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.

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.

Omega-3 Nutrition Therapy for the Treatment of Diabetic Sensorimotor Polyneuropathy.

Despite advances in clinical and translational research, an effective therapeutic option for diabetic sensorimotor polyneuropathy (DSP) has remained elusive. The pathomechanisms of DSP are diverse, and along with hyperglycemia, the roles of inflammatory mediators and lipotoxicity in the development of microangiopathy have been well elucidated. Omega-3 (n-3) polyunsaturated fatty acids (PUFA) are essential fatty acids with a vital role in a number of physiological processes, including neural health, membrane structure integrity, anti-inflammatory processes, and lipid metabolism. Identification of n-3 PUFA derived specialised proresolving mediators (SPM), namely resolvins, neuroprotectin, and maresins which also favour nerve regeneration, have positioned n-3 PUFA as potential treatment options in DSP. Studies in n-3 PUFA treated animal models of DSP showed positive nerve benefits in functional, electrophysiological, and pathological indices. Clinical trials in humans are limited, but recent proof-of-concept evidence suggests n-3 PUFA has a positive effect on small nerve fibre regeneration with an increase in the small nerve fiber measure of corneal nerve fibre length (CNFL). Further randomized control trials with a longer duration of treatment, higher n-3 PUFA doses, and more rigorous neuropathy measures are needed to provide a definitive understanding of the benefits of n-3 PUFA supplementation in DSP.

Corneal Confocal Microscopy Predicts the Development of Diabetic Neuropathy: A Longitudinal Diagnostic Multinational Consortium Study.

OBJECTIVE: Corneal nerve fiber length (CNFL) has been shown in research studies to identify diabetic peripheral neuropathy (DPN). In this longitudinal diagnostic study, we assessed the ability of CNFL to predict the development of DPN. RESEARCH DESIGN AND METHODS: From a multinational cohort of 998 participants with type 1 and type 2 diabetes, we studied the subset of 261 participants who were free of DPN at baseline and completed at least 4 years of follow-up for incident DPN. The predictive validity of CNFL for the development of DPN was determined using time-dependent receiver operating characteristic (ROC) curves. RESULTS: A total of 203 participants had type 1 and 58 had type 2 diabetes. Mean follow-up time was 5.8 years (interquartile range 4.2-7.0). New-onset DPN occurred in 60 participants (23%; 4.29 events per 100 person-years). Participants who developed DPN were older and had a higher prevalence of type 2 diabetes, higher BMI, and longer duration of diabetes. The baseline electrophysiology and corneal confocal microscopy parameters were in the normal range but were all significantly lower in participants who developed DPN. The time-dependent area under the ROC curve for CNFL ranged between 0.61 and 0.69 for years 1-5 and was 0.80 at year 6. The optimal diagnostic threshold for a baseline CNFL of 14.1 mm/mm2 was associated with 67% sensitivity, 71% specificity, and a hazard ratio of 2.95 (95% CI 1.70-5.11; P < 0.001) for new-onset DPN. CONCLUSIONS: CNFL showed good predictive validity for identifying patients at higher risk of developing DPN ∼6 years in the future.

Baseline omega-3 level is associated with nerve regeneration following 12-months of omega-3 nutrition therapy in patients with type 1 diabetes.

