Blandine Laferrere - US grants

The aim of this experiment is to investigate whether the mechanisms by which glucocorticoids and food intake stimulate leptin in vivo involve change in the leptin diurnal cycle and whether this effect is different between lean and obese human subjects.

enzyme activity; hydroxysteroid dehydrogenases; eating; fasting; adipose tissue; obesity; behavioral /social science research tag; human subject; nutrition related tag; female; clinical research;

DESCRIPTION (provided by applicant): The intestinal incretin GLP-1 is a potent glucose-mediated insulin secretagogue. Patients with type 2 diabetes (DM2) have a blunted incretin effect on insulin secretion but the administration of GLP-1 is able to restore ?-cell sensitivity t glucose in DM. Patients who experienced DM2 remission after gastric bypass surgery (GBP) have rapid (within weeks), and sustained (years), exaggerated post-prandial GLP-1 release, with normalization of the incretin effect on insulin secretion. In vitro and/or rodent studies show that GLP-1 can stimulate ?-cell growth and differentiation. Whether the sustained enhanced GLP-1 release after GBP results in greater ?-cell function is unknown. In this proposal we will examine: 1) The role of endogenous GLP-1 in the recovery of ?-cell function in response to oral glucose, by using exendin 9-39, a GLP- 1 receptor antagonist; 2) The change of maximal ?-cell response to glucose infusion and arginine administration after GBP; 3) Insulin sensitivity and body composition, in patients with severe obesity and DM2, before and up to 2 years after GBP; 4) Determinants of DM2 remission after GBP. Understanding the mechanisms of DM2 remission, or lack of, after GBP will help identify predictors of outcome as well as develop medical alternatives for the treatment of severe obesity and DM2.

? DESCRIPTION (provided by applicant): The sustainability of bariatric surgery on weight loss and metabolic benefits is highly variable between surgery types and individuals. In addition the mechanisms of the superior effect of gastric bypass (GBP) compared to restrictive procedures are not known. Our specific goals are: 1) To identify biomarker predictors of long-term weight loss and metabolic improvement after bariatric surgery; and 2) To identify the different mechanisms by which GBP and adjustable gastric banding (LAGB) exert their effects, i.e. to characterize mechanisms underlying the superior metabolic effects of GBP vs. LAGB. To achieve these goals we will apply metabolomic profiling to samples collected from well-characterized patients that have undergone GBP and LAGB and followed up to 7 years in the Longitudinal Assessment of Bariatric Surgery (LABS) study, and will compare them to non-operated controls with T2DM , matched on initial BMI, who participated in a lifestyle intervention (LSI) from the Action for Health in Diabetes (Look AHEAD) study and followed up to 7/8 years. In Aim 1, we will test the hypothesis that baseline targeted metabolomics signatures, including amino acids and their metabolites, can predict successful long term surgical weight loss. In Aim 2, we will test the hypothesis that baseline metabolomics signatures will show incremental risk predictive capability for T2DM remission at 3 and 7 years, above and beyond well-known clinical predictors. In both aims, we will test the hypothesis that the change of the metabolomic signature will differ between types of intervention, at matched weight loss. This will help identif mechanisms of the superior effect of GBP, independent of weight loss. Both targeted (Aims 1 and 2) and non-targeted (Aim 3) mass spectrometry-based metabolomics and pathway analysis will be performed. Results from this award would support a more personalized approach for the surgical treatment of obesity and T2DM, based on a model integrating patient clinical factors and metabolite levels measured prior to weight loss intervention, rather than simply on BMI and surgeons' preference. Moreover, our data will help uncover novel pathways related to the mechanisms of the effect of GBP, independent of weight loss.

