ResearchPad - emerging-technologies-pharmacology-and-therapeutics https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Non-invasive monitoring of pharmacodynamics during the skin wound healing process using multimodal optical microscopy]]> https://www.researchpad.co/article/elastic_article_9076 Impaired diabetic wound healing is one of the serious complications associated with diabetes. In patients with diabetes, this impairment is characterized by several physiological abnormalities such as metabolic changes, reduced collagen production, and diminished angiogenesis. We designed and developed a multimodal optical imaging system that can longitudinally monitor formation of new blood vessels, metabolic changes, and collagen deposition in a non-invasive, label-free manner.Research design and methodsThe closure of a skin wound in (db/db) mice, which presents delayed wound healing pathologically similar to conditions in human type 2 diabetes mellitus, was non-invasively followed using the custom-built multimodal microscope. In this microscope, optical coherence tomography angiography was used for studying neovascularization, fluorescence lifetime imaging microscopy for nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) assessment, fluorescence intensity changes of NAD(P)H and flavin adenine dinucleotide (FAD) cofactors for evaluating metabolic changes, and second harmonic generation microscopy for analyzing collagen deposition and organization. The animals were separated into four groups: control, placebo, low concentration (LC), and high concentration (HC) treatment. Images of the wound and surrounding areas were acquired at different time points during a 28-day period.ResultsVarious physiological changes measured using the optical imaging modalities at different phases of wound healing were compared. A statistically significant improvement in the functional relationship between angiogenesis, metabolism, and structural integrity was observed in the HC group.ConclusionsThis study demonstrated the capability of multimodal optical imaging to non-invasively monitor various physiological aspects of the wound healing process, and thus become a promising tool in the development of better diagnostic, treatment, and monitoring strategies for diabetic wound care. ]]> <![CDATA[Response evaluation of SGLT2 inhibitor therapy in patients with type 2 diabetes mellitus using <sup>18</sup>F-FDG PET/MRI]]> https://www.researchpad.co/article/Nf44d434e-9bc4-4ab4-b2e6-d6b544cfaaac Inhibitors of sodium-glucose linked transporter-2 (SGLT2i) are enhancing glucose excretion in the proximal renal tubules, and thus are increasingly used to lower blood glucose levels in patients with type 2 diabetes mellitus (T2DM). The glucose analog 2-deoxy-2-(18F) fluoro-D-glucose (FDG) can be used to quantify renal function in vivo, and due to an affinity for SGLT2 could also provide information about SGLT2 transporter function. Our objectives in this study were, therefore, to assess the impact of SGLT2i on renal function parameters in patients with T2DM and identify predictive parameters of long-term response to SGLT2i using dynamic FDG positron emission tomography (PET)/MRI.MethodsPET FDG renal function measures such as mean transit time (MTT) and general renal performance (GRP) together with glomerular filtration rate (GFR) were determined in 20 patients with T2DM before (T2DMbaseline) and 2 weeks after initiation of therapy with SGLT2i (T2DMSGLT2i). Additionally, dynamic FDG PET data of 24 healthy subjects were used as controls.ResultsMTT in T2DMbaseline was significantly higher than in healthy controls (5.7 min vs 4.3 min, p=0.012) and significantly decreased to 4.4 min in T2DMSGLT2i (p=0.004). GRP of T2DMSGLT2i was higher than of T2DMbaseline (5.2 vs 4.7, p=0.02) and higher but not significantly than of healthy individuals (5.2 vs 5.1, p=0.34). Expectedly, GFR of healthy participants was significantly higher than of T2DMbaseline and T2DMSGLT2i (122 vs 92 and 86 mL/min/1.73 m², respectively; p<0.001). The higher the GRP value in kidneys of T2DMSGLT2i, the lower was the glycated hemoglobin level 3 months after therapy initiation.ConclusionMTT and GRP values of patients with T2DM shifted significantly toward values of healthy control 2 weeks after therapy with SGLT2i begins. GRP in T2DMSGLT2i was associated with better long-term glycemic response 3 months after initiation of therapy.Trial registration numberNCT03557138. ]]> <![CDATA[Flash glucose monitoring reduces glycemic variability and hypoglycemia: real-world data from Spain]]> https://www.researchpad.co/article/N7997a7b4-f7b9-4cbb-b1c4-65a93ca1949f

Objective

Observations in real-world settings support and extend findings demonstrated in randomized controlled trials that show flash glucose monitoring improves glycemic control. In this study, Spain-specific relationships between testing frequency and glycemic parameters were investigated under real-world settings.

