Comparison of Hormonal Response to a Mixed-Meal Challenge in Hypoglycemia After Sleeve Gastrectomy vs Gastric Bypass.

CONTEXT: Exaggerated postprandial incretin and insulin responses are well documented in postbariatric surgery hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB). However, less is known about PBH after sleeve gastrectomy (SG). OBJECTIVE: We sought to compare meal-stimulated hormonal response in those with PBH after SG vs RYGB. METHODS: We enrolled 23 post-SG (12 with and 11 without PBH) and 20 post-RYGB (7 with and 13 without PBH) individuals who underwent bariatric surgery at our institution. PBH was defined as plasma glucose less than 60 mg/dL on 4-hour mixed-meal tolerance test (MTT). Islet and incretin hormones were compared across the 4 groups. RESULTS: Participants (N = 43) were on average 5 years post surgery, with a mean age of 48 years, mean preoperative body mass index of 48.4, 81% female, 61% White, and 53% post SG. Regardless of PBH, the SG group showed lower glucose, glucagon, and glucagon-like peptide 1 (GLP-1) responses to MTT and similar insulin and glucose-dependent insulinotropic polypeptide (GIP) responses compared to the RYGB group. Among those with PBH, the SG group following the MTT showed a lower peak glucose (P = .02), a similar peak insulin (90.3 mU/L vs 171mU/L; P = .18), lower glucagon (P < .01), early GLP-1 response (AUC0-60 min; P = .01), and slower time to peak GIP (P = .02) compared to PBH after RYGB. CONCLUSION: Among individuals with PBH, those who underwent SG were significantly different compared to RYGB in meal-stimulated hormonal responses, including lower glucagon and GLP-1 responses, but similar insulin and GIP responses. Future studies are needed to better understand the differential contribution of insulin and non-insulin-mediated mechanisms behind PBH after SG vs RYGB.

GDF15 and Cortisol Response to Meal Tolerance Test in Post-Sleeve Gastrectomy Patients with Weight Regain.

BACKGROUND: Hormonal factors behind weight regain (WR) after surgical weight loss remain inadequately understood. Growth/differentiation factor 15 (GDF15) has emerged as a potential therapeutic target in obesity treatment. Cortisol, another stress hormone, has also been associated with weight gain at both low and high circulating concentrations. We aimed to compare meal-stimulated GDF15 and cortisol response in adults with and without WR after sleeve gastrectomy (SG). We hypothesized that GDF15 and cortisol response to meal tolerance test (MTT) will be lower in those with versus without WR after SG. METHODS: Cross-sectional study comprised 21 adults without diabetes, who underwent SG. WR was defined as 100 × (current weight - nadir)/(preoperative weight - nadir) > 10%. GDF15, cortisol, insulin, glucose, and incretins (total glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) circulating concentrations) were measured during MTT (0-240 min) after 3-6 years post-bariatric surgery. RESULTS: All participants were 48% White, 85% female, with mean (SD) age: 43(10) years, and BMI: 36.2(7.6) kg/m2. Compared to the non-WR group (n = 6), the WR group (n = 15) had significantly higher BMI (WR: 38.6 ± 7.6 kg/m2, non-WR: 30.3 ± 3.5 kg/m2, p = 0.02) and showed lower GDF15 response (WR AUC vs non-WR AUC (116143 ± 13973 vs 185798 ± 38884 ng*min/L, p = 0.047)) and lower cortisol response (WR AUC vs non-WR AUC (3492 ± 210 vs 4880 ± 655 µg*min/dL, p = 0.015)). Incretin response did not differ between the groups. CONCLUSIONS: GDF15 and cortisol responses to MTT were lower in those who regained the weight after SG compared to those who did not, suggesting that dysregulation in GDF15 and cortisol response following bariatric surgery.

A Pilot Study of Exenatide Actions in Alzheimer's Disease.

