Leptin metabolically licenses T cells for activation to link nutrition and immunity.

Immune responses are highly energy-dependent processes. Activated T cells increase glucose uptake and aerobic glycolysis to survive and function. Malnutrition and starvation limit nutrients and are associated with immune deficiency and increased susceptibility to infection. Although it is clear that immunity is suppressed in times of nutrient stress, mechanisms that link systemic nutrition to T cell function are poorly understood. We show in this study that fasting leads to persistent defects in T cell activation and metabolism, as T cells from fasted animals had low glucose uptake and decreased ability to produce inflammatory cytokines, even when stimulated in nutrient-rich media. To explore the mechanism of this long-lasting T cell metabolic defect, we examined leptin, an adipokine reduced in fasting that regulates systemic metabolism and promotes effector T cell function. We show that leptin is essential for activated T cells to upregulate glucose uptake and metabolism. This effect was cell intrinsic and specific to activated effector T cells, as naive T cells and regulatory T cells did not require leptin for metabolic regulation. Importantly, either leptin addition to cultured T cells from fasted animals or leptin injections to fasting animals was sufficient to rescue both T cell metabolic and functional defects. Leptin-mediated metabolic regulation was critical, as transgenic expression of the glucose transporter Glut1 rescued cytokine production of T cells from fasted mice. Together, these data demonstrate that induction of T cell metabolism upon activation is dependent on systemic nutritional status, and leptin links adipocytes to metabolically license activated T cells in states of nutritional sufficiency.

Impact of Genetic Testing and Family Health History Based Risk Counseling on Behavior Change and Cognitive Precursors for Type 2 Diabetes.

Family health history (FHH) in the context of risk assessment has been shown to positively impact risk perception and behavior change. The added value of genetic risk testing is less certain. The aim of this study was to determine the impact of Type 2 Diabetes (T2D) FHH and genetic risk counseling on behavior and its cognitive precursors. Subjects were non-diabetic patients randomized to counseling that included FHH +/- T2D genetic testing. Measurements included weight, BMI, fasting glucose at baseline and 12 months and behavioral and cognitive precursor (T2D risk perception and control over disease development) surveys at baseline, 3, and 12 months. 391 subjects enrolled of which 312 completed the study. Behavioral and clinical outcomes did not differ across FHH or genetic risk but cognitive precursors did. Higher FHH risk was associated with a stronger perceived T2D risk (pKendall < 0.001) and with a perception of "serious" risk (pKendall < 0.001). Genetic risk did not influence risk perception, but was correlated with an increase in perception of "serious" risk for moderate (pKendall = 0.04) and average FHH risk subjects (pKendall = 0.01), though not for the high FHH risk group. Perceived control over T2D risk was high and not affected by FHH or genetic risk. FHH appears to have a strong impact on cognitive precursors of behavior change, suggesting it could be leveraged to enhance risk counseling, particularly when lifestyle change is desirable. Genetic risk was able to alter perceptions about the seriousness of T2D risk in those with moderate and average FHH risk, suggesting that FHH could be used to selectively identify individuals who may benefit from genetic risk testing.

Fluid management and goal-directed therapy as an adjunct to Enhanced Recovery After Surgery (ERAS)

© 2014, Canadian Anesthesiologists' Society.Optimal perioperative fluid management is an important component of Enhanced Recovery After Surgery (ERAS) pathways. Fluid management within ERAS should be viewed as a continuum through the preoperative, intraoperative, and postoperative phases. Each phase is important for improving patient outcomes, and suboptimal care in one phase can undermine best practice within the rest of the ERAS pathway. The goal of preoperative fluid management is for the patient to arrive in the operating room in a hydrated and euvolemic state. To achieve this, prolonged fasting is not recommended, and routine mechanical bowel preparation should be avoided. Patients should be encouraged to ingest a clear carbohydrate drink two to three hours before surgery. The goals of intraoperative fluid management are to maintain central euvolemia and to avoid excess salt and water. To achieve this, patients undergoing surgery within an enhanced recovery protocol should have an individualized fluid management plan. As part of this plan, excess crystalloid should be avoided in all patients. For low-risk patients undergoing low-risk surgery, a “zero-balance” approach might be sufficient. In addition, for most patients undergoing major surgery, individualized goal-directed fluid therapy (GDFT) is recommended. Ultimately, however, the additional benefit of GDFT should be determined based on surgical and patient risk factors. Postoperatively, once fluid intake is established, intravenous fluid administration can be discontinued and restarted only if clinically indicated. In the absence of other concerns, detrimental postoperative fluid overload is not justified and “permissive oliguria” could be tolerated.