AIM: Omega-3 (n-3) polyunsaturated fatty-acids are essential for the development and maintenance of nerve function, but the relationship of plasma n-3 to the presence of diabetic distal-symmetric-polyneuropathy (DSP) and the effect of n-3 therapy on plasma levels and small nerve fibre morphology in T1D are unknown. METHODS: Participants with T1D (n = 40, 53% female, aged (mean ±â€¯SD) 48 ±â€¯14 years, BMI 28.1 ±â€¯5.8 kg/m2, diabetes duration 27 ±â€¯18 years), 23 of whom had DSP, took seal-oil (10 mL/day; 750 mg eicosapentaenoic acid (EPA), 560 mg docosapentaenoic acid (DPAn-3), and 1020 mg docosahexaenoic acid (DHA)) for 12-months in a single-arm open-label study. The improvement in corneal nerve fibre length (CNFL) (primary outcome) was previously reported. In this secondary analysis, plasma n-3s were measured at baseline, 4, 8 and 12-months. RESULTS: At baseline, participants with DSP had lower DHA than those without (1.73 ±â€¯0.89 vs. 2.27 ±â€¯0.70%, p = 0.049). Twelve-months seal-oil therapy increased mean plasma EPA by 185%, DPA by 29%, DHA by 79% (p < 0.001) and CNFL by 29% (p = 0.001). Change in CNFL was positively associated with higher baseline total n-3 (Spearman's correlation coefficient r = 0.41, p = 0.013), DPA (r = 0.33, p = 0.047) and DHA (r = 0.42, p = 0.012). CONCLUSION: In conclusion, low plasma DHA was associated with prevalent DSP, n-3 therapy increased blood n-3 levels and higher baseline n-3s were associated with greater nerve regeneration.

Rapid Corneal Nerve Fiber Loss: A Marker of Diabetic Neuropathy Onset and Progression.

OBJECTIVE: Corneal nerve fiber length (CNFL) represents a biomarker for diabetic distal symmetric polyneuropathy (DSP). We aimed to determine the reference distribution of annual CNFL change, the prevalence of abnormal change in diabetes, and its associated clinical variables. RESEARCH DESIGN AND METHODS: We examined 590 participants with diabetes (399 with type 1 diabetes [T1D] and 191 with type 2 diabetes [T2D]) and 204 control patients without diabetes with at least 1 year of follow-up and classified them according to rapid corneal nerve fiber loss (RCNFL) if CNFL change was below the 5th percentile of the control patients without diabetes. RESULTS: Control patients without diabetes were 37.9 ± 19.8 years old, had median follow-up of three visits over 3.0 years, and mean annual change in CNFL was -0.1% (90% CI -5.9% to 5.0%). RCNFL was defined by values exceeding the 5th percentile of 6% loss. Participants with T1D were 39.9 ± 18.7 years old, had median follow-up of three visits over 4.4 years, and mean annual change in CNFL was -0.8% (90% CI -14.0% to 9.9%). Participants with T2D were 60.4 ± 8.2 years old, had median follow-up of three visits over 5.3 years, and mean annual change in CNFL was -0.2% (90% CI -14.1% to 14.3%). RCNFL prevalence was 17% overall and was similar by diabetes type (64 T1D [16.0%], 37 T2D [19.4%], P = 0.31). RNCFL was more common in those with baseline DSP (47% vs. 30% in those without baseline DSP, P = 0.001), which was associated with lower peroneal conduction velocity but not with baseline HbA1c or its change over follow-up. CONCLUSIONS: An abnormally rapid loss of CNFL of 6% per year or more occurs in 17% of diabetes patients. RCNFL may identify patients at highest risk for the development and progression of DSP.

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.

Effect of omega-3 supplementation on neuropathy in type 1 diabetes: A 12-month pilot trial.

OBJECTIVE: To test the hypothesis that 12 months of seal oil omega-3 polyunsaturated fatty acids (ω-3 PUFA) supplementation will stop the known progression of diabetic sensorimotor polyneuropathy (DSP) in type 1 diabetes mellitus (T1DM). METHODS: Individuals with T1DM and evidence of DSP as determined by a Toronto Clinical Neuropathy Score ≥1 were recruited to participate in a single-arm, open-label trial of seal oil ω-3 PUFA supplementation (10 mL·d-1; 750 mg eicosapentaenoic acid, 560 mg docosapentaenoic acid, and 1,020 mg docosahexaenoic acid) for 1 year. The primary outcome was the 1-year change in corneal nerve fiber length (CNFL) measured by in vivo corneal confocal microscopy, with sensory and nerve conduction measures as secondary outcomes. RESULTS: Forty participants (53% female), aged 48 ± 14 years, body mass index 28.1 ± 5.8 with diabetes duration of 27 ± 18 years, were enrolled. At baseline, 23 participants had clinical DSP and 17 did not. Baseline CNFL was 8.3 ± 2.9 mm/mm2 and increased 29% to 10.1 ± 3.7 mm/mm2 (p = 0.002) after 12 months of supplementation. There was no change in nerve conduction or sensory function. CONCLUSIONS: Twelve months of ω-3 supplementation was associated with increase in CNFL in T1DM. CLINICALTRIALSGOVIDENTIFIER: NCT02034266. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with T1DM and evidence of DSP, 12 months of seal oil omega-3 supplementation increases CNFL.

