A Causative Role for Amylin in Diabetic Peripheral Neuropathy

Three pieces of information lead to the basis for this study:

1. Individuals with Type-2 diabetes commonly develop peripheral neuropathy.
2. Increased production of the hormone amylin occurs in individuals who have Type-2 diabetes.
3. Aggregations of amylin was found in the peripheral vasculature of rats that overexpressed human amylin.

The purpose of this study is to determine whether a correlation exists between the amount of amylin present in the upper extremities of human subjects with Type-2 diabetes and the extent to which symptoms of peripheral neuropathy are expressed in those subjects. The investigators will be testing this by initially collecting blood and skin biopsy samples from subjects, followed by measuring patient sensation and pain responses to heat, cold, and pressure in the upper extremities.

Study Overview

• Status: Recruiting
• Conditions: Type2 Diabetes; Peripheral Neuropathy

Detailed Description

Impaired blood flow through microvessels (arterioles and capillaries) leads to irreversible damage to cells within the affected watershed. In addition to hypertension and age, Type-2 diabetes (DMII) independently contributes to microvascular disease. Distinct from other diabetic complications, the impact of diabetes on neurovascular function has not clearly been shown to correlate with measures of hyperglycemia or peripheral glucose regulation. The pathophysiology underlying the association between type-2 diabetes, vascular injury and neural damage, including CNS parenchymal loss and PNS neuropathy, remains uncertain.

Normally amylin, a byproduct of the synthesis of insulin by pancreatic β-cells, crosses the blood brain barrier and binds to neurons in feeding centers where it is believed to induce anorexic effects. Amylin aggregates are found in microvessels of pancreas, brain, hearts and kidneys of individuals with DMII or obesity. The investigators have demonstrated amylin aggregates in microvessels of peripheral nerves in rats overexpressing human amylin (unpublished). It is unknown whether amylin deposits are a consequence or a trigger of vascular injury, but they are clearly associated and may present a potential target for reducing diabetes-associated microvascular disease. Furthermore, their accumulation in peripheral nerve microvasculature and red blood cells (RBCs) offers possible foci for a peripheral biomarker of diabetes-induced CNS microvascular disease.

Hypothesis: Patients with DMII have significant amylin deposition in the peripheral vasa nervorum and on RBCs that correlates with severity of clinical peripheral polyneuropathy and reduction of peripheral nerve conduction velocities (NCVs); these amylin measures thereby become surrogates of microvascular disease and may serve as metrics of disease severity.

Aim: Obtain serum HbA1c, skin punch biopsy, RBCs, NCVs and clinical sensory examination from forty consenting adults previously diagnosed with DMII. Skin biopsy from volar forearm and red blood cell samples will be processed for amylin deposition.

This pilot study will provide preliminary data to fuel a larger, potentially multi-center, clinical trial investigating the utility of peripheral amylin or RBC amylin as a quantitative biomarker of microvascular disease that would include monitoring the effect of potential therapies. Measuring serum HbA1c will allow for possible correlation to chronic extracellular glucose concentration. Based on our preliminary data from a rat model of type-2 diabetes that expresses human amylin in the pancreas, the investigators anticipate an increased amylin deposition in the skin blood vessels with the progression of type-2 diabetes as measured by sensory examination and NCVs. Although not directly measured in this study, our preliminary data from the analysis of amylin deposition in cerebral blood vessels of patients with type-2 diabetes suggest that APOE 4 carriers, at risk for developing dementia, may have an increased propensity to accumulate amylin deposits in blood vessels. Thus, the ability to easily identify and target a potential driver of microvascular disease may help prevent the devastating effects of the vascular complications of DMII, including cardiovascular disease, retinopathy, nephropathy and dementia.