? DESCRIPTION (provided by applicant): Over 25% of the US population >65 years of age have type 2 diabetes and 80% of these individuals are overweight or obese. These individuals face shortened lifespans, increased health care needs, greater medical complications, and lower quality of life relative to those of similar age without these conditions. Lifestyle interventions focused on weight loss are recommended for overweight and obese individuals with type 2 diabetes, but whether these interventions meaningfully improve the lives of older individuals with diabetes over extended follow-up is unknown. Look AHEAD is a randomized trial comparing the effects of intensive lifestyle intervention (ILI) focused on weight loss achieved through healthy eating and increased physical activity versus a control group given Diabetes Support and Education (DSE) in overweight and obese individuals with type 2 diabetes. Although ILI did not produce beneficial effects on the primary and secondary outcomes related to cardiovascular disease, it did produce beneficial effects on a broad spectrum of health parameters during the period of the intervention. The LA Extension (LA-E) will examine whether ILI, provided for 10 years during mid- life, has enduring benefits that persist beyond the period of the intervention for older individuals with diabetes. We propose to follow approximately 3,800 participants (current ages 58-89 years) for 4.5 additional years with biennial clinic visits and 6-month outcomes phone calls. The primary aims of LA-E are to test whether ILI relative to DSE has long term legacy effects on 1) increased lifespan and 2) reduced health care costs. Secondary aims test whether ILI relative to DSE has long-term effects on key dimensions of healthy aging: less frailty, reduced diabetic microvascular complications, and improved quality of life. LA-E will also compare long- term trajectories of weight, physical activity, fat and lean mass, and bone density and examine how these are related to outcomes. LA-E focuses on the clinical outcomes that are most relevant to healthy aging and resilience and will provide the long-term data needed to frame guidelines related to lifestyle intervention in the care of older overweight or obese individuals with type 2 diabetes.

? DESCRIPTION (provided by applicant): Abnormal regulation of glycemia (dysglycemia) has a very long time course, from its earliest stage, labeled pre-diabetes, to the onset of Type 2 diabetes (T2D), to the development of clinically detectable microvascular changes and measurable atherosclerosis, to clinically manifest complications with attendant morbidity and mortality. The Diabetes Prevention Program (DPP) focused on the pre-diabetes stage of dysglycemia and demonstrated powerful beneficial effects of lifestyle intervention (ILS) and metformin (MET), compared with placebo (PLBO), in preventing or delaying the onset of T2D over a 3-year period in a high-risk population (n=3234). The DPP also investigated and described the interventions, phenotypic and genotypic risk factors associated with T2D development, the effects of the interventions in the setting of these risk factors, the health economic implications of T2D prevention, and other outcomes of interest. Based on these results, the DPP lifestyle program has been widely implemented. The 11-year follow-up DPP Outcomes Study (DPPOS) explored the longer-term effects of T2D prevention, bridging the period between pre-diabetes and T2D, and examined outcomes that required more time to develop than the relatively brief 3-years of DPP. DPPOS showed longer-term salutary effects of the original interventions on T2D prevention and on cardiovascular disease (CVD) risk factors. Prevention was cost-saving with MET and cost-effective with ILS. Overall, the risk for microvascular disease was significantly greater in subjects who developed T2D and increased with longer duration and higher hemoglobin A1c (A1C). There were no significant differences by treatment group in the prevalence of the aggregate microvascular outcome; however, compared with PLBO and MET, ILS significantly reduced the risk of microvascular disease among women and those who had A1C ?6.5% at study end. The proposed DPPOS Phase 3 will study the DPPOS cohort for 10 more years, taking advantage of the long-term randomized exposure to MET and the densely phenotyped and genotyped DPPOS cohort (n=2778), which includes nearly 1600 patients with known T2D duration and ~1200 who have not developed T2D, to address yet unanswered questions about long-term exposure to MET and ILS initiated during pre-diabetes. DPPOS Phase 3 will examine outcomes that are of increasing public health concern in the aging population with pre-diabetes and T2D, including the putative benefits of MET on development of CVD and cancer. The main goals of DPPOS Phase 3 are to examine efficiently: 1) the long-term effects of metformin therapy begun in the pre-diabetic phase on risk for CVD and cancer; 2) the long-term effects by intention-to-treat of ILS and MET on further development of T2D and on traditional and more recently recognized complications of dysglycemia, and of their economic impact; and 3) the clinical course of dysglycemia, evaluated by categorical diagnoses (pre-diabetes vs diabetes) and as a continuum, and their associations with the development of complications, including analyses of interactions with DPP interventions and established and novel risk factors.