BACKGROUND: Strong preclinical evidence suggests that exenatide, a glucagon-like peptide-1 (GLP- 1) receptor agonist used for treating type 2 diabetes, is neuroprotective and disease-modifying in Alzheimer's Disease (AD). OBJECTIVE: We performed an 18-month double-blind randomized placebo-controlled Phase II clinical trial to assess the safety and tolerability of exenatide and explore treatment responses for clinical, cognitive, and biomarker outcomes in early AD. METHOD: Eighteen participants with high probability AD based on cerebrospinal fluid (CSF) biomarkers completed the entire study prior to its early termination by the sponsor; partial outcomes were available for twentyone. RESULTS: Exenatide was safe and well-tolerated, showing an expectedly higher incidence of nausea and decreased appetite compared to placebo and decreasing glucose and GLP-1 during Oral Glucose Tolerance Tests. Exenatide treatment produced no differences or trends compared to placebo for clinical and cognitive measures, MRI cortical thickness and volume, or biomarkers in CSF, plasma, and plasma neuronal extracellular vesicles (EV) except for a reduction of Aß42 in EVs. CONCLUSION: The positive finding of lower EV Aß42 supports emerging evidence that plasma neuronal EVs provide an effective platform for demonstrating biomarker responses in clinical trials in AD. The study was underpowered due to early termination and therefore we cannot draw any firm conclusions. However, the analysis of secondary outcomes shows no trends in support of the hypothesis that exenatide is diseasemodifying in clinical AD, and lowering EV Aß42 in and of itself may not improve cognitive outcomes in AD.

Muscle cannabinoid 1 receptor regulates Il-6 and myostatin expression, governing physical performance and whole-body metabolism.

Sarcopenic obesity, the combination of skeletal muscle mass and function loss with an increase in body fat, is associated with physical limitations, cardiovascular diseases, metabolic stress, and increased risk of mortality. Cannabinoid receptor type 1 (CB1R) plays a critical role in the regulation of whole-body energy metabolism because of its involvement in controlling appetite, fuel distribution, and utilization. Inhibition of CB1R improves insulin secretion and insulin sensitivity in pancreatic ß-cells and hepatocytes. We have now developed a skeletal muscle-specific CB1R-knockout (Skm-CB1R-/-) mouse to study the specific role of CB1R in muscle. Muscle-CB1R ablation prevented diet-induced and age-induced insulin resistance by increasing IR signaling. Moreover, muscle-CB1R ablation enhanced AKT signaling, reducing myostatin expression and increasing IL-6 secretion. Subsequently, muscle-CB1R ablation increased myogenesis through its action on MAPK-mediated myogenic gene expression. Consequently, Skm-CB1R-/- mice had increased muscle mass and whole-body lean/fat ratio in obesity and aging. Muscle-CB1R ablation improved mitochondrial performance, leading to increased whole-body muscle energy expenditure and improved physical endurance, with no change in body weight. These results collectively show that CB1R in muscle is sufficient to regulate whole-body metabolism and physical performance and is a novel target for the treatment of sarcopenic obesity. -González-Mariscal, I., Montoro, R. A., O'Connell, J. F., Kim, Y., Gonzalez-Freire, M., Liu, Q.-R., Alfaras, I., Carlson, O. D., Lehrmann, E., Zhang, Y., Becker, K. G., Hardivillé, S., Ghosh, P., Egan, J. M. Muscle cannabinoid 1 receptor regulates Il-6 and myostatin expression, governing physical performance and whole-body metabolism.

Longitudinal Relationship Between Interleukin-6 and Perceived Fatigability Among Well-Functioning Adults in Mid-to-Late Life.

BACKGROUND: Chronically elevated interleukin-6 (IL-6) levels contribute to fatigue and functional decline via multiple pathways that often lead to frailty. Lesser known is the contribution of IL-6 to fatigue in relation to a standardized workload (fatigability), a precursor to functional decline. Therefore, the purpose of this study was to examine the longitudinal relationship between IL-6 and fatigability. METHODS: About 985 participants from the Baltimore Longitudinal Study of Aging (mean age: 70 ± 10 years) were evaluated every 1-4 years. IL-6 was measured in fasting serum samples at each visit and log-transformed for analyses. Perceived fatigability (PF) was defined as self-reported exertion (rate of perceived exertion; RPE) after a 5-min, 0.67 m/s, 0% grade treadmill walk. Continuous and categorical associations between IL-6 (baseline and repeated measures) and PF were assessed using generalized estimating equations, adjusting for demographics, behavioral factors, and comorbid conditions. RESULTS: In fully adjusted continuous models, twofold higher baseline IL-6 was associated with a 0.28 higher RPE (p = .03). This relationship tended to remain constant annually (baseline log IL-6 by time interaction p = .29). To provide clinical relevance, the sample median (3.7 pg/mL) was used to examine high versus low IL-6 levels. Over time, the high group reported an average 0.25 higher RPE (p = .03) than the low group. Annual change in logged IL-6 was not associated with annual change in PF (p = .48). CONCLUSION: Findings suggest that elevated IL-6 is a biomarker of physiological dysregulation associated with greater fatigability, but there is no longitudinal association between IL-6 and fatigability. Future studies should evaluate whether interventions that aim to reduce inflammation also attenuate fatigability.

