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To determine the relationship between renal hemodynamic function and neuropathy in adults with ≥50-years of type 1 diabetes (T1D) compared to nondiabetic controls.Glomerular filtration rate (GFR, inulin), effective renal plasma flow (ERPF, p-aminohippurate), modified Toronto Clinical Neuropathy Score (mTCNS), corneal confocal microscopy, nerve conduction, and heart rate variability (autonomic function) were measured; afferent (RHigher mTCNS associated with lower renal blood flow (β ± SE:-9.29 ± 4.20, p = 0.03) and greater RAlthough neurological dysfunction in the presence of diabetes may contribute to impaired renal blood flow resulting in ischemic injury in patients with T1D, early autonomic dysfunction does not appear to be associated with kidney function changes.

Introduction: Glomerular filtration rate (GFR) is routinely used for clinical assessment of kidney function. However, the accuracy of estimating equations in older adults is uncertain. Methods: In 66 adults with ≥50 years type 1 diabetes (T1D) duration and 73 nondiabetic controls from age/sex-matched subgroups (65 ± 8 years old and 77[55%] were women) we evaluated the performance of estimated GFR (eGFR) by creatinine (Modification of Diet and Renal Disease [MDRD], Chronic Kidney Disease–Epidemiology [CKD-EPI]cr), cystatin C (CKD-EPIcys, CKD-EPIcr-cys), and β2-microglobulin (β2M) compared with measured GFR by inulin clearance (mGFR). Performance was evaluated using metrics of bias (mean difference), precision (SD), and accuracy (proportion of eGFR that differed by >20% of mGFR). Results: Mean mGFR was 104 ± 18 ml/min per 1.73 m2 (range: 70–154 ml/min per 1.73 m2) and was not different between T1D and controls (103 ± 17 vs. 105 ± 19 ml/min per 1.73 m2, P = 0.39). All equations significantly underestimated mGFR (bias: −15 to −30 ml/min per 1.73 m2, P < 0.001 for all comparisons) except for β2M, which had bias of 1.9 ml/min per 1.73 m2 (P = 0.61). Bias was greatest in cystatin C–based equations. Precision was lowest for β2M (SD: 43.5 ml/min per 1.73 m2, P < 0.001 for each comparison). Accuracy was lowest for CKD-EPIcysC (69.1%, P < 0.001 for each comparison). Cystatin C–based equations demonstrated greater bias and lower accuracy in older age subgroups (

AIMS To examine the relationship between normal plasma uric acid (PUA) levels, renal haemodynamic function, arterial stiffness and plasma renin and aldosterone over a wide range of type 1 diabetes (T1D) durations in adolescents, young adults and older adults. MATERIALS AND METHODS PUA, glomerular filtration rate (GFR), effective renal plasma flow (ERPF), vascular stiffness parameters (aortic augmentation index [AIx], carotid AIx, carotid femoral pulse wave velocity [cfPWV]), and plasma renin and aldosterone were measured during a euglycaemic clamp in people with T1D: 27 adolescents (mean ± SD age 16.8 ± 1.9 years), 52 young adults (mean ± SD age 25.6 ± 5.5 years) and 66 older adults (mean ± SD age 65.7 ± 7.5 years). RESULTS PUA was highest in patients with the longest T1D duration: 197 ± 44 μmol/L in adolescents versus 264 ± 82 μmol/L in older adults (P

Objectives: Diabetic kidney disease (DKD) is an independent predictor of cardiovascular morbidity and mortality in type 1 diabetes (T1D). We aimed to explore clinical and biochemical factors, including the achievement of American Diabetes Association (ADA) recommended targets associated with DKD in people living with T1D for ≥50 years. Methods: This was a post hoc analysis of a cross-sectional study of 75 participants enrolled in the Canadian Study of Longevity in T1D. We explored diabetes-related complications, including neuropathy, retinopathy, cardiovascular disease, and DKD. Study participants were dichotomized based on the achievement of ADA recommended targets as the low-target group (achieving ≤4 targets, n = 31) and high-target group (achieving >4 targets, n = 44). The outcome of interest was DKD defined by estimated glomerular filtration rate (eGFR) values 30 mg. Multivariable logistic regression models were employed to estimate odds ratios (ORs) for DKD with 95% confidence intervals (CIs). Results: Of the 75 participants with prolonged T1D duration (45% male, mean age 66 years), 25 participants had DKD and 50 did not. There was no statistical difference between the high- and low-target groups in terms of age and body mass index. eGFR was significantly higher and the prevalence of diabetic retinopathy was significantly lower in the high-target group. Older age at diagnosis of T1D and lower frequency component to high-frequency component ratio increased the odds of having DKD. Conclusions: In adults with prolonged T1D duration, older age at diagnosis and lower heart rate variability may be associated with DKD.

OBJECTIVE The importance of renin-angiotensin-aldosterone system (RAAS) activation in retinopathy for long-standing diabetes is not well understood. We determined retinopathy stage and evaluated associations with other vascular complications before and after physiological RAAS activation in adults with long-standing (≥50 years duration) type 1 diabetes. RESEARCH DESIGN AND METHODS Participants underwent retinal examination by digital funduscopic photography and optical coherence tomography and were classified as having nonproliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR), or no diabetic retinopathy (NDR) with or without diabetic macular edema (DME). Neuropathy was measured by clinical neuropathy examination scores, electrophysiologically, and by corneal confocal microscopy. Renal function was measured by inulin and para-aminohippurate clearance methods. Arterial stiffness was measured by applanation tonometry. Renal function, blood pressure, and arterial stiffness were measured before and after RAAS activation with angiotensin II (ANGII). Associations were determined using linear regression. RESULTS Twelve (16%) of the 75 participants had NDR, 24 (32%) had NPDR, and 39 (52%) had PDR. A low overall prevalence of DME (4%) was observed. Those with PDR had worse nerve function and reduced corneal nerve density, were more likely to have macrovascular disease, and had increased arterial stiffness in response to ANGII compared with those with NPDR or NDR. Prevalence of kidney disease or renal hemodynamic function did not differ by retinopathy status. CONCLUSIONS PDR was associated with neuropathy severity and cardiovascular and peripheral vascular disease. In those with PDR, RAAS activation may be linked to vascular stiffening, an effect that persists in long-standing type 1 diabetes.