Using in vivo corneal confocal microscopy to identify diabetic sensorimotor polyneuropathy risk profiles in patients with type 1 diabetes.

OBJECTIVE: Diabetic sensorimotor peripheral neuropathy (DSP) is the most prevalent complication in diabetes mellitus. Identifying DSP risk is essential for intervening early in the natural history of the disease. Small nerve fibers are affected earliest in the disease progression and evidence of this damage can be identified using in vivo corneal confocal microscopy (IVCCM). RESEARCH DESIGN AND METHODS: We applied IVCCM to a cohort of 40 patients with type 1 diabetes to identify their DSP risk profile. We measured standard IVCCM parameters including corneal nerve fiber length (CNFL), and performed nerve conduction studies and quantitative sensory testing. RESULTS: 40 patients (53% female), with a mean age of 48±14, BMI 28.1±5.8, and diabetes duration of 27±18 years were enrolled between March 2014 and June 2015. Mean IVCCM CNFL was 12.0±5.2 mm/mm2 (normal ≥15 mm/mm2). Ten patients (26%) without DSP were identified as being at risk of future DSP with mean CNFL 11.0±2.1 mm/mm2. Six patients (15%) were at low risk of future DSP with mean CNFL 19.0±4.6 mm/mm2, while 23 (59%) had established DSP with mean CNFL 10.5±4.5 mm/mm2. CONCLUSIONS: IVCCM can be used successfully to identify the risk profile for DSP in patients with type 1 diabetes. This methodology may prove useful to classify patients for DSP intervention clinical trials.

Neuromuscular adaptations to sprint interval training and the effect of mammalian omega-3 fatty acid supplementation.

PURPOSE: Sprint interval training (SIT) stimulates rapid metabolic adaptations within skeletal muscle but the nature of neuromuscular adaptions is unknown. Omega-3 polyunsaturated fatty acids (N-3 PUFA) are suggested to enhance neuromuscular adaptations to exercise. METHODS: We measured the neuromuscular adaptations to SIT (Study-1) and conducted a placebo-controlled randomized double blinded study to determine the effect of N-3 PUFA supplementation on neuromuscular adaptations to SIT (Study-2). In Study-1, seven active men (24.4 ± 2.6 years, VO2 peak 43.8 ± 8.7 ml kg min-1) completed 2-weeks of SIT with pre- and post-training 10 km cycling time trials (TT). In Study-2, 30 active men (24.5 ± 4.2 years, VO2 peak 41.0 ± 5.1 ml kg min-1) were randomly assigned to receive N-3 PUFA (2330 mg day-1) (n = 14) or olive oil (n = 16) during 2-weeks of SIT with pre- and post-training TTs. Four week post-training, a SIT session and TT were also performed. Change in neuromuscular function was assessed from resting twitches, quadriceps maximal voluntary contraction (MVC) force, and potentiated twitch force (Q tw). RESULTS: Study-1 showed that SIT did not elicit significant neuromuscular adaptations. Study-2 showed that N-3 PUFA supplementation had no significant effect on neuromuscular adaptations. Training caused lower MVC force [mean ± SD; N-3 PUFA -9 ± 11%, placebo -9 ± 13% (p < 0.05 time)] and Q tw peripheral fatigue [N-3 PUFA -10 ± 19%, placebo -14 ± 13% (p < 0.05 time)]. TT time was lower after training in all groups [Study-1 -10%, Study-2 N-3 PUFA -8%, placebo -12% (p < 0.05 time)]. CONCLUSION: Two weeks of SIT improved TT performance in the absence of measurable neuromuscular adaptations. N-3 PUFA supplementation had no significant effect on SIT training adaptations.