Relationship of Circulating Growth and Differentiation Factors 8 and 11 and Their Antagonists as Measured Using Liquid Chromatography-Tandem Mass Spectrometry With Age and Skeletal Muscle Strength in Healthy Adults.

Background: Growth and differentiation factors 8 (GDF8) and 11 (GDF11) have attracted attention as targets for rejuvenating interventions. The biological activity of these proteins may be affected by circulating antagonists such as their respective prodomains, follistatin (FST315), WFIKKN1, and WFIKKN2. Reports of the relationship of GDF8 and GDF11 and their antagonists with aging and aging phenotypes such as skeletal muscle strength have been conflicting possibly because of difficulties in measuring these proteins and polypeptides. Methods: Plasma GDF8 and GDF11 and their antagonists were measured using a multiplexed selected reaction monitoring assay and liquid chromatography-tandem mass spectrometry in 160 healthy adults aged 22-93 years. Quadriceps strength was measured by knee extensor torque using isokinetic dynamometry. Results: Spearman correlations with age were the following: GDF11 prodomain (r = .30, p = .001), GDF11 mature protein (r = .23, p = .004), FST315 (r = .32, p < .0001), WFIKKN1 (r = -.21, p = 0.008), and WFIKKN2 (r = .18, p = .02). Independent of age, FST315 and WFIKKN1 were negatively associated with knee strength (p = .02, p = .03, respectively) in a multivariable model that included both GDF8 and GDF11 mature proteins. Conclusions: When measured by an antibody-free selected reaction monitoring assay, GDF8, GDF11, and their antagonists are found in the circulation in the ng/mL range. In healthy adults, plasma GDF11 and antagonists FST315, WFIKKN1, and WFIKKN2 differed by age. Antagonists of GDF8 and GDF11, but not GDF8 and GDF11, were independently associated with skeletal muscle strength. Further work is needed to characterize the relationship of these protein and polypeptides with sarcopenia-related phenotypes such as physical function and walking disability.

Oral glucose load and mixed meal feeding lowers testosterone levels in healthy eugonadal men.

PURPOSE: Precise evaluation of serum testosterone levels is important in making an accurate diagnosis of androgen deficiency. Recent practice guidelines on male androgen deficiency recommend that testosterone be measured in the morning while fasting. Although there is ample evidence regarding morning measurement of testosterone, studies that evaluated the effect of glucose load or meals were limited by inclusion of hypogonadal or diabetic men, and measurement of testosterone was not performed using mass spectrometry. METHODS: Sixty men (23-97 years) without pre-diabetes or diabetes who had normal total testosterone (TT) levels underwent either an oral glucose tolerance test (OGTT) or a mixed meal tolerance test (MMTT) after an overnight fast. Serum samples were collected before and at regular intervals for 2 h (OGTT cohort) or 3 h (MMTT cohort). TT was measured by LC-MS/MS. LH and prolactin were also measured. RESULTS: TT decreased after a glucose load (mean drop at nadir = 100 ng/dL) and after a mixed meal (drop at nadir = 123 ng/dL). Approximately 11% of men undergoing OGTT and 56% undergoing MMTT experienced a transient decrease in TT below 300 ng/dL, the lower normal limit. Testosterone started declining 20 min into the tests, with average maximum decline at 60 min. Most men still had TT lower than baseline at 120 min. This effect was independent of changes in LH or prolactin. CONCLUSION: A glucose load or a mixed meal transiently, but significantly, lowers TT levels in healthy, non-diabetic eugonadal men. These findings support the recommendations that measurement of serum testosterone to diagnose androgen deficiency should be performed while fasting.

