Symposium on Molecular and Physiological Aspects of Diabetes Mellitus

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1 PROGRAM AND ABSTRACTS FOR THE CONFERENCE NFEREN O C ET SK S Photo: Science Photo Library CE K A R OLIN 2014 A IN TITUT S Symposium on Molecular and Physiological Aspects of Diabetes Mellitus Karolinska Institutet, November 21, 2014

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3 21 KAROLINSKA NOVEMBER 2014, AT AULA MEDICA INSTITUTET, SOLNA WELCOME NOTE Juleen Zierath Chair: Helena Edlund DIABETES, BARIATRIC SURGERY, AND THE GUT Tony K.T. Lam, Dept. of Physiology and Medicine, Toronto General Research Institute and University of Toronto, Canada ROLE OF GLP-1 IN THE PATHOGENESIS AND TREATMENT OF TYPE 2 DIABETES Jens Juul Holst, Dept. of Biomedical Sciences, The Panum Institute, University of Copenhagen, Denmark COFFEE BREAK Chair: Jorge Ruas NOVEL DRUG TREATMENTS FOR METABOLIC DISEASE: FROM GUT HORMONES TO POLYPHARMACY Richard DiMarchi, Dept. of Biomolecular Sciences, Indiana University, USA MECHANISMS OTHER THAN WEIGHT LOSS IN IMPROVED GLUCOSE CONTROL AFTER RY-GASTRIC BYPASS SURGERY Blandine Laferrère, New York Obesity Research Center, Columbia University, USA LUNCH Chair: Peter Arner INVOLVEMENT OF THE GUT MICROBIOTA IN THE CONTROL OF ADIPOSITY AND RELATED METABOLIC DISORDERS Nathalie M. Delzenne, Metabolism and Nutrition Research Group, Catholic University of Louvain, Louvain Drug Research Institute (LDRI), Belgium CARDIOVASCULAR DISEASE IN DIABETES: RISKS, RESEARCH AND REALITY Naveed Sattar, Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK COFFEE BREAK Chair: Anna Krook EXERCISE: NOVEL MECHANISMS FOR THE REGULATION OF GLUCOSE METABOLISM Laurie J. Goodyear, Joslin Diabetes Center, Harvard Medical School, USA COMMON THREADS: EPIGENETICS, METABOLISM AND THE CLOCK Paolo Sassone-Corsi, Center for Epigenetics and Metabolism, University of California, Irvine, USA CLOSING REMARKS

4 DIABETES, BARIATRIC SURGERY, AND THE GUT TONY K.T. LAM Dept. of Physiology and Medicine, Toronto General Research Institute and University of Toronto, Canada Our main focus has been to elucidate nutrient and hormone sensing mechanisms in the gut that regulate glucose homeostasis. We have discovered nutrient sensing in the duodenum triggers hormonal signaling and a gut-brain-liver axis to inhibit glucose production and lower plasma glucose levels. We have identified intestinal signaling defects that are acquired by diabetes and obesity and have characterized novel molecular signaling pathways that can be activated to bypass intestinal signaling defects and restore glucose homeostasis. In addition, we have discovered that jejunual nutrient and leptin sensing is necessary for duodenal-jejunal bypasss to rapidly lower glucose levels in uncontrolled diabetes. In summary, our discoveries reveal molecular targets in the gut that may carry therapeutic potential to lower blood glucose levels in diabetes and obesity. ROLE OF GLP-1 IN THE PATHOGENESIS AND TREATMENT OF TYPE 2 DIABETES JENS JUUL HOLST Dept. of Biomedical Sciences, the Panum Institute, University of Copenhagen, Denmark GLP-1, a brain and gut product of the proglucagon, was searched for because of data indicating that glucose-dependent insulinotropic polypeptide (GIP) could not be the only incretin (intestinal insulin-stimulating hormone). Neither of the 2 glucagon-like sequences (GLPs) identified in the predicted proglucagon precursor were insulinotropic, but the natural peptide (Holst et al FEBS Lett 211: , 1987), a truncated, amidated peptide (GLP amide) strongly stimulated insulin secretion and inhibited glucagon secretion, and was subsequently shown to have powerful glucose-lowering effects in patients with type 2 diabetes (T2DM), consistent with the loss of incretin effect in these patients. This may be due to an impaired secretion of GLP-1, which is frequently observed, but in addition there is loss of insulinotropic potency of GLP-1 and insulinotropic efficacy of GIP. Both defects appear to be secondary to T2DM: similar losses are seen early in secondary diabetes (chronic pancreatitis) and induction of glucose intolerance (gestational diabetes, glucocorticoid treatment) leads to a similar loss of the incretin effect. Intensive metabolic control in T2DM improves incretin function and activity of GLP-1 and GIP. Therefore, the loss of the incretin effect contributes to diabetic hyperglycemia, and restoration of the effect (with GLP-1 agonists) greatly improves metabolic control. Conversely, accelerated gastric emptying causes exaggerated GLP-1 secretion and this explains the postprandial reactive hypoglycemia in insulin sensitive individuals. GLP-1 has also turned out to be a physiological negative regulator of appetite and food intake, and chronic administration leads to weight losses. BMI is inversely correlated to meal-induced GLP-1 secretion, and loss of gut-derived appetite regulation may represent a pathophysiological trait of obesity. Gastric-bypass operations in morbidly obese T2DM subjects are associated with rapid transfer of nutrients to the distal small intestine and hugely elevated (10- fold) GLP-1 responses. Because of its effects on appetite and metabolic control, GLP-1 is likely to contribute to the beneficial results of these operations. Currently, GLP-1-based therapy of T2DM includes several GLP-1 receptor agonists and a growing number of dipeptidyl-peptidase-4 (DPP-4) inhibitors, which improve the survival of endogenous GLP-1 and thereby enhances its actions as shown in our laboratory in Current research is directed towards identifying a means to stimulate the endogenous secretion of GLP-1 in an attempt to mimic the success of bariatric surgery with respect to both weight loss and diabetes therapy.

