Söderberg Prize 2014

WEBCAST: Söderberg Prize seminar on diabetes research in retrospect

Professor Leif Groop, The Söderberg Prize Laureate 2014.

Professor Leif Groop  was awarded the Söderberg Prize for medicine 2014 for his pioneering work in diabetes research both in relation to general and clinical research. In connection with the prize ceremony a scientific research seminar on diabetes was held at the Swedish Society of Physicians. The lectures can now be watched in retrospect.

Lecturers and abstracts

On the Trail of Type 2 Diabetes – Fishing Genes and Cleaning Phenotypes

Professor Leif Groop, Lund University Diabetes Centre

Diabetes mellitus is a lifelong, incapacitating disease affecting multiple organs. Worldwide prevalence figures estimate that there are 350 million diabetic patients in 2013 and more than 550 million in 2030. The rapid increase in the incidence of type 2 diabetes (T2D) has been ascribed to a collision between genes and an affluent environment. A person develops T2D if he/she cannot increase insulin secretion 2-3-fold to meet the increased demands imposed by insulin resistance and obesity. While we know a lot about the environmental triggers of diabetes our understanding of the genetic causes is still limited even though marked progress has been made in the past years.
However, the rapid development of the tools of molecular genetics promises an even better future. The dream to sequence the 3 billion bases containing human genome for less than $1,000 has already become true, and we can start to build a more complete picture of the molecular defects leading to T2D than ever before. It is very likely that T2D is not a distinct disease but rather represents a spectrum of disorders which potentially will require specific treatments. A better genetic and phenotypic characterization of T2D may pave the way to amore personalized medicine. There probably never have been a better time to be in science, we have the tools, the only limitation is our own imagination. Even though we today can see the whole human genome, it does not mean that we understand everything we see, but seeing is a prerequisite for understanding.

Ten Causes of Type 2 Diabetes

Professor Ralph De Fronzo, San Antonio, Texas

Insulin resistance in muscle and liver and β-cell failure represent the core pathophysiologic defects in type 2 diabetes. It now is recognized that the β-cell failure occurs much earlier and is more severe than previously thought. Subjects in the upper tertile of impaired glucose tolerance (IGT) are maximally/near-maximally insulin resistant and have lost over 80% of their β-cell function. In addition to the muscle, liver, and β-cell (triumvirate), the fat cell (accelerated lipolysis), gastrointestinal tract (incretin deficiency/ resistance), α-cell (hyperglucagonemia), kidney (increased glucose reabsorption), and brain (insulin resistance) all play important
roles in the development of glucose intolerance in type 2 diabetic individuals. Collectively, these eight players comprise the ominous octet and dictate that: 1) multiple drugs used in combination will be required to correct the multiple pathophysiological defects, 2) treatment should be based upon reversal of known pathogenic abnormalities and not simply on reducing the A1C, and 3) therapy must be started early to prevent/slow the progressive β-cell failure that already is well established in IGT subjects. A treatment paradigm shift is recommended in which combination therapy is initiated with diet/exercise, metformin (which improves insulin sensitivity and has antiatherogenic effects), a thiazolidinedione (TZD) (which improves insulin sensitivity, preserves β-cell function, and exerts antiatherogenic effects), and exenatide (which preserves β-cell function and promotes weight loss). Sulfonylureas are not recommended because, after an initial improvement in glycemic control, they are associated with a progressive rise in A1C and progressive loss of β-cell function.

Genomic Variation and the Inherited Basis of Common Disease

Professor David Altshuler, Boston, Massachusetts

Despite great progress in medical science, we have limited knowledge of the molecular causes of most disease in human populations. This ignorance is one of the gatingfactors in efforts to design rationale approaches to prevent and treat disease. Genetic mapping offers an approach to study disease that is (a) unbiased by prior hypotheses about disease mechanisms, and (b) supports causal inference directly in the human population. We have worked to make possible genetic mapping of common diseases by developing maps of human sequence variation (the SNP Consortium HapMap, and 1,000 Genomes Projects), and by developing technologies and analytical methods to enable genome-wide studies that relate genetic variation to diseases.

Over the last five years the first generation of these methods (based on common SNP’s, and on copy number variations) have led to the identification of over 1,000 novel and reproducible associations between genomic regions and a wide variety of common diseases, including our own work on type 2 diabetes, hyperlipidemia, prostate cancer, age related macular degeneration, rheumatoid arthritis, and systemic lupus erythematosis. We are now focusing on discovering the genes and mutations responsible at each locus, extending the mapping approach to query rare genetic variation using nextgeneration sequencing, and to studies spanning multiple ethnic groups.
I will focus my presentation on the next rate limiting step: moving from the discovery of novel genes to the application of this information to gain new insights into disease mechanisms, with the ultimate goal of developing new and more effective approaches to prevention and treatment of disease in the population.