IGFBP-2 and aging: a 20-year longitudinal study on IGFBP-2, IGF-I, BMI, insulin sensitivity and mortality in an aging population.

Objective Insulin-like growth factor-binding protein-2 (IGFBP-2) concentrations are low in subjects with metabolic syndrome and type 2 diabetes. Intriguingly, recent studies have demonstrated an association between high IGFBP-2 concentrations and increased mortality not only in populations with certain types of cancer, but also in relatively healthy populations. We evaluated the role of IGFBP-2 in relation to BMI and mortality. Design and Participants BMI, insulin sensitivity, insulin-like growth factor 1 (IGF-I) and IGFBP-2 were assessed repeatedly in 539 participants of the Baltimore Longitudinal Study of Aging around the ages of 55, 65 and 75 years. Results IGFBP-2 concentrations positively correlated with insulin sensitivity and inversely with BMI, both at baseline and follow-up. Independent of IGF-I, sex, BMI and insulin sensitivity, circulating IGFBP-2 levels positively correlated with age (P < 0.001). Changes over time in BMI were associated with an inverse correlation in IGFBP-2 concentrations. Furthermore, we found indications of a relationship between low baseline IGFBP-2 levels and mortality. Remarkably, after adjustment for insulin sensitivity, the opposite association was found, as a unit increase of log(IGFBP2) was associated with an increase in the log hazard by 1.43 (95% CI: 0.3-2.6). This accounted for both baseline (P = 0.02) as well as serial (P < 0.001) measurements of IGFBP2. Finally, in this longitudinal study, we found that IGF-I concentrations increased with age (0.82 ± 0.2 (µg/L)/year, P < 0.001). Conclusion This is the first study investigating the relationship between IGFBP-2 levels and age in a longitudinal setting. Serum IGFBP-2 levels increase with age after the age of 50 years and evolve in parallel with insulin sensitivity. IGFBP-2 may therefore be a potential marker for insulin sensitivity. We further show that IGFBP-2 levels can predict mortality in this aging population. However, its predictive value for mortality can only be interpreted in relation to insulin sensitivity. After adjustment for insulin sensitivity, high IGFBP-2 levels are predictive of increased mortality.

Commensal bacteria contribute to insulin resistance in aging by activating innate B1a cells.

Aging in humans is associated with increased hyperglycemia and insulin resistance (collectively termed IR) and dysregulation of the immune system. However, the causative factors underlying their association remain unknown. Here, using "healthy" aged mice and macaques, we found that IR was induced by activated innate 4-1BBL+ B1a cells. These cells (also known as 4BL cells) accumulated in aging in response to changes in gut commensals and a decrease in beneficial metabolites such as butyrate. We found evidence suggesting that loss of the commensal bacterium Akkermansia muciniphila impaired intestinal integrity, causing leakage of bacterial products such as endotoxin, which activated CCR2+ monocytes when butyrate was decreased. Upon infiltration into the omentum, CCR2+ monocytes converted B1a cells into 4BL cells, which, in turn, induced IR by expressing 4-1BBL, presumably to trigger 4-1BB receptor signaling as in obesity-induced metabolic disorders. This pathway and IR were reversible, as supplementation with either A. muciniphila or the antibiotic enrofloxacin, which increased the abundance of A. muciniphila, restored normal insulin response in aged mice and macaques. In addition, treatment with butyrate or antibodies that depleted CCR2+ monocytes or 4BL cells had the same effect on IR. These results underscore the pathological function of B1a cells and suggest that the microbiome-monocyte-B cell axis could potentially be targeted to reverse age-associated IR.

Altered Plasma Amino Acids and Lipids Associated With Abnormal Glucose Metabolism and Insulin Resistance in Older Adults.