5 NOVEL DRUG TREATMENTS FOR METABOLIC DISEASE: FROM GUT HORMONES TO POLYPHARMACY RICHARD DIMARCHI Dept. of Biomolecular Sciences, Indiana University, USA Glucagon, Glucagon-like Peptide-1 (GLP-1), and Glucose-dependent Insulinotropic Polypeptide (GIP) are regulatory hormones responsible for maintaining control of metabolism, most notably glucose homeostasis. Each hormone possesses unique pharmacology by virtue of a high affinity interaction with its specific receptor. In the course of our structure-activity studies we have developed a series of novel peptides that exhibit high potency and balanced activity across these three receptors. Dual-agonists have demonstrated superior, sustained efficacy in lowering body weight and glucose in animal models. These results have established the basis for several ongoing clinical studies with co-agonists of GLP-1/glucagon and separately with GLP-1/GIP. The systematic N-terminal truncation of the native glucagon sequence yields potent and selective glucagon receptor antagonism. Stabilization of the backbone secondary conformation in these shortened peptide antagonists introduces full GLP-1 agonism. Further structural refinement produced single peptides possessing balanced, low nanomolar glucagon antagonism and GLP-1 agonism. These peptides, when administered in mice exhibit both activities to additively lower blood glucose. The molecular basis for the observed mixed action at two homologous receptors constitutes a conundrum. Homology analysis and receptor mutagenesis are ongoing and suggests the three extracellular receptor loops to be the likely source of the differential activity. The quest for combinatorial efficacy across the traditional large/small molecule medicinal boundary has been explored with estrogen-incretin hybrid hormones. Rodent and human clinical studies have established that estrogen possesses anti-diabetic and weight-lowering action. However, the clinical application is compromised by adverse gynecological and oncogenic potential. We have studied tissue targeting of estrogen through the use of incretin-based peptide conjugates that minimize action at endometrial sites. A set of peptide-estrogen conjugates possessing full GLP-1 agonism with linker chemistries that enable differential estrogen release were prepared. In metabolically-challenged non-diabetic mice, a fully active GLP-1 agonist with a stably-linked estrogen consistently proved to be more efficacious in lowering body weight than the comparable individual GLP-1 and estrogen controls. In addition, highly potent GLP-estrogen conjugates were found to be devoid of uterine hypertrophy. The molecular mechanism by which these beneficial effects are achieved remains a focus of our ongoing studies.. References 1. A New Glucagon and GLP-1 co-agonist Eliminates Obesity in Rodents, Nature Chemical Biology (2009), 5: A Novel Human- Based Receptor Antagonist of Sustained Action Reveals Body Weight Control by Endogenous GLP-1 ACS Chemical Biology (2011), 6(2), Targeted Estrogen Delivery Reverses The Metabolic Syndrome Nature Medicine Nature Medicine (2012) 18: ) 4. Unimolecular Dual Incretins Maximize Metabolic Benefits in Rodents, Monkeys, and Humans Sci Transl (2013) Med 5, 209. MECHANISMS OTHER THAN WEIGHT LOSS IN IMPROVED GLUCOSE CONTROL AFTER RY-GASTRIC BYPASS SURGERY BLANDINE LAFERRÈRE New York Obesity Research Center, Columbia University, USA Large amount of weight loss after bariatric surgery results in remission of type 2 diabetes (T2DM). Roux-en-Y gastric bypass (RYGBP), with shunting of the upper gastrointestinal (GI) tract from ingested nutrients, has a higher and more rapid remission rate of T2DM than laparoscopic adjustable gastric banding (LAGB), a procedure that only restricts the stomach capacity. This suggests that the altered nutrient route after RYGBP improves T2DM independently of weight loss. To single out a possible GI effect, insulin sensitivity and secretion were measured after oral and isoglycemic matched IV glucose challenge in obese individuals with T2DM before and up to 3 years after RYGBP. Beta-cell glucose sensitivity (βcgs) in response to an oral glucose load, was severely impaired in T2DM, and normalized to the levels of lean individuals after RYGBP. Interestingly, βcgs is minimally improved if glucose is given IV, in spite of sustained weight loss and T2DM remission. Blocking GLP-1 receptor with Exendin 9-39 prevents the effect of RYGBP on βcgs, and worsens glucose levels, attesting the role of endogenous GLP-1. In a subsequent study, to circumvent the confounding effect of the amount of weight loss, we compared the effect of RYGBP to that of LAGB, at 10% and 20% weight loss in T2DM patients. βcgs in response to an oral glucose load was significantly improved more after RYGBP than after LAGB. However, weight loss by either surgery improved β-cell function similarly in response to IV glucose. Our data point out the importance of large sustained surgical weight loss and the role of the gut derivation in GLP-1-mediated improvements in glucose control. Other mechanisms such as altered bile acid, branched chain amino acids, or alterations in microbiota, may contribute to improved glucose homeostasis in T2DM after RYGBP independent of weight loss and will be discussed.

