Prolonged impacts of sodium glucose cotransporter-2 inhibitors on metabolic dysfunction-associated steatotic liver disease in type 2 diabetes: a retrospective analysis through magnetic resonance imaging.

The beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in people with type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD) have been suggested in several reports based on serological markers, imaging data, and histopathology associated with steatotic liver disease. However, evidence regarding their long-term effects is currently insufficient. In this retrospective observational study, 34 people with T2D and MASLD, treated with SGLT2 inhibitors, were examined by proton density fat fraction derived by magnetic resonance imaging (MRI-PDFF) and other clinical data before, one year after the treatment. Furthermore, 22 of 34 participants underwent MRI-PDFF five years after SGLT2 inhibitors were initiated. HbA1c decreased from 8.9 ± 1.8% to 7.8 ± 1.0% at 1 year (p = 0.006) and 8.0 ± 1.1% at 5 years (p = 0.122). Body weight and fat mass significantly reduced from baseline to 1 and 5 year(s), respectively. MRI-PDFF significantly decreased from 15.3 ± 7.8% at baseline to 11.9 ± 7.6% (p = 0.001) at 1 year and further decreased to 11.3 ± 5.7% (p = 0.013) at 5 years. Thus, a 5-year observation demonstrated that SGLT2 inhibitors have beneficial effects on liver steatosis in people with T2D and MASLD.

Arteriolar Hyalinosis Predicts the Onset of Both Macroalbuminuria and Impaired Renal Function in Patients with Type 2 Diabetes.

INTRODUCTION: Arteriolar hyalinosis (AH) has been shown to be associated with albuminuria and GFR. In this study, we investigated whether or not index of AH (IAH) is a predictor of the onset of macroalbuminuria and impaired renal function (eGFR <60 mL/min/1.73 m2 [eGFR <60]) in type 2 diabetic patients with early diabetic nephropathy. METHODS: The study population consisted of 35 patients with type 2 diabetes (25 men; age: 47 ± 9 years; eGFR: 92.7 ± 18.0 mL/min/1.73 m2) with normo- or microalbuminuria who underwent percutaneous renal biopsy. These patients were followed for at least 5 (18 ± 6, range: 6-28) years. The study endpoint was the onset of macroalbuminuria or eGFR <60. Light and electron microscopy-based morphometric analyses were performed to quantitatively evaluate glomerular and interstitial structural changes. RESULTS: During the observation period, 9 out of the 35 patients progressed to macroalbuminuria, and 15 out of the 35 patients developed eGFR <60. The annual rate of eGFR decline was significantly correlated with IAH (r = -0.40, p = 0.016). Kaplan-Meier analysis demonstrated that AH was associated with a significantly higher risk of onset of macroalbuminuria and eGFR <60, and microalbuminuria is associated with the onset of macroalbuminuria but not the onset of eGFR <60. CONCLUSIONS: Aggravated AH is a histological risk factor which predicts the onset of macroalbuminuria and eGFR <60 in patients with type 2 diabetes. These findings provide novel insights into the mechanism of progression of diabetic nephropathy.

Novel clinical associations between time in range and microangiopathies in people with type 2 diabetes mellitus on hemodialysis.

AIMS/HYPOTHESIS: We investigated associations among glucose time in range (TIR, 70-180 mg/dL), glycemic markers and prevalence of diabetic microangiopathy in people with diabetes undergoing hemodialysis (HD). METHODS: A total of 107 people with type 2 diabetes undergoing HD (HbA1c 6.4 %; glycated albumin [GA] 20.6 %) using continuous glucose monitoring were analyzed in this observational and cross-sectional study. RESULTS: HbA1c and GA levels significantly negatively correlated with TIR, and positively correlated with time rate of hyperglycemia, but not with time rate of hypoglycemia. TIR of 70 % corresponded to HbA1c of 6.5 % and GA of 21.2 %. The estimated HbA1c level corresponding to TIR of 70 % in this study was lower than that previously reported in people with diabetes without HD. The prevalence of diabetic neuropathy was not significantly different between people with TIR ≥ 70 % and those with TIR < 70 % (P = 0.1925), but the prevalence of diabetic retinopathy in people with TIR ≥ 70 % was significantly lower than in those with TIR < 70 % (P = 0.0071). CONCLUSION/INTERPRETATION: TIR correlated with HbA1c and GA levels in people with type 2 diabetes on HD. Additionally, a higher TIR resulted in a lower rate of diabetic retinopathy. RESEARCH IN CONTEXT: What is already known about this subject? What is the key question? What are the new findings? How might this impact on clinical practice in the foreseeable future?

