Research Highlights

Dr. Rhonda Bell is the lead investigator on ENRICH, a group of fifteen investigators, plus students and staff that came together under a research program funded for five years by Alberta Innovates - Health Solutions (AIHS). All ENRICH studies are aimed at improving maternal health in pregnancy and postpartum by finding innovative ways to promote healthy weights and healthy eating. Researchers work closely with Alberta Health Services and community partners in Edmonton, Calgary Zone and Maskwacis rolling out and evaluating different strategies to support women, their care providers and their communities to improve pregnancy and postpartum care. Strategies make the most of the extensive data collected about energy expenditure and body composition in the postpartum period, as well as the ongoing cohort of women and their families, the Alberta Pregnancy Outcomes and Nutrition (APrON) study. Drs Cathy Chan and Rhonda Bell were awarded the U of A Community Scholar Award in 2016 for their book, Pure Prairie Eating Plan. The eating plan and recipies were inspired by the Mediterranean diet, but focuses on foods more rediably available in a prairie setting. The authors are planning future guides for groups such as Asian-Albertans and Aboriginals that are prone to T2D. Bell was also awarded the Earl McHenry Award for Distinguished Service to Human Nutrition from the Canadian Nutrition Society in 2016.

The human gut has a complex ecosystem of over 100 trillion microbial cells which impact metabolism, nutrition and immune function. Not surprisingly, aberrations in the microbiome are linked with a host of diseases that include diabetes, and this area of study has become the subject of extensive research in recent years. In 2015 the Alberta Diabetes Institute welcomed new member Dr Jens Walter whose research in GI microbiota has provided insight into how and why the microbiome differs between populations having contrasting disease profiles. In a study that was featured on the cover of Cell Reports (and in a Research Commentary of Nature), Walter and fellow researchers that included postdoctoral fellow Dr Ines Martinez-Ramos compared fecal microbiota of adults from two non-industrial regions of Papua New Guinea with that of United States residents. They found that Papua New Guineans harbor much less inter-individual diversity and a more complex array of microbial species compared with Americans, including a few species completely absent in the latter population. For microbial species shared between the two cultures, there were vastly different abundance profiles. While most of these findings were consistent with similar studies that compared western and non-industrialized populations, their study was the first to use ecological theory to suggest the differences were a result of dissimilar 'assembly processes' of the local microbial community. In particular, dispersal, which in the setting of the gut is the ability of organisms to move horizontally through GI space - is considered a major process by which microbial diversity is achieved. It appears that dietary and environmental factors characteristic of western cultures like low fibre, access to antibiotics, formula vs breastfeeding, and chlorinated water impede microbial dispersion. While that is successful for achieving a reduction in pathogenic microbes that cause infectious diseases, it is also correlated with a higher incidence of non-communicable diseases like diabetes, arthritis, lupus and MS. With the decline in populations still living a non-westernized lifestyle, this study by Jens and others is valuable for demonstrating the influence of westernization on gut microbiota and the correlation with disease and relating this to an ecological framework (Cell Reports, 11:527-38, 2015).

While exciting advancements are being made in the treatment of type 1 diabetes including closed loop management systems and cell replacement therapy, bolus insulin injections are still the primary means for managing this disease. Several years ago Dr Edmond Ryan embarked on the development of a unique smartphone app that would personalize insulin injection regimes based on patient updates. While numerous apps exist for managing insulin bolus schedules, these are typically based on a feed-back approach and do not incorporate changes in medication until after blood glucose is affected. Ryan, along with fellow Alberta Diabetes Institute member Dr Peter Senior and Drs. Russ Greiner and Michael Bowling (Computing Science), took a different approach. By collecting information about how clinicians make decisions for patients to normalize glucose based on nutritional, physical activity and lifestyle information, the researchers aimed to develop an algorithm that would allow this same proactive decision-making using an intelligent device. The first step in this process was a two year trial involving app users interfacing with the Edmonton Automated Sugar Intelligence (EASI) website where information received from patients was used by clinicians to provide advice through the app. The initial objective was to study how well the approach was accepted by patents with T1D: whether they used it on an ongoing basis and whether it led to an improvement in glycemic control. Results of this research will be made available in late 2016, setting the stage for final design of the algorithm and testing of a fully automated app.

