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OBJECTIVE To explore the complementary effects of a combination of dipeptidyl peptidase 4 and sodium-glucose cotransporter 2 inhibitors added to metformin on hormonal and metabolic responses to meal ingestion. RESEARCH DESIGN AND METHODS Forty-five patients (age 58 ± 8 years; HbA1c 58 ± 6 mmol/mol; BMI 30.7 ± 3.2 kg/m²) with type 2 diabetes uncontrolled with metformin were evaluated at baseline and 3 and 28 days after 5 mg saxagliptin (SAXA), 10 mg dapagliflozin (DAPA), or 5 mg saxagliptin plus 10 mg dapagliflozin (SAXA+DAPA) using a mixed-meal tolerance test (MMTT) spiked with dual-tracer glucose to assess glucose metabolism, insulin secretion, and sensitivity. RESULTS At day 3, fasting and mean MMTT glucose levels were lower with SAXA+DAPA (-31.1 ± 1.6 and -91.5 ± 12.4 mg/dL) than with SAXA (-7.1 ± 2.1 and -53 ± 10.5 mg/dL) or DAPA (-17.0 ± 1.1 and -42.6 ± 10.0 mg/dL, respectively; P < 0.001). Insulin secretion rate (SAXA+DAPA +75%; SAXA +11%; DAPA +3%) and insulin sensitivity (+2.2 ± 1.7, +0.4 ± 0.7, and +0.4 ± 0.4 mg · kg-1 · min-1, respectively) improved with SAXA+DAPA (P < 0.007). Mean glucagon-like peptide 1 (GLP-1) was higher with SAXA+DAPA than with SAXA or DAPA. Fasting glucagon increased with DAPA and SAXA+DAPA but not with SAXA. Fasting endogenous glucose production (EGP) increased with SAXA+DAPA and DAPA. During MMTT, EGP suppression was greater (48%) with SAXA+DAPA (vs. SAXA 44%; P = 0.02 or DAPA 34%; P = 0.2). Metabolic clearance rate of glucose (MCRglu) increased more with SAXA+DAPA. At week 4, insulin secretion rate, β-cell glucose sensitivity, and insulin sensitivity had further increased in the SAXA+DAPA group (P = 0.02), with no additional changes in GLP-1, glucagon, fasting or MMTT EGP, or MCRglu. CONCLUSIONS SAXA+DAPA provided superior glycemic control compared with DAPA or SAXA, with improved β-cell function, insulin sensitivity, GLP-1 availability, and glucose clearance. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To explore the associations among mannose, indexes of insulin resistance (IR) and secretion, and long-term cardiovascular outcomes. RESEARCH DESIGN AND METHODS: Fasting mannose was assayed in 1,403 participants, one-half of which had a first myocardial infarction (MI) with either normal glucose tolerance (n = 1,045) or newly detected dysglycemia (i.e., impaired glucose tolerance or type 2 diabetes; n = 358). Regression models were used to explore mannose associations with surrogate indexes of IR/insulin secretion. Multivariate Cox models were used to investigate the independent association between high (higher quartile) versus low (lower three quartiles) mannose and major adverse cardiac events (MACE) (n = 163) during the 10-year follow-up. RESULTS: Mannose was independently associated with IR indexes (all P ≤ 0.001). High versus low mannose was independently associated with MACE (hazard ratio 1.54, 95% CI 1.07–2.20) in the overall population. CONCLUSIONS: Mannose might represent a new biomarker able to track early, potentially detrimental glucometabolic alterations independently of glycemic state. [ABSTRACT FROM AUTHOR]

Background: Hypovitaminosis D has been suggested to play a possible role in coronavirus disease 2019 (COVID-19) infection. Methods: The aim of this study is to analyze the relationship between vitamin D status and a biochemical panel of inflammatory markers in a cohort of patients with COVID-19. A secondary endpoint was to evaluate the correlation between 25OHD levels and the severity of the disease. Ninety-three consecutive patients with COVID-19-related pneumonia were evaluated from March to May 2020 in two hospital units in Pisa, in whom biochemical inflammatory markers, 25OHD levels, P/F ratio at nadir during hospitalization, and complete clinical data were available. Results: Sixty-five percent of patients presented hypovitaminosis D (25OHD ≤ 20 ng/ml) and showed significantly higher IL-6 [20.8 (10.9–45.6) vs. 12.9 (8.7–21.1) pg/ml, p = 0.02], CRP [10.7 (4.2–19.2) vs. 5.9 (1.6–8.1) mg/dl, p = 0.003], TNF-α [8.9 (6.0–14.8) vs. 4.4 (1.5–10.6) pg/ml, p = 0.01], D-dimer [0.53 (0.25–0.72) vs. 0.22 (0.17–0.35) mg/l, p = 0.002], and IL-10 [3.7 (1.8–6.9) vs. 2.3 (0.5–5.8) pg/ml, p = 0.03]. A significant inverse correlation was found between 25OHD and all these markers, even adjusted for age and sex. Hypovitaminosis D was prevalent in patients with severe ARDS, compared with the other groups (75% vs. 68% vs. 55%, p < 0.001), and 25OHD levels were lower in non-survivor patients. Conclusions: The relationship between 25OHD levels and inflammatory markers suggests that vitamin D status needs to be taken into account in the management of these patients. If vitamin D is a marker of poor prognosis or a possible risk factor with beneficial effects from supplementation, this still needs to be elucidated. [ABSTRACT FROM AUTHOR]

