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OBJECTIVE A subset of people with long-standing type 1 diabetes (T1D) appears to be protected from microvascular and macrovascular complications. Previous studies have focused on improved abilities to respond to glucose and its downstream effects as protective mechanisms. It is unclear whether lipoproteins play a role in the vascular health of these people. We therefore determined whether HDL particle concentration, size, function, and/or protein composition associate with protection from vascular complications. RESEARCH DESIGN AND METHODS We studied two independent cross-sectional cohorts with T1D: the T1D Exchange Living Biobank (n = 47) and the Joslin Medalist Study (n = 100). Some of the subjects had vascular complications, whereas others never exhibited vascular complications, despite an average duration of diabetes in the cohorts of 45 years. We assessed HDL particle size and concentration by calibrated ion mobility analysis, the HDL proteome by targeted mass spectrometry, and HDL function ex vivo by quantifying cholesterol efflux capacity and inhibition of monocyte adhesion to endothelial cells. RESULTS In both cohorts, people without vascular complications exhibited significantly higher concentrations of medium-sized HDL particles (M-HDL) independently of total and HDL cholesterol levels. While no consistent differences in HDL functions were observed ex vivo, people without vascular complications had higher levels of HDL-associated paraoxonase 1 (PON1), an enzyme that inhibits atherosclerosis in animal models. CONCLUSIONS Elevated concentrations of M-HDL particles and elevated levels of HDL-associated PON1 may contribute to long-term protection from the vascular complications of diabetes by pathways that are independent of total cholesterol and HDL cholesterol.

OBJECTIVE Elevated glycolytic enzymes in renal glomeruli correlated with preservation of renal function in the Medalist Study, individuals with ≥50 years of type 1 diabetes. Specifically, pyruvate kinase M2 (PKM2) activation protected insulin-deficient diabetic mice from hyperglycemia-induced glomerular pathology. This study aims to extend these findings in a separate cohort of individuals with type 1 and type 2 diabetes and discover new circulatory biomarkers for renal protection through proteomics and metabolomics of Medalists’ plasma. We hypothesize that increased glycolytic flux and improved mitochondrial biogenesis will halt the progression of diabetic nephropathy. RESEARCH DESIGN AND METHODS Immunoblots analyzed selected glycolytic and mitochondrial enzymes in postmortem glomeruli of non-Medalists with type 1 diabetes (n = 15), type 2 diabetes (n = 19), and no diabetes (n = 5). Plasma proteomic (SOMAscan) (n = 180) and metabolomic screens (n = 214) of Medalists with and without stage 3b chronic kidney disease (CKD) were conducted and significant markers validated by ELISA. RESULTS Glycolytic (PKM1, PKM2, and ENO1) and mitochondrial (MTCO2) enzymes were significantly elevated in glomeruli of CKD− versus CKD+ individuals with type 2 diabetes. Medalists’ plasma PKM2 correlated with estimated glomerular filtration rate (r2 = 0.077; P = 0.0002). Several glucose and mitochondrial enzymes in circulation were upregulated with corresponding downregulation of toxic metabolites in CKD-protected Medalists. Amyloid precursor protein was also significantly upregulated, tumor necrosis factor receptors downregulated, and both confirmed by ELISA. CONCLUSIONS Elevation of enzymes involved in the metabolism of intracellular free glucose and its metabolites in renal glomeruli is connected to preserving kidney function in both type 1 and type 2 diabetes. The renal profile of elevated glycolytic enzymes and reduced toxic glucose metabolites is reflected in the circulation, supporting their use as biomarkers for endogenous renal protective factors in people with diabetes.

