Here is what our members Andreas Brønden, Niels Jessen, Dorte Møller Jensen, Peter Rossing, Reimar W. Thomsen, Susanne Mandrup and Thomas Mandrup-Poulsen reported about their experience from different sessions at the American Diabetes Association's 76th Scientific Sessions that took place in New Orleans on 10-14 June 2016. The reports invovle following topics:
- New insights into the modes of action of metformin
- Metformin - is it still relevant?
- Diabetes and pregnancy
- Microbiota and diabetic cardiovascular disease
- Clinical epidemiology
- Human brown adipse tissue
- The biological clock - a ticking bomb in diabetes?
The Annual Meeting of the American Diabetes Association (ADA) 2016 in New Orleans included a very interesting session dedicated to the drug metformin. This drug has been applied for several decades as an anti-hyperglycemic agent and still maintains the position as the first-line treatment in most patients with type 2 diabetes. However, in recent years the modes of action of this drug have to a large extent been reassessed.
The aforementioned session in particular focused on gut-based mechanisms of metformin including activation of intestinal AMPK and bile acid-mediated secretion of incretin hormones such as glucagon-like peptide-1 (GLP-1). In relation to this latter mechanism, it was emphasized that metformin due to its inhibitory effects on the intestinal bile acid transporter ASBT could modulate bile acid circulation and thereby potentiate GLP-1 secretion. This was indeed of special interest to me, as my PhD project at Center for Diabetes Research, Gentofte Hospital is based on the concept of bile acids as a glucometabolic integrator. The presenter highlighted the work of my colleague Dr. Ulrich Rohde (Rohde et al. Cholecystokinin-Induced Gallbladder Emptying and Metformin Elicit Additive Glucagon-Like Peptide-1 Responses. J Clin Endocrinol Metab. 2016;101:2076-83) demonstrating synergistic effects of bile acids and metformin with respect to GLP-1 secretion in healthy young male individuals.
One of the clinical studies included in my PhD project is very much a follow up on this previous work conducted in our lab. However, in my ongoing project we investigate the potential effects of metformin and bile acids in patients with type 2 diabetes. The awareness to this field demonstrated at a big venue as ADA of course makes me even more focused on completing this study and getting the opportunity to look into data.
This year’s scientific sessions started out with the symposium entitled “Metformin Revisited 2016 —New Insights, New Directions”. The session was extraordinarily well-attended and although the focus was on a drug that has been in clinical use for more than 60 years it was undoubtedly an ADA-highlight.
Professor Clifford Bailey walked us through the story of the drug. How it was rescued from oblivion and deployed to exploit its unique breadth of medicinal properties. He especially focused on metformin action in the intestine, and reviewed data demonstrating increased GLP-1 secretion during metformin treatment. Identifications of these putative metformin targets is rapidly changing our understanding of the drug action and is likely to draw much scientific attention in the near future.
Professor Rury Holman then continued to give updates on the cardiovascular outcomes of clinical trials involving metformin. As a senior investigator on the UKPDS Rury Holman has had profound impact on guidelines for diabetes treatment worldwide and this landmark study continues to produce interesting findings. Rury Holman revisited a subgroup analysis indicating increased cardiovascular mortality among patients where metformin was added to an existing SU-therapy. This finding has stirred much controversy over the years. Follow-up data showed that the cardiovascular mortality had normalized after the trial had ended, and subsequent analysis of the initial finding indicated imbalanced baseline characteristics.
Dr. Kasia Lipska followed with an update of attempts to widen the indications for metformin treatment to also include patients with mild impairments of kidney function. A careful review of clinical data indicates that the risk of lactate acidosis in these patients is not increased during metformin treatment, and Kasia Lipska and colleagues have been successful in convincing the regulatory authorities in the US to update their recommendations.
The final talk of this session was by Michael Pollak, Professor in oncology, and he gave an update on the role of metformin in cancer. This topic has been debated intensely over the last decade, but according to Michael Pollak this can largely be explained by the peculiar pharmacokinetic properties of metformin. He showed data that demonstrate how metformin when transported in the cancer cell have beneficial effects on both mTOR-signaling and mitochondrial function, and a key factor in investigating the potential role of metformin in cancer treatment according to Michael Pollak is to determine the tissue distribution of the drug.
Overall the symposium addressed a broad spectrum of questions related to the commonly used anti-diabetic drug and demonstrated without doubt that metformin is still relevant in 2016.