Potassium Measures and Their Associations with Glucose and Diabetes Risk: The Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Recent studies have found low-normal potassium (K) to be associated with increased diabetes risk. We sought to verify these associations in a multi-ethnic US cohort; and to determine if these associations extend to US Hispanics and Asian-Americans. METHODS: We analyzed data from Multi-Ethnic Study of Atherosclerosis (MESA) participants who were free-of-diabetes at baseline. We examined cross-sectional associations between measures of K-serum, dietary, and urine-with fasting glucose and HOMA-IR. We examined longitudinal associations between K and diabetes risk over 8 years. FINDINGS: In multivariable models, compared to those with higher serum K (≥4.5mmol/L), those with lower serum K (<4.0mmol/L) had significantly higher fasting glucose [1.3 mg/dL (95%CI 0.2, 2.4), P-value = 0.03]. Incident diabetes developed in 1281 of 5415 at-risk participants. In minimally-adjusted models, we found inverse associations between serum and dietary K and diabetes risk. Compared to those with higher serum K, those with lower serum K had an HR (95% CI) of incident diabetes of 1.23 (1.04, 1.47), P-value = 0.02. However, these associations were attenuated in fully-adjusted models. We found no significant interaction between potassium and ethnicity. CONCLUSIONS: In this multi-ethnic cohort, we found a significant inverse association between serum K and fasting glucose but no significant association with longer-term diabetes risk. This inverse association between potassium and glucose must be studied further to understand the physiology and its potential impact on chronic health.

Ghrelin suppresses glucose-stimulated insulin secretion and deteriorates glucose tolerance in healthy humans.

OBJECTIVE: The orexigenic gut hormone ghrelin and its receptor are present in pancreatic islets. Although ghrelin reduces insulin secretion in rodents, its effect on insulin secretion in humans has not been established. The goal of this study was to test the hypothesis that circulating ghrelin suppresses glucose-stimulated insulin secretion in healthy subjects. RESEARCH DESIGN AND METHODS: Ghrelin (0.3, 0.9 and 1.5 nmol/kg/h) or saline was infused for more than 65 min in 12 healthy patients (8 male/4 female) on 4 separate occasions in a counterbalanced fashion. An intravenous glucose tolerance test was performed during steady state plasma ghrelin levels. The acute insulin response to intravenous glucose (AIRg) was calculated from plasma insulin concentrations between 2 and 10 min after the glucose bolus. Intravenous glucose tolerance was measured as the glucose disappearance constant (Kg) from 10 to 30 min. RESULTS: The three ghrelin infusions raised plasma total ghrelin concentrations to 4-, 15-, and 23-fold above the fasting level, respectively. Ghrelin infusion did not alter fasting plasma insulin or glucose, but compared with saline, the 0.3, 0.9, and 1.5 nmol/kg/h doses decreased AIRg (2,152 +/- 448 vs. 1,478 +/- 2,889, 1,419 +/- 275, and 1,120 +/- 174 pmol/l) and Kg (0.3 and 1.5 nmol/kg/h doses only) significantly (P < 0.05 for all). Ghrelin infusion raised plasma growth hormone and serum cortisol concentrations significantly (P < 0.001 for both), but had no effect on glucagon, epinephrine, or norepinephrine levels (P = 0.44, 0.74, and 0.48, respectively). CONCLUSIONS: This is a robust proof-of-concept study showing that exogenous ghrelin reduces glucose-stimulated insulin secretion and glucose disappearance in healthy humans. Our findings raise the possibility that endogenous ghrelin has a role in physiologic insulin secretion, and that ghrelin antagonists could improve beta-cell function.