Management of type 2 diabetes, obesity, or nonalcoholic steatohepatitis with high-dose GLP-1 receptor agonists and GLP-1 receptor-based co-agonists.

Type 2 diabetes (T2D), obesity, and nonalcoholic fatty liver disease/nonalacoholic steatohepatitis (NAFLD/NASH) share mutual causalities. Medications that may offer clinical benefits to all three conditions are being developed. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of T2D and obesity and there is great interest in evaluating higher doses of available GLP-1RAs and developing novel GLP-1RA-based co-agonists to provide greater reductions in glycated hemoglobin (HbA1c) and body weight as well as modifying NAFLD/NASH complications in clinically meaningful ways. High-dose GLP-1RAs and multi-hormonal strategies including GLP-1R agonism have either already been approved or are in development for managing T2D, obesity, or NASH. We provide a mechanistic outline with a detailed summary of the available clinical data and ongoing trials that are adjudicating the impact of high-dose GLP-1RAs, unimolecular, and multimolecular GLP-1R-based co-agonists in populations living with T2D, obesity, or NASH. The available trial findings are aligned with preclinical observations, showing clinical efficacy and safety thus providing optimism for the expansion of GLP-1R-based drug classes for managing the triad of T2D, obesity and NASH. Development, access, and wide-spread utilization of these new therapeutic approaches will offer important opportunities to markedly improve the collective global burden of T2D, obesity, and NASH.

Fasted C-Peptide Distribution and Associated Clinical Factors in Adults With Longstanding Type 1 Diabetes: Analysis of the Canadian Study of Longevity in Type 1 Diabetes.

OBJECTIVE: Although insulin production is reportedly retained in many people with longstanding type 1 diabetes (T1D), the magnitude and relevance of connecting peptide (C-peptide) production are uncertain. In this study, we aimed to define fasted C-peptide distributions and associated clinical factors. METHODS: In a cross-sectional analysis of the Canadian Study of Longevity, fasted serum and urinary C-peptide was measured in 74 patients with longstanding T1D (duration ≥50 years) and 75 age- and sex-matched controls. Extensive phenotyping for complications was performed and patient-reported variables were included. C-peptide distributions were analyzed, and multivariable logistic regression was used to assess the variable association in participants with T1D. RESULTS: The 74 participants with T1D had a mean age of 66±8 years, a disease duration of 54 (interquartile range 52 to 58) years, and a glycated hemoglobin (A1C) of 7.4%±0.8% (56.8±9.15 mmol/mol). The 75 controls had a mean age of 65±8 years and an A1C of 5.7%±0.4% (38.4±4.05 mmol/mol). Participants with T1D had lower fasted serum C-peptide than controls (0.013±0.022 vs 1.595±1.099 nmol/L, p<0.001). Of the participants with T1D, C-peptide was detectable in 30 of 73 (41%) serum samples, 32 of 74 (43%) urine samples, and 48 of 74 (65%) for either serum or urine. The variables independently associated with detectable serum or urinary C-peptide were lower total daily insulin requirement (odds ratio 2.351 [for 1 lower unit/kg], p=0.013) and lower hypoglycemia worry score (odds ratio 1.059 [for 1 point lower on the worry subscore of the Hypoglycemia Fear Survey], p=0.030). CONCLUSIONS: Although detectable C-peptide in longstanding diabetes was common, the magnitude of concentration was extremely low when compared with age- and sex-matched controls. Despite minimal detectability, its presence is validated by lower insulin requirements and strongly associated with lower hypoglycemia worry.

Estimated glomerular filtration rate calculated by serum creatinine lacks precision and accuracy in adults with type 2 diabetes with preserved renal function.

