Peroxisome proliferator-activated receptors as stimulants of angiogenesis in cardiovascular disease and diabetes

The incidence of diabetes is directly related to the incidence of obesity, which is at epidemic proportions in the US. Cardiovascular disease is a common complication of diabetes, which results in high morbidity and mortality. Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear hormone receptors that regulate lipid and glucose metabolism. PPAR-α agonists such as fenofibrate and PPAR-γ agonists such as the thiozolidinediones have been used to treat dyslipidemia and insulin resistance in diabetes. Over the past few years research has discovered the role of PPARs in the regulation of inflammation, proliferation, and angiogenesis. Clinical trials looking at the effect of PPAR agonists on cardiovascular outcomes have produced controversial results. Studies looking at angiogenesis and proliferation in various animal models and cell lines have shown a wide variation in results. This may be due to the differential effects of PPARs on proliferation and angiogenesis in various tissues and pathologic states. This review discusses the role of PPARs in stimulating angiogenesis. It also reviews the settings in which stimulation of angiogenesis may be either beneficial or harmful

Glucose Control, Sleep, Obesity, and Real-World Driver Safety at Stop Intersections in Type 1 Diabetes

Background: Diabetes is associated with obesity, poor glucose control and sleep dysfunction which impair cognitive and psychomotor functions, and, in turn, increase driver risk. How this risk plays out in the real-world driving settings is terra incognita. Addressing this knowledge gap requires comprehensive observations of diabetes driver behavior and physiology in challenging settings where crashes are more likely to occur, such as stop-controlled traffic intersections, as in the current study of drivers with Type 1 Diabetes (T1DM). Methods: 32 active drivers from around Omaha, NE participated in 4-week, real-world study. Each participant's own vehicle was instrumented with an advanced telematics and camera system collecting driving sensor data and video. Videos were analyzed using computer vision models detecting traffic elements to identify stop signs. Stop sign detections and driver stopping trajectories were clustered to geolocate and extract driver-visited stop intersections. Driver videos were then annotated to record stopping behavior and key traffic characteristics. Stops were categorized as safe or unsafe based on traffic law. Results: Mixed effects logistic regression models examined how stopping behavior (safe vs. unsafe) in T1DM drivers was affected by 1) abnormal sleep, 2) obesity, and 3) poor glucose control. Model results indicate that one standard deviation increase in BMI (~7 points) in T1DM drivers associated with a 14.96 increase in unsafe stopping odds compared to similar controls. Abnormal sleep and glucose control were not associated with increased unsafe stopping. Conclusion: This study links chronic patterns of abnormal T1DM driver physiology, sleep, and health to driver safety risk at intersections, advancing models to identify real-world safety risk in diabetes drivers for clinical intervention and development of in-vehicle safety assistance technology.Comment: 23 pages, 7 figures, 10 table

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

Targeting inflammation using salsalate in patients with type 2 diabetes: effects on flow-mediated dilation (TINSAL-FMD).

OBJECTIVE: To test whether inhibiting inflammation with salsalate improves endothelial function in patients with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: We conducted an ancillary study to the National Institutes of Health-sponsored, multicenter, randomized, double-masked, placebo-controlled trial evaluating the safety and efficacy of salsalate in targeting inflammation to improve glycemia in patients with T2D. Flow-mediated, endothelium-dependent dilation (FMD) and endothelium-independent, nitroglycerin-mediated dilation (NMD) of the brachial artery were assessed at baseline and 3 and 6 months following randomization to either salsalate 3.5 g/day or placebo. The primary end point was change in FMD at 6 months. RESULTS: A total of 88 participants were enrolled in the study, and data after randomization were available for 75. Patients in the treatment and control groups had similar ages (56 years), BMI (33 kg/m(2)), sex (64% male), ethnicity, current treatment, and baseline HbA1c (7.7% [61 mmol/mol]). In patients treated with salsalate versus placebo, HbA1c was reduced by 0.46% (5.0 mmol/mol; P \u3c 0.001), fasting glucose by 16.1 mg/dL (P \u3c 0.001), and white blood cell count by 430 cells/µL (P \u3c 0.02). There was no difference in the mean change in either FMD (0.70% [95% CI -0.86 to 2.25%]; P = 0.38) or NMD (-0.59% [95% CI -2.70 to 1.51%]; P = 0.57) between the groups treated with salsalate and placebo at 6 months. Total and LDL cholesterol were 11 and 16 mg/dL higher, respectively, and urinary albumin was 2.0 µg/mg creatinine higher in the patients treated with salsalate compared with those treated with placebo (all P \u3c 0.009). CONCLUSIONS: Salsalate does not change FMD in peripheral conduit arteries in patients with T2D despite lowering HbA1c. This finding suggests that salsalate does not have an effect on vascular inflammation, inflammation does not cause endothelial dysfunction in T2D, or confounding effects of salsalate mitigate favorable effects on endothelial function

