Tumor necrosis factor (TNF) signaling is required for inflammatory nociceptive (pain) sensitization in Drosophila and vertebrates. Nociceptive sensitization in Drosophila larvae following UV-induced tissue damage is accompanied by epidermal apoptosis and requires epidermal-derived TNF/Eiger and the initiator caspase, Dronc. Major gaps remain regarding TNF function in sensitization, including the relationship between apoptosis/tissue damage and TNF production, the downstream signaling in this context, and the target genes that modulate nociceptive behaviors. Here, apoptotic cell death and thermal nociceptive sensitization are genetically and procedurally separable in a Drosophila model of UV-induced nociceptive sensitization. Activation of epidermal Dronc induces TNF-dependent but effector caspase-independent nociceptive sensitization in the absence of UV. In addition, knockdown of Dronc attenuated nociceptive sensitization induced by full-length TNF/Eiger but not by a constitutively soluble form. UV irradiation induced TNF production in both in vitro and in vivo, but TNF secretion into hemolymph was not sufficient to induce thermal nociceptive sensitization. Downstream mediators of TNF-induced sensitization included two TNF receptor-associated factors, a p38 kinase, and the transcription factor nuclear factor kappa B. Finally, sensory neuron-specific microarray analysis revealed downstream TNF target genes induced during thermal nociceptive sensitization. One of these, enhancer of zeste (E(z)), functions downstream of TNF during thermal nociceptive sensitization. Our findings suggest that an initiator caspase is involved in TNF processing/secretion during nociceptive sensitization, and that TNF activation leads to a specific downstream signaling cascade and gene transcription required for sensitization. These findings have implications for both the evolution of inflammatory caspase function following tissue damage signals and the action of TNF during sensitization in vertebrates.

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in type 2 diabetes (T2D) patients. Recent cardiovascular outcome trials demonstrated clear cardiovascular benefits of novel classes of glucose-lowering agents. We performed retrospective electronic health record review at two major healthcare systems in the USA to determine the relative frequencies of outpatient encounters (hence prescribing opportunities) that a patient with T2D and CVD had with a cardiologist vs. an endocrinologist over one-year period. Of 109 747 T2D patients, 42.6% had established CVD. The ratio of cardiology-to-endocrinology outpatient encounters was 2.0:1 for all T2D patients, and 4.1:1 for those with T2D and CVD. Because each outpatient encounter provides an opportunity to discuss glucose-lowering medications with cardiovascular benefits, the much greater frequency of cardiology encounters highlights the emerging potential for cardiovascular specialists to influence or even implement evidence-based glucose-lowering therapies, thereby improving cardiovascular outcomes in their T2D patients.

Background : A large proportion of patients with type 2 diabetes (T2D) have established cardiovascular (CV) disease (D). Recent large CV outcome trials demonstrated clear CV benefits of 2 novel classes of glucose-lowering agents (GLA), SGLT2 inhibitors and GLP-1 receptor agonists. Guidelines now stipulate that these should be favored in patients with T2D and overt CVD. Not surprisingly, endocrinologists prescribe these GLAs more frequently than cardiologists. Some, however, have proposed that cardiologists should take a more active role in prescribing these GLAs for CV risk reduction. We therefore endeavored to compare prescribing opportunities for these GLAs, by assessing the likelihood that a patient with T2D and CVD had an outpatient encounter with a cardiologist vs. an endocrinologist over a 1-year period in a large academic healthcare system in New England. Methods : We reviewed electronic health records of adult patients (age ≥18) with T2D who had outpatient encounters within the Yale New Haven Hospital System (YNHHS) during 2017. We analyzed demographic information, CVD diagnostic categories (coronary artery disease [CAD], congestive heart failure [CHF], cerebrovascular disease [CBD], peripheral vascular disease [PVD]), number of cardiology and endocrinology encounters, provider types, and visit diagnoses. Results : Of 78,878 T2D patients (mean age 66.7 ±14.4 years; 51% female), 31,639 (40.1%) had established CVD. The ratio of cardiologist:endocrinologist outpatient encounters was 2.6 (51,954 vs. 20,337 encounters) for all T2D patients and 5.3 (43,482 vs. 8,264 encounters) for those with T2D and CVD. Of the 4 CVD diagnostic categories, patients with CHF had the highest cardiologist:endocrinologist encounter ratio at 8.4 (24,477 vs. 2,931 encounters), followed by patients with CAD at 6.0 (33,722 vs 5,579 encounters). Conclusion : In our health system, over the course of a single year, a patient with T2D was nearly 3 times more likely to have an outpatient encounter with a cardiologist than an endocrinologist. With coexisting CVD, the likelihood increased to greater than 5-fold. In order to capitalize on the CV benefits of the newer GLAs, prescriptions by cardiologists are apt to hasten adherence to the latest guidelines and improve patient outcomes. Educational programs pertaining to these emerging treatment paradigms should target cardiologists in addition to endocrinologists (and primary care physicians).