AIMS: We evaluated the performance of creatinine-based equations that are currently used to estimate glomerular filtration rate (GFR) in people with type 2 diabetes compared to measured GFR using gold-standard methods. METHODS: In this post-hoc analysis, 32 participants underwent repeated measurement of GFR by inulin clearance (mGFR). GFR was estimated by serum creatinine using the MDRD (eGFRMDRD) and CKD-EPI (eGFRCKD-EPI) equations four times over the course of one month. Performance was evaluated using measurements of bias (mean difference), precision (SD), and inaccuracy (proportion of eGFR that differed by >20 % of mGFR). Treatment and time effects on bias were evaluated using linear mixed effects models. RESULTS: At baseline, participants (38 % female) were age 60 ± 8 years, had diabetes duration of 9 ± 7 years, HbA1c 56 ± 9 mmol/mol (7.2 ± 0.8 %), and BMI 31.0 ± 6.2 kg/m2. Mean mGFR was 113 ± 24, mean eGFRMDRD was 93 ± 12, and mean eGFRCKD-EPI was 94 ± 9 mL/min/1.73 m2. When 128 observations (32 participants measured 4 times) were evaluated, both equations substantially underestimated mGFR. For eGFRMDRD, mean bias was -21.5 mL/min/1.73 m2, precision was 22.7 mL/min/1.73 m2, and 46 % of observations differed by >20 %. Results were similar for eGFRCKD-EPI. No time or treatment effects on bias were observed. CONCLUSIONS: In adults with type 2 diabetes and preserved renal function, eGFR equations underestimated mGFR, lacked precision and accuracy, and performance was lower at higher ranges of mGFR. Current eGFR equations by serum creatinine are inaccurate in adults with type 2 diabetes with preserved renal function, highlighting the necessity to develop new methods to measure kidney function at earlier stages of diabetic kidney disease.

Diabetic retinopathy screening integrated in a multidisciplinary diabetes care clinic: a pilot project.

OBJECTIVE: To characterize patients referred for diabetic retinopathy (DR) screening in a unique multidisciplinary diabetes care clinic at a tertiary care centre. METHODS: A retrospective study was conducted involving patients who were referred to the Cardiac and Renal Endocrine Clinic at a tertiary care centre (University Health Network) for DR screening between April 2019-March 2020 and November 2020-August 2021. Patients' demographics; micro- and macrovascular disease measurements; visual acuity, intraocular pressure, fundus imaging, and optical coherence tomography results were collected and analyzed. RESULTS: Of the 64 patients who attended the clinic, 21 patients (33%) with type 2 diabetes had on-site DR screening. The remaining 43 patients had DR screening within 6 months of the appointment or were under ophthalmology care with annual screening visits elsewhere. Of the 21 patients who underwent retinopathy screening, 7 patients (33%) had DR: 4 had mild nonproliferative DR, 2 had moderate nonproliferative DR, 1 had proliferative DR, and 1 had macular edema. Patients with DR had a significantly longer diabetes duration than patients without DR (24.5 ± 10.2 years vs 12.5 ± 5.8 years; p = 0.0247). No significant differences were observed in glycemic control, blood pressure, lipid profiles, kidney function, visual acuity, or intraocular pressure. CONCLUSIONS: Our analysis suggests a potential benefit of integrated DR screening in patients with long-standing diabetes as part of a multidisciplinary diabetes care clinic to diagnose and manage DR. Future work is needed to further develop such clinics and investigate their long-term effect on patient outcomes.

Renal hemodynamic dysfunction and neuropathy in longstanding type 1 diabetes: Results from the Canadian study of longevity in type 1 diabetes.

AIMS: To determine the relationship between renal hemodynamic function and neuropathy in adults with ≥50-years of type 1 diabetes (T1D) compared to nondiabetic controls. METHODS: 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 (RA) and efferent (RE) arteriolar resistances were estimated using the Gomez equations in 74 participants with T1D and in 75 controls. Diabetic kidney disease (DKD) non-resistors were defined by eGFRMDRD < 60 ml/min/1.73 m2 or 24-h urine albumin excretion >30 mg/day. Linear regression was applied to examine the relationships between renal function (dependent variable) and neuropathy measures (independent variable), adjusted for age, sex, HbA1c, systolic blood pressure, low density lipoprotein cholesterol, and 24-h urine albumin to creatinine ratio. RESULTS: Higher mTCNS associated with lower renal blood flow (ß ± SE:-9.29 ± 4.20, p = 0.03) and greater RE (ß ± SE:32.97 ± 15.43, p = 0.04) in participants with T1D, but not in controls. DKD non-resistors had a higher mTCNS and worse measures of corneal nerve morphology compared to those without DKD. Renal hemodynamic parameters did not associate with autonomic nerve function. CONCLUSIONS: Although 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.

The association between physical activity time and neuropathy in longstanding type 1 diabetes: A cross-sectional analysis of the Canadian study of longevity in type 1 diabetes.

AIM: 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. METHODS: 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. RESULTS: Participants were 66 ± 8 years old with diabetes duration of 54 [52,58] years, HbA1c was 7.3 ± 0.8, 65(89%) had DSPN. Weekly PA time was 156 ± 132 min, and 35(47%) reported ≧150 min/week. Participants with DSPN reported lower PA time compared to individuals without DSPN (141 ± 124 min/week vs. 258 ± 129 min/week; p = 0.015). PA time was associated with better cooling detection threshold (r = 0.24; p = 0.043), peroneal and sural amplitude (r = 0.36; p = 0.0017, rs = 0.26; p = 0.024) and conduction velocity (rs = 0.28; p = 0.015, r = 0.23; p = 0.050). Linear regression adjusting for age and HbA1c, showed that for each 30-min of PA there was a 0.09mv higher peroneal amplitude (p = 0.032) and 0.048 ms lower peroneal F-wave latency (p = 0.022). CONCLUSION: In 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.