Context and Objectives: Glucose metabolism becomes progressively impaired with older age. Fasting glucose and insulin resistance are risk factors for premature death and other adverse outcomes. We aimed to identifying plasma metabolites associated with altered glucose metabolism and insulin resistance in older community-dwelling adults. Participants and Methods: A targeted metabolomics approach was used to identify plasma metabolites associated with impaired fasting plasma glucose, 2-hour plasma glucose on oral glucose tolerance testing, and homeostatic model assessment insulin resistance (HOMA-IR) in 472 participants who participated in the Baltimore Longitudinal Study of Aging, with a mean (SD) age of 70.7 (9.9) years. Results: We measured 143 plasma metabolites. In ordinal logistic regression analyses, using a false discovery rate of 5% and adjusting for potential confounders, we found that alanine, glutamic acid, and proline were significantly associated with increased odds of abnormal fasting plasma glucose. Phosphatidylcholine (diacyl C34:4, alkyl-acyl C32:1, C32:2, C34:2, C34:3, and C36:3) was associated with decreased odds of abnormal fasting plasma glucose. Glutamic and acid phosphatidylcholine alkyl-acyl C34:2 were associated with increased and decreased odds of 2-hour plasma glucose, respectively. Glutamic acid was associated with increased odds of higher tertiles of HOMA-IR. Glycine; phosphatidylcholine (diacyl C32:0, alkyl-acyl C32:1, C32:2, C34:1, C34:2, C34:3, C36:2, C36:3, C40:5, C40:6, C42:3, C42:4, and C42:5); sphingomyelin C16:0, C24:1, and C26:1; and lysophosphatidylcholine C18:1 were associated with decreased odds of abnormal HOMA-IR. Conclusions: Targeted metabolomics identified four plasma amino acids and 16 plasma lipid species, primarily containing polyunsaturated fatty acids, that were associated with abnormal glucose metabolism and insulin resistance in older adults.

Regular low-calorie sweetener consumption is associated with increased secretion of glucose-dependent insulinotropic polypeptide.

Low-calorie sweeteners (LCSs) are widely used for weight control despite limited evidence of their effectiveness and studies linking LCS consumption with incident obesity. We tested the hypothesis that regular LCS consumption is associated with higher postprandial glucose-dependent insulinotropic polypeptide (GIP) secretion, which has been linked to obesity. We used data from participants in the Baltimore Longitudinal Study of Aging who had completed a diet diary, had at least one visit during which they underwent an oral glucose tolerance test (OGTT), and had no diabetes. Of 232 participants, 166 contributed 1, 39 contributed 2, and 27 contributed 3 visits, and 96 (41%) reported using LCS. Plasma OGTT samples were analysed for glucose, insulin and GIP. Fasting glucose, insulin and GIP levels were no different between LCS users and non-users. The association of LCS use with 2-hour OGTT responses after adjustment for covariates was non-significant for glucose (P = .98) and insulin (P = .18), but significant for greater increase in GIP in LCS users (P = .037). Regular consumption of LCSs was associated with greater increases in GIP secretion after food intake, which may potentially lead to weight gain through the lipogenic properties of GIP.

Absence of cannabinoid 1 receptor in beta cells protects against high-fat/high-sugar diet-induced beta cell dysfunction and inflammation in murine islets.

AIMS/HYPOTHESIS: The cannabinoid 1 receptor (CB1R) regulates insulin sensitivity and glucose metabolism in peripheral tissues. CB1R is expressed on pancreatic beta cells and is coupled to the G protein Gαi, suggesting a negative regulation of endogenous signalling in the beta cell. Deciphering the exact function of CB1R in beta cells has been confounded by the expression of this receptor on multiple tissues involved in regulating metabolism. Thus, in models of global genetic or pharmacological CB1R blockade, it is difficult to distinguish the indirect effects of improved insulin sensitivity in peripheral tissues from the direct effects of inhibiting CB1R in beta cells per se. To assess the direct contribution of beta cell CB1R to metabolism, we designed a mouse model that allows us to determine the role of CB1R specifically in beta cells in the context of whole-body metabolism. METHODS: We generated a beta cell specific Cnr1 (CB1R) knockout mouse (ß-CB1R-/-) to study the long-term consequences of CB1R ablation on beta cell function in adult mice. We measured beta cell function, proliferation and viability in these mice in response to a high-fat/high-sugar diet and induction of acute insulin resistance with the insulin receptor antagonist S961. RESULTS: ß-CB1R-/- mice had increased fasting (153 ± 23% increase at 10 weeks of age) and stimulated insulin secretion and increased intra-islet cAMP levels (217 ± 33% increase at 10 weeks of age), resulting in primary hyperinsulinaemia, as well as increased beta cell viability, proliferation and islet area (1.9-fold increase at 10 weeks of age). Hyperinsulinaemia led to insulin resistance, which was aggravated by a high-fat/high-sugar diet and weight gain, although beta cells maintained their insulin secretory capacity in response to glucose. Strikingly, islets from ß-CB1R-/- mice were protected from diet-induced inflammation. Mechanistically, we show that this is a consequence of curtailment of oxidative stress and reduced activation of the NLRP3 inflammasome in beta cells. CONCLUSIONS/INTERPRETATION: Our data demonstrate CB1R to be a negative regulator of beta cell function and a mediator of islet inflammation under conditions of metabolic stress. Our findings point to beta cell CB1R as a therapeutic target, and broaden its potential to include anti-inflammatory effects in both major forms of diabetes. DATA AVAILABILITY: Microarray data have been deposited at GEO (GSE102027).

