Investigating the Role of the Polyol Pathway in the Central Nervous System Production of Fructose

Investigating the Role of the Polyol Pathway in the Central Nervous System Production of Fructose: an Intervention Study

To investigate whether longer-term improvement of glycemic control in poorly controlled diabetes patients with a 12-week intensified insulin treatment regimen will lead to decreased polyol pathway activity.

Study Overview

• Status: Completed
• Conditions: Hyperglycaemia (Diabetic)
• Intervention / Treatment: Drug: Insulin; Behavioral: exercise; Dietary supplement: Dietary counseling

Detailed Description

Polyol pathway activity will decrease in diabetic individuals who undergo intensification of their insulin treatment regimens as reflected by lower baseline brain intracellular fructose levels and higher intracellular glutathione levels. Furthermore, following longer-term improved glycemic control, patients may also have down-regulation of the pathway as reflected by decreased production of intracellular fructose in response to hyperglycemic clamp.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06511
      • The Anylan Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 15 Type 2 DM subjects with HbA1C > 7.5%
• 15 Type 1 DM subjects with HbA1C > 7.5%
• Age 18-60
• BMI ≥18 kg/m2
• Weight ≤ 285 pounds

Exclusion Criteria:

• Creatinine > 1.5 mg/dL, Hgb < 10 mg/dL, ALT > 2.5 X ULN,
• untreated thyroid disease,
• uncontrolled hypertension,
• known neurological disorders,
• untreated psychiatric disorders,
• malignancy,
• bleeding disorders,
• current or recent steroid use in last 3 months,
• illicit drug use;
• for women: pregnancy, actively seeking pregnancy, or breastfeeding; inability to enter
• MRI/MRS

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: type 2 diabetes mellitus; Subjects with type 2 diabetes on insulin.	Drug: Insulin; Insulin regimens will be adjusted on a weekly basis as needed to achieve a target blood glucose level.; Behavioral: exercise; Exercise in accordance to the guidelines established by the American Diabetes Association.; Dietary supplement: Dietary counseling; Dietary counseling in accordance to the guidelines established by the American Diabetes Association.
Active Comparator: type 1 diabetes mellitus; Subjects with type 1 diabetes on insulin.	Drug: Insulin; Insulin regimens will be adjusted on a weekly basis as needed to achieve a target blood glucose level.; Behavioral: exercise; Exercise in accordance to the guidelines established by the American Diabetes Association.; Dietary supplement: Dietary counseling; Dietary counseling in accordance to the guidelines established by the American Diabetes Association.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in HbA1c Levels	HbA1c levels measured by MRS scanning during a hyperglycaemic clamp. Result reported is the mean decrease in HbA1C. A decrease in HbA1c indicates improvement in brain glucose levels.	Baseline and 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gluthathione	baseline MRS scan to measure gluthathione	0 weeks
Gluthathione	MRS scan to measure gluthathione	12 weeks
Plasma Glucose	MRS scan to measure plasma glucose	0 weeks
Plasma Glucose	MRS scan to measure plasma glucose	12 weeks
Plasma Fructose	MRS scan to measure plasma fructose	0 weeks
Plasma Fructose	MRS scan to measure plasma fructose	12 weeks
Plasma Insulin	MRS scan to measure plasma insulin	0 weeks
Plasma Insulin	MRS scan to measure plasma insulin	12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Optional Hyperglycemic Clamp	Hyperglycemic clamp administered to measure glucose levels. Data represented is the number of participants the clamp was used on successfully.	upon enrollment

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Janice Hwang, MD, Section of Endocrinology

Publications and helpful links

General Publications

• Sanchez-Rangel E, Gunawan F, Jiang L, Savoye M, Dai F, Coppoli A, Rothman DL, Mason GF, Hwang JJ. Reversibility of brain glucose kinetics in type 2 diabetes mellitus. Diabetologia. 2022 May;65(5):895-905. doi: 10.1007/s00125-022-05664-y. Epub 2022 Mar 5.

Study record dates

Study Major Dates

• Study Start (Actual): January 18, 2018
• Primary Completion (Actual): March 20, 2020
• Study Completion (Actual): March 20, 2020

Study Registration Dates

• First Submitted: January 11, 2018
• First Submitted That Met QC Criteria: March 16, 2018
• First Posted (Actual): March 19, 2018

Study Record Updates

• Last Update Posted (Estimated): February 5, 2024
• Last Update Submitted That Met QC Criteria: February 1, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperglycemia; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin
• Other Study ID Numbers: 1602017151; 1K23DK109284-01 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes