Alogliptin: a new addition to the class of DPP-4 inhibitors

Radha Andukuri, Andjela Drincic, Marc RendellDivision of Endocrinology, Department of Medicine, Creighton University School of Medicine, Omaha, Nebraska, USABackground: Alogliptin is an oral antihyperglycemic agent that is a selective inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4). Inhibition of DPP-4 elevates levels of the incretin hormones glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) by preventing their degradation.Objective: To review the evolution of alogliptin and its pharmacokinetics, pharmacodynamics, clinical efficacy and adverse effects. In addition, we compared alogliptin to other DPP-4 inhibitors.Methods: A comprehensive literature search was performed using the term ‘alogliptin’. Original research articles and review articles as well as scientific abstracts were included. Results: Alogliptin raises postprandial levels of GLP-1. It has excellent bioavailability exhibiting a median Tmax ranging from 1 to 2 hours and a mean half-life of 12.4 to 21.4 hours across all doses. When given as monotherapy, mean hemoglobin A1c (HbA1c) reductions achieved were 0.5% to 0.6%. Combination therapy yielded similar reductions (−0.5% with metformin, −0.6% with glyburide, −0.8% with pioglitazone and –0.6% with insulin). Administration of alogliptin does not promote weight loss but has not resulted in weight gain. The agent is relatively well tolerated with few adverse effects, the major finding being a marginally higher rate of skin events, primarily pruritus.Conclusions: Alogliptin causes significant reductions in HbA1c when used alone or in combination with other oral agents in patients with type 2 diabetes similar to other DPP-4 inhibitors in current clinical use. The side effect profile also does not differ from that of other DPP-4 inhibitors. However, long-term studies are necessary before the place of alogliptin in the management of type 2 diabetes can be established.Keywords: alogliptin, DPP-4 inhibitors, GLP-1, vildagliptin, sitagliptin, saxaglipti

Quantifying vehicle control from physiology in type 1 diabetes

Objective: Our goal is to measure real-world effects of at-risk driver physiology on safety-critical tasks like driving by monitoring driver behavior and physiology in real-time. Drivers with type 1 diabetes (T1D) have an elevated crash risk that is linked to abnormal blood glucose, particularly hypoglycemia. We tested the hypotheses that (1) T1D drivers would have overall impaired vehicle control behavior relative to control drivers without diabetes, (2) At-risk patterns of vehicle control in T1D drivers would be linked to at-risk, in-vehicle physiology, and (3) T1D drivers would show impaired vehicle control with more recent hypoglycemia prior to driving. Methods: Drivers (18 T1D, 14 control) were monitored continuously (4 weeks) using in-vehicle sensors (e.g., video, accelerometer, speed) and wearable continuous glucose monitors (CGMs) that measured each T1D driver’s real-time blood glucose. Driver vehicle control was measured by vehicle acceleration variability (AV) across lateral (AVY, steering) and longitudinal (AVX, braking/accelerating) axes in 45-second segments (N = 61,635). Average vehicle speed for each segment was modeled as a covariate of AV and mixed-effects linear regression models were used. Results: We analyzed 3,687 drives (21,231 miles). T1D drivers had significantly higher overall AVX, Y compared to control drivers (BX = 2.5 × 10−2 BY = 1.6 × 10−2, p \u3c 0.01)—which is linked to erratic steering or swerving and harsh braking/accelerating. At-risk vehicle control patterns were particularly associated with at-risk physiology, namely hypo- and hyperglycemia (higher overall AVX,Y). Impairments from hypoglycemia persisted for hours after hypoglycemia resolved, with drivers who had hypoglycemia within 2–3 h of driving showing higher AVX and AVY. State Department of Motor Vehicle records for the 3 years preceding the study showed that at-risk T1D drivers accounted for all crashes (N = 3) and 85% of citations (N = 13) observed. Conclusions: Our results show that T1D driver risk can be linked to real-time patterns of at-risk driver physiology, particularly hypoglycemia, and driver risk can be detected during and prior to driving. Such naturalistic studies monitoring driver vehicle controls can inform methods for early detection of hypoglycemia-related driving risks, fitness to drive assessments, thereby helping to preserve safety in at-risk drivers with diabetes

Highly Aggressive and Radiation-Resistant, “Atypical” and Silent Pituitary Corticotrophic Carcinoma: A Case Report and Review of the Literature

Background: Pituitary tumors typically remain silent unless interaction with nearby structures occurs. Rare subsets of pituitary tumors display aggressive phenotypes: highly mitotic, locally invasive, metastatic, chemotherapy and radiation resistant, etc. Disease progression and response to therapy is ill-defined in these subtypes, and their true prognostic potential is debated. Thus, identifying tumor characteristics with prognostic value and efficacious treatment options remains a challenge in aggressive pituitary tumors. Case Presentation: A 45-year-old female presented with a nonfunctioning corticotropic pituitary macroadenoma with biomarkers suggestive of an “atypical” subtype: Ki-67 of 8–12%, increased mitosis, and locally invasive. Despite resections and radiation, growth continued, eventually affecting her vision. Although histologically ACTH positive, the patient remained clinically asymptomatic. Twelve months later, an episode of Cushing’s disease-induced psychosis prompted a PET-CT scan, identifying sites of metastasis. Temozolomide was added to her medical regimen, and her metastatic liver lesions and boney metastases were treated with radiofrequency ablation and stereotactic body radiation therapy, respectively. Systemic treatment resulted in a drop in her ACTH levels, with her most recent scans/labs at 12 months following RFA suggesting remission. Conclusions: This is a unique presentation of a pituitary tumor, displaying characteristics of both clinically silent corticotropic and “atypical” macroadenoma subtypes. Although initially ACTH positive while clinically silent, the patient’s disease ultimately recurred metastatically with manifestations of Cushing’s disease and psychosis. With the addition of temozolomide to her treatment plan, her primary and metastatic sites have responded favorably to radiation therapy. Thus, the addition of temozolomide may be beneficial in the treatment of aggressive pituitary tumors

Delineating the role of FANCA in glucose-stimulated insulin secretion in β cells through its protein interactome

Hyperinsulinemia affects 72% of Fanconi anemia (FA) patients and an additional 25% experience lowered glucose tolerance or frank diabetes. The underlying molecular mechanisms contributing to the dysfunction of FA pancreas β cells is unknown. Therefore, we sought to evaluate the functional role of FANCA, the most commonly mutated gene in FA, in glucosestimulated insulin secretion (GSIS). This study reveals that FANCA or FANCB knockdown impairs GSIS in human pancreas β cell line EndoC-βH3. To identify potential pathways by which FANCA might regulate GSIS, we employed a proteomics approach to identify FANCA protein interactions in EndoC-βH3 differentially regulated in response to elevated glucose levels. Glucose-dependent changes in the FANCA interaction network were observed, including increased association with other FA family proteins, suggesting an activation of the DNA damage response in response to elevated glucose levels. Reactive oxygen species increase in response to glucose stimulation and are necessary for GSIS in EndoC-βH3 cells. Glucose-induced activation of the DNA damage response was also observed as an increase in the DNA damage foci marker γ-H2AX and dependent upon the presence of reactive oxygen species. These results illuminate the role of FANCA in GSIS and its protein interactions regulated by glucose stimulation that may explain the prevalence of β cell-specific endocrinopathies in FA patients

The effect of diabetes case management and Diabetes Resource Nurse program on readmissions of patients with diabetes mellitus

Aims: Patients with diabetes have higher readmission rates than those without diabetes, yet limited data on efforts to reduce their readmissions are available. We describe a novel model of inpatient diabetes care, expanding the role of diabetes educators to include case management, and establishment of a Diabetes Resource Nurse program, aimed at increasing the knowledge of staff nurses, and evaluate the impact of this program on readmission rates. Methods: We performed retrospective analysis of 30-day readmission rates of patients with diabetes before (July 2010–December 2011), and after (January 2012–June 2013) starting the implementation of this tiered inpatient diabetes care delivery model. Results: We analyzed 34,472 discharged patient records from the 18-month pre-intervention period, and 32,046 records from the 18-month post-intervention period. The overall 30-day readmission rate for patients with diabetes decreased significantly from 20.1% (pre) to 17.6% (post) intervention (p < 0.0001). Patients seen by diabetes educators had the lowest 30-day readmission rates (∼15% during the whole study), a rate approaching the overall hospital readmission rates in those without diabetes in our institution. Conclusion: The Diabetes Resource Nurse program is effective in decreasing readmission rates. Patients seen by the diabetes educators have the lowest rates of readmission

Delineating the role of FANCA in glucose-stimulated insulin secretion in β cells through its protein interactome