Physical activity (PA) is recommended to improve glycemic control in T1D; however, the effect of PA on distal symmetric polyneuropathy (DSPN) and cardiac autonomic function in longstanding T1D is unknown.Data from 75 participants were collected as part of the Canadian Study of Longevity in T1D. Participants completed a physical exam, medical history, extensive complications phenotyping and reported their daily PA from the preceding 12-months. Pearson and Spearman correlations were used to assess PA time and complications variables. Linear regression was used to test associations between PA time, neurological and electrophysiological measures. Univariable regression was used to indicate the change in the given independent variables associated with a 30-min increase in PA per week.Participants were 66 ± 8 years old with diabetes duration of 54 [52,58] years, HbAIn longstanding T1D, PA time is associated with superior large nerve fibre function in the lower limbs and some better measures of small nerve fibre function.

The relationship between renal function and neuropathy is not well established in T1D. Our objective was to determine the relationship between renal hemodynamic function and neuropathy in adults with a ≥50-year history of T1D compared to nondiabetic controls. GFR (inulin), effective renal plasma flow (ERPF, p-aminohippurate) and modified Toronto Clinical Neuropathy Score (mTCNS) were measured in 66 patients with T1D for ≥50-years and in 73 patients without diabetes matched for age and sex. Afferent (RA), efferent (RE) arteriolar resistances and glomerular hydrostatic pressure (PGLO) were estimated using Gomez’s equations. Presence of DKD was defined as eGFRMDRD30mg/day at the screening visit. Linear regressions were applied to examine the relationships between renal function (dependent variable) and measures of neuropathy (independent variable), adjusted for age, sex and HbA1c in participants with T1D and for age and sex in nondiabetic controls. Greater mTCNS, a measure of neuropathy signs and symptoms, was associated with lower renal blood flow (β=-9.57±4.15, p=0.024) and greater RE (β=32.79±15.13, p=0.034) in adults with T1D after adjusting for age, sex and HbA1c. Participants with T1D and DKD had a greater mTCNS compared to those without DKD (6.3±5.2 vs. 3.8±3.6, p=0.016). In contrast, renal hemodynamic parameters did not associate with measures of neuropathy in nondiabetic controls in multivariable models. Neuropathy score was associated with lower renal perfusion in adults with longstanding T1D. Neurological dysfunction in the presence of diabetes may contribute to impaired renal perfusion resulting in ischemic injury in patients with T1D. Further work is required to understand factors - including the autonomic nervous system - that contribute to maintaining normal renal perfusion in longstanding T1D. Disclosure Y. Lytvyn: None. P. Bjornstad: Advisory Panel; Self; XORTX Therapeutics Inc. Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Novo Nordisk Foundation. Research Support; Self; Horizon Pharma. L. Lovblom: None. H. Liu: None. J.A. Lovshin: Consultant; Self; AstraZeneca. Consultant; Spouse/Partner; Bayer Inc. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk Inc. Research Support; Self; Novo Nordisk Inc. G. Boulet: Advisory Panel; Self; Medtronic. M. Farooqi: None. A. Weisman: None. H.A. Keenan: None. M.H. Brent: Advisory Panel; Self; Bayer AG, Novartis Pharmaceuticals Canada Inc., Roche Canada. N. Paul: None. V. Bril: Advisory Panel; Self; Alexion Pharmaceuticals, Inc., Alnylam Pharmaceuticals, Takeda Canada. Consultant; Self; Akcea Therapeutics, CSL Behring, Sanofi. Research Support; Self; Biogen, Grifols, Momenta Pharmaceuticals. B.A. Perkins: Consultant; Self; Abbott, Boehringer Ingelheim International GmbH, Insulet Corporation. Research Support; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Other Relationship; Self; Medtronic. D. Cherney: Research Support; Self; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca and Novo-Nordisk. Other Relationship; Self; from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, Abbvie, Janssen, Bayer, Prometic, BMS and Novo-Nordisk.

OBJECTIVE Our aim was to define the relationships between plasma biomarkers of kidney injury and intrarenal haemodynamic function (glomerular filtration rate [GFR], effective renal plasma flow [ERPF], renal vascular resistance [RVR]) in adults with type 1 diabetes (T1D). METHODS The study sample comprised patients with longstanding T1D (duration ≥50 years), among whom 44 were diabetic kidney disease (DKD) resistors (eGFR >60 mL/min/1.73 m2 and

OBJECTIVE To assess national differences in diabetes care and quality of life (QOL) between individuals with long-standing type 1 diabetes (≥50 years) in Canada and the U.S. RESEARCH DESIGN AND METHODS Cross-sectional data from identical surveys administered in the Canadian Study of Longevity in Diabetes and the Joslin Medalist Study, collected in 2013–2016 and 2005–2011, respectively, were compared. Laboratory values and ophthalmic examination were completed by clinical care physicians for Canadians and the Joslin Clinic for Americans. Univariate comparisons and multivariable regression for HbA1c, QOL, insulin pump use, and coronary artery disease (CAD) were performed. Nephropathy, CAD, and peripheral arterial disease (PAD) were self-reported; neuropathy was defined by a Michigan Neuropathy Screening Instrument (Questionnaire component) score ≥3, and proliferative retinopathy was documented from ophthalmic examination. QOL was self-reported on an ordinal scale. RESULTS Three hundred sixty-one Canadians and 668 Americans had similar ages (mean 65.78 years [SD 8.67] vs. 66.38 years [7.66], P = 0.27) and durations of diabetes (median 53.00 years [interquartile range 51.00, 58.00] vs. 53.00 years [51.00, 57.00], P = 0.51). Canadians had higher HbA1c (mean 7.53% [SD 1.03] [59 mmol/mol] vs. 7.22% [0.98] [55 mmol/mol], P < 0.0001), lower QOL (36.9% vs. 48.7% with “excellent” QOL, P = 0.0002), and less CAD (29.7% vs. 41.2%, P = 0.0003) and insulin pump use (43.3% vs. 55.6%, P = 0.0002). Other complication rates were similar. Residual differences for Canadians compared with Americans remained after adjustment for age, sex, CAD, PAD, education, and relevant a priori selected variables: 0.28% higher HbA1c (P = 0.0004); and odds ratios of 0.68 (95% CI 0.51, 0.90), 0.46 (0.31, 0.68), and 0.71 (0.52, 0.96) for higher QOL, CAD, and insulin pump use, respectively. CONCLUSIONS Although Canadians and Americans have similar rates of complications other than CAD, further research is required to understand why Canadians have higher HbA1c levels, lower QOL, and less insulin pump use.