Context Cognitive dysfunction is a growing and understudied public health issue in the aging type 1 diabetic population and is difficult and time-consuming to diagnose. Studies in long duration type 1 diabetes have reported the presence of proliferative diabetic retinopathy was associated with cognitive dysfunction. Objective This study assessed whether structural and vascular abnormalities of the retina, representing an extension of the central nervous system, are associated with cognitive impairment and other complications of type 1 diabetes. Methods An observational cross-sectional study of individuals with 50 or more years of type 1 diabetes (Joslin Medalist Study) was conducted at a university hospital in the United States. The study included 129 participants with complete cognitive testing. Validated cognitive testing measures included psychomotor speed, and immediate, and delayed memory. Optical coherence tomography (OCT) and OCT angiography (OCTA) were performed to obtain neural retinal layer thicknesses and vascular density for superficial (SCP) and deep retinal capillary plexus (DCP). Multivariable modeling was adjusted for potential confounders associated with outcomes in unadjusted analyses. Results Decreased vessel density of the SCP and DCP was associated with worse delayed memory (DCP: P = .002) and dominant hand psychomotor speed (SCP: P = .01). Thinning of the retinal outer nuclear layer was associated with worse psychomotor speed both in nondominant and dominant hands (P = .01 and P = .05, respectively). Outer plexiform layer thickness was associated with delayed memory (P = .04). Conclusion These findings suggest that noninvasive retinal imaging using OCT and OCTA may assist in estimating the risks for cognitive dysfunction in people with type 1 diabetes.

In the Joslin Medalist Study (“Medalists”), which enrolled people with ≥50 years of type 1 diabetes (T1D), factors have been shown to individually protect against vascular complications, such as proliferative retinopathy (PDR), and possibly, cardiovascular disease (CVD). However, shared protective factors against these disease outcomes have not been demonstrated. Recently, Medalists underwent cardiac computed tomography (CT; n=67) and cardiac magnetic resonance imaging (CMR; n=54) for assessment of coronary artery calcification (CAC) and myocardial and aortic structure and function, respectively; as well as optical coherence tomography angiography for assessment of superficial (SCP) and deep (DCP) retinal capillary plexus density (n=28 eyes). In this cohort, CAC severity was associated with self-reported CVD history (p=0.04). CAC>200 was associated with PDR (p=0.03) and with lower density of both SCP (p=0.002) and DCP (p=0.047). Among the CMR parameters, lower ascending aortic distensibility, indicating higher stiffness, was found among participants with PDR (p=0.009), and was also associated with lower SCP density (p=0.037). Meanwhile, measures of myocardial strain (longitudinal, circumferential, and radial) were significantly lower in women and in those with CAC>200 (all p200 were also less likely to be female (p=0.02). The common association of CAC and aortic stiffness with PDR and SCP density suggests that protective markers of progression to angiogenesis (PDR) may have similarities with those protecting against coronary calcification and aortic dysfunction. Furthermore, the results highlight the important relationship between CAC, gender, and myocardial biomechanics in Medalists. Future proteomic and metabolomic studies using circulatory and retinal biosamples could be helpful in identifying common factors that can delay the onset of CVD and PDR. Disclosure M. Yu: None. H. Shah: None. E. Wolfson: None. V. Bahnam: None. J. Gauthier: None. Q. Cai: None. V. Jha: None. C. Tsao: None. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc. Funding American Diabetes Association (9-18-CVD1-005 to M.G.Y.); Thomas J. Beatson, Jr. Foundation (2185, 20008, 2800200)