Aims/hypothesis We have previously shown that individuals with uncontrolled type 2 diabetes have a blunted rise in brain glucose levels measured by 1H magnetic resonance spectroscopy. Here, we investigate whether reductions in HbA1c normalise intracerebral glucose levels. Methods Eight individuals (two men, six women) with poorly controlled type 2 diabetes and mean ± SD age 44.8 ± 8.3 years, BMI 31.4 ± 6.1 kg/m2 and HbA1c 84.1 ± 16.2 mmol/mol (9.8 ± 1.4%) underwent 1H MRS scanning at 4 Tesla during a hyperglycaemic clamp (~12.21 mmol/l) to measure changes in cerebral glucose at baseline and after a 12 week intervention that improved glycaemic control through the use of continuous glucose monitoring, diabetes regimen intensification and frequent visits to an endocrinologist and nutritionist. Results Following the intervention, mean ± SD HbA1c decreased by 24.3 ± 15.3 mmol/mol (2.1 ± 1.5%) (p=0.006), with minimal weight changes (p=0.242). Using a linear mixed-effects regression model to compare glucose time courses during the clamp pre and post intervention, the pre-intervention brain glucose level during the hyperglycaemic clamp was significantly lower than the post-intervention brain glucose (p<0.001) despite plasma glucose levels during the hyperglycaemic clamp being similar (p=0.266). Furthermore, the increases in brain glucose were correlated with the magnitude of improvement in HbA1c (r = 0.71, p=0.048). Conclusion/interpretation These findings highlight the potential reversibility of cerebral glucose transport capacity and metabolism that can occur in individuals with type 2 diabetes following improvement of glycaemic control. Trial registrationClinicalTrials.gov NCT03469492. Graphical abstract

Poor glycemic control is associated with central nervous system complications. We have previously shown that compared to healthy controls, individuals with uncontrolled T2DM have a blunted rise in brain glucose levels measured by 1H magnetic resonance spectroscopy (MRS). In this study, we investigate whether reduction in HbA1C improves intracerebral glucose levels. Six T2DM subjects with poor glycemic control were recruited (4F, age 46.0 ± 8.8 yrs, BMI 34.2 ± 4.1 kg/m2, HgbA1c 9.6 ± 1.1%) to participate in 1HMRS scanning at 4 Tesla during a hyperglycemic clamp (∼220 mg/dl) before and after a 12-week intervention to improve glycemic control through use of continuous glucose monitoring, intensification of diabetes regimen, and frequent visits with an endocrinologist and nutritionist. Following the intervention, HbA1c decreased by 2.1%±1.5 (P=0.02) with minimal BMI changes (P=0.10). Using a hierarchical linear regression model to compare glucose time courses during the clamp pre and post intervention, brain glucose levels were modestly and significantly higher during the clamp after the intervention (P=0.02) despite no differences in plasma glucose levels during the clamp (P=0.45). These findings suggest that brain glucose levels increase after improvement of glycemic control and provide evidence that reducing HbA1C may improve brain glucose transport and/or metabolism. Disclosure E. Sanchez Rangel: None. F. Gunawan: None. L. Jiang: None. M. Savoye: None. F. Dai: None. D.L. Rothman: None. G.F. Mason: None. J.J. Hwang: Research Support; Self; General Electric. Funding National Institutes of Health (DK109284)

Quality Improvement Success Stories are published by the American Diabetes Association in collaboration with the American College of Physicians and the National Diabetes Education Program. This series is intended to highlight best practices and strategies from programs and clinics that have successfully improved the quality of care for people with diabetes or related conditions. Each article in the series is reviewed and follows a standard format developed by the editors of Clinical Diabetes. The following article describes an initiative aimed at improving access to diabetes specialty care for patients within a safety-net health system in Dallas County, TX, through the implementation of electronic consultations.

