Medalist Study Updates

50-Year Medalist Update

Fall 2012

            Greetings from Joslin Diabetes Center’s 50-Year Medalist Program!  As we have now completed the seventh year of the Medalist Study, we are learning a lot from you and your spouses, who generously serve as controls.  We hope that you are having a relaxing and enjoyable summer so far.  We have been busy with our research and expanding our focus into new and exciting areas related to long duration type 1 diabetes.

            In June, we attended the annual American Diabetes Association Scientific Sessions in Philadelphia, Pennsylvania.  While there, we presented a number of different topics related to the Medalist Study.  The abstracts for these presentations are attached.

·         Dr. Hillary Keenan gave a presentation on the correlation of biochemical markers of disease and post-mortem histology in the 50-Year Medalist Study participants.  Key findings included disease-free kidneys despite long-term diabetes and that clinical markers of kidney disease should be further validated before invasive treatment. 

·         Dr. Susan Bonner-Weir presented data documenting insulin-positive cells in every pancreas donated by deceased Medalists – a total of 28 pancreases – even if there was no measureable level when the individual was alive.  This work shows that insulin-positive cells can persist in long-term diabetes, even in the absence of measureable circulating C-peptide.

·         Dr. Shweta Bhatt and Dr. Adrian Teo presented work on induced pluripotent stem cells from Medalists’ post-mortem skin samples. These cells are capable of differentiating into different types of tissue.  This research will help us understand why Medalist cells respond differently than others in hyperglycemic environments.

·         Stephanie Hastings and Sara Turek spoke on sexual dysfunction in male Medalists.  Sara and Stephanie found a significant association between cardiovascular disease, the inflammatory marker IL-6, and sexual dysfunction, independent of age and body mass index.  These findings indicate that dysfunction may be a marker of cardiovascular disease in the Medalists.

·         Dr. Abumere Akinwale from the Beetham Eye Clinic at Joslin demonstrated that those Medalists who did not develop diabetic retinopathy also did not experience diminished eyesight with age, suggesting that long-term protection from advanced eye disease may begin early in diabetes.

As an example of the useful information derived from your updated health information, a very small proportion (2%) of you have reported a decreased bone mineral density, which is highly unusual in a diabetic population.  As such, if you have had a bone mineral density scan (also known as a DXA scan) in the past year, we would appreciate it if you would send us a copy.  Please contact us for additional information.

Additionally, if you are planning to have cataract surgery in the near future, we are currently examining small amounts of vitreous material from the eye that is usually discarded during cataract surgery.  These samples help us to determine whether the factors we suspect offer protection against retinopathy really help.  If you are willing to donate some of this material from your surgery, please contact us for further information and an explanation of the process.

            In other news, we are already looking ahead to Spring of 2013 and our next Joslin Medalist Celebration.  Our 2011 Celebration had a record 96 Medalists attend, and we hope to match or exceed that number next year. We are still in the early stages of planning, but it is likely that next year’s celebration will include attending a Boston Pops concert, a presentation of our most up-to-date research, and the opportunity to meet other Medalists from around the country.  Please “save-the-date” for May 10 and 11, 2013.  Watch the mail for more information to follow, and keep in mind that our space is limited, so be sure to RSVP when you receive the invitation!

            Feel free to visit our Joslin Facebook page (www.facebook.com/joslindiabetes) and our Medalist webpage (www.joslin.org/joslin_medalist_program.html) to stay in touch. 

Very best regards,

Dr. George King, Dr. Hillary Keenan, Sara Turek, and Stephanie Hastings

50-Year Medalist Team

Recent Abstracts from the 50-Year Medalist Study

Correlation of Renal Physiology and Pathology in Deceased Donor Kidneys Following 50-Years of Type 1 Diabetes (T1DM): 50-Year Medalist Study

Hillary A. Keenan, Isaac E. Stillman, Stephanie Hastings, Sara Turek, Robert C. Stanton, Jennifer K. Sun, George L. King.

The 50-Year Medalist Study has characterized renal function and pathology of 22 Medalist donors to document the extent of glomerulopathy after 50+ y of T1DM. This study examines individuals (n=685, male=48.7%, duration=58.6±6.6 y age=69.7±8.5 y) with 50+ y of T1DM by clinical exam and extensive medical history and has found low rates of microvascular complications including microalbuminuria (11.8%; ACR >30 mcg/mg) and chronic kidney disease (4.28%; CKD >4: CKD-EPI). Whole kidneys were procured post-mortem from 22 Medalists and classified by an experienced nephropathologist into diabetic nephropathy (DN) class using the method of Tervaert et al (JASN 2010) by degree of mesangial expansion (0+I, IIa+b) and presence of Kimmelstiel-Wilson lesions (III) (n=6, class 0+I; 8, class IIa; 3, class IIb; 5, class III). Surprisingly, 28% of these longstanding T1DM patients had no to only mild, nonspecific changes by light and electron microscopy (Class 0+I) even though 33% of these had co-existing proliferative diabetic retinopathy (PDR). There were no differences in sex, A1c, age, duration, age at diagnosis, BMI, lipids or c-peptide across DN classes (p>0.05). Mean eGFRs declined across class, 0+I: 58.5±27.2; IIa: 53.8 ±13.0, IIb: 47.7 ±6.5, III: 35.0±18.2 mL/min/1.73m². However, ACR did not consistently increase across the classes: 0+I: 18.0 ±10.9, IIa: 17.8 ±16.2, IIb: 142.4±179.3, III: 1016.4 ±1743.6 mcg/mg. Two of the 22 cases were positive for IgA; 10 had score 1 tubulo-interstitial scarring, 11 had score 2 and 1 had score 3. Medalists’ kidneys classified in class 0+1 demonstrate that it is possible to have normal glomerular morphology even after 50+ y of T1DM. The presence of PDR in the Class 0+1 group indicates protective factors for diabetic kidney disease may differ from those of the retina. Finally, greater use of the kidney biopsy in diabetic patients with normal ACR and low GFR might provide unexpected diagnoses and new pathophysiologic insights.