Relationships between inflammation, hemodynamic function and RAAS in longstanding type 1 diabetes and diabetic kidney disease.

The renin angiotensin aldosterone system (RAAS) is associated with renal disease and inflammation in a diabetes setting, however, little is known about the implicated mechanisms in individuals with long standing diabetes. Accordingly, our aim was to perform an observational study to quantify urinary excretion of inflammatory biomarkers in participants with long standing type 1 diabetes (T1D) (with and without diabetic kidney disease [DKD]) and controls, at baseline and in response to RAAS activation. GFRINULIN, ERPFPAH, and 42 urine inflammatory biomarkers were measured in 74 participants with T1D for ≥50 years (21 with DKD and 44 without DKD [DKD resistors]) and 73 healthy controls. Additionally, inflammatory biomarkers were measured before and after an angiotensin II infusion (ANGII, 1 ng∙kg-1∙min-1). Significantly lower urinary excretion of cytokines (IL-18, IL-1RA, IL-8), chemokines (MCP1, RANTES) and growth factors (TGF-α, PDGFAA, PDGFBB, VEGF-A) was observed in participants with T1D at baseline compared to controls. Urinary IL-6 was higher in DKD than in DKD resistors in an exploratory analysis unadjusted for multiple comparisons. In T1D only, lower GFRINULIN correlated with greater excretion of proinflammatory biomarkers (IL-18, IP-10, & RANTES), growth factors (PDGF-AA & VEGFAA), and chemokines (eotaxin & MCP-1). ANGII increased 31 of 42 inflammatory biomarkers in T1D vs controls (p < 0.05), regardless of DKD resistor status. In conclusion, lower GFR and intra-renal RAAS activation were associated with increased inflammation even after longstanding T1D. The increased urinary IL-6 in patients with DKD requires further investigation to determine whether IL-6 is a candidate protective biomarker for prognostication or targeted therapy in DKD.

Renal physiology of glucose handling and therapeutic implications.

The rationale for using sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes (T2D) has evolved over the last decade. Due to the effects on glucosuria and body weight loss, SGLT2 inhibitors were originally approved for glycemic control in T2D. Since glucosuria is attenuated in chronic kidney disease (CKD) Stages 3-5, initial regulatory approval for SGLT2 inhibitor use was limited to patients with T2D and preserved estimated glomerular filtration rate. Over time, however, it has become increasingly apparent that these therapies have a variety of important pharmacodynamic and clinical effects beyond glycemic lowering, including antihypertensive and antialbuminuric properties, and the ability to reduce glomerular hypertension. Importantly, these sodium-related effects are preserved across CKD stages, despite attenuated glycemic effects, which are lost at CKD Stage 4. With the completion of cardiovascular (CV) outcome safety trials-EMPA-REG OUTCOME, CANVAS Program and DECLARE TIMI-58-in addition to reductions in CV events, SGLT2 inhibition consistently reduces hard renal endpoints. Importantly, these CV and renal effects are independent of glycemic control. Subsequent data from the recent CREDENCE trial-the first dedicated renal protection trial with SGLT-2 inhibition-demonstrated renal and CV benefits in albuminuric T2D patients, pivotal results that have expanded the clinical importance of these therapies. Ongoing trials will ultimately determine whether SGLT2 inhibition will have a role in renal protection in other clinical settings, including nondiabetic CKD and type 1 diabetes.

Glucagon-Like Peptide-1 Receptor Agonists in Adult Patients With Type 2 Diabetes: Review of Cardiovascular Outcome Trials.

