Clinical trial NCT02662010: The Relationship Between Advanced Glycation Endproducts and Diabetes
Official title: The Relationship of Advanced Glycation Endproducts in the Anterior Lens Capsule to Glycemic Status and Diabetic Retinopathy: A Cross Sectional Study of Patients With and Without Type 2 Diabetes Mellitus Undergoing Cataract Surgery
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Diabetic Retinopathy
Type 2 Diabetes Mellitus
Keywords: AGEs
glycemic control
T2DM
Lead sponsor: University of Colorado, Denver
Sponsor class: OTHER
First posted: 2016-01-25
Enrollment: 157
Sex: ALL
Minimum age (years): 60
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The Investigators propose recruiting 80 subjects (40 with no diabetes, 20 with diabetes and no diabetic retinopathy and 20 with diabetes and diabetic retinopathy).

Within the 40 control patients without a clinical diagnosis of T2DM, 20 will have an abnormal HbA1C at the time of surgery. It is important to enroll the patients with an abnormal HbA1C in order to see if there are early manifestations of an abnormal glucose level as detected by AGEs in the anterior lens capsule.

Brief summary: The overall purpose of this COMIRB application is to perform a cross-sectional pilot study to aid in the design of a prospective epidemiologic study for an NIH grant application. The long term goal of this research is to determine if AGEs are predictors of glycemic control and the development of diabetic retinopathy in patients with T2DM. Understanding these relationships could lead to a prospective prediction of the onset/worsening of diabetic retinopathy in T2DM patients and in pre-diabetic individuals.

Detailed description: Below are the specific aims and research hypotheses for the pilot study:

Specific Aim 1: To successfully recruit 80 subjects (40 with no diabetes, 20 with diabetes and no diabetic retinopathy and 20 with diabetes and diabetic retinopathy) and obtain adequate samples (blood and lens capsule) for further testing.

Hypothesis 1:

Recruitment of subjects with and without diabetes and diabetic retinopathy is feasible within our clinic and the process for collecting, processing and storing samples is adequate to support the full study.

Specific Aim 2: To measure anterior lens capsule AGEs and HbA1c levels in recruited patients.

Hypothesis 2:

Levels of AGEs and HbA1c will be quantifiable in collected samples.

The pilot study aims are necessary to determine the feasibility of the full study, as well as to provide estimates of the (1) proportion of non-diabetic subjects with Abnormal HbA1c, (2) effect sizes and (3) variances for planning the full study.

The planned specific aims and research hypotheses for the full study are as follows:

Specific Aim 1: To determine whether anterior lens capsule AGEs differ in patients with and without a clinical diagnosis of T2DM.

Hypothesis 1:

Levels of AGEs will be higher in patients with a clinical diagnosis of T2DM compared with patients without a clinical diagnosis of diabetes.

Specific Aim 2: To determine if levels of AGEs measured from the anterior lens capsule are correlated with levels of Hemoglobin A1c (HbA1c) in patients without T2DM.

Hypothesis 2:

Levels of HbA1c will positively correlate with levels of HbA1c in all patients.

Specific Aim 3: To determine among patients with T2DM if levels of AGEs measured from the anterior lens capsule are higher in the group with diabetic retinopathy compared with the group with no diabetic retinopathy.

Hypothesis 3:

That among patients with T2DM: Levels of AGEs will be higher in the patients with diabetic retinopathy compared with the patients with no diabetic retinopathy.

AGEs are elevated in patients with diabetes (1, 3) and are reported to have a role in diabetic complications. (4, 5) Hyperglycemia results in higher intracellular glucose levels and the formation of metabolites from many complex interactions which in turn increase the production of AGEs. AGEs are a source of reactive oxygen species (ROS) with results in oxidative stress to tissues.(4) As reported, oxidative stress plays an important role in the microvascular and cardiovascular pathologic processed described in T2DM. (6) Importantly, oxidative stress is causal in the development of b cell dysfunction and insulin resistance, the two hallmarks of T2DM. (4)

Eligibility criteria: Inclusion criteria (cases):

* T2DM as documented by the referring physician, an HbA1C level of greater than 5.7 mmol/mol, or on T2DM medications beyond Metformin.
* 50% of the cases will have diabetic retinopathy as documented by the attending ophthalmologist and 50% will have no retinopathy.
* Age 60-80 years old.