Sexual Dysfunction as a Marker of CVD in Males with 50 or More Years of Type 1 Diabetes

Sara Turek, Stephanie Hastings, Jennifer K. Sun, George L. King, Hillary A. Keenan.

Increasing rates of diabetes and associated cardiovascular (CV) complications have a substantial adverse effect on quality of life and financial burden on the healthcare system. There is increasing evidence that sexual dysfunction may be a predictor of increased cardiometabolic risk in aging men. The goal of this analysis was to investigate the association of sexual dysfunction with clinical markers of vascular disease among males using data from the 50 Year Medalist Study who have documented 50+ years of type 1 diabetes. Males (48.8%, n=316/658) in this group had mean age of 71.3 (±8.41) y, mean diabetes duration of 59.1 (±7.22) y, mean BMI of 26.3 (±3.74) kg/m2 and mean HbA1c of 7.04% (±0.89). Prevalence of sexual dysfunction was characterized by a “yes” response to the question: “Have you ever had sexual problems?”(69.8%). Risk factors associated with sexual dysfunction included elevated HbA1c (7.1± 0.9% v. 6.8 ±0.8%, p<0.001), BMI (26.7 ±3.9 v. 25.2 ±3.1 kg/m2, p=0.02), higher total cholesterol (159.9 ±31.8 v. 150.1 ±30.6 mg/dL, 0.02), and lower HDL (54.9 ±16.1 v. 61.7 ±17.4 mg/dL, p<0.01). Age and duration (71.4 ±8.1 v. 71.2 ±9.1 y, p=0.7; 59.3 ±7.8 v. 59.0 ±7.0 y, p=1.0, respectively) were not associated with dysfunction. In this group, sexual dysfunction was not significantly associated with any microvascular complication (p>0.05); however, dysfunction was associated with CVD OR: 1.7 (95% CI:1.02, 2.7) independent of age (CV OR adjusted for age 1.7 (1.02, 2.8)) and BMI (CV OR adjusted for BMI 2.3 (1.1, 4.6)). Congruent with its association with CV, levels of inflammatory markers including IL-6 (median 0.1 [Q2 0.06, Q3 0.3] v. 0.09 [0.04, 0.19] pg/mL, p=0.03) and PAI-1 (204.1 [ 106.4, 246.5] v. 160.0 [99.0, 203.5], pg/mL p=0.08) were also higher in those reporting dysfunction. These findings indicate that sexual dysfunction may be a marker for CV in those with extreme duration diabetes. This finding is of clinical importance as sexual dysfunction is a more overt sign of CV risk than clinical markers of the disease.

50-Year Medalist Study: Pattern of Insulin Positive Cells and its Correlation with C-peptide Levels and Age at Onset

Susan Bonner-Weir, Hillary A. Keenan, Brooke Morris, Stephanie Hastings, Sara Turek, Jennifer K. Sun, George L. King.

The Medalist Study provides a unique opportunity to compare physiological factors and post-mortem pancreatic morphology of T1DM patients with >50 years duration. We studied 21 Medalist pancreases and all were found to have insulin positive beta cells. The distribution and quantity of insulin positive cells were categorized as: C1) few scattered singlet or clusters (n=6), C2) similarly scattered with additional occasional insulin positive cells within islets (n=11) and C3) at least 30% of the islets having significant number of insulin positive cells (n=4). Most islets in Medalists were atrophic comprised mainly of glucagon positive cells; some scattered glucagon cells were in or near ducts. Clinical data was analyzed across categories, only age of onset and c-peptide levels were significantly different (p ≤ 0.01). Those in C1 were the youngest at onset (3.8±2.0 y) and had the lowest c-peptide (0.07±0.07 ng/dl) while those in C2 had a mean age at onset of 9.3±7.1 y and a c-peptide of 0.21±0.01 ng/dl, and C3 had a later onset at 25.3±6.3 y and a higher c-peptide level, 2.2±2.2 ng/dl. All but 2 (in C2) had high risk DR3 and/or DR4 alleles. Antibody positivity (IA2 or GAD65) spanned categories with 2 in C1, 4 in C2 and 1 in C3. C3 had the most diverse morphology: 2 having at least half the pancreas with few scattered insulin positive cells and no islets with insulin positive cells and the rest of the pancreas having islets composed of at least 30% insulin positive cells and many with amyloid deposits. One of these was IA2+.