People with type 2 diabetes are at heightened risk for developing cardiovascular (CV) events. CV disease is the leading cause of premature death among adults with type 2 diabetes. Unfortunately, historically, some antidiabetes agents were implicated in worsening CV function, despite improving glycemic and metabolic control. Accordingly, over a decade ago, health regulatory bodies modified approval requirements for novel antidiabetes pharmacotherapies, requiring prospective evaluation of CV safety through cardiovascular outcome trials (CVOTs). To meet regulatory requirements, CVOTs were primarily designed around establishing CV safety by demonstrating noninferiority to placebo in addition to standard of care, without significant differences in blood glucose. If appropriately designed and powered, however, these CVOTs could also determine superiority, and hence CV protection. Although many of these CVOTs were initiated several years ago, the recent reporting of the results for these CVOTs has been pivotal and practice-changing. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are one such class of antidiabetes therapies, wherein multiple GLP-1RA CVOTs, but interestingly, not all, have demonstrated CV benefits. In this review, we provide a comprehensive summary of all the reported CVOTs completed with GLP-1RAs to date. Although it remains unclear why some GLP-1RAs are associated with reducing CV events, whereas others have been consistent with CV safety alone, we highlight and provide an overview of some key differences between the various GLP-1RAs and their respective CVOTs and possible implications of study design differences. We also speculate on potential mechanisms of action for glucagon-like peptide-1 receptor signalling in the CV system.

Estimating GFR by Serum Creatinine, Cystatin C, and ß2-Microglobulin in Older Adults: Results From the Canadian Study of Longevity in Type 1 Diabetes.

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 ß2-microglobulin (ß2M) 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 ß2M, 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 ß2M (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 (<60, 60-69, ≥70 years). All equations demonstrated greater bias across higher ranges of mGFR (60-89, 90-119, ≥120 ml/min per 1.73 m2). Results were similar between T1D and controls except that ß2M had lower performance in T1D. CONCLUSION: Better estimates of GFR in older adults are needed for research and clinical practice, as this subgroup of the population has an amplified risk for the development of chronic kidney disease (CKD) that requires accurate GFR estimation methods.

Elevated plasma cyclic guanosine monophosphate may explain greater efferent arteriolar tone in adults with longstanding type 1 diabetes: A brief report.

Cyclic guanosine monophosphate (cGMP) influences intrarenal hemodynamics in animal models, but the relationship between cGMP and renal function in adults with type 1 diabetes (T1D) remains unclear. In this study, plasma cGMP correlated with efferent arteriolar resistance, effective renal plasma flow, and renal vascular resistance in adults with T1D.

Risk factors for diabetic kidney disease in adults with longstanding type 1 diabetes: results from the Canadian Study of Longevity in Diabetes.

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 <60/mL/min/1.73 m2 and/or 24-h albumin excretion >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.

Bone mineral density in patients with longstanding type 1 diabetes: Results from the Canadian Study of Longevity in Type 1 Diabetes.

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 ±â€¯0.8%. T1D females had higher LS T-scores compared to female controls (-0.3 ±â€¯1.2 vs. -1.1 ±â€¯1.4, p = 0.014), lower FN T-scores (-1.5 ±â€¯1.0 vs. -1.2 ±â€¯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.

Renal Hemodynamic Function and RAAS Activation Over the Natural History of Type 1 Diabetes.

RATIONALE & OBJECTIVE: The renin-angiotensin-aldosterone system (RAAS) is associated with renal and cardiovascular disease in diabetes. Unfortunately, early RAAS blockade in patients with type 1 diabetes mellitus (T1DM) does not prevent the development of complications. We sought to examine the role of hyperfiltration and RAAS activation across a wide range of T1DM duration to better understand renal hemodynamic status in patients with T1DM. STUDY DESIGN: Post hoc analysis of blood samples. SETTING & PARTICIPANTS: 148 Canadian patients with T1DM: 28 adolescents (aged 16.2±2.0 years), 54 young adults (25.4±5.6 years), and 66 older adults (65.7±7.5 years) studied in a clinical investigation unit. EXPOSURE: Angiotensin II infusion (1ng/kg/min; a measure of RAAS activation) during a euglycemic clamp. OUTCOMES: Glomerular filtration rate measured using inulin clearance, effective renal plasma flow measured using para-aminohippurate, afferent (RA) and efferent (RE) arteriolar resistances, and glomerular hydrostatic pressure estimated using the Gomez equations. RESULTS: In a stepwise fashion, glomerular filtration rate, effective renal plasma flow, and glomerular hydrostatic pressure were higher, while renal vascular resistance and RA were lower in adolescents versus young adults versus older adults. RE was similar in adolescents versus young adults but was higher in older adults. Angiotensin II resulted in blunted renal hemodynamic responses in older adults (renal vascular resistance increase of 3.3% ± 1.6% vs 4.9% ± 1.9% in adolescents; P<0.001), suggesting a state of enhanced RAAS activation. LIMITATIONS: Homogeneous study participants limit the generalizability of findings to other populations. Studying older adult participants with T1DM may be associated with a survivorship bias. CONCLUSIONS: A state of relatively low RAAS activity and predominant afferent dilation rather than efferent constriction characterize early adolescents and young adults with T1DM. This state of endogenous RAAS inactivity in early T1DM may explain why pharmacologic blockade of this neurohormonal system is often ineffective in reducing kidney disease progression in this setting. Older adults with long-standing T1DM who have predominant afferent constriction and RAAS activation may experience renoprotection from therapies that target the afferent arteriole. Further work is required to understand the potential role of non-RAAS pharmacologic agents that target RA in patients with early and long-standing T1DM.

