups including healthy lean, obese and type II diabetic individuals and by establishing cell cultures to characterize potential functional differences of the brown fat cells from these individuals.  

LINE HJORT

The first 9 months of life and the development –and prevention of metabolic disease 

Main goal of our research is to provide more knowledge of how the first 9 months of life may be important in development – and prevention of – metabolic disease, e.g. Type 2 Diabetes (T2D), later in life. More specifically I study how an adverse intrauterine environment may affect the epigenome of the offspring and I investigate if this can be a possible molecular mechanism behind future metabolic disease among these children. 

Besides the increased risk of T2D development later in life among the mothers, several studies have shown that also the offspring are at increased risk of developing metabolic diseases. 

We hypothesize that during fetal development, time windows exists in early life where the individual is particular susceptible for influences and has an organ plasticity which might determine a future development of certain diseases. An epigenetic regulation of gene expression could be a link between the prenatal environment and T2D susceptibility, by an interplay between maternal diet and health and the DNA methylation of the fetal metabolic important genes. 

THERESIA SCHNURR

Greenlandic Inuit with specific gene variant can greatly benefit from physical activity 

As part of my PhD studies, I am studying well-characterized population-based Danish cohorts and a cohort of Greenlandic Inuit with genetic data and information on physical activity and/or fitness. 

In one of my projects we found that highly physically active Greenlandic Inuits that are carriers of a gene variant that dramatically increases the risk of type 2 diabetes had an improved ability to remove sugar from the blood after drinking sugar water (a standard way of testing for diabetes and preliminary stages to diabetes). 

These findings show that Greenlandic Inuit with this specific gene variant can greatly benefit from physical activity and therefore lower their risk to develop type 2 diabetes. The results of our study can eventually also teach more about biology and how exercise regulates sugar removal from the blood.  

TINA FLØYEL

Cathepsin H might form the basis for the development of future type 1 diabetes treatment

Type 1 diabetes is a chronic disease that breaks out when the body's immune system is destroying the insulin producing beta cells in the pancreas. Patients are therefore dependent on daily insulin injections to survive, but the disease still increases the risc for premature death and reduced quality of life because of its complications.

Genes and environmental factors both have influence on the development of type 1 diabetes. More than 50 genetic regions are linked to type 1 diabetes, but the majority of the specific disease candidate genes are still unknown.

We have identified CTSH (Cathepsin H) as a new interesting candidate gene that affects beta cell function and survival - both in cell linies and at children diagnosed with type 1 diabetes. The aim of our research project is to identify the role of the Cathepsin family in the development of type 1 diabetes.

Our results show that higher levels of Cathepsin H is likely to protect against immune-mediated damage and preserve/increase β-cell function, thereby representing a possible target for β-cell therapy.