6 INVOLVEMENT OF THE GUT MICROBIOTA IN THE CONTROL OF ADIPOSITY AND RELATED METABOLIC DISORDERS NATHALIE M. DELZENNE Metabolism and Nutrition Research Group, Catholic University of Louvain, Louvain Drug Research Institute, Belgium Experimental data in animal models, but also observational studies in patients, suggest that dysbiosis, meaning changes in the composition and/or of the metabolic activity of the gut microbiota, occur upon the development of obesity and related metabolic diseases This dysbiosis is associated with alterations of the host gut physiology and energy metabolism. Different approaches have been proposed in order to modulate the gut microbiome (representing a hundred-fold more genes than the human genome) namely a procedure of gut microbiota transplantation from healthy donors probiotic approaches (consisting of an oral administration of selected bacteria) or prebiotic approaches (consisting of an administration of dietary fermentable carbohydrates). We will show that several prebiotics present in the diet (i.e. glucans, arabinoxylans, fructans) can modulate host gene expression and metabolism, and thereby may positively influence host adiposity and metabolic disorders, including insulin sensitivity, steatosis and vascular functions. Even if the increase in Bifidobacteria remains the major and common signature of the prebiotic approach, a complex modulation of the gut microbial ecology occurs upon prebiotic treatment in obese individuals. The promotion of gut hormone release, changes in the gut barrier integrity, and/or the production of bacterial-derived metabolites could all participate in the improvement of host health by probiotics and prebiotics in the particular context of overfeeding and obesity. Appropriate human intervention studies are needed in order to evaluate the interaction between the gut microbiota and food components and how this knowledge might contribute to adequate nutritional advice for the management of obesity, non-alcoholic steatosis, diabetes and cardio-metabolic risk. Several related references Dewulf E.M., Cani P.D., Claus S.P., Fuentes S., Puylaert P.G., Neyrinck A.M., Bindels L.B., de Vos W.M., Gibson G.R., Thissen J.P., Delzenne N.M. Insight into the prebiotic concept: lessons from an exploratory, double blind intervention study with inulin-type fructans in obese women. Gut 2013, 62(8), Everard A., Belzer C., Geurts L., Ouwerkerk J.P., Druart C., Bindels L.B., Guiot Y., Derrien M., Muccioli G.G., Delzenne N.M., de Vos W.M., Cani P.D Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity Proc. Natl. Acad. Sci. U.S.A. 2013, 110(22): Druart C., Alligier M., Salazar N., Neyrinck A., Delzenne N. Modulation of the gut microbiota by nutrients with prebiotic and probiotic properties. Advances in Nutrition in press CARDIOVASCULAR DISEASE IN DIABETES: RISKS, RESEARCH AND REALITY NAVEED SATTAR Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK We all know cardiovascular disease risk is elevated in individuals with type 2 diabetes (T2DM), but by how much? This talk will provide some of the best evidence on risks for different vascular outcomes in T2DM, show that most outcome risks have declined substantially over time and discuss the mechanisms behind such changes, focusing in particular on lipid and blood pressure management, as recently reviewed (1). The talk will also discuss whether we need to risk score in T2DM and will give some insights into new CVD risk data for Type 1 diabetic patients, with implications for guidelines. Finally, the importance of glucose lowering to CVD risk in diabetes will be discussed with reference to recent major trials, as well as ongoing trials of newer agents. The overall findings bring us to a new level of understanding (2) of how best to reduce CVD risk in T2DM and what the future holds in terms of disease burden. 1. Sattar N. Revisiting the links between glycaemia, diabetes and cardiovascular disease. Diabetologia Apr;56(4): Sattar N. Advances in managing type 2 diabetes: challenging old paradigms and developing new ones. F1000Prime Rep Jun 2;6:42. doi: / P6-42. ecollection 2014.