Research design and methods

Deidentified glucose and user scanning data were analyzed and readers were rank ordered into 20 equal sized groups by daily scan frequency. Glucose parameters were calculated for each group: estimated HbA1c, time below range (<70 and ≤54 mg/dL), within range (70–180 mg/dL), and above range (>180 mg/dL). Glycemic variability (GV) metrics were described and data obtained from sensors in Spain and worldwide were compared.

Results

Spanish users (n=22 949) collected 37.1 million glucose scans, 250 million automatically recorded glucose readings, and checked glucose values via a mean of 13 scans/day. Estimated HbA1c, time below 70 mg/dL, at or below 54 mg/dL, above 180 mg/dL, and GV metrics were significantly lower in the highest compared with lowest scan rate group (39.6 to 3.9 scans/day). Time-in-range was higher for the highest versus lowest scan rate group at 15.6 vs 11.5 hours/day, respectively. GV metrics correlated positively with time below 70 mg/dL, at or below 54 mg/dL, above 180 mg/dL, and negatively with time-in-range. The relationship between glucose metrics and scan rate was similar in Spain and worldwide. However, time in hypoglycemia in Spain was higher in the groups with lower scan rates.

Conclusions

As seen in clinical trials, flash glucose monitoring in real-world settings allows frequent glucose checks. High scan rates are associated with the favorable glycemic markers of increased time-in-range and reduced time in hyperglycemia and hypoglycemia, and GV. The same trends, with unique nuances, are observed in both Spanish and global data.

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<![CDATA[Development of a multivariable prediction model for plantar foot ulcer recurrence in high-risk people with diabetes]]> https://www.researchpad.co/article/N0a4817a6-d6fe-4a37-acec-575f1137c064

Introduction

Forty per cent of people with diabetes who heal from a foot ulcer recur within 1 year. The aim was to develop a prediction model for plantar foot ulcer recurrence and to validate its predictive performance.

Research design and methods

Data were retrieved from a prospective analysis of 171 high-risk patients with 18 months follow-up. Demographic, disease-related, biomechanical and behavioral factors were included as potential predictors. Two logistic regression models were created. Model 1 for all recurrent plantar foot ulcers (71 cases) and model 2 for those ulcers indicated to be the result of unrecognized repetitive stress (41 cases). Ten-fold cross-validation, each including five multiple imputation sets, was used to internally validate the prediction strategy; model performance was assessed in terms of discrimination and calibration.

Results

The presence of a minor lesion, living alone, increased barefoot peak plantar pressure, longer duration of having a previous foot ulcer and less variation in daily stride count were predictors of the first model. The area under the receiver operating curve was 0.68 (IQR 0.61–0.80) and the Brier score was 0.24 (IQR 0.20–0.28). The predictors of the second model were presence of a minor lesion, longer duration of having a previous foot ulcer and location of the previous foot ulcer. The area under the receiver operating curve was 0.76 (IQR 0.66–0.87) and the Brier score was 0.17 (IQR 0.15–0.18).

Conclusions

These validated prediction models help identify those patients that are at increased risk of plantar foot ulcer recurrence and for that reason should be monitored more carefully and treated more intensively.

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<![CDATA[Glucagon receptor antagonist upregulates circulating GLP-1 level by promoting intestinal L-cell proliferation and GLP-1 production in type 2 diabetes]]> https://www.researchpad.co/article/Nac0e5097-1176-4e09-8191-51217ee72c4e

Objective

Glucagon receptor (GCGR) blockage improves glycemic control and increases circulating glucagon-like peptide-1 (GLP-1) level in diabetic animals and humans. The elevated GLP-1 has been reported to be involved in the hypoglycemic effect of GCGR blockage. However, the source of this elevation remains to be clarified.