Background: N-acetylaspartate (NAA) is synthesized only by neurons and is involved in neuronal metabolism and axonal myelination. NAA is the strongest signal on brain magnetic resonance spectroscopy, and its concentration have been associated with cognitive dysfunction in neurodegenerative diseases, obesity, and type 2 diabetes (T2D). Materials and Methods: We explored the impact of obesity and T2D on circulating NAA as well as the impact of bariatric surgery and antidiabetic treatments. We developed an LC-MS method for the accurate measurements of fasting plasma NAA levels in 505 subjects (156 subjects with normal glucose tolerance, 24 subjects with impaired glucose tolerance, and 325 patients with T2D) to examine the associations of NAA with obesity and dysglycemia. To validate cross-sectional findings, plasma NAA was measured 6 months after Roux-en-Y Gastric Bypass (RYGB) in 55 morbidly obese subjects, and after 1 year of antidiabetic treatment (with dapagliflozin, exenatide, or dapagliflozin plus exenatide) in 192 T2D patients. Results: In the whole population, NAA was associated with age (r = 0.31, p <0.0001) and BMI (r = −0.20, p <0.0001). Independently of age and BMI, NAA was reciprocally related to HbA1c and fasting plasma glucose (partial r = −0.13, both p = 0.01). Surgically-induced weight loss raised NAA (by 18 nmol/L on average, p <0.02). Glucose lowering treatment increased NAA in proportion to the drop in HbA1c (r = 0.31, p <0.0001) regardless of the agent used. Conclusions: Circulating NAA concentrations are modulated by age, obesity, and glycemic control. Whether they may mark for the corresponding metabolic effects on brain function remains to be established by joint measurements of spectroscopic signal and cognitive function. [ABSTRACT FROM AUTHOR]

The present paper describes the development and the validation process – in compliance with the EMA guidelines – of a method based on tandem mass spectrometry coupled to liquid chromatography for the accurate quantification of mannose in human plasma samples. The quick sample preparation procedure, simplified by the absence of any derivatization step, makes the assay suitable for routine use in a clinical chemistry laboratory. The method validation yielded satisfactory selectivity, with a good separation of mannose from its epimers (glucose and galactose), linearity over the whole concentration range of interest (0.31–40 μg/mL), reproducibility with RSD <10%, and accuracy in the range 96–104%. Instrumental LLOD (0.31 μg/mL) and LLOQ (1.25 μg/mL) were good enough to detect endogenous plasma mannose levels and in agreement with recent data from the literature. Sensitivity was affected by a 5-fold dilution factor, which, if necessary, can be reduced. The method robustness was proven in >600 injections, most of them being of plasma samples, used also to assess the reference ranges in healthy subjects (9.93 ± 3.37 μg/mL) and type 2 diabetic patients (23.47 ± 6.19 μg/mL). • We developed and validated an HPLC-MS-MS assay method to detect d -mannose. • It was validated in compliance with EMA guidelines. • Reproducibility (RSD) <10% and accuracy was in the range 96–104%. • Instrumental LLOD and LLOQ were 0.31 and 1.25 μg/mL, respectively. • Reference concentrations: 9.93 ± 3.37 μg/mL (controls)and 23.47 ± 6.19 μg/mL (diabetics). [ABSTRACT FROM AUTHOR]

In the clinical laboratories, dehydroepiandrostenedione (DHEA) is usually quantified by immunoassay-based methods, which are often affected by cross-reactivity with endogenous interferences, such as 4-androsten-3β-ol-17-one. The interfering compounds lead to a poor accuracy of the measurements, mainly at a low concentration level. The present paper describes a validated method based on tandem mass spectrometry coupled to liquid chromatography, for the accurate quantification of DHEA in serum. The peculiarity of this method is the use of calibrators and quality controls prepared by adding measured amounts of DHEA-D, a stable isotope-labeled analogue of DHEA, to real serum from healthy subjects. DHEA-D is used in place of DHEA, which is usually present in unstripped serum at physiological levels, as it has the same basic structure, provides an equivalent instrumental response, and can be easily distinguish by DHEA by mass spectrometry due to its different m/ z value. The method proved to be sensitive, with a LLOD of 0.09 ng/mL and a LLOQ of 0.23 ng/mL, and selective, with overall performances that allow its use on a routine basis. [ABSTRACT FROM AUTHOR]

