Deficits in brain glucose transport among younger adults with obesity.

OBJECTIVE: Obesity is associated with alterations in eating behavior and neurocognitive function. In this study, we investigate the effect of obesity on brain energy utilization, including brain glucose transport and metabolism. METHODS: A total of 11 lean participants and 7 young healthy participants with obesity (mean age, 27 years) underwent magnetic resonance spectroscopy scanning coupled with a hyperglycemic clamp (target, ~180 mg/dL) using [1-13C] glucose to measure brain glucose uptake and metabolism, as well as peripheral markers of insulin resistance. RESULTS: Individuals with obesity demonstrated an ~20% lower ratio of brain glucose uptake to cerebral glucose metabolic rate (Tmax/CMRglucose) than lean participants (2.12 ± 0.51 vs. 2.67 ± 0.51; p = 0.04). The cerebral tricarboxylic acid cycle flux (VTCA) was similar between the two groups (p = 0.64). There was a negative correlation between total nonesterified fatty acids and Tmax/CMRglucose (r = -0.477; p = 0.045). CONCLUSIONS: We conclude that CMRglucose is unlikely to differ between groups due to similar VTCA, and, therefore, the glucose transport Tmax is lower in individuals with obesity. These human findings suggest that obesity is associated with reduced cerebral glucose transport capacity even at a young age and in the absence of other cardiometabolic comorbidities, which may have implications for long-term brain function and health.

Benefits of Electronic Consultations in Improving Diabetes Care Within a Safety-Net Health System.

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.

Reversibility of brain glucose kinetics in type 2 diabetes mellitus.

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 registration ClinicalTrials.gov NCT03469492.

ATYPICAL RECURRENCE OF PARATHYROID CARCINOMA FOLLOWING INFLIXIMAB THERAPY IN A PATIENT WITH ULCERATIVE COLITIS.

OBJECTIVE: Parathyroid carcinoma (PTC) has a high rate of recurrence, which typically occurs within 5 years of diagnosis involving locoregional sites. Immunosuppressive therapies pose a theoretical increased risk of malignancy. We report an atypical case of PTC recurrence in a patient receiving infliximab therapy for ulcerative colitis (UC). METHODS: Main diagnostic tests performed included calcium and parathyroid hormone (PTH) levels, computed tomography, and a venous sampling study. RESULTS: A patient with PTC, who was "cured" by parathyroidectomy, presented with recurrent hypercalcemia 21 years after his initial diagnosis. He had recently been diagnosed with UC and was started on infliximab. His serum PTH level was elevated. After negative routine neck imaging studies and sestamibi scan, he underwent selective venous sampling with PTH measurements, which localized the source lesion to the thoracic wall. Subsequent imaging showed multiple left lung and pleural nodules, which were surgically resected. Hypercalcemia abated after surgery, but quickly returned and was recalcitrant to treatment with cinacalcet and zoledronic acid. Further imaging demonstrated recurrent lung metastases, some along the left diaphragm. He underwent 2 additional surgical resections, after which PTH and calcium levels normalized. Infliximab was replaced with vedolizumab for treatment of UC. CONCLUSION: Atypical presentation of PTC may occur in the context of immunosuppressive therapy. Venous sampling with PTH measurements can aid in localization of atypical metastatic PTC. Additional surveillance for PTC recurrence may be prudent following the initiation of immunosuppressive therapy in patients with a history of PTC.

Relative frequency of cardiology vs. endocrinology visits by type 2 diabetes patients with cardiovascular disease in the USA: implications for implementing evidence-based use of glucose-lowering medications.

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.

Drosophila caspase activity is required independently of apoptosis to produce active TNF/Eiger during nociceptive sensitization.

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.