PUA is associated with renin angiotensin aldosterone system (RAAS) activation, which promotes hypertension and kidney disease in T1D. Our aims were to examine (1) the effect of an ANG II infusion on PUA and (2) the association between PUA and systemic and renal hemodynamic responses to ANG II over a wide range of T1D duration. In this post hoc analysis, blood pressure, PUA, GFRinulin and ERPFPAH were measured during a euglycemic clamp before and after an ANG II infusion (1 ng·kg-1·min-1) in participants with T1D: 49 young (26.2±5.5 years) and 62 older (66.0±7.9 years) adults and healthy controls (HC): 27 young (25.1±4.6 years), and 72 older (64.6±8.0 years) adults. ANG II infusion caused a greater decline in GFRinulin in older vs. younger adults with T1D; there was no such difference between older vs. younger HC adults. ANG II decreased PUA more in HC than T1D in both age groups (p Our findings suggest that ANG II infusion reduces PUA, potentially through direct effects on the ANG II type 1 receptor (AT1R). The presence of T1D attenuates PUA lowering effects irrespective of diabetes duration, suggesting an interaction between hyperglycemia, RAAS signaling pathways and PUA. Further studies are required to better understand the effects of AT1R receptor signaling on PUA concentrations. Disclosure Y. Lytvyn: None. J.A. Lovshin: Consultant; Self; Eli Lilly and Company, Intarcia Therapeutics, Inc., Prometic Life Sciences Inc. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc. P. Bjornstad: Advisory Panel; Self; Horizon, XORTX. Consultant; Self; Bayer US, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company. L. Lovblom: None. A. Katz: None. A. Lytvyn: None. G. Boulet: Other Relationship; Self; Medtronic. M.A. Farooqi: None. A. Weisman: None. H.A. Keenan: Employee; Self; Sanofi Genzyme. M.H. Brent: Advisory Panel; Self; AbbVie Inc., Bayer Canada, Novartis Canada. Research Support; Self; Bayer Canada, Novartis Canada, Roche Canada. N. Paul: Consultant; Self; Bayer AG. V. Bril: Advisory Panel; Self; Akcea Therapeutics, Alexion Pharmaceuticals, Inc., Alnylam, CSL Behring. Consultant; Self; Pfizer Inc. Research Support; Self; Baxter, Biogen, Grifols, UCB, Inc. A. Advani: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Dexcom, Inc., Novo Nordisk A/S. Research Support; Self; Boehringer Ingelheim International GmbH. B.A. Perkins: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Boehringer Ingelheim International GmbH, Insulet Corporation. Research Support; Self; Boehringer Ingelheim International GmbH. Other Relationship; Self; Abbott, Boehringer Ingelheim International GmbH, Lilly Diabetes, Medtronic, Novo Nordisk Inc., Sanofi. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Prometic Life Sciences Inc., Sanofi. Funding JDRF (17-2013-312)

We aimed to determine cross-sectional insulin pump prevalence and factors associated with measures of glycemic control as a secondary analysis in a long-standing type 1 diabetes mellitus (T1DM) national cohort.Canadian participants with ≥50 years of T1DM (n = 305) were administered a comprehensive mail-based questionnaire including acquisition of contemporaneous laboratory results. Factors associated with pump use, glycosylated hemoglobin (HbA1c), and hypoglycemia were analyzed by regression.The 305 participants had a median age of 65 [interquartile range, 59, 71] years, median diabetes duration of 54 [51, 59] years, and mean HbA1c level of 7.5 ± 1.1%. Prevalence of pump use was 44% (133/305), with median duration of use 8 [4, 13] years. Compared with the non-pump subgroup, the pump subgroup had numerically lower but similar HbA1c levels (7.4 ± 0.9% vs. 7.6 ± 1.2%; P = 0.22) and reported greater numbers of minor hypoglycemia events (6.5 vs. 5.1 events/patient·month; P = 0.004) and fewer severe hypoglycemia events (0.5 vs. 1.3 events/patient·year; P = 0.02) in the past year. More frequent daily glucose tests and more frequent minor hypoglycemia events-but not pump therapy or its prescription parameters-were independently associated with lower HbA1c level in multivariable regression. However, use of insulin pump and habitual use of continuous glucose monitoring (≥1 week/month) were each independently associated with lower risk of severe hypoglycemia (risk ratio = 0.50 [P 0.0001] and 0.30 [P = 0.001], respectively).Insulin pump and continuous glucose monitoring technologies were associated with lower risk of severe hypoglycemia, while frequent daily glucose testing was associated with lower HbA1c level. These findings imply that basic self-management skill and technology play complementary roles in glycemic control among older adults with long-standing T1DM.

OBJECTIVE Type 1 diabetes carries a significant risk for cardiovascular mortality, but it is unclear how atherosclerosis associates with microvascular complications. We aimed to determine the relationships between atherosclerotic burden and neuropathy, retinopathy, and diabetic kidney disease (DKD) in adults with a ≥50-year history of type 1 diabetes. RESEARCH DESIGN AND METHODS Adults with type 1 diabetes (n = 69) underwent coronary artery calcification (CAC) volume scoring by wide-volume computerized tomography. Microvascular complications were graded as follows: neuropathy by clinical assessment, electrophysiology, vibration and cooling detection thresholds, heart rate variability, and corneal confocal microscopy; retinopathy by ultra–wide-field retinal imaging; and DKD by renal hemodynamic function measured by inulin and para-aminohippurate clearance at baseline and after intravenous infusion of angiotensin II. The cohort was dichotomized to high (≥300 Agatston units [AU]) or low ( RESULTS CAC scores were higher in participants with type 1 diabetes (median Agatston score 1,000 [interquartile range = 222, 2,373] AU vs. 1 [0.75] AU in comparators, P < 0.001). In participants with type 1 diabetes, high CAC scores associated with markers of neuropathy and retinopathy, but not with DKD, or renal hemodynamic function at baseline or in response to angiotensin II. CONCLUSIONS The presence of high CAC in adults with longstanding type 1 diabetes was associated with large nerve fiber neuropathy and retinopathy but not with renal hemodynamic function, suggesting that neuropathy, retinopathy, and macrovascular calcification share common risk factors.