Background: The glucosuria induced by sodium-glucose cotransporter-2 inhibitors (SGLT2i) stimulates endogenous (hepatic) glucose production (EGP) blunting the decline in HbA1c. We hypothesized that, in response to glucosuria, a renal signal is generated and stimulated EGP. Aim: To examine the effect of acute administration of dapagliflozin (DAPA) in nondiabetic, renal transplant subjects on SGLT2i-induced stimulation of EGP. Methods: 20 subjects [10 with intact native kidneys (IK) and 10 with bilateral nephrectomy (NK)] underwent measurement of EGP ([6,6-2H2]-glucose) before and for 6 hours after administration of DAPA or placebo (PLC) on 2 separate days. Results: DAPA induced greater glucosuria in subjects with IK versus NK (8.6±1.1 vs. 5.5±0.5 grams/6-hrs; p=0.02). During 6-hour, plasma glucose decreased slightly and similarly in both groups, with no difference compared to PLC. Following PLC, there was a progressive time-related decline in EGP that was similar in both groups. Following DAPA, EGP declined in both groups but the decrement in EGP was 56% greater in the NK. During DAPA, urinary glucose excretion was correlated with EGP (r = 0.34, p<0.05). Plasma insulin, C-peptide, glucagon, pre-hepatic insulin/glucagon ratio, lactate, alanine and pyruvate concentrations were similar in PLC and DAPA. β-hydroxybutyrate increased with DAPA in the IK, while a small increase was observed only at 360 min in the NK. Plasma epinephrine did not change after DAPA and PLC in both groups. Following DAPA, plasma norepinephrine increased slightly in the IK and decreased in the NK. Conclusions: In NK subjects the hepatic compensatory response to acute SGLT2i-induced glucosuria was attenuated compared to diabetic subjects with IK, suggesting a SGLT2i-mediated stimulation of hepatic glucose production via efferent renal nerves in an attempt to compensate for the urinary glucose loss, i.e., a renal-hepatic axis. Disclosure: G. Daniele: None. C. Solis-Herrera: Consultant; Self; Lexicon Pharmaceuticals, Inc. A. Dardano: None. A. Mari: Consultant; Self; Lilly Diabetes. Research Support; Self; Boehringer Ingelheim International GmbH. A. Tura: None. L. Giusti: None. J.J. Kurumthodathu: None. A.A.G. Brocchi: None. B. Campi: None. A. Saba: None. A. Bianchi: None. C. Tregnaghi: None. M. Egidi: None. M. Abdul-Ghani: None. R.A. DeFronzo: None. S. DelPrato: None. [ABSTRACT FROM AUTHOR]

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High mannose has previously associated with insulin resistance and cardiovascular disease (CVD). Our objective is to establish whether mannose is associated with anatomical evidence of coronary artery disease (CAD). Plasma mannose concentrations were measured by liquid chromatography/tandem mass spectrometry in a discovery cohort (n = 513) and a validation cohort (n = 221) of carefully phenotyped individuals. In both cohorts CAD was quantitated using state-of-the-art imaging techniques (coronary computed coronary tomography angiography (CCTA), invasive coronary angiography and optical coherence tomography). Information on subsequent CVD events/death was collected. Associations of mannose with angiographic variables and biomarkers were tested using univariate and multivariate regression models. Survival analysis was performed using the Kaplan-Meier estimator. Mannose was related to indices of CAD and features of plaque vulnerability. In the discovery cohort, mannose was a marker of quantity and quality of CCTA-proven CAD and subjects with a mannose level in the top quartile had a significantly higher risk of CVD events/death (p = 3.6e-5). In the validation cohort, mannose was significantly associated with fibrous cap thickness < 65 μm (odds ratio = 1.32 per each 10 μmol/L mannose change [95% confidence interval, 1.05–1.65]) and was an independent predictor of death (hazard ratio for mannose≥ vs < 84.6 μmol/L: 4.0(95%CI, 1.4–11.3), p = 0.006). The current data add novel evidence that high mannose is a signature of CAD with a vulnerable plaque phenotype, consistently across measures of severity of vessel involvement and independent of the traditional correlates of CVD, and that it is an independent predictor of incident adverse outcomes. • High mannose concentration is emerging as a novel marker of cardiovascular disease • In the discovery cohort, mannose was a marker of coronary artery disease (CAD). • In the validation cohort, mannose was associated with fibrous cap thickness. • In both cohorts high mannose was an independent predictor of adverse outcomes. • High mannose might be a signature of CAD with a vulnerable plaque phenotype. [ABSTRACT FROM AUTHOR]