21 days of mammalian omega-3 fatty acid supplementation improves aspects of neuromuscular function and performance in male athletes compared to olive oil placebo.

BACKGROUND: Omega-3 polyunsaturated fatty acids (N-3) are essential nutrients for human health and integral components of neural tissues. There is evidence that N-3 supplementation may benefit exercise performance, however, no study has investigated the ergogenic potential of N-3 supplementation. Our objective was to determine the effect of short-term N-3 supplementation on neuromuscular-function and physical-performance in well-trained athletes. METHODS: Male athletes (n = 30), 25 years (SD 4.6), training 17 h(.)wk(-1) (SD 5) completed this randomized, placebo-controlled, parallel-design study. At baseline a blood sample was collected, maximal voluntary isometric contractions (MVC) with electromyography (EMG) recordings were measured, and participants underwent various performance tests including a Wingate test and 250 kJ time trial (TT) followed by repeated MVC and EMG measurement. Participants were then randomly assigned to receive N-3 (5 ml seal oil, 375 mg EPA, 230 mg DPA, 510 mg DHA) or placebo (5 ml olive oil) for 21-days after which baseline testing was repeated. The magnitude-based inference approach was used to estimate the probability that N-3 had a beneficial effect on neuromuscular-function and performance of at least ±1%. Data are shown as mean ± 90% confidence-interval. RESULTS: Plasma EPA was higher on N-3 than placebo (p = 0.004) but the increases in DPA and DHA were not significant (p = 0.087, p = 0.058). N-3 supplementation had an unclear effect on MVC force (4.1 ± 6.6%) but increased vastus lateralis EMG by 20 ± 18% vs placebo (very likely beneficial). N-3 supplementation reduced Wingate percent power drop by 4.76 ± 3.4 % vs placebo (very likely beneficial), but the difference in TT performance was unclear (-1.9 ± 4.8%). CONCLUSION: Our data indicates N-3 PUFA supplementation improved peripheral neuromuscular function and aspects of fatigue with an unclear effect on central neuromuscular function. Clinical trial registration NCT0201433.

Mild eccentric exercise increases Hsp72 content in skeletal muscles from adult and late middle-aged rats.

The loss of muscle mass with age or sarcopenia contributes to increased morbidity and mortality. Thus, preventing muscle loss with age is important for maintaining health. Hsp72, the inducible member of the Hsp70 family, is known to provide protection to skeletal muscle and can be increased by exercise. However, ability to increase Hsp72 by exercise is intensity-dependent and appears to diminish with advanced age. Thus, other exercise modalities capable of increasing HSP content and potentially preventing the age related loss of muscle need to be explored. The purpose of this study was to determine if the stress from one bout of mild eccentric exercise was sufficient to elicit an increase in Hsp72 content in the vastus intermedius (VI) and white gastrocnemius (WG) muscles, and if the Hsp72 response differed between adult and late middle-aged rats. To do this, 30 adult (6 months) and late middle-aged (24 months) F344BN rats were randomly divided into three groups (n = 6/group): control (C), level exercise (16 m x min(-1)) and eccentric exercise (16 m x min(-1), 16 degree decline). Exercised animals were sacrificed immediately post-exercise or after 48 hours. Hematoxylin and Eosin staining was used to assess muscle damage, while Western Blotting was used to measure muscle Hsp72 content. A nested ANOVA with Tukey post hoc analysis was performed to determine significant difference (p < 0.05) between groups. Hsp72 content was increased in the VI for both adult and late middle-aged rats 48 hours after eccentric exercise when compared to level and control groups but no differences between age groups was observed. Hsp72 was not detected in the WG following any type of exercise. In conclusion, mild eccentric exercise can increase Hsp72 content in the rat VI muscle and this response is maintained into late middle-age.