Elevated Markers of Inflammation Are Associated With Longitudinal Changes in Brain Function in Older Adults.

Background: Chronic inflammation has been linked to memory and other cognitive impairments, as well as Alzheimer's disease. Here, we investigate the association between inflammatory markers and changes in brain activity measured by regional cerebral blood flow (rCBF) to assess the relationship between inflammation and brain function in older individuals. Methods: Annual 15O water resting-state positron emission tomography (PET) scans collected over a 5-year period were assessed in 138 cognitively normal older participants (77 males; mean age at baseline = 71.3; mean scans per participant = 3.5) in the Baltimore Longitudinal Study of Aging. Voxel-wise linear mixed models were used to investigate associations between rCBF and C-reactive protein (CRP) and interleukin-6 (IL-6) at the time of scanning. We examined relationships between baseline CRP and IL-6 levels and baseline rCBF, and relationships between baseline and mean inflammatory levels over time and longitudinal rCBF changes. Results: Higher baseline CRP and IL-6 were each associated with lower baseline rCBF primarily in frontal and occipital regions, with only the lingual gyrus surviving atrophy correction. Higher baseline and mean CRP were also associated with greater rCBF declines over time in anterior cingulate and hippocampal regions, whereas higher baseline and mean IL-6 levels were associated with greater rCBF declines in orbitofrontal and hippocampal regions. Conclusions: Higher levels of inflammation are associated with longitudinal changes in brain function in regions important for cognition. These results, along with previous studies, suggest that chronic inflammation in older adults may contribute to age-associated declines in cognitive function.

Incretin secretion in humans is under the influence of cannabinoid receptors.

The mechanisms regulating incretin secretion are not fully known. Human obesity is associated with altered incretin secretion and elevated endocannabinoid levels. Since cannabinoid receptors (CBRs) are expressed on incretin-secreting cells in rodents, we hypothesized that endocannabinoids are involved in the regulation of incretin secretion. We compared plasma glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) responses during oral glucose tolerance test (OGTT) in 20 lean and 20 obese participants from the Baltimore Longitudinal Study of Aging (BLSA). Next, we recruited 20 healthy men to evaluate GIP and GLP-1 responses during OGTT after administering placebo or nabilone (CBR agonist) in a randomized, double-blind, crossover fashion. Compared with the BLSA lean group, the BLSA obese group had significantly higher fasting and post-OGTT GIP levels, but similar fasting GLP-1 and significantly lower post-OGTT GLP-1 levels. In the nabilone vs. placebo study, when compared with placebo, nabilone resulted in significantly elevated post-dose fasting GIP levels and post-OGTT GIP levels, but no change in post-dose fasting GLP-1 levels together with significantly lower post-OGTT GLP-1 levels. Glucose levels were not different with both interventions. We conclude that elevated GIP levels in obesity are likely a consequence of increased endocannabinoid levels. CBRs exert tonic control over GIP secretion, which may have a homeostatic effect in suppressing GLP-1 secretion. This raises the possibility that gut hormones are influenced by endocannabinoids.

Effects of transdermal testosterone gel or an aromatase inhibitor on serum concentration and pulsatility of growth hormone in older men with age-related low testosterone.