We aimed to measure the prevalence of retinopathy in a T1D cohort of 75 adults with T1D duration of ≥50 years, and to determine association with other vascular complications. Participants underwent ultra-widefield retinal imaging and optimal coherence tomography. Neuropathy was characterized by electrophysiology and corneal confocal microscopy. Intrarenal hemodynamic function was determined by inulin and para-aminohippurate clearance, and arterial stiffness was measured by applanation tonometry, both at baseline and in responses to intravenous angiotensin II (ANGII). Participants were classified as having no diabetic retinopathy (ⱷDR), non-proliferative (NPDR), or proliferative (PDR), and associations were determined using multivariable linear regression adjusting for age, sex, and HbA1c. Thirty-nine (52%) participants had PDR, 24 (32%) had NPDR, and 12 (16%) had ⱷDR. Those without retinopathy had lower HbA1c vs. those with NDPR and PDR (6.7±0.6% vs. 7.4±0.7% and 7.5±0.9%, p=0.019). PDR was associated with lower corneal nerve fibre density, worse electrophysiology, and a greater number of signs and symptoms of neuropathy, but not with intrarenal hemodynamic function. Retinopathy severity was associated with greater response to ANGII for carotid-radial pulse wave velocity (mean change -4.9±11.4% vs. 8.2±18.5% vs. 12.9±20.2% for ⱷDR, NPDR, and PDR respectively, p=0.043). In longstanding T1D, retinopathy associated strongly with neuropathy and arterial stiffening, but not with renal hemodynamic function. Greater understanding of the co-occurrence of microvascular complications in patients with T1D, and relationships with macrovascular abnormalities such as arterial stiffness, may improve early detection and management of diabetes-related diseases. Disclosure J.A. Lovshin: Other Relationship; Self; AstraZeneca. Consultant; Self; Novo Nordisk Inc.. Research Support; Self; Sanofi, Merck Sharp & Dohme Corp.. Other Relationship; Self; Novo Nordisk Inc.. L. Lovblom: None. P. Bjornstad: Consultant; Self; Boehringer Ingelheim GmbH. Y. Lytvyn: None. G. Boulet: Advisory Panel; Self; Medtronic, Sanofi, Novo Nordisk Inc.. Other Relationship; Self; Janssen Global Services, LLC., Abbott. A. Weisman: None. V.S. Lai: None. J.M. Tse: None. L. Cham: None. A. Orszag: None. H.A. Keenan: Research Support; Self; Sanofi. Employee; Self; Sanofi Genzyme. N. Paul: None. V. Bril: Consultant; Self; Alexion Pharmaceuticals, Inc.. Research Support; Self; CSL Behring, Grifols. Advisory Panel; Self; CSL Behring. Consultant; Self; Grifols. Research Support; Self; Shire. Advisory Panel; Self; Pfizer Inc. M.H. Brent: Research Support; Self; Novartis Canada. Advisory Panel; Self; Novartis Canada. Research Support; Self; Bayer Canada. Advisory Panel; Self; Bayer Canada, Allergan Canada. Research Support; Self; Roche Canada. B.A. Perkins: Advisory Panel; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH, Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc., Abbott. Speaker's Bureau; Self; Abbott, Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Insulet Corporation. Speaker's Bureau; Self; Insulet Corporation, Dexcom, Inc. D. Cherney: Consultant; Self; AbbVie Inc.. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company. Consultant; Self; Sanofi. Other Relationship; Self; Merck & Co., Inc.. Consultant; Self; Mitsubishi Tanabe Pharma Corporation. Other Relationship; Self; Janssen Pharmaceuticals, Inc..

Our aim was to better understand kidney function changes and RAAS activation over the natural history of T1D in patients with a wide range of T1D duration. GFRinulin and ERPFPAH were measured during a euglycemic clamp before and after an angiotensin II infusion (ANGII, 3 ng·kg-1·min-1-a measure of RAAS activation) in patients with T1D: 28 adolescents (age 16.2±2.0 years), 54 young adults (25.4±5.6 years) and 66 adults with ≥50 years of T1D (65.7±7.5 years) from the Canadian Study of Longevity. Gomez’s equations were used to estimate afferent (RA) and efferent (RE) arteriolar resistances and glomerular hydrostatic pressure (PGLO). In a step-wise fashion, GFRinulin, ERPFPAH, PGLO decreased, renal vascular resistance (RVR) and RA increased in adolescents vs. young adults vs. adults with ≥50 years of T1D (Figure 1). RE was similar in adolescents vs. young adults, but was higher in patients with ≥50 years of T1D. ANGII resulted in blunted renal hemodynamic responses in patients with ≥50 years of T1D (RVR increase of 0.033±0.016 vs. 0.049±0.019mmHg/L/min in adolescents, p=0.0006) suggesting a state of enhanced RAAS activation. With longer duration of disease, patients with T1D have evidence of renal vasoconstriction, leading to lower GFRinulin, ERPFPAH, elevated RVR and RAAS activation. Further work is required to understand the potential role of non-RAAS, pharmacologic agents that target RA in patients with early T1D. Disclosure Y. Lytvyn: None. P. Bjornstad: Consultant; Self; Boehringer Ingelheim GmbH. J.A. Lovshin: Other Relationship; Self; AstraZeneca. Consultant; Self; Novo Nordisk Inc.. Research Support; Self; Sanofi, Merck Sharp & Dohme Corp.. Other Relationship; Self; Novo Nordisk Inc. G. Boulet: Advisory Panel; Self; Medtronic, Sanofi, Novo Nordisk Inc.. Other Relationship; Self; Janssen Global Services, LLC., Abbott. M. Farooqi: None. V.S. Lai: None. J.M. Tse: None. L. Cham: None. L. Lovblom: None. A. Weisman: None. H.A. Keenan: Research Support; Self; Sanofi. Employee; Self; Sanofi Genzyme. M.H. Brent: Research Support; Self; Novartis Canada. Advisory Panel; Self; Novartis Canada. Research Support; Self; Bayer Canada. Advisory Panel; Self; Bayer Canada, Allergan Canada. Research Support; Self; Roche Canada. N. Paul: None. V. Bril: Consultant; Self; Alexion Pharmaceuticals, Inc.. Research Support; Self; CSL Behring, Grifols. Advisory Panel; Self; CSL Behring. Consultant; Self; Grifols. Research Support; Self; Shire. Advisory Panel; Self; Pfizer Inc. A. Advani: Research Support; Self; AstraZeneca, Boehringer Ingelheim GmbH. Other Relationship; Self; Boehringer Ingelheim GmbH. E.B. Sochett: None. B.A. Perkins: Advisory Panel; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH, Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc., Abbott. Speaker's Bureau; Self; Abbott, Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Insulet Corporation. Speaker's Bureau; Self; Insulet Corporation, Dexcom, Inc. D. Cherney: Consultant; Self; AbbVie Inc.. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company. Consultant; Self; Sanofi. Other Relationship; Self; Merck & Co., Inc.. Consultant; Self; Mitsubishi Tanabe Pharma Corporation. Other Relationship; Self; Janssen Pharmaceuticals, Inc..

