Microcirculation and Bone Metabolism in Patients With Type 2 Diabetes Mellitus and Charcot Foot - A Pilot Study

NCT02435329 | Completed

• 2 other identifiers: Charcodiab1315/NI/0043
• Study Type: observational
• Target: 31
• Locations: 1 country
• Sites: 1

Brief Summary

This study is part of a research project for a University MD Program. This is an observational study aimed at comparing the differences in bone metabolism and microcirculation in patients with type 2 diabetes mellitus (with and without diabetic neuropathy and Charcot foot) with healthy subjects. Diabetes is gradually becoming a global epidemic along with its associated complications. Diabetes can affect several systems in our body particularly the eyes, nerves and the kidneys. The damaging effects occur at the level of the small blood vessels (microcirculation) that supply these vital structures. Normally, the inner lining of these blood vessels (endothelium) plays a very important role in maintaining adequate blood flow. The endothelium releases a chemical substance called nitric oxide, which relaxes these small blood vessels thereby ensuring sufficient blood supply to these key structures. Nitric oxide also prevents blockage of these vessels. Any form of metabolic stress like hyperglycaemia (raised blood sugar as seen in diabetes) can cause abnormal changes in the normal behaviour of the endothelium (endothelial dysfunction). Therefore hyperglycaemia promotes endothelial dysfunction by lowering nitric oxide levels, which may lead to diabetic complications like diabetic retinopathy (eye damage), nephropathy (kidney damage) or neuropathy (nerve damage). In addition, patients with diabetes also suffer from osteoporosis (thinning of bones). Osteoporosis is a bone disorder characterised by a reduction in bone mineral content leading to an increased risk of developing fractures. The increased risk of fractures in patients with type 2 diabetes is attributed to poor bone quality resulting from the harmful effects of high blood glucose. Studies have also shown that nitric oxide has a bone protective effect as demonstrated by its ability to prevent bone fragmentation and improve bone strength. Study of markers of endothelial function and bone metabolism will facilitate a better understanding about the origin of diabetic complications. This will aid in the development of novel therapeutic agents that target the harmful triggers in diabetes and eventually may prevent and retard the onset of the debilitating diabetic complications.

Conditions

Diabetic Angiopathies; Bone Diseases, Metabolic

Outcome Measures

Primary Outcomes (4)

• Impaired endothelial function in patients with type 2 DM with/ without diabetic neuropathy and Charcot foot compared to their healthy counterparts as measured by:

  Endothelial-dependent and independent vasodilatations

  At baseline

• Impaired endothelial function in patients with type 2 DM with/ without diabetic neuropathy and Charcot foot compared to their healthy counterparts as measured by:

  Markers of endothelial activation, which include adhesion molecules like ICAM, VCAM and inflammatory molecules.

  at baseline

• Impaired endothelial function in patients with type 2 DM with/ without diabetic neuropathy and Charcot foot compared to their healthy counterparts as measured by:

  Serum Nitric oxide

  at baseline

• Impaired endothelial function in patients with type 2 DM with/ without diabetic neuropathy and Charcot foot compared to their healthy counterparts as measured by:

  Advanced glycation end-products

  at baseline

Secondary Outcomes (2)

• Impaired bone metabolism in patients with type 2 DM with/ without diabetic neuropathy and Charcot foot compared to their healthy counterparts as assessed by:

  At baseline

• Impaired bone metabolism in patients with type 2 DM with/ without diabetic neuropathy and Charcot foot compared to their healthy counterparts as assessed by:

  At baseline

Study Arms (5)

Healthy volunteers

10 healthy volunteers * Anthropometric measures: Height, weight, BMI, waist circumference * Vital parameters: supine and standing blood pressure, pulse, respiratory rate and temperature * Laboratory assessment that includes markers of endothelial activation, inflammation and bone metabolism. * Assessment of skin microcirculation with Laser Doppler Iontophoresis * Assessment of calcaneal bone mineral density (BMD) with Bone Sonometer (ultrasound) * Advanced glycation end-products will be assessed by an AGE reader which uses the technique of skin autofluorescence