Strategies for weight loss diets have varied considerably over the years (to put it mildly), including whether caloric restriction should involve targeting fat or carbohydrates. Low carb diets have regained popularity in recent years, with advocates going so far as to claim any successful dieting relies on decreasing carbohydrate intake and elevating the release of free fatty acids/fatty acid oxidation, in turn leading to a greater loss of body fat compared with a low fat diet. Is it true? Dr Carla Prado, Director of the Human Nutrition Research Unit in the Alberta Diabetes Institute's Clinical Research Unit, was part of a collaborative research team that explored the relative benefits of the two approaches, studying a variety of metabolic endpoints in males and females. In an intricate cross-over study, obese subjects started out on a eucaloric baseline diet (50% carbohydrate, 35% fat, 15% protein) for 5 days, then alternated between low fat, LF (72% carbohydrate, 7% fat, 21% protein) and low carbohydrate, LC (30% carbohydrate, 49% fat, 21% protein) diets for 6 days each with a washout period in between. Body fat loss was calculated as the difference between daily fat intake and net fat oxidation, measure while residing in a metabolic whole body calorimetry unit. The results of experimentation confirmed that an LC diet did in fact result in more weight lost compared with the LF diet (1.9 vs 1.3 kg, p=0.05). But the fat metabolic balance in the two diets was somewhat surprising: the LC diet resulted in a significant increase in fat oxidation, whereas the LF diet did not alter fat oxidation. When the difference between fat intake and fat oxidation were compared for the two diets though, the LF diet was associated with a greater turnover of fat. While it is expected that fat oxidation during prolonged LC or LF dieting would diminish over time, the data generated by Prado et al. suggest that a greater fat imbalance is likely to persist with the LF diet, leading to more long-term body fat loss compared with restricted carbohydrate dieting. Results of the study were published in Cell Metabolism (22:427-426, 2015).

Traditionally, fasting blood lipid biomarkers like triglycerides (TGs) and low density lipoproteins (LDLs) or 'bad cholesterol' have been used diagnostically to identify risk for developing cardiovascular disease. We know that those with diabetes have increased risk of CVD, but usually this is not associated with an increase in traditional blood lipids. But Dr Spencer Proctor is challenging that view, especially in light of recent epidemiological data showing patients diagnosed with cardiac events have normal fasting lipids and that intestinal-derived lipids (remnant cholesterol) might be playing a more prominent role in pathogenesis than previously thought (Copenhagen Heart Study). Non-fasting plasma levels of cholesterol are a result of both liver production and dietary absorption, but there is a more complex, reciprocal relationship that influences each other's rate. This is reflected by studies that demonstrate how a drug like ezetimibe is used to block the absorption of gut-derived cholesterol, but not without a concomitant rise in cholesterol production in the liver. It is also noted that statins, designed to lower the hepatic production of cholesterol, are associated with an increase in the intestinal absorption of cholesterol from the lumen. 'These are very similar to the observations we see during diabetes' say Proctor. Proctor, along with Alberta Diabetes Institute member Dr Donna Vine and post-doctoral fellow Dr Rabban Mangat wanted to examine whether simvastatin administered to an animal model of diabetes and metabolic syndrome (JCR:LA-cp) increased the absorption of intestinal-derived 'remnant' cholesterol. Researchers found that rats also receiving simvastatin had 1.9-fold and 1.5 fold increases in the absorption both cholesterol and triglycerides. In addition, statin treatment increased the expression of key genes involved in lipid synthesis, including Hmgcr, Srebp1, Fas and Acc. The results of their research suggest that the perceived clinical benefits from statin treatment may be questionable (Atherosclerosis, 232:141-148, 2014) and appear to increase remnant forms of cholesterol in the blood. More recently, Proctor and his research team have been collaborating with a group of researchers from 6 Quebec universities on the QUALITY (QUebec Adipose and Lifestyle InvesTigation in Youth) study, looking at risk factors for overweight children. Their results suggest that levels of fasting LDLs and triglycerides aren't as well-correlated with cardiovascular disease as a 'remnant' or diet-derived apolipoprotein called apo B48. In fact when they compared blood samples from lean and age-matched overweight children, apo B48 was three times higher in the latter, far more than the difference in their LDLs or TGs. Proctor's work makes a strong case for utilizing apo B48 as an alternative screening biomarker for cardiovascular risk (Journalof Clinical Endocrinology and Metabolism, 101:2915-22, 2016).