Vitamin D Supplementation and Prevention of Type 2 Diabetes

BACKGROUND Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation lowers the risk of diabetes is unknown. METHODS We randomly assigned adults who met at least two of three glycemic criteria for prediabetes (fasting plasma glucose level, 100 to 125 mg per deciliter; plasma glucose level 2 hours after a 75-g oral glucose load, 140 to 199 mg per deciliter; and glycated hemoglobin level, 5.7 to 6.4%) and no diagnostic criteria for diabetes to receive 4000 IU per day of vitamin D3 or placebo, regardless of the baseline serum 25-hydroxyvitamin D level. The primary outcome in this time-to-event analysis was new-onset diabetes, and the trial design was event-driven, with a target number of diabetes events of 508. RESULTS A total of 2423 participants underwent randomization (1211 to the vitamin D group and 1212 to the placebo group). By month 24, the mean serum 25-hydroxyvitamin D level in the vitamin D group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the vitamin D group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years, respectively). The hazard ratio for vitamin D as compared with placebo was 0.88 (95% confidence interval, 0.75 to 1.04; P = 0.12). The incidence of adverse events did not differ significantly between the two groups. CONCLUSIONS Among persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D3 supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; D2d ClinicalTrials.gov number, NCT01942694.

Prevalence of Microvascular and Macrovascular Disease in the Glycemia Reduction Approaches in Diabetes - A Comparative Effectiveness (GRADE) Study Cohort

Aims: The Glycemia Reduction Approaches in Diabetes - A Comparative Effectiveness (GRADE) trial is a randomized clinical trial comparing glycemic effects of four diabetes medications added to metformin in type 2 diabetes (T2D). Microvascular and macrovascular diseases are secondary outcomes. We evaluated the prevalence and risk factor relationships for microvascular and macrovascular complications in the GRADE cohort at study entry. Methods: Complication prevalence and risk factors were analyzed based on data from screening in all consenting participants meeting GRADE eligibility. Logistic regression and Z-statistics were used to assess risk factor relationships with complications. Results: We enrolled 5047 T2D participants [mean age 57 years; 36% female; mean known T2D duration 4 years (all < 10 years); mean HbA1c 8.0% (∼64 mmol/mol) at screening]. Urinary albumin/creatinine ratio (ACR) ≥ 30 mg/gram was present in 15.9% participants; peripheral neuropathy (by Michigan Neuropathy Screening Instrument) in 21.5%; cardiovascular autonomic neuropathy by electrocardiography-derived indices in 9.7%; self-reported retinopathy in 1.0%. Myocardial infarction ascertained by self-report or electrocardiogram was present in 7.3%, and self-reported history of stroke in 2.0%. Conclusions: In the GRADE cohort with < 10 years of T2D and a mean HbA1c of 8.0%, diabetes complications were present in a substantial fraction of participants, more so than might otherwise have been expected

Vitamin D Supplementation and Prevention of Type 2 Diabetes

BACKGROUND Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation lowers the risk of diabetes is unknown. METHODS We randomly assigned adults who met at least two of three glycemic criteria for prediabetes (fasting plasma glucose level, 100 to 125 mg per deciliter; plasma glucose level 2 hours after a 75-g oral glucose load, 140 to 199 mg per deciliter; and glycated hemoglobin level, 5.7 to 6.4%) and no diagnostic criteria for diabetes to receive 4000 IU per day of vitamin D3 or placebo, regardless of the baseline serum 25-hydroxyvitamin D level. The primary outcome in this time-to-event analysis was new-onset diabetes, and the trial design was event-driven, with a target number of diabetes events of 508. RESULTS A total of 2423 participants underwent randomization (1211 to the vitamin D group and 1212 to the placebo group). By month 24, the mean serum 25-hydroxyvitamin D level in the vitamin D group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the vitamin D group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years, respectively). The hazard ratio for vitamin D as compared with placebo was 0.88 (95% confidence interval, 0.75 to 1.04; P = 0.12). The incidence of adverse events did not differ significantly between the two groups. CONCLUSIONS Among persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D3 supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; D2d ClinicalTrials.gov number, NCT01942694.

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years