Other: Baseline comparison of microcirculation and bone metabolism

Type 2 diabetes without neuropathy

10 patients * Anthropometric measures: Height, weight, BMI, waist circumference * Vital parameters: supine and standing blood pressure, pulse, respiratory rate and temperature * Laboratory assessment that includes markers of endothelial activation, inflammation and bone metabolism. * Assessment of skin microcirculation with Laser Doppler Iontophoresis * Assessment of calcaneal bone mineral density (BMD) with Bone Sonometer (ultrasound) * Advanced glycation end-products will be assessed by an AGE reader which uses the technique of skin autofluorescence

Other: Baseline comparison of microcirculation and bone metabolism

Type 2 diabetes with painful neuropathy

10 patients * Anthropometric measures: Height, weight, BMI, waist circumference * Vital parameters: supine and standing blood pressure, pulse, respiratory rate and temperature * Laboratory assessment that includes markers of endothelial activation, inflammation and bone metabolism. * Assessment of skin microcirculation with Laser Doppler Iontophoresis * Assessment of calcaneal bone mineral density (BMD) with Bone Sonometer (ultrasound) * Advanced glycation end-products will be assessed by an AGE reader which uses the technique of skin autofluorescence

Other: Baseline comparison of microcirculation and bone metabolism

Type 2 diabetes with painless neuropathy

10 patients * Anthropometric measures: Height, weight, BMI, waist circumference * Vital parameters: supine and standing blood pressure, pulse, respiratory rate and temperature * Laboratory assessment that includes markers of endothelial activation, inflammation and bone metabolism. * Assessment of skin microcirculation with Laser Doppler Iontophoresis * Assessment of calcaneal bone mineral density (BMD) with Bone Sonometer (ultrasound) * Advanced glycation end-products will be assessed by an AGE reader which uses the technique of skin autofluorescence

Other: Baseline comparison of microcirculation and bone metabolism

Type 2 diabetes with Charcot foot

10 patients * Anthropometric measures: Height, weight, BMI, waist circumference * Vital parameters: supine and standing blood pressure, pulse, respiratory rate and temperature * Laboratory assessment that includes markers of endothelial activation, inflammation and bone metabolism. * Assessment of skin microcirculation with Laser Doppler Iontophoresis * Assessment of calcaneal bone mineral density (BMD) with Bone Sonometer (ultrasound) * Advanced glycation end-products will be assessed by an AGE reader which uses the technique of skin autofluorescence

Other: Baseline comparison of microcirculation and bone metabolism

Interventions

Baseline comparison of microcirculation and bone metabolism OTHER

Baseline comparison of microcirculation and bone metabolism among the 5 different groups

Healthy volunteers; Type 2 diabetes with Charcot foot; Type 2 diabetes with painful neuropathy; Type 2 diabetes with painless neuropathy; Type 2 diabetes without neuropathy

Eligibility Criteria

• Age: 40 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

40 patients with type 2 diabetes mellitus will be considered eligible for the study. Patients with a previous diagnosis of type 2 diabetes mellitus and newly diagnosed type 2 DM seen at Tameside Hospital will be recruited into the study. In addition, eligible patients will be identified and referred from University Hospital of South Manchester (UHSM) and appropriate GP practices (from Oldham, Tameside and Wythenshawe). Source of healthy controls: Hospital staff and spouses/ partners of patients will volunteer as healthy subjects.

You may qualify if:

• Subjects aged between 40-75 years
• Healthy subjects or non-diabetic subjects for the control group.
• A diagnosis of type 2 DM based on one of the following criteria (ADA - 2010):
• Fasting plasma glucose (FPG) ≥ 126 mg/dL (7.0 mmol/L) or
• h plasma glucose ≥ 200 mg/dl (11.1 mmol/L) during an OGTT or
• Classic symptoms of hyperglycaemia or hyperglycaemic crisis with a random plasma glucose ≥ 200 mg/dL (11.1 mmol/L).
• Patients on treatment for type 2 diabetes mellitus
• Presence of diabetic neuropathy will be confirmed when 2 of the following neurological tests are positive on examination (vibration perception threshold, 10 gm. monofilament, 128 Hz tuning fork, ankle reflex, pin-prick)
• Painful diabetic neuropathy diagnosed according to LANSS (Leeds Assessment of Neuropathic Symptoms and Signs) scoring
• For patients with chronic Charcot foot, the diagnosis should be confirmed by clinical judgment and by radiologic examination - X-ray, technetium-labeled bisphosphonate bone scan or MRI)