Do We Know What Type 2 Diabetes Is?

MD Tiinamaija Tuomi, Helsinki, Finland

Diabetes mellitus is defined as a condition of chronic hyperglycemia which has traditionally been subdivided into type 1 diabetes (T1D) with autoimmune destruction of insulinsecreting beta-cells and type 2 diabetes (T2D) with insulin resistance and features of the metabolic syndrome. However, this subdivision into T1D and T2D is a gross oversimplification and poorly reflects the true spectrum of diabetes, which includes also monogenic forms (MODY) and overlapping forms of diabetes, such as Latent Autoimmune Diabetes in Adults (LADA).
There are also major ethnic differences in the phenotype of “type 2 diabetic” patients. The complex regulation of glucose homeostasis involves several metabolic pathways, enzymes, hormones and transcription factors in the pancreatic alpha- and beta-cells as well as in the liver and intestine. Defective insulin secretion can result from developmental disturbances of the pancreas, destruction of beta-cells (by e.g. autoimmunity) or defective control of insulin secretion in response to glucose. The identification of genetic variants increasing the risk of T2D have shed new light on the mechanisms affecting insulin-response to glucose, but also some commonly used medicines, like statins and melatonin, affect insulin secretion in some people. Moreover, at least in populations with a high frequency of T1D, as in Finland and Sweden, family history for T1D and autoimmunity affect insulin secretion and the phwnotype of patients with T2D. Thus, T2D represents a mixture of patients with different coctails of aetiopathogenetic factors rather than a homogenous group of . patients

Diamonds in the Dirt: Biological Insights and Translational Opportunities from Type 2 Diabetes Genetics

Professor Mark McCarthy, Oxford, UK

Type 2 diabetes represents a major challenge for global health, yet poor understanding of the biological basis of disease compromises efforts to develop effective strategies for treatment and prevention. Common variant genome wide association studies have identified over 80 loci influencing risk of T2D, but, until recently, progress in translating these signals into mechanistic insights has been slow. I will describe how the integration of exome variant data, along with the improved regulatory maps that emerge from genomic analysis of relevant tissues, is helping to unpick the Gordian knot of disease biology. These studies will, in time, reveal whether or not the mechanistic basis of a complex disease such as T2D will converge on a limited set of pathogenetic processes.

Dietary Triggers of Type 2 Diabetes

Professor Marju Orho-Melander, Lund

Although type 2 diabetes is known to result from interplay between genetic predisposition and unfavorable environment, very little is known about such interactions. Could it be that a healthy diet is dependent on genetic susceptibility and that genetic susceptibility for type 2 diabetes is dependent on diet? To be able to answer these key questions it is of great importance to better understand interactions between genetic susceptibility and dietary factors and their effects on physiological mechanisms involved in the development of type 2 diabetes and associated traits. Our recent epidemiological studies indicate that our genetic make-up modifies how diet affects our susceptibility to obesity and diabetes indicating that dietary habits may accentuate or diminish the effects of our genetic susceptibility.

Closing in on Islet Dysfunction

Professor Patrik Rorsman, Oxford, UK

In my lecture I will consider the normal regulation of insulin and glucagon secretion in human pancreatic islets. With this background I will move on and consider the bihormonal nature of diabetes mellitus and how diabetic hyperglycaemia results from the combination of insulin and glucagon secretion being too low and too high, respectively. I will then present data that indicating that a single cellular defect accounts for both the reduced insulin secretion and hypersecretion of glucagon at high glucose (and perhaps also the impaired counterregulation at low glucose) and the nature of this defect. My lecture will highlight the decisive role of alpha- and beta-cell electrical activity in the understanding of both the physiological control of insulin and glucagon secretion and the defects associated with diabetes.

Can Exercise Prevent Diabetes?

Associated professor Ola Hansson, Lund

Skeletal muscle is one of the largest organs in the human body and as we age we lose muscle mass, strength and increase the levels of fat and connective tissue. This natural muscle aging, termed sarcopenia, is also connected to metabolic effects like reduced insulin sensitivity and increased risk of metabolic disease. Genetic predisposition is another major risk factor of metabolic disease and healthy first-degree relatives of type 2 diabetics have an altered metabolic state, with metabolic inflexibility, decreased basal energy expenditure and decreased expression of mitochondrial genes. One way to counteract muscle aging is by physical exercise, however, we all respond differently to exercise and it is not known who will benefit most from witch type of exercise or if genetic predisposition may limit the effects of exercise.

Last updated: April 28, 2014
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