Several bariatric operations are currently used to produce sustained weight loss and treat obesity- related comorbidities. Currently considered the gold standard in bariatric surgical procedures, Roux-en-Y Gastric Bypass (RYGB) stimulates a considerable and sustained weight-loss in obese individuals. This reduced adiposity is often accompanied by profound improvement in glucose control of type 2 diabetic subjects. While some of the effects of RYGB on glucose control are secondary to reduced body weight, dramatic changes in gut nutrient sensing/presentation and hormone profile may contribute to the resolution of T2D in many individuals. Accumulating evidence indicates that duodenal nutrient exclusion (DNE) may be an important contributor to the metabolic benefits of RYGB. We can directly test such DNE without gastric restriction or altering the path of ingested nutrients using duodenal, barrier-endolumenal sleeves (DES) that prevent ingested nutrients from interacting with the upper intestine. Early pre-clinical experiments in rodents and clinical experiments in humans point to beneficial effects of DES in individuals with impaired glucose homeostasis. We have successfully established a rodent model of a DES that will allow for the careful mechanistic testing of DES that is not possible in humans. In our hands, we observe that DES results in a small in fat mass and a clear improvement in glucose tolerance, which is above and beyond the effect of the weight loss alone. This proposal will dissect components of glucose handling via hyperinsulinemic-euglycemic clamps. It will also investigate the role of the vagus and the central nervous system in the DES-enhancement of glucose metabolism. Together these studies will test the hypothesis that duodenal nutrient exclusion restores the ability of this nutrient-sensing circuitry to regulate glucose homeostasis.

Public Health Relevance

Several bariatric operations are currently used to produce sustained weight loss and treat obesity-related comorbidities. Several of these procedures, including Roux-en-Y Gastric Bypass (RYGB), include intestinal reconfiguration resulting in exclusion of nutrients from the upper-most region of the small intestine (duodenum). As such, a targeted search to elucidate the underlying molecular mechanism/s of duodenal nutrient exclusion, especially that stimulated by an endolumenal barrier device, will provide insight into current and future therapies for multiple components of the metabolic syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK098319-03
Application #
9130160
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Spain, Lisa M
Project Start
2014-09-01
Project End
2017-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Kim, Teayoun; Holleman, Cassie L; Nason, Shelly et al. (2018) Hepatic Glucagon Receptor Signaling Enhances Insulin-Stimulated Glucose Disposal in Rodents. Diabetes 67:2157-2166
Kim, Teayoun; Nason, Shelly; Holleman, Cassie et al. (2018) Glucagon Receptor Signaling Regulates Energy Metabolism via Hepatic Farnesoid X Receptor and Fibroblast Growth Factor 21. Diabetes 67:1773-1782
Kim, T; Holleman, C L; Ptacek, T et al. (2017) Duodenal endoluminal barrier sleeve alters gut microbiota of ZDF rats. Int J Obes (Lond) 41:381-389
Loyd, Christine; Liu, Yanping; Kim, Teayoun et al. (2017) LDB1 Regulates Energy Homeostasis During Diet-Induced Obesity. Endocrinology 158:1289-1297
Stemmer, Kerstin; Zani, Fabio; Habegger, Kirk M et al. (2015) FGF21 is not required for glucose homeostasis, ketosis or tumour suppression associated with ketogenic diets in mice. Diabetologia 58:2414-23