You may not qualify if:

• At screening, age below 40 years and above 75 years.
• Type 1 diabetes mellitus (patients with a history of ketoacidosis, age of onset of DM before 25 years of age, BMI \<21 kg/m2 and use of insulin without a concomitant oral hypoglycemic agent)
• Major cardiovascular complications within 3 months prior to screening
• Recent history of smoking within the last 6 months
• Scars, tattoos or rashes over the forearm
• Recent or current oral steroid therapy or topical steroids applied to the forearm
• Patients with uncontrolled hypertension (systolic blood pressure \[SBP\] \> 160/90 mmHg) or hypotension (SBP ≤ 100 mm Hg or a diastolic BP of ≤60 mm Hg) at screening.
• History of general systemic illness including cardiac, hepatic or renal insufficiency
• Patients with renal insufficiency characterized by a creatinine clearance of less than 60 ml/min or a serum creatinine of more than 130 μmol/l
• Receiving treatment for inflammatory disease or malignancy
• Other non-diabetic causes of neuropathy
• History of chronic alcohol consumption
• History of metabolic bone disorders (Osteoporosis, Paget's disease, etc.) or treatment for bone disorders (past or current treatment for osteoporosis, bisphosphonate therapy within the last 3 years)
• History of malignancy
• History of active foot ulcers

Sponsors & Collaborators

• Tameside General Hospital: lead
• Manchester Metropolitan University: collaborator

Study Sites (1)

Tameside Hospital NHS Foundation Trust

Ashton-under-Lyne, Greater Manchester, OL6 9RW, United Kingdom

Location

Related Publications (6)

• Mascarenhas JV, Jude EB. Pathogenesis and medical management of diabetic Charcot neuroarthropathy. Med Clin North Am. 2013 Sep;97(5):857-72. doi: 10.1016/j.mcna.2013.05.002.

  PMID: 23992897 BACKGROUND

• Hofbauer LC, Brueck CC, Singh SK, Dobnig H. Osteoporosis in patients with diabetes mellitus. J Bone Miner Res. 2007 Sep;22(9):1317-28. doi: 10.1359/jbmr.070510.

  PMID: 17501667 BACKGROUND

• Vestergaard P. Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes--a meta-analysis. Osteoporos Int. 2007 Apr;18(4):427-44. doi: 10.1007/s00198-006-0253-4. Epub 2006 Oct 27.

  PMID: 17068657 BACKGROUND

• Wimalawansa SJ. Nitric oxide: new evidence for novel therapeutic indications. Expert Opin Pharmacother. 2008 Aug;9(11):1935-54. doi: 10.1517/14656566.9.11.1935.

  PMID: 18627331 BACKGROUND

• Roberts AC, Porter KE. Cellular and molecular mechanisms of endothelial dysfunction in diabetes. Diab Vasc Dis Res. 2013 Nov;10(6):472-82. doi: 10.1177/1479164113500680. Epub 2013 Sep 3.

  PMID: 24002671 BACKGROUND

• Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007 Jan;87(1):315-424. doi: 10.1152/physrev.00029.2006.

  PMID: 17237348 BACKGROUND

Biospecimen

Retention: SAMPLES WITHOUT DNA

Analysis of serum samples for markers of endothelial function, inflammation and bone metabolism

MeSH Terms

Conditions

Diabetic Angiopathies; Bone Diseases, Metabolic

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus; Endocrine System Diseases; Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Edward Jude, MD, MRCP

  Tameside Hospital NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: OTHER
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 27, 2015
• First Posted: May 6, 2015
• Study Start: June 1, 2015
• Primary Completion: November 1, 2016
• Study Completion: November 1, 2016
• Last Updated: September 16, 2019

Record last verified: 2019-09

Locations

GB (1)