Neuropathy and neuropathic pain are common complications in T1D. We aimed to determine if sex-specific differences in the prevalence of neuropathic pain and neuropathy exist in patients with longstanding T1D. In Phase 1 of the study, 361 Canadians with ≥50 years of T1D completed questionnaires which included subjective assessment for neuropathy defined by Michigan Neuropathy Screening Instrument Questionnaire score ≥3, termed NEUROPATHYMNSI-Q. In Phase 2 of the study, we studied a sub-cohort of 75 diabetes participants and 75 age- and sex-matched nondiabetic controls who completed objective neurological examinations which included assessment of abnormal nerve conduction studies (NCS) for neuropathy, termed NEUROPATHYNCS. In the Phase 1 cohort, more females than males reported neuropathic pain [87(42%) vs. 41(27%); p=0.003)], but the presence of neuropathy (NEUROPATHYMNSI-Q) did not differ by sex [87(42%) females vs. 66(43%) males, p=0.82], and thus neuropathic pain was independent of the presence of neuropathy [adjusted OR for neuropathic pain in females compared to males, 2.7 (1.4-5.0; p=0.002)]. In the Phase 2 participants, neuropathic pain was similar between the sexes (29% females vs. 21% males, p=0.43) while NEUROPATHYNCS was less prevalent among females (83% females vs. 97% males, p=0.05). Though not statistically significant, in a combined analysis of Phase 2 participants adjusted for NEUROPATHYNCS, females had a tendency to a higher adjusted OR for neuropathic pain compared to males [OR 2.0 (95% CI 0.8-4.7), p=0.11]. In conclusion, in patients with longstanding TID, neuropathic pain appears to be greater among females compared to males independent of the presence of neuropathy. Further research using larger datasets with objective neuropathy measures are required to further confirm and address these sex-specific differences. Disclosure N. Cardinez: None. L. Lovblom: None. J. Bai: None. A. Abraham: None. E.J. Lewis: Employee; Self; Nutarniq Corp. D. Scarr: None. J.A. Lovshin: Other Relationship; Self; AstraZeneca. Consultant; Self; Novo Nordisk Inc.. Research Support; Self; Sanofi, Merck Sharp & Dohme Corp.. Other Relationship; Self; Novo Nordisk Inc.. Y. Lytvyn: None. G. Boulet: Advisory Panel; Self; Medtronic, Sanofi, Novo Nordisk Inc.. Other Relationship; Self; Janssen Global Services, LLC., Abbott. M. Farooqi: None. A. Orszag: None. A. Weisman: None. H.A. Keenan: Research Support; Self; Sanofi. Employee; Self; Sanofi Genzyme. M.H. Brent: Research Support; Self; Novartis Canada. Advisory Panel; Self; Novartis Canada. Research Support; Self; Bayer Canada. Advisory Panel; Self; Bayer Canada, Allergan Canada. Research Support; Self; Roche Canada. N. Paul: None. V. Bril: Consultant; Self; Alexion Pharmaceuticals, Inc.. Research Support; Self; CSL Behring, Grifols. Advisory Panel; Self; CSL Behring. Consultant; Self; Grifols. Research Support; Self; Shire. Advisory Panel; Self; Pfizer Inc. D. Cherney: Consultant; Self; AbbVie Inc.. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company. Consultant; Self; Sanofi. Other Relationship; Self; Merck & Co., Inc.. Consultant; Self; Mitsubishi Tanabe Pharma Corporation. Other Relationship; Self; Janssen Pharmaceuticals, Inc. B.A. Perkins: Advisory Panel; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH, Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc., Abbott. Speaker's Bureau; Self; Abbott, Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Insulet Corporation. Speaker's Bureau; Self; Insulet Corporation, Dexcom, Inc..