7 EXERCISE: NOVEL MECHANISMS FOR THE REGULATION OF GLUCOSE METABOLISM LAURIE J. GOODYEAR Joslin Diabetes Center, Harvard Medical School, USA While the incidence of type 2 diabetes continues to escalate worldwide, there is increasing evidence that regular physical activity can prevent or delay the onset of this disease. Studies in our laboratory have focused on understanding the molecular mechanisms through which exercise improves glucose homeostasis and metabolic health. In this talk, I will discuss our recent work investigating the effects of exercise before and during pregnancy on the metabolic health of offspring. These mouse studies include investigating the effects of maternal exercise on glucose tolerance, insulin sensitivity and skeletal muscle and liver metabolism in offspring. Translational research resulting from these basic exercise science studies could provide a new paradigm for diabetes prevention and have a tremendous impact on health care worldwide. COMMON THREADS: EPIGENETICS, METABOLISM AND THE CLOCK PAOLO SASSONE-CORSI Center for Epigenetics and Metabolism, University of California, Irvine, USA Circadian rhythms govern a number of fundamental physiological functions in almost all organisms, from prokaryotes to humans. The circadian clocks are intrinsic time-tracking systems with which organisms can anticipate environmental changes and adapt to the appropriate time of day. Disruption of these rhythms can have a profound influence to human health and has been linked to depression, insomnia, jet lag, coronary heart disease, neurodegenerative disorders and cancer. At the heart of circadian regulatory pathways is the clock machinery, a remarkably coordinated transcription-translation system that utilizes also dynamic changes in chromatin transitions and epigenetic control. Recent findings indicate that regulation goes also the other way, since specific elements of the clock are able to sense changes in the cellular metabolism. We have uncovered the role of the deacetylases SIRT1 and SIRT6 in partitioning of the circadian epigenome, as well as the contribution of MLL1 as H3K4 methyltransferase. Notably, chromosome capture 4C studies have revealed that circadian genes are organized in nuclear interactomes that dictate their coordinated expression. Understanding in full detail the intimate links between cellular metabolism and the circadian clock machinery will provide not only critical insights into system physiology and endocrinology, but also novel avenues for pharmacological intervention towards metabolic disorders.

8 The Strategic Research Programme in Diabetes at Karolinska Institutet ki.se/en/srp-diabetes