Plasma and serum prorenin concentrations in diabetes, hypertension, and renal disease.

Although the renin-angiotensin-aldosterone system plays a crucial role in fluid homeostasis and cardiovascular disease pathophysiology, measurements of plasma prorenin levels are still unavailable in clinical practice. We previously found that prorenin molecules in human blood underwent significant posttranslational modifications and were undetectable using immunological assays that utilized antibodies specifically recognizing unmodified recombinant prorenin. Using a sandwich enzyme-linked immunosorbent assay that captures posttranslationally modified prorenins with their prosegment antibodies, we measured plasma and serum prorenin concentrations in 219 patients with diabetes mellitus, hypertension and/or renal disease and compared them with those of 40 healthy controls. The measured values were not significantly different from those of the healthy controls and were 1,000- to 100,000-fold higher than previously reported levels determined using conventional assay kits. Multiple regression analyses showed that body weight, serum albumin levels, and serum creatinine levels negatively correlated with plasma prorenin levels, while the use of loop diuretics was associated with elevated plasma prorenin levels. Blood pressure, HbA1c, and plasma renin activity were not independent variables affecting plasma prorenin levels. In contrast, serum prorenin levels were unaffected by any of the above clinical parameters. The association of the plasma prorenin concentration with indices reflecting body fluid status suggests the need to scrutinize its role as a biomarker, while serum prorenins are less likely to have immediate diagnostic value.

Discordance in the reduction rate between glycated albumin and glycated hemoglobin levels in type 2 diabetes patients receiving SGLT2 inhibitors.

AIMS: Although the difference in HbA1c reduction between sodium-glucose cotransporter 2 (SGLT2) inhibitors and other oral glucose-lowering agents is relatively small, SGLT2 inhibitors exhibit beneficial cardiorenal protection. This study was based on the hypothesis that changes of HbA1c in patients treated with SGLT2 inhibitors may not accurately reflect an improved glycemic profile. METHODS: Two studies were conducted: 1) a retrospective cohort study of 3039 patients administered with either an SGLT2 or a dipeptidyl peptidase-4 (DPP4) inhibitor for 12 months comparing the changes in glycated albumin (GA) and HbA1c levels and 2) a pilot study of 10 patients whose glycemic dynamics were evaluated using flash glucose monitoring at baseline and 2 months after treatment with an SGLT2 inhibitor. RESULTS: SGLT2 inhibitors reduced GA more markedly than HbA1c in both studies. DPP4 inhibitors decreased both GA and HbA1c to a comparable degree. The mean glucose levels and glycemic standard deviation were significantly reduced after treatment with an SGLT2 inhibitor, in concordance with GA decline, although the lowering of HbA1c was marginal. CONCLUSIONS: Changes in HbA1c levels underestimated the glucose-lowering effect and the diminished glycemic fluctuation induced by SGLT2 inhibitors. Thus, the distinct biomarker roles of GA and HbA1c should be reevaluated.

Glucose control, diabetic retinopathy, and hemodialysis induction in subjects with normo-microalbuminuric type 2 diabetic patients with normal renal function followed for 15 years.