Higher PUA levels are associated with renal vasoconstriction, renin angiotensin aldosterone system (RAAS) activation and vascular stiffness, however the timeline for these associations in T1D is not clear. Our aim was to compare adolescents vs. young adults vs. adults with ≥50 years of T1D from the Canadian Study of Longevity to determine the relationship between PUA and changes in renal hemodynamic function, arterial stiffness and plasma renin and aldosterone over a wide range of diabetes duration. PUA, GFRinulin, ERPFPAH, vascular stiffness parameters (aortic augmentation index [AIx], carotid AIx, carotid femoral pulse wave velocity [cfPWV]), plasma renin and aldosterone were measured during a euglycemic clamp in participants with T1D: 27 adolescents (age 16.8±1.9 years), 52 young adults (25.6±5.5 years) and 66 older adults (65.7±7.5 years). PUA levels were highest in the cohort with the longest T1D duration: 197±44 in adolescents vs. 264±82µmol/L in older adults (p The relationship between higher PUA with lower GFR, increased arterial stiffness and RAAS activation was observed only in adults with longstanding T1D. T1D may modify the association between PUA, renal hemodynamic function and RAAS activation, leading to renal vasoconstriction and ischemia. Further work is required to determine whether pharmacological PUA lowering prevents injurious hemodynamic and neurohormonal sequelae of longstanding T1D, thereby improving clinical outcomes. Disclosure Y. Lytvyn: None. P. Bjornstad: Consultant; Self; Boehringer Ingelheim GmbH. J.A. Lovshin: Other Relationship; Self; AstraZeneca. Consultant; Self; Novo Nordisk Inc.. Research Support; Self; Sanofi, Merck Sharp & Dohme Corp.. Other Relationship; Self; Novo Nordisk Inc. G. Boulet: Advisory Panel; Self; Medtronic, Sanofi, Novo Nordisk Inc.. Other Relationship; Self; Janssen Global Services, LLC., Abbott. M. Farooqi: None. V.S. Lai: None. J.M. Tse: None. L. Cham: None. L. Lovblom: None. A. Weisman: None. H.A. Keenan: Research Support; Self; Sanofi. Employee; Self; Sanofi Genzyme. M.H. Brent: Research Support; Self; Novartis Canada. Advisory Panel; Self; Novartis Canada. Research Support; Self; Bayer Canada. Advisory Panel; Self; Bayer Canada, Allergan Canada. Research Support; Self; Roche Canada. N. Paul: None. V. Bril: Consultant; Self; Alexion Pharmaceuticals, Inc.. Research Support; Self; CSL Behring, Grifols. Advisory Panel; Self; CSL Behring. Consultant; Self; Grifols. Research Support; Self; Shire. Advisory Panel; Self; Pfizer Inc. A. Advani: Research Support; Self; AstraZeneca, Boehringer Ingelheim GmbH. Other Relationship; Self; Boehringer Ingelheim GmbH. E.B. Sochett: None. B.A. Perkins: Advisory Panel; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH, Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc., Abbott. Speaker's Bureau; Self; Abbott, Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Insulet Corporation. Speaker's Bureau; Self; Insulet Corporation, Dexcom, Inc. D. Cherney: Consultant; Self; AbbVie Inc.. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company. Consultant; Self; Sanofi. Other Relationship; Self; Merck & Co., Inc.. Consultant; Self; Mitsubishi Tanabe Pharma Corporation. Other Relationship; Self; Janssen Pharmaceuticals, Inc..

Aim Neuropathy and neuropathic pain are common complications of type 1 diabetes (T1D). We aimed to determine if sex-specific differences in neuropathic pain are present in adults with longstanding T1D. Methods Canadians with ≥50 years of T1D (n = 361) completed health history questionnaires that included assessment of neuropathy (defined by Michigan Neuropathy Screening Instrument questionnaire components ≥3; NEUROPATHYMNSI-Q) and neuropathic pain. Multivariable logistic regression was used to determine sex-differences in neuropathic pain controlling for neuropathy. Results Participants had mean age 66 ± 9 years, median diabetes duration 53[51,58] years, mean HbA1c 7.5 ± 1.0%, and 207(57%) were female. Neuropathic pain was present in 128(36%) of all participants, more prevalent among those with NEUROPATHYMNSI-Q compared to those without [96(63%) vs. 31(15%), p Conclusions We demonstrated a novel sex-specific difference in neuropathic pain in females compared to males with longstanding T1D, independent of the presence of neuropathy. Further research using more objective measures of neuropathy than the MNSI is justified to further understand this sex-specific difference.

OBJECTIVE Central adiposity is considered to be an important cardiorenal risk factor in the general population and in type 1 diabetes. We sought to determine the relationship between central adiposity and intrarenal hemodynamic function in adults with long-standing type 1 diabetes with and without diabetic nephropathy (DN). RESEARCH DESIGN AND METHODS Patients with type 1 diabetes (n = 66, duration ≥50 years) and age-/sex-matched control subjects (n = 73) were studied. The cohort was stratified into 44 DN Resistors (estimated glomerular filtration rate [eGFR] >60 mL/min/1.73 m2 and RESULTS Whereas measures of adiposity did not associate with GFRINULIN or ERPFPAH in healthy control subjects, trunk fat mass inversely correlated with GFRINULIN (r = −0.46, P < 0.0001) and ERPFPAH (r = −0.31, P = 0.01) and positively correlated with RVR (r = 0.53, P = 0.0003) in type 1 diabetes. In analyses stratified by DN status, greater central adiposity related to lower GFRINULIN values in DN and DN Resistors, but the relationships between central adiposity and ERPFPAH and RVR were attenuated and/or reversed in patients with DN compared with DN Resistors. CONCLUSIONS The adiposity-intrarenal hemodynamic function relationship may be modified by the presence of type 1 diabetes and DN, requiring further study of the mechanisms by which adiposity influences renal hemodynamic function.

To determine the association of neuropathy and other complications with emotional distress and depression among patients with longstanding type 1 diabetes (T1DM).Canadians with ≥50years of T1DM completed a questionnaire including assessment of distress and depression by the Problem Areas in Diabetes Scale (PAID) and Geriatric Depression Scale (GDS), respectively. Complications were determined using the Michigan Neuropathy Screening Instrument (Questionnaire Component), fundoscopy reports, renal function tests, and self-reported peripheral-(PVD) and cardiovascular (CVD) disease. Associations were analyzed by Poisson regression.Among 323 participants, 137 (42.4%) had neuropathy, 113 (36.5%) nephropathy, 207 (69.5%) retinopathy, 95 (29.4%) CVD, and 31 (9.8%) PVD. The neuropathy subgroup had higher prevalence of distress (13 (9.5%) vs. 6 (3.3%), p=0.029) and depression (34 (24.9%) vs. 12 (6.5%), p0.001). Adjusting for diabetes complications, neuropathy was associated with higher PAID (adjusted RR 1.44 (95% CI 1.14-1.82), p=0.003) and GDS scores (adjusted RR1.57 (1.18-2.11), p=0.002). Independent of potential confounders, neuropathy remained associated with higher PAID (adjusted RR 1.39 (1.10-1.76), p=0.006) and GDS scores (adjusted RR 1.37 (1.03-1.83), p=0.032). Associations with neuropathy were not fully explained by neuropathic pain.Compared to other complications, neuropathy had the greatest association with distress and depression in longstanding T1DM, independent of pain. Strategies beyond pain management are needed to improve quality of life in diabetic neuropathy.