As usual the ADA meeting had an extensive and inspiring program on diabetes and pregnancy. The main clinical focus of the symposia and debates were on Gestational Diabetes Mellitus (GDM). Big controversies still exist whether screening for GDM should be performed already in early pregnancy and what methods and glucose thresholds should be chosen. The concept of “fetal glucose steal” (that fetal hyperinsulinism in early pregnancy can be a driver for excess glucose flux in the placenta despite normal maternal glucose levels) were discussed. The challenges of implementation of lifestyle intervention in pregnancy to improve obstetric outcomes were debated. Further, new modalities for pregnancy care including group sessions, insulin pumps and closed loop systems during labor and delivery, telemedicine with remote glucose data and eHealth technologies (Apps and websites) were presented.
Long term follow-up in women with GDM and interventions to prevent unplanned pregnancies with hyperglycemia and future type 2 diabetes was also addressed. This included breastfeeding, long-acting reversible contraception, medical treatment and targeting of risk groups.
The sessions on fetal programming and early life exposures revealed new knowledge on associations between GDM and earlier pubertal timing in offspring of GDM (Exploring Perinatal Outcomes in Children - EPOCH study). Data from The Health Start Study showed independent associations between maternal pre-gestational BMI, gestational weight gain and breastfeeding and early infant growth and body composition. A study in 1600 offspring from the Hyperglycemia and Adverse Outcome study (HAPO) showed that the maternal obesity and glycemia had differential impact on the fetal metabolome consistent with their independent effects on fetal adiposity. Maternal BMI and insulin sensitivity were associated with newborn Branched Chain Amino Acids (BCAA) and their catabolism.
The significance of the human microbiome in the new-born and metabolic phenotypes in later life was highlighted with focus on components of breast milk and evolution of the infant microbiome and the early microbiome and risk for development of type 1 diabetes. Important issues on breastfeeding and use of antibiotics during pregnancy, delivery and in early life were raised.
Danish researchers presented data from Rigshospitalet showing that daily carbohydrate consumption and glycemic index were positively associated with HbA1c in early pregnancy in women with type 1 diabetes. The findings suggest that glycemic control might be improved by the use of carbohydrate counting (1347-P). Data from the EPICOM study (a study in teenage offspring of Danish women with type 1 diabetes) showed that exposure to intrauterine hyperglycemia was associated with higher levels of leptin (male and female offspring) and lower levels of adiponectin (female offspring only). These adipokines are might be important playes in the increased metabolic risk in offspring of women with type 1 diabetes (1359-P). Data from the Danish National Birth Cohort addressed the relation between maternal n-3 long chain polyunsaturated fatty acids/fish intake in pregnancy and offspring metabolic outcomes and found no overall association. In a subsample of GDM women fish intake seemed beneficial (190-LB). A study from Steno Diabetes Center found that exposure to famine in utero in an Ukrainian population was associated with susceptibility to diabetes complications through involvement of genomic regions regulating immune response, nutrient sensing, imprinting and organ development (1651-P).
A Randomized Controlled Trail with GLP-1 receptor agonist in women with previous GDM was presented by researchers from Copenhagen. They found that one year of treatment with Liraglutide improved fasting plasma glucose, HbA1c and glucose tolerance significantly compared to placebo (1904-P). Treatment was also associated with significant weight loss and reduced hepatic steatosis as measured by controlled attenuation parameter. There was no effect on the presence of Non-Alcoholic Fatty Liver Disease (1824-P).
The Danish Diabetes Academy was also represented in the Debate. Screening and Treatment for Early Gestational Diabetes – sensible or unsupported? (3-CT-IG09).
Taken together, the meeting brought new insight into molecular mechanisms but also dealt with important questions of how to implement this knowledge in a clinical setting.
Numbers in brackets refer to posters or session numbers to identify these on website and webcast.
The possibilities to study gut microbiota by sequencing bacterial DNA has made it possible to characterize and study the many different bacteria in our intestinal tract, which previously could not be studied as they could not be cultured. This has created interest in the impact of gut microbiota on the human health and disease partly through the metabolites and potential toxins from the bacteria, but also through the interaction between the microbiota and the host metabolism.
Initial interest has been focused on effects on obesity and type 2 diabetes but also many other conditions. Tuesday June 14 an ADA symposium focused on the impact of gut microbiota on inflammation and cardiovascular disease in diabetes. C Ron Kahn gave an introduction to the field from animal studies and described how this field is still in its infancy. The interaction between genes, environment, microbiota and health was described from experimental studies, illustrating the delicate balance where genes, nutrition and other environmental factors such as medication were described.
Karin Bornfeldt described the role of inflammation in atherosclerosis in diabetes, and emphasised the potential impact of bacterial toxins such as LPS for the inflammatory process leading to atherosclerosis. Subsequently WC Wilson Tang elegantly described the clinical studies he has performed with collaborators assessing the impact of TMAO (Trimethylamine N-oxide). Some types of normal gut bacteria in the human microbiome convert dietary carnitine to TMAO. TMAO alters cholesterol metabolism in the intestines, in the liver, and in artery wall. In the presence of TMAO, there is increased deposition of cholesterol in, and decreased removal of cholesterol from, peripheral cells such as those in the artery wall. They described how high levels of TMAO in the blood are associated with an increased risk of CVD, and potentially also hypertension, thrombosis and renal disease. Furthermore this could potentially be modified with dietary (ex. reduction in meat intake) or pharmacological interventions.