Research design and methods

REMD 2.59, a human GCGR monoclonal antibody (mAb), was administrated for 12 weeks in db/db mice and high-fat diet+streptozotocin (HFD/STZ)-induced type 2 diabetic (T2D) mice. Blood glucose, glucose tolerance and plasma GLP-1 were evaluated during the treatment. The gut length, epithelial area, and L-cell number and proliferation were detected after the mice were sacrificed. Cell proliferation and GLP-1 production were measured in mouse L-cell line GLUTag cells, and primary mouse and human enterocytes. Moreover, GLP-1 receptor (GLP-1R) antagonist or protein kinase A (PKA) inhibitor was used in GLUTag cells to determine the involved signaling pathways.

Results

Treatment with the GCGR mAb lowered blood glucose level, improved glucose tolerance and elevated plasma GLP-1 level in both db/db and HFD/STZ-induced T2D mice. Besides, the treatment promoted L-cell proliferation and LK-cell expansion, and increased the gut length, epithelial area and L-cell number in these two T2D mice. Similarly, our in vitro study showed that the GCGR mAb promoted L-cell proliferation and increased GLP-1 production in GLUTag cells, and primary mouse and human enterocytes. Furthermore, either GLP-1R antagonist or PKA inhibitor diminished the effects of GCGR mAb on L-cell proliferation and GLP-1 production.

Conclusions

The elevated circulating GLP-1 level by GCGR mAb is mainly due to intestinal L-cell proliferation and GLP-1 production, which may be mediated via GLP-1R/PKA signaling pathways. Therefore, GCGR mAb represents a promising strategy to improve glycemic control and restore the impaired GLP-1 production in T2D.

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<![CDATA[Response evaluation of SGLT2 inhibitor therapy in patients with type 2 diabetes mellitus using 18F-FDG PET/MRI]]> https://www.researchpad.co/article/N9b271def-a406-486c-812a-cc773dba96e6

Introduction

Inhibitors of sodium-glucose linked transporter-2 (SGLT2i) are enhancing glucose excretion in the proximal renal tubules, and thus are increasingly used to lower blood glucose levels in patients with type 2 diabetes mellitus (T2DM). The glucose analog 2-deoxy-2-(18F) fluoro-D-glucose (FDG) can be used to quantify renal function in vivo, and due to an affinity for SGLT2 could also provide information about SGLT2 transporter function. Our objectives in this study were, therefore, to assess the impact of SGLT2i on renal function parameters in patients with T2DM and identify predictive parameters of long-term response to SGLT2i using dynamic FDG positron emission tomography (PET)/MRI.

Methods

PET FDG renal function measures such as mean transit time (MTT) and general renal performance (GRP) together with glomerular filtration rate (GFR) were determined in 20 patients with T2DM before (T2DMbaseline) and 2 weeks after initiation of therapy with SGLT2i (T2DMSGLT2i). Additionally, dynamic FDG PET data of 24 healthy subjects were used as controls.

Results

MTT in T2DMbaseline was significantly higher than in healthy controls (5.7 min vs 4.3 min, p=0.012) and significantly decreased to 4.4 min in T2DMSGLT2i (p=0.004). GRP of T2DMSGLT2i was higher than of T2DMbaseline (5.2 vs 4.7, p=0.02) and higher but not significantly than of healthy individuals (5.2 vs 5.1, p=0.34). Expectedly, GFR of healthy participants was significantly higher than of T2DMbaseline and T2DMSGLT2i (122 vs 92 and 86 mL/min/1.73 m², respectively; p<0.001). The higher the GRP value in kidneys of T2DMSGLT2i, the lower was the glycated hemoglobin level 3 months after therapy initiation.

Conclusion

MTT and GRP values of patients with T2DM shifted significantly toward values of healthy control 2 weeks after therapy with SGLT2i begins. GRP in T2DMSGLT2i was associated with better long-term glycemic response 3 months after initiation of therapy.

Trial registration number

NCT03557138.

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