The Role of the Duodenum in the Pathogenesis of Insulin Resistance and Type 2 Diabetes Mellitus

In parallel with the increasing prevalence of obesity worldwide, type 2 diabetes mellitus (T2DM) has reached epidemic proportions. Despite a multitude of available therapies, only bariatric surgery (e.g., roux-en-Y gastric bypass (GBP)) has proven to be an effective long term treatment modality for morbid obesity. Moreover, the majority of T2DM patients who undergo GBP experience normalization of their blood glucose and are able to discontinue their anti-diabetes medications soon after the procedure. The insulin resistant state commonly seen in non-diabetic obese subjects also improves after GBP. Evidence from recent animal studies suggests that the rapid return to euglycemia seen in T2DM patients after GBP might in part result from excluding the duodenum from the flow of nutrients. With the use of enteral feeding tubes, we hope to better understand the factors in the human gut that may predispose obese individuals to the development of insulin resistance and T2DM.

Study Overview

• Status: Completed
• Conditions: Insulin Resistance and Type 2 Diabetes
• Intervention / Treatment: Procedure: Placement of nasogastric feeding tube; Procedure: Nasojejunal feeding tube

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Inclusion criteria for lean, healthy control subjects:

1. Fasting plasma glucose (FPG) < 100
2. Age 18 to 55
3. BMI 18.5 to 24.9 kg/m2
4. Stable weight for prior 3 months

Inclusion criteria for prediabetic individuals:

1. Based on American Diabetes Association criteria of FPG > 100 and <126
2. Age 18 to 55
3. BMI 35 to 60 kg/m2
4. Stable weight for prior 3 months

Inclusion criteria for diabetic individuals:

1. Diagnosis of type 2 diabetes mellitus (T2DM) for < 5 years
2. Hemoglobin A1c < 8%
3. Age 18 to 55
4. BMI 35 to 60 kg/m2
5. Stable weight for prior 3 months

Exclusion Criteria:

Exclusion criteria for all study subjects:

1. Use of any of the following medications: Thiazolidinediones, dipeptidyl-peptidase IV (DPP-IV) inhibitors (e.g., sitagliptin), GLP-1 analogs (e.g., exenatide).
2. Subjects with T2DM who are unable to maintain adequate glycemic control (i.e., having a fasting blood glucose that exceeds 250mg/dL on two consecutive tests) while temporarily discontinuing their oral diabetes medications for the study and in whom the study physician determines insulin therapy would not be appropriate.
3. Females with a positive pregnancy test

5. Prior gastric, duodenal, proximal jejunal surgery or pancreas resection 6. Known malabsorptive disorder 7. History of cancer in past 5 years 8. Renal insufficiency defined by serum creatinine > 1.5 mg/dl 9. Hepatic enzyme elevations of greater than twice the upper limits of normal 10. Current use of warfarin or clopidogrel 11. Intercurrent infections 12. Contraindication to nasogastric or nasojejunal feeding tube (e.g., deviated nasal septum, prior upper gastrointestinal bleed, or history of easy bleeding) 13. Residence outside the greater Nashville, TN area

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1: Nasogastric feeding tube	Procedure: Placement of nasogastric feeding tube; Glucose tolerance test via nasogastric feeding tube 50 g glucose tolerance test on day 1; 50 g glucose tolerance test with 30 mL oil on day 2; Intravenous glucose tolerance test on day 3
Experimental: 2: Placement of nasojejunal feeding tube	Procedure: Nasojejunal feeding tube; Glucose tolerance test via nasojejunal feeding tube 50 g glucose tolerance test on day 1; 50 g glucose tolerance test with 30 mL oil on day 2; Intravenous glucose tolerance test on day 3

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Insulin sensitivity	3 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Incretin effect	3 days

Collaborators and Investigators

• Sponsor: Vanderbilt University
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Publications and helpful links

General Publications

• Tamboli RA, Sidani RM, Garcia AE, Antoun J, Isbell JM, Albaugh VL, Abumrad NN. Jejunal administration of glucose enhances acyl ghrelin suppression in obese humans. Am J Physiol Endocrinol Metab. 2016 Jul 1;311(1):E252-9. doi: 10.1152/ajpendo.00082.2016. Epub 2016 Jun 7.

Study record dates

Study Major Dates

• Study Start: May 1, 2008
• Primary Completion (Actual): June 1, 2012
• Study Completion (Actual): September 1, 2016

Study Registration Dates

• First Submitted: December 4, 2007
• First Submitted That Met QC Criteria: December 4, 2007
• First Posted (Estimate): December 6, 2007

Study Record Updates

• Last Update Posted (Estimate): November 1, 2016
• Last Update Submitted That Met QC Criteria: October 31, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Hyperinsulinism; Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin Resistance
• Other Study ID Numbers: IRB#070770; R01DK070860 (U.S. NIH Grant/Contract); GCRC #1710