The last speaker Max Nieuwdorp has been a pioneer in clinical studies modifying the gut microbiota with faecal transplantations and described how transfer of gut microbiota from healthy might improve health, with clostridium difficile diarrhoea as the so far most successful condition, but with the potential to modify metabolic conditions as well.
The characteristics of diabetes-related morbidity and mortality are changing rapidly in these years. Ed Gregg from the CDC received the Kelly West Award for Outstanding Achievement in Epidemiology 2016 at the ADA and gave a lecture on this topic Sunday at 2:15-3:00 pm in Great Hall A, which I enjoyed together with many others. Do we expect smooth sailing or troubled waters ahead? For a nice recent review on the topic, see (Gregg EW, Lancet Diabetes Endocrinol 2016).
US surveillance data show that rates of diabetes-related complications in adults with diabetes have declined much in the past 20 years, from 28% for renal disease to 68% for MI (Gregg EW, NEJM 2014). Recent Danish data from Danish Diabetes Academy researchers at Steno (Jørgensen ME, Diabet Med 2014) and Odense (Rasmussen BS, Diabetologia 2016) corroborate these findings, showing declining number of amputations among patients with diabetes.
The trend follows the general large reductions in risk of incident cardiovascular disease in the general population over the last 20-30 years, as also shown in our Danish longitudinal healthcare registries (Schmidt M, BMJ 2012). It is heavily debated how much honor we clinicians deserve for these trends.
Ed Gregg discussed this, i.e. primary and secondary medical prevention versus healthier lifestyle in general: the big eras of large smoking decreases in the 1970s-80s, blood pressure reductions in the 1980s-90s, lipid reductions in the 1990s-2000s. What then about glycemic control trends and clinical impact (Ali MK, NEJM 2013)? Large-scale population-based longitudinal data on HbA1c are few – we in Denmark are among those few who can study this, and have shown that glycemic control in T2D is improving (Thomsen RW, Diabetes Obes Metab 2015) and that early glycemic control is a strong predictor of reduced long-term cardiovascular outcomes (Thomsen RW, ADA2016 abstract 1092P). The joker is how much of this improvement is simply caused by earlier T2D diagnosis (lead-time bias) (Gregg EW, Lancet Diabetes Endocrinol 2016).
Ed Gregg discussed several megatrends in clinical epidemiology of type 2 diabetes we see right now. Diabetes incidence has started to level off or even decline in many places. However, this is accompanied by earlier onset of T2D, often in very obese young adults, leading to longer lifetime exposure to T2D in the population – will this break the improving complication curves? Early-onset T2D individuals seem to have an aggressive phenotype, and may not have seen the same improvement in general risk factors than elderly individuals with T2D. Diabetes Academy-supported PhD-student Anne Bo will present results on early-onset T2D, based on the DD2 study at the EASD in Munich 12-16 September 2016 (EASD2016, accepted). The increasing duration of exposure to diabetes in youth and young adults might thus lead to greater cumulative risk of complications in the future (Gregg EW, Lancet Diabetes Endocrinol 2016).
Moreover, we all live longer, and our reduced mortality will both increase our chance of getting T2D over lifetime, and maybe also increase risk of nonvascular diabetes complications, due to less competing risk by cardiovascular disease and mortality. Importantly, Gregg said there is now a diversification seen in the spectrum of diabetes outcomes (Seshasai SR, NEJM 2011). Deaths due to cancer, infections, mental diseases including dementia and depression, and osteoporosis/falls will increase on a relative scale in T2D.
We have fantastic options in Denmark to study these outcomes, as demonstrated for diabetes and infections by PhD-student Anil Mor at the ADA2016 (oral 361-OR). Thus the future looks bright, at least for Danish research in diabetes complications and epidemiology.
- Gregg EW et al. The changing face of diabetes complications. Lancet Diabetes Endocrinol 2016; 4: 537-47.
- Gregg EW et al. Changes in diabetes-related complications in the United States, 1990–2010. N Engl J Med 2014; 370: 1514-23.
- Jørgensen ME at al. Reduced incidence of lower-extremity amputations in a Danish diabetes population from 2000 to 2011. Diabet Med 2014; 31: 443-47.
- Rasmussen BS et al. Substantial reduction in the number of amputations among patients with diabetes: a cohort study over 16 years. Diabetologia 2016; 59: 121-29.