Analysis of the Medalist cohort (n=659) by categories defined by mean c-peptide level of C1, C2 and C3 showed a similarly significant increase in age at onset (p=0.04). Insulin positive cells persist in very long-term diabetes even in the absence of measurable c-peptide and a greater number of insulin positive cells correlates with higher c-peptide and later onset of disease. Beta cells persisted as scattered singlets more commonly than islets in T1DM patients of extreme duration.

Derivation of Induced Pluripotent Stem Cells from Patients with Greater Than 50 Years Duration of Type 1 Diabetes

Shweta Bhatt, Adrian K. Teo, Susana Silva, Chong Wee Liew, Dan Kawamori, Rebecca Windmueller, Hillary A. Keenan, George L. King, Amy J. Wagers, Rohit N. Kulkarni.

Type1 diabetes (T1D) is an autoimmune disorder characterized by the loss of insulin-producing β-cells. At Joslin, a cohort of patients who survived ≥50 years of T1D (“medalists”), with or without complications presented a unique opportunity to study mechanisms underlying the disease. The impetus for the study came from observation that serum from several medalists tested positive for C-peptide, and autopsied pancreases from 9 patients showed insulin+ β-cells, suggesting unique mechanism(s) protecting these β-cells and preventing some Medalists from developing complications. To investigate pathways protective towards the β-cells and underlying mechanisms for diabetic complications we obtained skin fibroblasts from medalists or age-matched controls and subjected them to in vitro reprogramming using excisable polycystronic lentivirus expressing OCT4, SOX2, KLF4 and c-MYC to induce pluripotent stem cells (iPSCs). Although reprogramming was normal in both groups, evidenced by positive staining for early (Alkaline phosphatase), intermediate (OCT4, NANOG, SOX2, SSEA4) and late (Tra1-60 and 1-81) markers of pluripotency, we observed significantly compromised efficiency in establishing iPSCs from medalists, both with (0.002%) and without (0.004%) complications, as compared to age-matched controls (0.02%) [p<0.001; n=3-5]. Intriguingly, medalist iPSCs also exhibited striking morphological differences and reduced proliferation rates (20% of controls, n=5). Further, iPSCs derived from medalists with complications demonstrated impaired spontaneous differentiation potential (10%), unlike the iPSCs from controls (90%) or from medalists without complications (70%) [p<0.001]. These data suggest that unique cellular mechanisms regulate the growth and differentiation of iPSCs from medalists, alterations in which, through genetic manipulation or in vitro disease modeling, may enable the discovery of novel therapeutics to reduce the burden of T1D.

Slow Progression of Diabetic Retinopathy (DR) in Patients with 50 or More Years of Type 1 Diabetes

Abumere Akinwale, Jennifer K. Sun, Hillary A. Keenan, Lloyd P. Aiello, George L. King.

Over 40% of patients with type 1 diabetes (DM) for >50 years (Medalists) have no-mild nonproliferative DR (NPDR) even after five or more decades of hyperglycemia. An important question with mechanistic implications is whether this long term protection from advanced DR is due to slowed DR progression or regression from more severe DR levels. We evaluated 158 Medalists (316 eyes) with longitudinal follow-up at Joslin Diabetes Center (mean+SD follow-up: 16±13 yrs; 27±33 total visits) by retrospective chart review. Evaluation of all available standard care ETDRS protocol fundus photographs was performed for eyes with moderate or severe NPDR that did not progress to PDR (N = 43) to document DR regression or progression. The Medalists had a mean age of 10±6yrs at diagnosis, 58±6yrs DM duration and current hemoglobin A1c (A1c) of 7.2±0.9%. In eyes with PDR, worse current renal function (p=0.003), older current age (p=0.0002), shorter DM duration (p < 0.0001) and higher current A1c (p=0.03) were significantly related to faster progression to PDR, but of these, only worse current renal function (p=0.003) was related to PDR as an outcome in the whole group. Eyes without baseline DR that did not progress to PDR (N=152) had a slower rate of DR worsening than eyes that progressed to PDR (N=61, p<0.001), and once a patient reached 20yrs of DM, only 2 eyes worsened from baseline thereafter. In eyes with moderate or severe NPDR that did not progress to PDR, regression of some DR lesions (hemorrhages, microaneurysms, hard exudates and cotton wool spots) was evident over time, but there was not substantial (>2 steps on the clinical ETDRS scale) regression of DR severity in any eye. These results suggest that Medalists protected from PDR have slow DR onset and/or progression rather than increased DR regression and are unlikely to experience DR worsening after 20 years of DM. Thus, protective factors may exist in some Medalists that ameliorate hyperglycemia-induced retinal pathology and prevent progression to neovascular DR.