Aim It is currently unclear if longstanding type 1 diabetes (T1D) affects bone mineral density (BMD). Methods BMD measured by dual-energy X-ray absorptiometry and history of fragility fracture was determined in 75 T1D participants with ≥50 years of diabetes duration and 75 age- and sex-matched non-diabetic controls. BMD T-scores were determined for the lumbar spine (LS), total hip (TH) and femoral neck (FN). Results T1D participants had median diabetes duration of 54 [52, 58] years, 41 (55%) were females, and mean A1c was 7.3 ± 0.8%. T1D females had higher LS T-scores compared to female controls (−0.3 ± 1.2 vs. −1.1 ± 1.4, p = 0.014), lower FN T-scores (−1.5 ± 1.0 vs. −1.2 ± 0.9, p = 0.042) and more fragility fractures (7 (17%) vs. 1 (2%), p = 0.021). In T1D, higher A1c was associated with higher adjusted odds of fragility fracture (p = 0.006). T1D males and controls showed no difference in BMD or fractures. Conclusions There were no substantial differences in T-score between T1D and matched controls; however, T1D females showed higher BMD at the LS and possibly paradoxically higher fragility fractures compared to matched controls. These findings suggest that lower T-scores may not be associated with a history of fragility fracture in females with longstanding T1D and that other factors should be investigated.

OBJECTIVE Elevated plasma free fatty acids (FFAs) are one important link between excess visceral adiposity, insulin resistance, and the development of type 2 diabetes. Effects of lifestyle interventions on FFA metabolism are poorly known. This open-label study was conducted to test the effects of a 1-year healthy eating/physical activity intervention program on plasma FFA homeostasis in 117 viscerally obese men with dyslipidemia associated with insulin resistance (waist circumference ≥90 cm, triglycerides ≥1.69 mmol/L, and/or HDL-cholesterol RESEARCH DESIGN AND METHODS Body weight, body composition, and fat distribution were assessed by dual-energy X-ray absorptiometry/computed tomography. Oral loads of lipid (60 g fat/m2 body surface area) and glucose (75 g) were measured before and after the intervention. RESULTS After 1 year of lifestyle intervention, visceral adiposity was reduced by −26% (95% CI −29 to −23), whereas cardiorespiratory fitness improved by +20% (95% CI +16 to +24). After 1 year, the suppression of FFAs after the glucose load improved, whereas insulin concentrations were drastically reduced. After the oral lipid load, the late increase in FFA was reduced together with reduced circulating insulin. We calculated an insulin sensitivity index to reflect the concentration of insulin needed to manage plasma FFAs after the oral lipid load, which increased after the intervention and was associated with improved glucose tolerance, independent of changes in visceral or total adiposity. CONCLUSIONS A 1-year healthy eating/physical activity intervention improved the suppression of FFAs after oral glucose and lipid load tests in viscerally obese men, possibly due to improved responsiveness to insulin. This insulin-mediated regulation of postprandial plasma FFA levels could be a link between visceral obesity and impaired glucose homeostasis.

Background Older patients with longstanding type 1 diabetes have high cardiovascular disease (CVD) risk such that statin therapy is recommended independent of prior CVD events. We aimed to determine self-reported CVD prevention guideline adherence in patients with longstanding diabetes. Research design and methods 309 Canadians with over 50 years of type 1 diabetes completed a medical questionnaire for presence of lifestyle and pharmacological interventions, stratified into primary or secondary CVD prevention subgroups based on absence or presence of self-reported CVD events, respectively. Associations with statin use were analyzed using multivariable logistic regression. Results The 309 participants had mean ± SD age 65.7 ± 8.5 years, median diabetes duration 54.0 [IQR 51.0, 59.0] years, and HbA1c of 7.5 ± 1.1 % (58 mmol/mol). 159 (52.7 %) participants reported diet adherence, 296 (95.8 %) smoking avoidance, 217 (70.5 %) physical activity, 218 (71.5 %) renin-angiotensin-system inhibitor use, and 220 (72.1 %) statin use. Physical activity was reported as less common in the secondary prevention subgroup, and current statin use was significantly lower in the primary prevention subgroup (65.5 % vs. 84.8 %, p = 0.0004). In multivariable logistic regression, the odds of statin use was 0.38 [95 % CI 0.15–0.95] in members of the primary compared to the secondary prevention subgroup, adjusting for age, sex, hypertension history, body mass, HbA1c, cholesterol, microvascular complications, acetylsalicylic acid use, and renin-angiotensin system inhibitor use. Conclusion Despite good self-reported adherence to general CVD prevention guidelines, against the principles of these guidelines we found that statin use was substantially lower in those without CVD history. Interventions are needed to improve statin use in older type 1 diabetes patients without a history of CVD.

Objective Point-of-care nerve conduction devices (POCD) have been studied in younger patients and may facilitate screening for polyneuropathy in non-specialized clinical settings. However, performance may be impaired with advanced age owing to age-related changes in nerve conduction. We aimed to evaluate the validity of a POCD as a proxy for standard nerve conduction studies (NCS) in older adults with type 1 diabetes (T1D). Methods Sural nerve amplitude potential (AMP) and sural nerve conduction velocity (CV) was measured in 68 participants with ≥ 50 years T1D duration and 71 controls (from age/sex-matched subgroups) using POCD and NCS protocols. Agreement was determined by the Bland-Altman method, and validity was determined by receiver operating characteristic curves. Results T1D were 53% female, aged 66±8yr and had diabetes duration 54yr[52,58]. Controls were 56%(p = 0.69) female and aged 65±8yr(p = 0.36). Mean AMPPOCD and CVPOCD for the 139 participants was 7.4±5.8μV and 45.7±11.2m/s and mean AMPNCS and CVNCS was 7.2±6.1μV and 43.3±8.3m/s. Mean difference of AMPPOCD−AMPNCS was 0.3±3.8μV and was 2.3±8.5m/s for CVPOCD−CVNCS. A AMPPOCD of ≤6μV had 80% sensitivity and 80% specificity for identifying abnormal AMPNCS, while a CVPOCD of ≤44m/s had 81% sensitivity and 82% specificity to identify abnormal CVNCS. Abnormality in AMPPOCD or CVPOCD was associated with 87% sensitivity, while abnormality in both measures was associated with 97% specificity for polyneuropathy identification. Conclusions The POCD has strong agreement and diagnostic accuracy for identification of polyneuropathy in a high-risk subgroup and thus may represent a sufficiently accurate and rapid test for routinely detecting those with electrophysiological dysfunction.