Association between uric acid, renal haemodynamics and arterial stiffness over the natural history of type 1 diabetes.

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 < 0.001). Higher PUA correlated with lower GFR only in older adults, even after correcting for age, glycated haemoglobin and sex (ß = -2.12 ± 0.56; P = 0.0003), but not in adolescents or young adults. Higher PUA correlated with lower carotid AIx (ß = -1.90, P = 0.02) in adolescents. In contrast, PUA correlated with higher cfPWV (P = 0.02) and higher plasma renin (P = 0.01) in older adults with T1D. CONCLUSIONS: The relationship between higher PUA with lower GFR, increased arterial stiffness and renin angiotensin aldosterone system (RAAS) activation was observed only in older adults with longstanding T1D. T1D duration may modify the association between PUA, renal haemodynamic function and RAAS activation, leading to renal vasoconstriction and ischaemia. Further work must determine whether pharmacological PUA-lowering prevents or reverses injurious haemodynamic and neurohormonal sequelae of longstanding T1D, thereby improving clinical outcomes.

Retinopathy and RAAS Activation: Results From the Canadian Study of Longevity in Type 1 Diabetes.

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.

The relationships between markers of tubular injury and intrarenal haemodynamic function in adults with and without type 1 diabetes: Results from the Canadian Study of Longevity in Type 1 Diabetes.

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 <30 mg/d urine albumin excretion) and 22 had DKD, in addition to 73 control participants. GFRINULIN and ERPFPAH were measured, RVR was calculated, and afferent (RA )/efferent (RE ) areteriolar resistances were derived from Gomez equations. Plasma neutrophil gelatinase-associated lipocalin (NGAL), ß2 microglobulin (B2M), osteopontin (OPN) and uromodulin (UMOD) were measured using immunoassay kits from Meso Scale Discovery. RESULTS: Plasma NGAL, B2M and OPN were higher and UMOD was lower in DKD patients vs DKD resistors and non-diabetic controls. In participants with T1D, plasma NGAL inversely correlated with GFR (r = -0.33; P = 0.006) and ERPF (r = -0.34; P = 0.006), and correlated positively with RA (r = 0.26; P = 0.03) and RVR (r = 0.31; P = 0.01). In participants without T1D, NGAL and B2M inversely correlated with GFR (NGAL r = -0.18; P = 0.13 and B2M r = -0.49; P < 0.0001) and with ERPF (NGAL r = -0.19; P = 0.1 and B2M r = -0.42; P = 0.0003), and correlated positively with RA (NGAL r = 0.19; P = 0.10 and B2M r = 0.3; P = 0.01) and with RVR (NGAL r = 0.20; P = 0.09 and B2M r = 0.34; P = 0.003). Differences were significant after adjusting for age, sex, HbA1c, SBP and LDL. There were statistical interactions between T1D status, B2M and intrarenal haemodynamic function (P < 0.05). CONCLUSIONS: Elevated NGAL relates to intrarenal haemodynamic dysfunction in T1D, whereas elevated NGAL and B2M relate to intrarenal haemodynamic dysfunction in adults without T1D. These data may define a diabetes-specific interplay between tubular injury and intrarenal haemodynamic dysfunction.

Atherosclerosis and Microvascular Complications: Results From the Canadian Study of Longevity in Type 1 Diabetes.

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 (<300 AU) CAC and was stratified by diabetes status. A comparator group without diabetes (n = 73) matched for age and sex also underwent all study procedures except for retinal imaging. 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.

Sex differences in neuropathic pain in longstanding diabetes: Results from the Canadian Study of Longevity in Type 1 Diabetes.

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 ±â€¯9 years, median diabetes duration 53[51,58] years, mean HbA1c 7.5 ±â€¯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 < 0.001], and more prevalent in females compared to males [87(42%) vs. 41(27%), p = 0.003]. Independent of the presence of NEUROPATHYMNSI-Q and other factors, female sex was associated with the presence of neuropathic pain [OR 2.68 (95% CI 1.4-5.0), p = 0.002]. 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.