Diabetes and hyperglycemia are risk factors for morbidity and mortality in hospitalized patients with COVID19. Subspecialty consultative resources to help front-line clinicians treat these conditions is often limited. We implemented a “Virtual Hyperglycemia Surveillance Service (VHSS)” to guide glucose management in COVID19 patients admitted to our 1541-bed academic medical center. From April 22 to June 9, 2020, hospitalized adult patients with COVID19 and 2 or more blood glucose (BG) values greater than 250 mg/dl over 24-h were identified using a daily BG report. The VHSS reviewed BGs and treatment plans, then made recommendations for future glycemic management via a one-time note, visible to all providers. Some patients with re-admission or persistently elevated BG after 1 week received a second VHSS note. We compared BGs from 24-h pre- and 72-h post-intervention starting at 6AM on the day following VHSS review. We also evaluated for hypoglycemia, insulin infusion use and use of formal diabetes consults. A subgroup analysis was performed on patients in the intensive care unit (ICU). At the end of the intervention, we identified a retrospective control cohort admitted to the same hospital from March 21 to April 21, 2020 who met the inclusion criteria for a VHSS assessment. The VHSS group consisted of 100 patients with 126 individual VHSS encounters, and the control group comprised 50 patients. Baseline characteristics in the VHSS and control groups, respectively, were: mean age 62.5 vs 62.1 years, % male 58 vs 56, mean weight 91.4 vs 93.4 kg, BMI 31.8 vs 33.0 kg/m2, and HbA1c 9.1 vs 8.8 %. There were fewer patients in the ICU in the VHSS than control group (44% vs 66%). In the VHSS group, mean BG pre- vs. post-intervention was 260.3 ±21.7 and 227.4 ±25.3 mg/dl (p&lt;0.001). In the control group, mean BG pre-and post- the day they met assessment criteria was 264.8 ± 6.5 mg/dl and 250.6 ± 8.6 mg/dl (p=0.18). There was no difference in the use of insulin infusions or diabetes consults between the two groups. More hypoglycemia (BG&lt;70 mg/dl) occurred in the VHSS than control group (8.3% vs 0%, p=0.04). Within the VHSS group, the average change in BG was significantly greater in ICU than non-ICU patients (-51.8 ±8.7 vs -19.6 ±5.0 mg/dl, p&lt;0.01) and the reduction in the % of BG over 250 mg/dl was also significantly greater in the ICU (-32.2% vs -16.8%, p=0.02). Implementation of a single virtual consult for severely hyperglycemic hospitalized COVID19 patients was associated with rapidly reduced BG concentrations, especially in the ICU. The mean reduction in BG with VHSS intervention was more than 2-fold greater than that observed in our control group. Glucose control remained suboptimal, however, suggesting the need for subsequent input from this specialty service.

Poor sleep quality has been associated with increased risk of metabolic syndrome and type 2 diabetes as well as acceleration of neurodegenerative diseases. In rodents, sleep restriction decreases glucose transport into the brain via downregulation of GLUT1, the primary glucose transporter at the blood-brain barrier. However, little is known about the association between sleep quality and glucose transport and metabolism in the human brain. In this exploratory analysis, we quantified cerebral glucose levels amongst individuals with good and poor sleep quality as defined by the widely used and well-validated Pittsburgh Sleep Quality Index (PSQI), which assesses 7 different components of sleep quality over a 1 month time period (PSQI≥5 = Poor sleep; PSQI&lt;5 = Good sleep). Twelve healthy subjects completed the PSQI questionnaire. Eight (6F, age 27.6 ± 5.7, BMI 26.6 ± 8.2 kg/m2, HgbA1c 5.4 ± 0.2%) had good and 4 (2F, age 29.5± 2.4, BMI 27.8 ± 6.5 kg/m2, HgbA1c 5.2 ± 0.2%) had poor sleep. All subjects underwent 13C magnetic resonance spectroscopy brain scanning at 4 Tesla during a 2-hour hyperglycemic clamp (plasma glucose target ∼180 mg/dl) to measure absolute cerebral glucose levels as part of a larger study to investigate obesity and cerebral glucose metabolism. There were no differences in age, BMI, or HbA1c levels between groups with good and poor sleep. Individuals with good sleep had 63% higher absolute cerebral glucose levels at steady state compared to those with poor sleep (3.4 ± 0.7 mmol/L vs. 2.1 ± 0.9 mmol/L, p=.017). Higher PSQI scores correlated with lower absolute cerebral glucose levels (r= -0.725, p=0.008, PSQI for all subjects (mean±SD) = 4 ± 2). In this pilot and exploratory study, individuals with poor sleep quality have significantly lower absolute cerebral glucose levels, which suggests an association between poor sleep and altered cerebral glucose transport and/or metabolism. These findings may have wide-ranging implications for understanding the effects of sleep on brain function. Disclosure T.K. Stanley: None. F. Gunawan: None. N.S. Redeker: None. L. Jiang: None. A. Coppoli: None. D.L. Rothman: None. G.F. Mason: None. J. Hwang: Research Support; Self; General Electric. Funding American Diabetes Association (1-17-ICTS-013 to J.H.); National Institutes of Health (1R03DK121048)