PWS is the most common syndromic form of obesity, characterized by excessive weight gain, obesity and hyperphagia. Dr Andrea Haqq's previous work suggests that PWS serves as a unique model of ghrelin excess, potentially explaining the ravenous appetite and progressive weight gain that characterize the condition. Her group has investigated the role of a number of additional hormones (peptide YY (PYY), GLP-1, insulin) and metabolites (amino acids, fatty acids) in the obesity associated with PWS. In 2014 Haqq conducted a collaborative study (with Dr Mike Freemark, Duke University), that compared the effects of a high carbohydrate versus a high fat meal on ghrelin, insulin and PYY in PWS children (n=14) and obese control (n=14) children. They found that children with PWS have fasting and postprandial hyperghrelinemia and an attenuated PYY response to fat, yielding a high ratio of ghrelin/PYY. Ultimately, they discovered that the ratio of Ghrelin/PYY appears to be a novel marker of orexigenic drive. This work is important because it forms the foundation for the development of therapies targeting these appetite-stimulating hormones, with the aim to ameliorate the difficult-to-treat obesity associated with PWS. Details of their research were published in the Journal of Clinical Endocrinology & Metabolism (100:3822-31, 2015). Their collaborative group has also shown that PWS children have reduced levels of branched chain amino acids (BCAA, Leu/Ile/Val), including interesting gender-based effects. Further, their results suggest that the hyperghrelinemia and increased insulin sensitivity of PWS may be related to these reduced levels of BCAAs. This data suggests increased proteolysis in PWS as a potential explanation for the reduced muscle mass, sarcopenia and decreased energy expenditure in PWS. Along with increasing the understanding of the endocrinology of PWS, her group (in collaboration with Dr Lonnie Zwaigenbaum) published a recent systematic review detailing the social-communication impairments present in PWS and evaluating the association between Autism Spectrum Disorder (ASD) and PWS. Meanwhile, fellow Alberta Diabetes Institute member Dr Rachel Wevrick continues her groundbreaking research into the genetic basis of PWS, including the MAGEL2 (MAGE Family Member L2) gene that is known to be inactivated in PWS children. Adult mice lacking MAGEL2 are insensitive to the typical anorexic effects of leptin treatment while exhibiting a lack of neuronal depolarization in hypothalamic pro-opiomelanocortin (POMC) neurons. With the hypothalamus playing a major role in development and endocrine functions, Wevrick and her co-investigators explored the question of whether the mutation inactivation of MAGEL2 was congenital or post-natal. In vitro experimentation using POMC neurons from hypothalamic slices of MAGEL2 mice of various ages revealed a progressive decline in leptin-invoked depolarization. Therefore it is possible that a similar, progressive loss of leptin sensitivity and loss of MAGEL2 in children could explain the delayed onset of hyperphagia and obesity (Human Molecular Genetics, 24:4276-4283, 2015).

The hormone serotonin has a number of physiological functions, including a role in energy metabolism through appetite suppression in the CNS where it is produced by the enzyme tryptophan hydroxylase 2 (Tph2). Peripheral serotonin is produced by Tph1, and previous research has shown that high systemic levels of Tph1 are associated with obesity although the mechanism for this has been unclear. A research team that included Alberta Diabetes Institute member Dr Jason Dyck and postdoctoral fellow Dr Shereen Hamza conducted an important study that showed Tph1-deficient mice fed a high-fat diet (HFD) were protected from obesity, insulin resistance (IR) and nonalcoholic fatty liver disease compared with controls, despite similar food intake and physical activity levels. By measuring [18F]fluorodeoxyglucose (FDG), a marker for tissue glucose uptake, their research showed that FDG uptake in interscapular brown adipose tissue (iBAT) was higher in the HFD-fed Tph1-/- mice. Consistent with this was a reduction of circulating serotonin and an increase in mitochondrial uncoupling protein 1 (UCP-1) in iBAT tissue of the Tph1-/- type mice, a higher basal oxygen consumption and interscapular surface temperature. These findings clearly indicated that the anti-obesity effects of genetic Tph1 deletion was related to an increase in BAT thermogenesis. Confirmation that these effects were mediated through serotonin was confirmed by implanting slow-release serotonin in the Tph1 deficient mice and seeing significantly increased epididymal white adipose tissue, obesity and IR, as well as lower basal metabolic rate. Additional experimentation gauging sympathetic tone revealed that iBAT of Tph1-/- mice have enhanced sensitivity to B-adrenergic stimulation, with serotonin acting directly on BAT to suppress induction of UCP1. The researchers went further to see if intraperitoneal administration of LP533401 - a small molecule used for treating irritable bowel syndrome and osteoporosis via inhibition of gut-derived serotonin - might have therapeutic value in wild mice fed a HFD. Similar to the effects of genetic Tph1 deletion, LP53401 resulted in lower weight gain/body fat accumulation, improved glucose homeostasis and greater insulin sensitivity versus controls. The results of their interesting research suggest a role for therapeutic inhibition of circulating serotonin (Nature Medicine, 21:166-172, 2015).

There has been a long-standing speculation about the association between vitamin D status and various diseases, including diabetes. Adults with diabetes and chronic kidney disease (CKD) are further compromised because the conversion of vitamin D to its biologically active form (calcitriol or 1,25(OH)2D) in the kidney is diminished, increasing the risk for insufficiency. Moreover, patients living in northern climates are at an even higher risk for vitamin D insufficiency due to lower sunlight exposure. Data suggests 93% of Canadians with CKD have vitamin D insufficiency, suggesting a need for supplementation, but there is a lack of guidelines for supplementation protocols based on sound clinical research. Dr. Diana Mager has led research aimed at validating the correlation between vitamin D status and various health benefits such as bone health, glycemic control and quality of life. In recent research Mager, along with Alberta Diabetes Institute members Drs. Peter Senior and Kailash Jindal conducted research that explored the relative benefits of daily (2,000 IU/day) versus monthly (40,000 IU/month) D3 supplementation for 6 months in adults having both diabetes mellitus and CKD. What they found was that daily or monthly supplementation was equally effective in producing significant increases in serum levels of vitamin D (including calcitriol), and both dosing regimens were safe and well-tolerated - important insight for health care providers. Supplementation produced little improvement in markers of bone health though, and future studies will be aimed at determining whether a longer duration of supplementation produces detectable benefits (Clinical Nutrition, in press).