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)
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<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)
Metabolic derangement triggered by a high fat diet has been associated with decreased brain glucose uptake in mice through downregulation of GLUT-1 expression at the blood-brain barrier. Likewise, a prior study by our group using 1H magnetic resonance spectroscopy (MRS) showed diminished change in brain glucose level during acute hyperglycemia in patients with obesity and diabetes. However, whether this reflected differences in absolute brain concentrations remains unknown. We utilized 13C MRS scanning at 4 Tesla to compare the rate of glucose transport (Tmax) and cerebral metabolic rate of glucose (CMRgl) in the occipital lobe during a 2-hour hyperglycemic clamp. Plasma glucose concentration of ∼180mg/dl was achieved using a variable 1-13C-glucose infusion. The study included 8 healthy lean (1M/7F, age 29 ± 5 years, BMI 21 ± 2 kg/m2, HgbA1c 5.4 ± 0.2%) and 6 obese participants (4M/2F, age 30 ± 3 years, BMI 33 ± 3 kg/m2, HgbA1c 5.5 ± 0.2%). Insulin and free fatty acids (FFA) levels were measured during the clamp. Despite nearly identical plasma glucose concentrations at steady state (lean 182.5 ± 9.0 mg/dL, obese 186.5 ± 13.5 mg/dL, P=0.55, averaged over time 60-120 minutes), the absolute brain glucose concentrations were 30% less in obese compared to lean participants (P=0.02). Moreover, using previously reported Michaelis-Menten Kt of 1.1 mM, the calculated Tmax/CMRgl at steady state were 37% less in obese participants (P=0.01), suggesting reduced glucose transport. A trend of higher insulin and FFA levels in obese participants during hyperglycemia was observed. In addition, FFA levels at steady state were negatively correlated with absolute brain glucose concentrations (r= -0.575, P=0.05). We conclude that obesity is associated with diminished absolute concentration of brain glucose during acute hyperglycemia, likely explained by reduced cerebral glucose transport capacity. These findings may have implications for understanding the impact of obesity on central regulation of feeding behavior as well as neurocognitive function. Disclosure F. Gunawan: None. L. Jiang: None. J. Leventhal: None. J.J. Pach: None. E. Sanchez Rangel: None. R. Belfort-DeAguiar: Research Support; Self; Silver Palate Kitchens, Inc. A. Coppoli: None. D.L. Rothman: None. R. Sherwin: Other Relationship; Self; ICON plc., IQVIA, MannKind Corporation. G.F. Mason: None. J.J. Hwang: None. Funding American Diabetes Association (1-17-ICTS-013 to J.J.H.)
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