AIMS: A high urinary albumin excretion (UAE) and low glomerular filtration rate (GFR) are risk factors for progressive renal function loss in type 2 diabetic patients. In addition, diabetic retinopathy (DR) is also a risk factor for progressive renal function decline in microalbuminuric type 2 diabetic patients. We aimed to elucidate the factors, including DR, associated with a more severe situation of diabetic nephropathy, i.e., hemodialysis (HD) induction in normo- and microalbuminuric type 2 diabetic patients without renal dysfunction. METHODS: Normo- and microalbuminuric type 2 diabetic patients with normal renal function whose GFRs had been measured by iohexol injection in 1995-1997 and had been followed for over 5 years were analyzed (n = 199). HbA1c levels was divided into HbA1c ≥ 7.0 (n = 146) and <7.0 (n = 53) groups. The UAE levels were classified as normoalbuminuria (NA, n = 114) and microalbuminuria (MA, n = 85). Seventy-two patients had DR, and 96 had hypertension. Patients were followed up for 15.7 ± 6.0 years and frequency of and duration to the HD induction were evaluated. RESULTS: During the study period, 8 patients received HD induction. There were no remarkable differences in the rates of HD induction between patients with and without HbA1c ≥7.0, microalbuminuria, DR or hypertension. A Kaplan-Meier analysis revealed that HbA1c ≥7.0 (p = 0.037) and DR (p = 0.037) were associated with a significantly higher risk of HD induction than HbA1c <7.0 and no DR, respectively while albuminuria grade and hypertension were not associated with the risk of HD induction. There was significant negative correlation between HbA1c and annual decline rate of eGFR and annual decline rate of eGFR in the patients with prepro-proliferative DR (PDR) was significantly higher than that in the patients without DR. In the multivariate analysis, HbA1c and PDR showed significant relationships with the annual decline rate of eGFR. CONCLUSIONS: It was reasonable that poorer glycemic control affected HD induction for 16 years follow-up. However, DR, especially PDR, should also be considered a substantial risk factor for HD induction although microalbuminuria and hypertension did not predict it at the early stage of diabetic nephropathy in type 2 diabetic patients with normal renal function.

Clinical feasibility of remote intermittently scanned continuous glucose monitoring in coronavirus disease 2019 patients with and without diabetes during dexamethasone therapy.

The clinical utility of intermittently scanned continuous glucose monitoring (isCGM) in patients with coronavirus disease 2019 (COVID-19) is unclear. Hence, we investigated the accuracy of isCGM in COVID-19 patients during dexamethasone therapy. We evaluated the accuracy of the FreeStyle Libre via smartphone isCGM device compared to point-of-care (POC) fingerstick glucose level monitoring in 16 patients with COVID-19 (10 with and 6 without diabetes, 13 men; HbA1c 6.9 ± 1.0%). Overall, isCGM correlated well with POC measurements (46.2% and 53.8% within areas A and B of the Parkes error grid, respectively). The overall mean absolute relative difference (MARD) for isCGM compared to POC measurements was 19.4%. The MARDs were 19.8% and 19.7% for POC blood glucose measurements ranging from 70 to 180 mg/dL and >180 mg/dL, respectively. When divided according to the presence and absence of diabetes, both groups of paired glucose measurements showed a good correlation (56.3% and 43.7%, and 27.1% and 72.9% within the A and B areas in patients with and without diabetes, respectively), but the MARD was not significant but higher in patients without diabetes (16.5% and 24.2% in patients with and without diabetes). In conclusion, although isCGM may not be as accurate as traditional blood glucose monitoring, it has good reliability in COVID-19 patients with and without diabetes during dexamethasone therapy.

Hemodialysis-Related Glycemic Disarray Proven by Continuous Glucose Monitoring; Glycemic Markers and Hypoglycemia.

OBJECTIVE: There is a high risk of asymptomatic hypoglycemia associated with hemodialysis (HD) using glucose-free dialysate; therefore, the inclusion of glucose in the dialysate is believed to prevent intradialytic hypoglycemia. However, the exact glycemic fluctuation profiles and frequency of asymptomatic hypoglycemia using dialysates containing >100 mg/dL glucose have not been determined. RESEARCH DESIGN AND METHODS: We evaluated the glycemic profiles of 98 patients, 68 of whom were men, with type 2 diabetes undergoing HD (HbA1c 6.4 ± 1.2%; glycated albumin 20.8 ± 6.8%) with a dialysate containing 100, 125, or 150 mg/dL glucose using continuous glucose monitoring. RESULTS: Sensor glucose level (SGL) showed a sustained decrease during HD, irrespective of the dialysate glucose concentration, and reached a nadir that was lower than the dialysate glucose concentration in 49 participants (50%). Twenty-one participants (21%) presented with HD-related hypoglycemia, defined by an SGL <70 mg/dL during HD and/or between the end of HD and their next meal. All these hypoglycemic episodes were asymptomatic. Measures of glycemic variability calculated using the SGL data (SD, coefficient of variation, and range of SGL) were higher and time below range (<70 mg/dL) was lower in participants who experienced HD-related hypoglycemia than in those who did not, whereas time in range between 70 and 180 mg/dL, time above range (>180 mg/dL), HbA1c, and glycated albumin of the two groups were similar. CONCLUSIONS: Despite the use of dialysate containing 100-150 mg/dL glucose, patients with diabetes undergoing HD experienced HD-related hypoglycemia unawareness frequently. SGL may fall well below the dialysate glucose concentration toward the end of HD.