- Schmidt M et al. 25 year trends in first time hospitalisation for acute myocardial infarction, subsequent short and long term mortality, and the prognostic impact of sex and comorbidity: a Danish nationwide cohort study. BMJ 2012, 344:e356.
- Ali MK et al. Achievement of goals in U.S. diabetes care, 1999–2010. N Engl J Med 2013; 368: 1613-24.
- Thomsen RW et al. Early glycaemic control among patients with type 2 diabetes and initial glucose-lowering treatment: a 13-year population-based cohort study. Diabetes Obes Metab 2015; 17: 771-80.
- Thomsen RW et al. Magnitude of HbA1c Reduction and Attainment of Early Glycemic Control Predict Cardiovascular Outcomes and Mortality: A Population-based Cohort Study of 24,752 People with Type 2 Diabetes Initiating First Metformin Therapy. ADA 2016, poster 1092P.
- Bo A et al. High burden of cardiovascular risk factors and poor glycaemic control in type 2 diabetes patients diagnosed before the age of 45 years in Denmark: results from the DD2 study. 52nd EASD Annual Meeting, Munich, 12-16 September 2016 (poster accepted).
- Seshasai SR et al. Diabetes mellitus, fasting glucose, and risk of cause-specifi c death. N Engl J Med 2011; 364: 829-41.
- Mor A et al. Rates of Community-based Antibiotic Use and Infection-related Hospital Contacts in Individuals With and Without Type 2 Diabetes: A Danish Nationwide Cohort Study. ADA 2016, oral 361-OR.
One of the highlights for me at the ADA 2016 meeting was the talk by Prof. Labros S. Sidossis in the session on human brown adipose tissue. In a study that has just appeared in Cell Metabolism his group has performed functional characterization of human brown adipose tissue and shown that it displays all the functional characteristics of brown fat in rodents. This includes histology as well as the ability to respond to cold by increasing glucose and fatty acid uptake and oxidation and by increasing expression of genes involved in lipid metabolism. Sidossis also reported evidence of functional uncoupling protein 1 and significant uncoupling of mitochondria in explant studies.
This work represents the most comprehensive to date regarding the functionality of human brown adipose tissue. Importantly, it also indicates that human brown adipose tissue based on functional measures is indeed brown and not inducible-brown/beige/brite as suggested by some recent studies focusing on selected molecular markers. The talk also included work published in Cell Metabolism in 2015 where his group demonstrates significant browning of white adipose tissue and increased basic metabolic rate in response to prolonged adrenergic stress following serious burn injury.
The core biological clock is regulated by the action of light via the suprachiasmatic nucleus in the hypothalamus. Disruptions of biological clock function by sleep disturbances, night shifts, nightly meals or jet lag are associated with adverse metabolic outcome and are risk factors for obesity, the metabolic syndrome and diabetes. In her fascinating talk Circadian Disruption, sleep apnea and metabolism – lessons from animal models, Dr. Deanna M. Arble, PhD, University of Michigan, gave two intriguing examples of the interplay between disturbance of circadian rhythmicity and metabolic risk.
The first example was based on the clock disrupting effect of sleep apnea in obesity associated with alterations in upper airway collapsibility during sleep. Obese, leptin-deficient mice demonstrate blunted ventilatory control, leading Polotsky et al (J Appl Physiol 2012) to hypothesize that obesity and leptin deficiency would predispose to worsening neuro-mechanical upper airway function and that leptin replacement would acutely reverse neuromuscular defects in the absence of weight loss. Both obesity and leptin deficiency were associated with significantly higher inspiratory flow limitation frequency and nasal pressure threshold and lower maximum inspiratory airflow. Leptin treatment of very obese ob−/ob− mice reversed these abnormalities. In elegant studies using leptin receptor knock-out or overexpression in periaqueductal neurons, Dr. Arble could show that leptin receptor stimulation inhibited neuronal activity and corrected the hypercapnic response in sleep apnea. She outlined a perspective of considerable clinical relevance of how sleep and thereby circadian disruption can lead to obesity and glucose disturbance, thereby creating a vicious cycle.
In the other example, Dr. Arble was wondering why bariatic surgery has poorer outcomes in shift workers than in obese subjects without clock disruption (Ketchum & Morton Ob Surgery 2007). Dr. Arble was able to reproduce this observation in obese mice undergoing ventricular major curvature resection, and to show that this was caused by an impaired incretin response in mice with transgenic clock disruption. Whether the effect was related to impaired Glp-1 secretion or sensitivity to Glp-1 in the hypothalamus needed clarification, but Dr. Arbler favored the latter possibility and underlined the obvious translational perspectives of restoring the intricate interplay between the clock and metabolic homeostasis.