Early cognitive decline, a dreaded complication of diabetes, is difficult and time consuming to diagnose. The Joslin Medalist Study, comprising individuals with ≥50 years of type 1 diabetes (T1D), reported that cognitive dysfunction was greater in T1D patients as compared to age-matched nondiabetic controls and was associated with proliferative diabetic retinopathy (PDR). We examined a larger Medalist sample to determine whether cognitive dysfunction is correlated with specific structural and vascular abnormalities in the retina, which embryonically is an extension of the central nervous system. Retinal imaging techniques such as optical coherence tomography (OCT) and OCT angiography (OCTA) can quantitate structural changes in individual retinal layers and the superficial and deep capillary plexus of the retinal microvasculature. We assessed Medalists (n=110) who underwent cognitive testing consisting of 5 validated measures in the following domains: executive functioning (EF), motor skills (MS), and immediate (IM), delayed (DM) and working memory (WM). Thinning of the neuroretinal ganglion cell layer (β: 0.69, P: 0.02) and inner plexiform layer (β: 0.56, P: 0.01) was associated with worse EF. PDR was associated with worse cognitive function (MS, dominant hand: OR: 1.02, P: 0.01; MS, non-dominant hand: OR: 1.01, P: 0.02; EF: OR: 0.83, P: 0.03) and decreased superficial retinal capillary plexus density (p=0.001). Decreased vessel density of the deep capillary plexus was associated with worse cognitive function including DM (β: 0.10, P: 0.01), IM (β: 0.10, P: 0.02), MS (dominant β: -0.07, P: 0.01; non-dominant β: -0.04, P: 0.03), even after adjusting for DR severity, T1D duration and visual acuity. These findings suggest that noninvasive ocular imaging techniques have potential to identify T1D individuals with early cognitive impairment, and provide insights into pathophysiological connections between cognitive function, diabetes and microvascular complications. Disclosure S.M. Paniagua: None. W. Fickweiler: None. V. Bahnam: None. K. Sampani: None. I. Wu: None. H. Shah: None. G. Musen: None. L.P. Aiello: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Decision Resources Group, KalVista Pharmaceuticals, Inc., Mingsight, Retinal Solutions. Stock/Shareholder; Self; KalVista Pharmaceuticals, Inc. Other Relationship; Self; Optos. J.K. Sun: Research Support; Self; Adaptive Sensory Technology, Boston Micromachines Corporation, Genentech, Inc., KalVista Pharmaceuticals, Inc., Optovue, Incorporated. Other Relationship; Self; Genentech, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc. G.L. King: Research Support; Self; Sanofi. Funding National Institute of Diabetes and Digestive and Kidney Diseases (P30DK036836, UL1RR025758-03, R24283DK083957-01, DP3DK094333-01, T32DK007260); JDRF (17-2013-310); Thomas J. Beatson, Jr. Foundation Inc.

The Joslin 50-Year Medalist Study discovered that elevated photoreceptor-secreted Retinol Binding Protein 3 (RBP3) in the retina and vitreous of individuals with extreme duration of type 1 diabetes is associated with long-term protection from advanced diabetic retinopathy (DR), independent of glycemic control. This represents the first neuroretinal protein identified with potential protective activity against the toxic effects of hyperglycemia on the retinal vasculature, a major cause of DR onset and worsening. We extended these findings by correlating vitreous and serum RBP3 concentrations and examining associated clinical characteristics. We developed a novel RBP3 ELISA assay with high sensitivity (0.1-1 nM), specificity (no detection of immunoglobulin G, albumin, or RBP4), and intra-and inter-assay correlations (p Disclosure W. Fickweiler: None. H. Yokomizo: None. K. Park: None. S.M. Paniagua: None. I. Wu: None. D.M. Pober: None. V. Bahnam: None. A. Clermont: Consultant; Self; KalVista Pharmaceuticals, Inc. L.P. Aiello: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Decision Resources Group, KalVista Pharmaceuticals, Inc., Mingsight, Retinal Solutions. Stock/Shareholder; Self; KalVista Pharmaceuticals, Inc. Other Relationship; Self; Optos. J.K. Sun: Research Support; Self; Adaptive Sensory Technology, Boston Micromachines Corporation, Genentech, Inc., KalVista Pharmaceuticals, Inc., Optovue, Incorporated. Other Relationship; Self; Genentech, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc. G.L. King: Research Support; Self; Sanofi. Funding National Eye Institute (R01EY026080-01); National Institute of Diabetes and Digestive and Kidney Diseases (DP3DK094333-01); JDRF (17-2013-310); Thomas J. Beatson, Jr. Foundation Inc.; Dianne Nunnally Hoppes Scholarship Fund