Assessment of the accuracy of an intermittent-scanning continuous glucose monitoring device in patients with type 2 diabetes mellitus undergoing hemodialysis (AIDT2H) study.

FreeStyle Libre has been approved for use in patients undergoing hemodialysis (HD) in Japan, unlike Europe and the United States; however, evidence regarding its accuracy in such patients is sparse. Forty-one participants with type 2 diabetes undergoing HD were recruited. The overall mean absolute relative difference and mean absolute difference were 23.4% and 33.9 mg/dL, respectively. Sensor glucose levels and capillary glucose levels were significantly correlated (r = 0.858, P < .01), although the sensor glucose levels were significantly lower than the capillary glucose levels. The accuracy of FreeStyle Libre in patients undergoing HD became deteriorated with the days of usage. The percentage of sensor results in Zones A and B in the consensus error grid analysis and in the Clarke error grid analysis were 99.7% and 99.0%, respectively. Its insufficient accuracy necessitates adjunct usage of FreeStyle Libre with self-monitoring of blood glucose in patients undergoing HD.

The effectiveness of growth hormone replacement on energy expenditure and body composition in patients with adult growth hormone deficiency.

Numerous studies have shown that growth hormone (GH) replacement in adult GH deficiency (AGHD) improves the body composition and metabolic rate; however, data about the relationship between body composition and energy expenditure in these patients is scarce. Our study aimed to investigate the changes in resting energy expenditure (REE) and body composition after GH replacement in patients with AGHD. We enrolled 15 patients diagnosed with AGHD and evaluated the effect of GH replacement administered once daily for 12 months on REE, body composition measured by bioelectrical impedance analysis, and serological markers. GH replacement therapy significantly increased the serum insulin growth factor-1 levels after 4, 8, and 12 months. The REE and REE/basal energy expenditure (REE/BEE) ratio significantly increased from 1278.0 ± 490.0 kcal/day and 0.87 ± 0.23 at baseline to 1505.5 ± 449.2 kcal/day and 1.11 ± 0.21 at 4 months, 1,918.7 ± 631.2 kcal/day and 1.29 ± 0.27 at 8 months, and 1,511.1 ± 271.2 kcal/day, 1.14 ± 0.29 at 12 months (p < 0.005, p < 0.005; p < 0.01, p < 0.01; p < 0.01, p < 0.005, respectively). There was no change in the body weight, while the lean body mass increased significantly from 45.8 ± 9.5 kg at baseline to 46.9 ± 9.4 kg at 4 months and 47.5 ± 10.1 kg at 8 months (p < 0.005, p < 0.01, respectively). The fat mass also decreased at 12 months. Lipid metabolism improved after 4 and 8 months. GH replacement therapy in patients with AGHD significantly improved the REE and body composition.

Short-term Change in Resting Energy Expenditure and Body Compositions in Therapeutic Process for Graves' Disease.

Objective In the medical treatment of Graves' disease, we sometimes encounter patients who gain weight after the onset of the disease. To estimate the energy required during the course of treatment when hyperthyroidism ameliorates, we measured the resting energy expenditure (REE) and body composition in patients with Graves' disease before and during treatment in the short-term. Methods Twenty patients with newly diagnosed Graves' disease were enrolled, and our REE data of 19 healthy volunteers were used. The REE was measured by a metabolic analyzer, and the basal energy expenditure (BEE) was estimated by the Harris-Benedict formula. The body composition, including body weight, fat mass (FM), muscle mass (MM) and lean body mass (LBM), were measured by a multi-frequency body composition analyzer. We tailored the nutritional guidance based on the measured REE. Results Serum thyrotropin levels were significantly increased at three and six months. Serum free thyroxine, free triiodothyronine and REE values were significantly decreased at one, three and six months. The REE/BEE ratio was 1.58±0.28 at the onset and significantly declined to 1.34±0.34, 1.06±0.19 and 1.01±0.16 at 1, 3 and 6 months, respectively. Body weight, MM and LBM significantly increased at three and six months. Conclusion The REE significantly decreased during treatment of Graves' disease. The decline was evident as early as one month after treatment. The REE after treatment was lower than in healthy volunteers, which may lead to weight gain. These data suggest that appropriate nutritional guidance is necessary with short-term treatment before the body weight normalizes in order to prevent an overweight condition and the emergence of metabolic disorders.