• Study Type: Observational
• Enrollment (Estimated): 40

Contacts and Locations

• Study Contact: Name: Rani Priyanka Vasireddy, MBBS, MHA; Phone Number: 859-218-5076; Email: rvasireddy@uky.edu
• Study Contact Backup: Name: John T Slevin, M.D., M.B.A.; Phone Number: 8593236702; Email: jslevin@email.uky.edu

Study Locations

• United States
  • Kentucky
    • Lexington, Kentucky, United States, 40508
      • Active, not recruiting
      • UK Robert Straus Behavioral Science Laboratory
    • Lexington, Kentucky, United States, 40536
      • Recruiting
      • University of Kentucky - Kentucky Neuroscience Institute
      • Contact: Rani Priyanka Vasireddy, MBBS, MHA; Phone Number: 859-218-5076; Email: rvasireddy@uky.edu
      • Contact: John T Slevin, M.D., M.B.A.; Phone Number: 8593236702; Email: jslevin@email.uky.edu
      • Principal Investigator: John T Slevin, MD, Ph.D.
      • Sub-Investigator: Zabeen K Mahuwala, MD
      • Sub-Investigator: Rani Priyanka Vasireddy, MBBS, MHA

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Forty patients, age 18 years or older, with previously diagnosed DMII and referred to the Kentucky Neuroscience Institute Neuromuscular Laboratory for nerve conduction velocity studies (NCVs) will be asked to participate in the study. Because this is a pilot study, every effort will be made to select a broad distribution of male and female patients, regardless of ethnicity, who are mildly to severely symptomatic based on NCVs.

Description

Inclusion Criteria:

• Subject has been diagnosed with Type-2 Diabetes.
• Subject shows mild-to-severe peripheral neuropathy, as determined by Nerve Conduction Velocity (NCV) tests.

Exclusion Criteria:

• Subject has not been diagnosed with Type-2 Diabetes.
• Subject shows average, or above average performance on Nerve Conduction Velocity (NCV) tests.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Red blood cell amylin level vs severity of peripheral neuropathy	RBCs will be harvested from whole blood samples of participants and quantified RBC-bound amylin will be correlated with severity of nerve conduction velocities.	Single time point. Blood sample will be obtained from patient participant immediately after nerve conduction studies are performed.
Blood vessel wall amylin deposition vs severity of peripheral neuropathy	A formalin-fixed 3 mm skin biopsy will be sectioned and stained with an anti-amylin antibody. Level of amylin deposition in blood vessel walls will be correlated with severity of peripheral neuropathy.	Single time point. Skin biopsy will be obtained from patient participant immediately after nerve conduction studies are performed.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pressure pain threshold vs RBC amylin and blood vessel wall amylin deposition	Participants' quantified pain threshold to applied pressure over the thenar eminence using a pressure algometer will be correlated to both RBC amylin and blood vessel wall amylin deposition.	Participants will undergo pressure test 1 week after providing blood and skin biopsy
Cold pressor test vs RBC amylin and blood vessel wall amylin deposition	Participants' quantified pain threshold to a cold water bath (1 deg C) emmersion of their non-dominant forearm will be correlated to both RBC amylin and blood vessel wall amylin deposition.	Participants will undergo cold pressor test 1 week after providing blood and skin biopsy
Heat thermode test vs RBC amylin and blood vessel wall amylin deposition	Participants' quantified pain threshold to a thermode placed on the dominant forearm will be correlated to both RBC amylin and blood vessel wall amylin deposition.	Participants will undergo heat thermode test 1 week after providing blood and skin biopsy

Collaborators and Investigators

• Sponsor: Zabeen Mahuwala, MD
• Investigators: Principal Investigator: John T Slevin, M.D., M.B.A., University of Kentucky Department of Neurology; Principal Investigator: Zabeen Mahuwala, MD, University of Kentucky

Study record dates

Study Major Dates

• Study Start (Actual): February 5, 2018
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: March 1, 2018
• First Submitted That Met QC Criteria: March 26, 2018
• First Posted (Actual): March 29, 2018

Study Record Updates

• Last Update Posted (Estimated): January 26, 2024
• Last Update Submitted That Met QC Criteria: January 24, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Amylin
• Additional Relevant MeSH Terms: Nervous System Diseases; Neuromuscular Diseases; Peripheral Nervous System Diseases
• Other Study ID Numbers: 42732

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No