Abnormal regulation of glycemia (?dysglycemia?) has a very long time course, from the earliest stage of pre-diabetes, to the onset of Type 2 diabetes (T2D), to the development of clinically detectable microvascular changes and measurable atherosclerosis, to clinically manifest complications with attendant morbidity and mortality. The Diabetes Prevention Program (DPP) focused on the pre-diabetes stage of dysglycemia and demonstrated powerful beneficial effects of lifestyle intervention (ILS) and metformin (MET), compared with placebo (PLBO), in preventing or delaying the onset of T2D over a 3-year period in a high-risk population (n=3234). The DPP also investigated and described the interventions, phenotypic and genotypic risk factors associated with T2D development, the effects of the interventions in the setting of these risk factors, the health economic implications of T2D prevention, and other outcomes of interest. Based on these results, the DPP lifestyle program has been widely implemented. The DPP Outcomes Study (DPPOS) has explored the longer-term effects of T2D prevention in the DPP cohort, bridging the period between pre-diabetes and T2D, and has examined outcomes that required more time to develop than the 3-years of DPP. DPPOS showed longer-term salutary effects of the original interventions on T2D prevention and on cardiovascular disease (CVD) risk factors. The risk for microvascular disease was significantly greater in subjects who developed T2D and increased with longer duration and higher hemoglobin A1c (HbA1c). There were no significant differences by treatment group in the prevalence of the aggregate microvascular outcome; however, compared with PLBO and MET, ILS significantly reduced the risk of microvascular disease among women and those with HbA1c ?6.5%. During the one-year extension of DPPOS Phase 3, we will maintain and continue to follow the well-characterized and valuable DPPOS cohort, and collect measurements of outcomes as described in the protocol. We will 1) perform new analyses to characterize the heterogeneous course of dysglycemia and its long-term complications and factors that define susceptibility or resistance to diabetes, its complications, and common chronic conditions of aging, and 2) explore the factors associated with participant retention, adherence to the protocol and completion of measurements, and determine if alternative methods can be implemented to improve retention and adherence and to expand data collection. These aims will provide important insights into prediabetes and diabetes and their long-term outcomes and could serve the potential further study of the DPPOS cohort.

Project Summary/Abstract American adults have a high prevalence of overweight, obesity and prediabetes. Small weight loss delays the progression to type 2 diabetes and decrease cardiovascular risk, yet adherence to long-term calorie restriction is difficult to sustain. There is an urgency to find effective, easy-to-implement and sustain, and affordable life style interventions. Restricting the food intake interval, or time restricted eating (TRE) has been shown in small-scale pilot studies to result in weight loss and improve metabolism, while being less challenging than calorie count. We propose to rigorously assess the efficacy of TRE, administered via a smartphone application, on weight loss and decreased cardiovascular risk. To achieve this goal, metabolically unhealthy mid-life adults with overweight or obesity who habitually eat for more than 14h/day, will be randomized to a restricted eating window to 10h/d (TRE) or to their habitual eating window (? 14h, HABIT), and followed up to 12 months. Ambulatory measures of food intake, sleep, physical activity and glucose, and in-patient 24-h well-controlled studies will be done to determine the effect of TRE versus habitual eating duration (HABIT), as well as the mediators of these effects. Hypotheses: 1) TRE vs. HABIT will result in decreased fat mass, measured by quantitative magnetic resonance, and effect mediated via decreased daily total energy intake, measured by double labeled water; 2) TRE vs. HABIT will result in lower insulin resistance, lower glycemia and shift in fuel utilization preferentially to lipid mobilization; 2) Adherence to TRE (measured by usage of the app and reduction of the eating window), and self-efficacy will associate with the short-term effect (3 months) and the long-term sustainability (12 months) of TRE on fat mass loss. Results from this study will provide important insights into understanding the physiological and molecular interactions between restricting daily eating interval and metabolic function, and could provide evidence for using TRE interventions to improve metabolic health and decrease cardiovascular risk in the large number of mid-life and older Americans in great need of life style intervention.