Comparison of accuracy between flash glucose monitoring and continuous glucose monitoring in patients with type 2 diabetes mellitus undergoing hemodialysis.

INTRODUCTION: We evaluated the accuracy and clinical utility of flash glucose monitoring (FGM) in comparison with continuous glucose monitoring (CGM) and self-monitoring blood glucose (SMBG) in patients with type 2 diabetes (T2D) undergoing hemodialysis (HD). METHODS: Simultaneous FGM (FreeStyle LibrePro), CGM (iPro2) and SMBG were performed on 13 T2D research subjects. RESULTS: There were good overall correlations between SMBG and FGM (64.7% and 30.8% within the A and B of Parkes Error Grid, respectively) and between SMBG and CGM (87.9% and 11.0% within the A and B, respectively). However, during HD, correlations between SMBG and FGM were only 49.7% and 37.2% within the A and B, respectively, while correlations of SMBG and CGM were 72.8% and 22.2% within the A and B, respectively. The percentage of FGM not in Zone A + B was more than 4 times higher than for CGM. The overall mean absolute relative difference (MARD) for FGM was 18.2%, this significantly higher than 11.2% for CGM. During HD, MARD for FGM was 22.8%, significantly higher than 15.0% for CGM. CONCLUSION: FGM has good clinical agreement in T2D patients undergoing HD. However, the accuracy of FGM relative to SMBG was worse than that of CGM.

Use of Noncontact Infrared Skin Thermometer for Peripheral Arterial Disease Screening in Patients With and Without Diabetes.

Peripheral arterial disease (PAD) poses a threat of limb amputation and cardiovascular events. However, PAD diagnostic procedure requiring time, cost, and technical skills preclude its application as a screening test in the general population. Although PAD tends to be associated with lower foot skin temperature, none has yet to appreciate its usefulness for diagnosis/screening. We measured foot skin temperatures at the first and fifth metatarsal head and heel areas using noncontact infrared thermometer at the time of ankle brachial pressure index (ABI) measurement and limb arterial ultrasonography in 176 patients (345 legs) in participants. Foot skin temperatures correlated with ABI and showed distinctly lower levels in legs with ultrasound-confirmed arterial stenosis/occlusion and in those with ABI ≤0.90. Receiver operating characteristics analyses revealed that the lowest temperature value of the 3-foot locations had a higher sensitivity than every single location in detecting lower extremity PAD. Diagnostic efficiency for the ABI cutoff of 0.90 showed sensitivity/specificity of 41%/94%, while that for the lowest skin temperature cutoff of 30.8°C showed sensitivity/specificity of 60%/64%. In conclusion, an accurate skin temperature measurement using noncontact handheld infrared skin thermometer could serve as a new, cost-effective screening strategy for earlier diagnosis of PAD.

Effects of canagliflozin on body composition and hepatic fat content in type 2 diabetes patients with non-alcoholic fatty liver disease.

AIMS/INTRODUCTION: Non-alcoholic fatty liver disease is frequently associated with type 2 diabetes, and constitutes an important risk factor for the development of hepatic fibrosis and hepatocellular carcinoma. Because there remains no effective drug therapy for non-alcoholic fatty liver disease associated with type 2 diabetes, we evaluated the efficacy of sodium-glucose cotransporter 2 inhibitor. METHODS AND MATERIALS: In the present pilot, prospective, non-randomized, open-label, single-arm study, we evaluated the effect of 100 mg canagliflozin administered once daily for 12 months on serological markers, body composition measured by bioelectrical impedance analysis method and hepatic fat fraction measured by magnetic resonance imaging in type 2 diabetes patients with non-alcoholic fatty liver disease. RESULTS: Canagliflozin significantly reduced body and fat mass, and induced a slight decrease in lean body or muscle mass that did not reach significance at 6 and 12 months. Reductions in fat mass in each body segment (trunk, arms and legs) were evident, whereas those in lean body mass were not. The hepatic fat fraction was reduced from a baseline of 17.6 ± 7.5% to 12.0 ± 4.6% after 6 months and 12.1 ± 6.1% after 12 months (P < 0.0005 and P < 0.005), whereas serum liver enzymes and type IV collagen concentrations improved. From a mean baseline hemoglobin A1c of 8.7 ± 1.4%, canagliflozin significantly reduced hemoglobin A1c after 6 and 12 months to 7.3 ± 0.6% and 7.7 ± 0.7% (P < 0.0005 and P < 0.01). CONCLUSIONS: Canagliflozin reduced body mass, fat mass and hepatic fat content without significantly reducing muscle mass.