Twenty-five percent of individuals with long-standing type 1 diabetes (T1D) are resistant to complications, and this is not entirely explained by superior glycemic control (1–4). Although associations between clinical variables and individual complications have been comprehensively examined (1–4), analysis of total complication burden may detect previously unrecognized associations. The Canadian Study of Longevity in Diabetes actively recruited 325 individuals who had T1D for 50 or more years (5). Subjects completed a questionnaire, and recent laboratory tests and eye reports were provided by primary care physicians and eye specialists, respectively. Nephropathy was defined by an albumin-to-creatinine ratio of >2 mg/mmol for participants on an ACE inhibitor or angiotensin receptor blocker (ARB) or >3.4 mg/mmol for participants not on an ACE inhibitor or ARB. Symptomatic neuropathy was defined by a score ≥3 on the Michigan Neuropathy Screening Instrument (MNSI) questionnaire component. Retinopathy was defined by documentation of nonproliferative or proliferative retinopathy in the eye specialist report. Coronary artery disease was defined by self-reported …

Objective Clinical protocols for basal rate testing and adjustment are needed for effective insulin pump therapy. We evaluated the effects of a continuous glucose monitoring (CGM)-based semiautomated basal algorithm on glycemia. Methods We developed and piloted a basal rate analyzer that interpreted CGM data from overnight fasts and recommended dose changes for subsequent nights. Subjects uploaded data online using sensor-augmented pumps for evaluation by the analyzer after each of 5 overnight fasts conducted over 2 to 8 weeks. It was designed to be conservative and iterative, making changes that did not exceed 10% at each iteration. The standard deviation and interquartile range of CGM values from midnight to 7 am (SD 12-7am and IQR 12-7am ) over 3 baseline and 3 postintervention nights, hypoglycemia incidence (CGM values Results Twenty subjects with mean ages of 38±13 years and A1C 7.6%±0.8% (60±8.7 mmol/mol) underwent the 5 iterations of basal assessments over 5±3 weeks. SD 12-7am and IQR 12-7am did not change from baseline to postintervention (1.57±0.8 to 1.63±0.8 mmol/L; p=0.35; 3.66±2.07 to 3.47±2.26 mmol/L; p=0.90). However, mean glucose values were lower between 2 to 3 am at baseline compared to postintervention; 3-night hypoglycemia incidence declined from 1.6±1.8 to 0.5±0.7 episodes (p=0.01), and A1C improved from 7.6%±0.8% to 7.4%±0.9% (60%±8.7% to 57%±9.8% mmol/mol; p=0.03). Conclusions The use of a basal rate analyzer was associated with reduced hypoglycemia and improved A1C. However, overnight glycemic stability was not improved. Further research into the efficacy of the CGM-based semiautomated algorithm is warranted.

In vivo corneal confocal microscopy (IVCCM) has been established in cross-sectional studies as a valid measure for the identification of diabetic sensorimotor polyneuropathy (DSP). We aimed to determine the predictive validity of a baseline IVCCM measure in identifying future DSP onset in patients with type 1 diabetes.We followed 65 patients with type 1 diabetes without DSP at baseline. They were followed longitudinally for a mean of 3.5±0.9 years and underwent IVCCM, clinical and electrophysiologic examinations at baseline and follow up. At the end of follow up, participants were assigned as new-onset cases of DSP or as controls. Predictive validity was assessed using receiver operating characteristic curves.At baseline, participants were 34±15 years of age with mean diabetes duration of 18±12 years. The 11 (17%) new-onset cases of DSP were similar to the 54 (83%) controls in baseline age, diabetes duration, gender, glycated hemoglobin levels and electrophysiologic parameters (p≥0.20). However, cases of new onset had significantly lower baseline corneal nerve fibre length (CNFL) and branch density (p0.05). For identification of new-onset cases, area under the receiver operating characteristic curve for CNFL was 0.78 with an optimal threshold of 14.9 mm/mm(2) (sensitivity=0.82, specificity=0.69).Despite similar clinical and electrophysiologic parameters, participants with type 1 diabetes at risk for future DSP had significantly lower baseline IVCCM measures. CNFL may have applicability in identifying high-risk patients for therapeutic intervention in clinical research and practice.

Objective In vivo Corneal Confocal Microscopy (IVCCM) is a validated, non-invasive test for diabetic sensorimotor polyneuropathy (DSP) detection, but its utility is limited by the image analysis time and expertise required. We aimed to determine the inter- and intra-observer reproducibility of a novel automated analysis program compared to manual analysis. Methods In a cross-sectional diagnostic study, 20 non-diabetes controls (mean age 41.4±17.3y, HbA1c 5.5±0.4%) and 26 participants with type 1 diabetes (42.8±16.9y, 8.0±1.9%) underwent two separate IVCCM examinations by one observer and a third by an independent observer. Along with nerve density and branch density, corneal nerve fibre length (CNFL) was obtained by manual analysis (CNFLMANUAL), a protocol in which images were manually selected for automated analysis (CNFLSEMI-AUTOMATED), and one in which selection and analysis were performed electronically (CNFLFULLY-AUTOMATED). Reproducibility of each protocol was determined using intraclass correlation coefficients (ICC) and, as a secondary objective, the method of Bland and Altman was used to explore agreement between protocols. Results Mean CNFLManual was 16.7±4.0, 13.9±4.2 mm/mm2 for non-diabetes controls and diabetes participants, while CNFLSemi-Automated was 10.2±3.3, 8.6±3.0 mm/mm2 and CNFLFully-Automated was 12.5±2.8, 10.9 ± 2.9 mm/mm2. Inter-observer ICC and 95% confidence intervals (95%CI) were 0.73(0.56, 0.84), 0.75(0.59, 0.85), and 0.78(0.63, 0.87), respectively (p = NS for all comparisons). Intra-observer ICC and 95%CI were 0.72(0.55, 0.83), 0.74(0.57, 0.85), and 0.84(0.73, 0.91), respectively (p