Hyperinsulinemia affects 72% of Fanconi anemia (FA) patients and an additional 25% experience lowered glucose tolerance or frank diabetes. The underlying molecular mechanisms contributing to the dysfunction of FA pancreas β cells is unknown. Therefore, we sought to evaluate the functional role of FANCA, the most commonly mutated gene in FA, in glucosestimulated insulin secretion (GSIS). This study reveals that FANCA or FANCB knockdown impairs GSIS in human pancreas β cell line EndoC-βH3. To identify potential pathways by which FANCA might regulate GSIS, we employed a proteomics approach to identify FANCA protein interactions in EndoC-βH3 differentially regulated in response to elevated glucose levels. Glucose-dependent changes in the FANCA interaction network were observed, including increased association with other FA family proteins, suggesting an activation of the DNA damage response in response to elevated glucose levels. Reactive oxygen species increase in response to glucose stimulation and are necessary for GSIS in EndoC-βH3 cells. Glucose-induced activation of the DNA damage response was also observed as an increase in the DNA damage foci marker γ-H2AX and dependent upon the presence of reactive oxygen species. These results illuminate the role of FANCA in GSIS and its protein interactions regulated by glucose stimulation that may explain the prevalence of β cell-specific endocrinopathies in FA patients

The Impact of Type 1 Diabetes on Neural Dynamics

Type 1 diabetes (T1D) has been shown to affect the structure and function of the brain. The current study sought to uncover the neural dynamics underlying cognitive processing in adults with T1D using non-invasive neuroimaging. Adults with T1D and without major complications and a demographically-matched control group underwent magnetoencephalography (MEG) while performing tasks tapping attention, working memory and motor functioning. MEG data from each task was examined using a beamformer source imaging approach and probed statistically for group differences. Our results for the flanker attention task indicated that neural activity in the anterior cingulate, paracentral lobule, and parietal function was altered, such that participants with T1D had stronger flanker interference responses in parietal and weaker responses in anterior cingulate regions (p \u3c .001). Further, the overall strength of the anterior cingulate and paracentral lobule responses significantly correlated with disease duration, r = -.46, p = .006, and r = -.42, p = .013, respectively. Group differences in parietal-occipital responses were found throughout encoding and maintenance phases of the working memory task, where participants with T1D had stronger parietal activity in encoding and weakened parietal-occipital activity in maintenance (ps \u3c .01). Activity in several regions correlated with duration and A1C in participants with T1D (ps \u3c .01). Motor responses were also altered in participants with T1D, where specific frequency responses differentially predicted behavioral outcomes. These findings demonstrate significant alterations in neurophysiology underlying major cognitive processes, likely affecting outcomes in later life

Quantifying vehicle control from physiology in type 1 diabetes

Objective: Our goal is to measure real-world effects of at-risk driver physiology on safety-critical tasks like driving by monitoring driver behavior and physiology in real-time. Drivers with type 1 diabetes (T1D) have an elevated crash risk that is linked to abnormal blood glucose, particularly hypoglycemia. We tested the hypotheses that (1) T1D drivers would have overall impaired vehicle control behavior relative to control drivers without diabetes, (2) At-risk patterns of vehicle control in T1D drivers would be linked to at-risk, in-vehicle physiology, and (3) T1D drivers would show impaired vehicle control with more recent hypoglycemia prior to driving. Methods: Drivers (18 T1D, 14 control) were monitored continuously (4 weeks) using in-vehicle sensors (e.g., video, accelerometer, speed) and wearable continuous glucose monitors (CGMs) that measured each T1D driver’s real-time blood glucose. Driver vehicle control was measured by vehicle acceleration variability (AV) across lateral (AVY, steering) and longitudinal (AVX, braking/accelerating) axes in 45-second segments (N = 61,635). Average vehicle speed for each segment was modeled as a covariate of AV and mixed-effects linear regression models were used. Results: We analyzed 3,687 drives (21,231 miles). T1D drivers had significantly higher overall AVX, Y compared to control drivers (BX = 2.5 × 10−2 BY = 1.6 × 10−2, p  Conclusions: Our results show that T1D driver risk can be linked to real-time patterns of at-risk driver physiology, particularly hypoglycemia, and driver risk can be detected during and prior to driving. Such naturalistic studies monitoring driver vehicle controls can inform methods for early detection of hypoglycemia-related driving risks, fitness to drive assessments, thereby helping to preserve safety in at-risk drivers with diabetes.This is an Accepted Manuscript of an article published by Taylor & Francis as Chakraborty, Pranamesh, Jennifer Merickel, Viraj Shah, Anuj Sharma, Chinmay Hegde, Cyrus Desouza, Andjela Drincic, Pujitha Gunaratne, and Matthew Rizzo. "Quantifying vehicle control from physiology in type 1 diabetes." Traffic Injury Prevention (2019): 1-6. Available online at DOI: 10.1080/15389588.2019.1665176. Posted with permission.</p