Identification and quantification of plasma free salusin-ß, an endogenous parasympathomimetic peptide.

Salusin-ß is an endogenous parasympathomimetic proatherosclerotic peptide. Salusin-ß was initially predicted from bioinformatic analyses and later immunologically detected in human biofluids. However, elucidation of salusin-ß bioactivity has faced enormous challenges because of its unique physicochemical characteristics that cause it to strongly adhere to laboratory apparatus materials. In the strictest sense, the discovery of bioactive peptides is not complete until their exact native sequences have been confirmed in the peripheral circulation. In this study, we determined the plasma molecular form and levels of free salusin-ß to determine its pathophysiological significance. Ultra-high-yield enrichment and preseparation of non-tryptic human plasma was followed by LC-MS/MS, and full-length salusin-ß and seven different endogenous fragment sequences were identified. We established a new ELISA that specifically detects plasma free salusin-ß without cross-reacting with any of its identified endogenous fragments. Free salusin-ß levels exhibited a profound early morning nadir and rapidly decreased in response to parasympathetic nervous augmentation. Our technical advance in plasma native peptide analysis successfully identified a hard-to-detect bioactive peptide, salusin-ß, together with its formerly unrecognized fragments, and further suggests that conventional immunological measurements of target peptides may not be fully representative.

Methionine sulfoxides in serum proteins as potential clinical biomarkers of oxidative stress.

Oxidative stress contributes to the pathophysiology of a variety of diseases, and circulating biomarkers of its severity remains a topic of great interest for researchers. Our peptidomic strategy enables accurate and reproducible analysis of circulating proteins/peptides with or without post-translational modifications. Conventional wisdom holds that hydrophobic methionines exposed to an aqueous environment or experimental handling procedures are vulnerable to oxidation. However, we show that the mass spectra intensity ratio of oxidized to non-oxidized methionine residues in serum tryptic proteins can be accurately quantified using a single drop of human serum and give stable and reproducible results. Our data demonstrate that two methionine residues in serum albumin (Met-111 and Met-147) are highly oxidized to methionine sulfoxide in patients with diabetes and renal failure and in healthy smokers versus non-smoker controls. This label-free mass spectrometry approach to quantify redox changes in methionine residues should facilitate the identification of additional circulating biomarkers suitable for predicting the development or progression of human diseases.

Distinct biomarker roles for HbA1c and glycated albumin in patients with type 2 diabetes on hemodialysis.

AIMS: HbA1c and glycated albumin (GA) are used to monitor glycemia, but their accuracy to represent glycemic profiles in hemodialysis remains controversial. METHODS: Continuous glucose monitoring in 97 patients with type 2 diabetes (41 on hemodialysis [HD] and 56 without nephropathy) was analyzed to evaluate whether HbA1c and/or GA serve as appropriate glycemic profile markers. RESULTS: The average glucose significantly correlated with HbA1c in both HD group and group without nephropathy (r=0.59, P<0.0001; r=0.40, P<0.005). The slopes of linear regression lines were statistically indistinguishable (F=0.30, P=0.744), while the y-intercepts were significantly different (F=57.86, P<0.0001). GA showed strong correlation with the glycemic standard deviation (r=0.68, P<0.0001), and with the average glucose (r=0.42, P<0.001). Least square analysis revealed that only HbA1c, but not GA, was significantly associated with the average glucose (F=10.20, P<0.0005; F=0.38, P=0.5427), while only GA was significantly associated with the glycemic variability in HD group. CONCLUSIONS: In HD participants, HbA1c correlates with the average glucose more than GA, but underestimates it, and a correction formula of HbA1c can be developed as an appreciable marker. GA value itself reflects the average glucose, but less accurately than HbA1c, while it could serve as an indicator for hyperglycemia/hypoglycemia excursion.

Levels of albuminuria and risk of developing macroalbuminuria in type 2 diabetes: historical cohort study.