Inclusion criteria (controls):

1. Normal HbA1C

   * No diabetes as documented by the referring physician, a HbA1C level of less than or equal to 5.7 mmol/mol, or not taking medications for T2DM with the exception of Metformin.
   * Age 60-80 years old.
2. Abnormal HbA1C

   * No diabetes as documented by the referring physician, a HbA1C level between 5.7 and 6.5 mmol/mol, and not taking medications for T2DM with the exception of Metformin.
   * Age 60-80 years old.

Exclusion criteria (cases):

* Type 1 diabetes as documented by the referring physician.
* \<60 years old or \>80 years old.
* If the patient has bilateral cataract surgery, the second surgery will be excluded
* Patients who have active cancer, being treated (receiving Chemotherapy or Radiation therapy) or disseminated, recent CVD event, MI or CVA within 6 months, and disease related weight loss of more than 10% in the past 3-6 months.

Exclusion criteria (controls):

* Type 1 or T2DM as documented by the referring physician.
* \<60 years old or \>80 years old.
* No treatment with Metformin or modifiers for risk of T1DM
* If the patient has bilateral cataract surgery, the second surgery will be excluded
* Patients who have active cancer, being treated (receiving Chemotherapy or Radiation therapy) or disseminated, recent CVD event, MI or CVA within 6 months, and disease related weight loss of more than 10% in the past 3-6 months.

Primary outcomes:
measure: Change in Advanced Glycation Endproducts (AGE) Levels
timeFrame: 1 year
Secondary outcomes:
measure: Change in HbA1C Levels
timeFrame: 1 year
Other outcomes:
Locations:
city: Aurora
country: United States
facility: Universtiy of Colorado
state: Colorado
Study officials:
affiliation: University of Colorado School of Medicine
name: Ram Nagaraj, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Milne R, Brownstein S. Advanced glycation end products and diabetic retinopathy. Amino Acids. 2013 Jun;44(6):1397-407. doi: 10.1007/s00726-011-1071-3. Epub 2011 Sep 11.
citation: Ulrich P, Cerami A. Protein glycation, diabetes, and aging. Recent Prog Horm Res. 2001;56:1-21. doi: 10.1210/rp.56.1.1.
citation: Yan SF, D'Agati V, Schmidt AM, Ramasamy R. Receptor for Advanced Glycation Endproducts (RAGE): a formidable force in the pathogenesis of the cardiovascular complications of diabetes & aging. Curr Mol Med. 2007 Dec;7(8):699-710.
citation: Nowotny K, Jung T, Hohn A, Weber D, Grune T. Advanced glycation end products and oxidative stress in type 2 diabetes mellitus. Biomolecules. 2015 Mar 16;5(1):194-222. doi: 10.3390/biom5010194.
citation: Monnier VM, Sell DR, Genuth S. Glycation products as markers and predictors of the progression of diabetic complications. Ann N Y Acad Sci. 2005 Jun;1043:567-81. doi: 10.1196/annals.1333.065.
citation: Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010 Oct 29;107(9):1058-70. doi: 10.1161/CIRCRESAHA.110.223545.
citation: Smuda M, Henning C, Raghavan CT, Johar K, Vasavada AR, Nagaraj RH, Glomb MA. Comprehensive analysis of maillard protein modifications in human lenses: effect of age and cataract. Biochemistry. 2015 Apr 21;54(15):2500-7. doi: 10.1021/bi5013194. Epub 2015 Apr 7.