BackgroundConfirmation of diabetic sensorimotor polyneuropathy (DSP) relies on standard nerve conduction studies (NCS) performed in specialized clinics. We explored the utility of a point-of-care device (POCD) for DSP detection by nontechnical personnel and a validation of diagnostic thresholds with those observed in a normative database.Research Design and Methods44 subjects with type 1 and type 2 diabetes underwent standard NCS (reference method). Two nontechnical examiners measured sural nerve amplitude potential (SNAP) and conduction velocity (SNCV) using the POCD. Reliability was determined by intraclass correlation coefficients (ICC [2], [1]). Validity was determined by Bland-Altman analysis and receiver operating characteristic curves.ResultsThe 44 subjects (50% female) with mean age 56±18 years had mean SNAP and SNCV of 8.0±8.6 µV and 41.5±8.2 m/s using standard NCS and 8.0±8.2 µV and 49.9±11.1 m/s using the POCD. Intrarater reproducibility ICC values were 0.97 for SNAP and 0.94 for SNCV while interrater reproducibility values were 0.83 and 0.79, respectively. Mean bias of the POCD was −0.1±3.6 µV for SNAP and +8.4±6.4 m/s for SNCV. A SNAP of ≤6 µV had 88% sensitivity and 94% specificity for identifying age-and height-standardized reference NCS values, while a SNCV of ≤48 m/s had 94% specificity and 82% sensitivity. Abnormality in one or more of these thresholds was associated with 95% sensitivity and 71% specificity for identification of DSP according to electrophysiological criteria.ConclusionsThe POCD demonstrated excellent reliability and acceptable accuracy. Threshold values for DSP identification validated those of published POCD normative values. We emphasize the presence of measurement bias – particularly for SNCV – that requires adjustment of threshold values to reflect those of standard NCS.

BackgroundWe recently reported improved glycemic control with reduced insulin dose in subjects with type 1 diabetes treated with the sodium glucose co-transporter-2 inhibitor empagliflozin. To further characterize the effects, we analyzed diurnal glycemic patterns by continuous glucose monitoring (CGM).MethodsIn an 8-week single-arm open-label pilot study of empagliflozin, we compared ambulatory glucose profiles produced from CGM data during 2-week intervals in a placebo run-in baseline period, end-of-treatment, and post-treatment. Change in glycemic exposure was evaluated by area under the median curve according to time of day (AUCTOTAL 12:00am-11:55pm; AUCDAY 7:05am-10:55pm, AUCNIGHT 11:00pm-7:00am), as well as glycemic variability, glycemic stability and time-in-target (≥70 to ≤140mg/dL).ResultsThe 40 patients (26 on insulin pump) were aged 24±5 years and BMI 24.5±3.2 kg/m2. Consistent with the observed HbA1c decrease (8.0±0.9% to 7.6±0.9%, p<0.0001), normalized AUCTOTAL CGM decreased from 153.7±25.4 to 149.0±30.2mg/dL∙h at end-of-treatment (p = 0.31), and significantly increased post-treatment (164.1±29.5mg/dL∙h, p = 0.02). The numerical decrease in normalized AUCNIGHT (152.0±36.6 to 141.9±34.4mg/dL∙h, p = 0.13) exceeded AUCDAY (154.5±24.5 to 152.6±30.4mg/dL∙h, p = 0.65). Trends toward lower glycemic variability (83.1±18.9 to 75.6±28.6mg/dL, p = 0.06) and little change in glycemic stability (10.8±3.6 to 10.3±4.5mg/dL/h, p = 0.51) were observed. When empagliflozin was discontinued, these worsened relative to baseline (89.3±19.3mg/dL, p = 0.04 and 11.8±3.7mg/dL/hr, p = 0.08). Time-in-target numerically increased (40.2±11.9 to 43.1±13.5%, p = 0.69) at end-of-treatment but reversed post-treatment. Findings were similar on stratification of pump and MDI subjects.ConclusionsWe observed that empagliflozin was associated with patterns of improved nighttime glycemia more prominent than daytime.Trial RegistrationClinicaltrials.gov NCT01392560

Increased protein glycation, oxidation and nitration is linked to the development of diabetic nephropathy. We reported levels of serum protein glycation, oxidation and nitration and related hydrolysis products, glycation, oxidation and nitration free adducts in patients with type 1 diabetes (T1DM) during onset of microalbuminuria (MA) from the First Joslin Kidney Study, a prospective case-control study of patients with T1DM with and without early decline in GFR. Herein we report urinary excretion of the latter analytes and related fractional excretion values, exploring the link to MA and early decline in GFR. We recruited patients with T1DM and normoalbuminuria (NA) (n = 30) or new onset MA with and without early GFR decline (n = 22 and 33, respectively) for this study. We determined urinary protein glycation, oxidation and nitration free adducts by stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry (LC-MS/MS) and deduced fractional excretion using reported plasma levels and urinary and plasma creatinine estimates. We found urinary excretion of pentosidine was increased ca. twofold in patients with MA, compared to normoalbuminuria (0.0442 vs 0.0103 nmol/mg creatinine, P < 0.0001), and increased ca. threefold in patients with early decline in GFR, compared to patients with stable GFR (0.0561 vs 0.0176 nmol/mg creatinine, P < 0.01). Urinary excretion of all other analytes was unchanged between the study groups. Remarkably, fractional excretions of 6 lysine and arginine-derived glycation free adducts were higher in patients with early decline in GFR, compared to those with stable GFR. Impaired tubular reuptake of glycation free adducts by lysine and arginine transporter proteins in patients with early GFR decline is likely involved. We conclude that higher fractional excretions of glycation adducts are potential biomarkers for early GFR decline in T1DM and MA. Measurement of these analytes could provide the basis for identifying patients at risk of early decline in renal function to target and intensify renoprotective treatment. Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD) and severely decreases likelihood of long-term survival of patients with diabetes 1. It has high occurrence linked to a high global prevalence of diabetes, 5% type 1 diabetes mellitus (T1DM) and 95% type 2 diabetes mellitus (T2DM), with ca. 40% of patients with diabetes developing diabetic nephropathy 2,3. Approximately half of patients with diabetic nephropathy progress to diabetic kidney disease and ESRD with increased risk of potentially fatal cardiovascular disease. Current treatment guidelines address modifiable risk factors through intensification of control of glycemic status, blood