Although increased urinary albumin excretion may increase the risk of adverse renal outcomes in patients with diabetes, it remains unclear whether microalbuminuria is associated with a higher incidence of macroalbuminuria in the absence of non-diabetic kidney events that frequently develop during the long-term course of type 2 diabetes. This historical cohort study included patients with type 2 diabetes, spot urine albumin:creatinine ratio (ACR) <300 mg/gCr and normal serum creatinine concentrations treated between August 1988 and April 2015. Patients with any evidence suggesting non-diabetic kidney diseases at baseline were excluded. Over a median follow-up of 50 months, 70 of the 1760 included patients developed macroalbuminuria. Twenty-one of these patients were diagnosed with non-diabetic renal events. The five-year cumulative incidence of macroalbuminuria in patients with ACRs of 0-7.5 mg/gCr, 7.5-30 mg/gCr, 30-150 mg/gCr, and 150-300 mg/gCr were 0%, 0.53%, 3.5%, and 36.0%, respectively, with significant differences between each pair of ACR categories. In type 2 diabetes, higher urinary ACR, even within a level of normoalbuminuria, was associated with a greater incidence of macroalbuminuria when non-diabetic renal events were excluded. These results conflict with findings suggesting that microalbuminuria is a poor indicator for the progression of diabetic nephropathy.

SGLT2 inhibitors provide an effective therapeutic option for diabetes complicated with insulin antibodies.

Diabetes mellitus complicated with insulin antibodies is rare in clinical practice but usually difficult to control. A high amount of insulin antibodies, especially with low affinity and high binding capacity, leads to unstable glycemic control characterized by hyperglycemia unresponsive to large volume of insulin and unanticipated hypoglycemia. There are several treatment options, such as changing insulin preparation, immunosupression with glucocorticoids, and plasmapheresis, most of which are of limited efficacy. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of drug which decrease renal glucose reabsorption and lowers plasma glucose level independent of insulin action. We report here a case with diabetes complicated with insulin antibodies who was effectively controlled by an SGLT2 inhibitor. A 47-year-old man with type 2 diabetes treated with insulin had very poor glycemic control characterized by postprandial hyperglycemia unresponsive to insulin therapy and repetitive hypoglycemia due to insulin antibodies. Treatment with ipragliflozin, an SGLT2 inhibitor, improved HbA1c from 8.4% to 6.0% and glycated albumin from 29.4% to 17.9%. Continuous glucose monitoring revealed improvement of glycemic profile (average glucose level from 212 mg/dL to 99 mg/dL and glycemic standard deviation from 92 mg/dL to 14 mg/dL) with disappearance of hypoglycemic events. This treatment further ameliorated the characteristics of insulin antibodies and resulted in reduced insulin requirement. SGLT2 inhibitors may offer an effective treatment option for managing the poor glycemic control in diabetes complicated with insulin antibodies.

Physiological fluctuations of human plasma total salusin-ß, an endogenous parasympathomimetic/proatherosclerotic peptide.

Salusin-ß is an endogenous bioactive peptide that systemically exerts acute parasympathomimetic hemodynamic actions and locally induces atherogenesis. Due to its unique physicochemical characteristics to immediately adhere to all types of plastic and glassware, its plasma concentrations have only been successfully determined very recently. Using a total of 50 healthy adults (median age 28 years, range 24-57 years), we evaluated whether circulating salusin-ß levels are affected by the autonomic nervous functions. Plasma total salusin-ß levels obtained during daytime ambulatory monitoring of heart rate variability showed strong negative correlations with variables reflecting parasympathetic nervous activity, high frequency amplitude (HF; r=-0.27, p=0.0018) and the square root of the mean squared differences of successive normal-to-normal intervals (RMSSD; r=-0.19, p=0.0292), but did not with low frequency amplitude (LF) or LF/HF, variables influenced by sympathetic nervous activity. Because early morning nadir in the diurnal variation of plasma total salusin-ß levels appeared to follow the nighttime parasympathetic nervous activity peak as quantified by HF and RMSSD, we determined whether parasympathetic stimulation reduces plasma salusin-ß levels. Both Valsalva maneuver (p<0.05) and urination (p<0.05) significantly reduced plasma total salusin-ß levels. Despite the fact that salusin-ß is the sole endogenous parasympathomimetic peptide identified to date, the current results argue against the contention that physiological parasympathetic augmentation is the consequences of upregulated circulating salusin-ß. Rather, circulating salusin-ß levels are suppressed following physiological parasympathetic stimulation and appear to constitute a negative feedback relationship with the parasympathetic nervous system.