Growth hormone is the major regulator of growth and body composition. Pulsatile GH secretion declines exponentially with age. Testosterone replacement is being increasingly offered to older men with age-related low testosterone. Testosterone administration has been shown to stimulate GH secretion. However, little is known about the effect of testosterone aromatization to estradiol on GH pulsatility and its impact on IGF-1 in older men. OBJECTIVE: This randomized controlled proof-of-concept trial investigated the relative effects of testosterone and estradiol on GH pulsatility and IGF-1 in older men with low testosterone. DESIGN: Thirty-seven men, ≥65years with total testosterone <350ng/dL were randomized to 5g transdermal testosterone gel (TT), 1mg oral aromatase inhibitor (AI) or placebo daily for 12months. Primary outcome was deconvolution and approximate entropy analyses of pulsatile including basal and entropic modes of secretion performed at baseline and 3months. Secondary outcomes included IGF-1 evaluated at baseline, 3 and 6months. RESULTS: At 3months, mean GH and in IGF-1 were similar between the three groups. At 6months, IGF-1 significantly increased by Δ 15.3±10.3ng/ml in the TT-group compared to placebo (P=0.03). Both intervention groups significantly increased GH pulse frequency (TT-group, P=0.04; AI-group, P=0.05) compared to placebo. The GH secretory-burst mode (duration) significantly decreased in the TT-group (P=0.0018) compared to placebo while it remained unchanged in the AI-group (P=0.059). CONCLUSIONS: In older men, testosterone increases GH pulse frequency while the aromatization to estradiol is involved in the rise of IGF-1 levels.

Human CB1 Receptor Isoforms, present in Hepatocytes and ß-cells, are Involved in Regulating Metabolism.

Therapeutics aimed at blocking the cannabinoid 1 (CB1) receptor for treatment of obesity resulted in significant improvements in liver function, glucose uptake and pancreatic ß-cell function independent of weight loss or CB1 receptor blockade in the brain, suggesting that peripherally-acting only CB1 receptor blockers may be useful therapeutic agents. Neuropsychiatric side effects and lack of tissue specificity precluded clinical use of first-generation, centrally acting CB1 receptor blockers. In this study we specifically analyzed the potential relevance to diabetes of human CB1 receptor isoforms in extraneural tissues involved in glucose metabolism. We identified an isoform of the human CB1 receptor (CB1b) that is highly expressed in ß-cells and hepatocytes but not in the brain. Importantly, CB1b shows stronger affinity for the inverse agonist JD-5037 than for rimonabant compared to CB1 full length. Most relevant to the field, CB1b is a potent regulator of adenylyl cyclase activity in peripheral metabolic tissues. CB1b blockade by JD-5037 results in stronger adenylyl cyclase activation compared to rimonabant and it is a better enhancer of insulin secretion in ß-cells. We propose this isoform as a principal pharmacological target for the treatment of metabolic disorders involving glucose metabolism.

Plasma Biomarkers of Poor Muscle Quality in Older Men and Women from the Baltimore Longitudinal Study of Aging.

Aging is characterized by progressive decline in muscle mass, strength, and quality all of which contribute to functional impairment, falls, mobility disability, and frailty. Circulating factors may provide clues on the mechanisms for decline in muscle quality with aging. Characterizing the metabolic profile associated with reduced muscle quality in older persons could have important translational implications for the early identification of subjects at high risk of developing sarcopenia and the identification of targets for new preventive strategies and treatments. In a pilot cross-sectional, case-control study nested in the Baltimore Longitudinal Study on Aging, we compared circulating metabolites between 79 participants with low muscle quality ratio and 79 controls with high muscle quality, matched by age, sex, and height. The concentrations of 180 metabolites were determined by LC MS/MS, using the Biocrates p180 system, a targeted metabolomics approach. Participants with low muscle quality had significantly higher levels of leucine, isoleucine, tryptophan, serotonin, and methionine, while those with high muscle quality had significantly lower levels of putrescine and the selected phophatidylcholine (PCs) and lysoPCs. The results of this study open a new road for future investigations aimed at identifying new metabolic pathways involved in the decline of muscle quality with aging.

Does GLP-1 suppress its own basal secretion?

PURPOSE/AIM: Negative feedback controls in endocrine regulatory systems are well recognized. The incretins and their role in glucose regulation have been of major interest recently. Whether the same negative control system applies to the regulation of incretin secretion is not clear. We sought to examine the hypothesis that exogenous administration of glucagon like peptide-1, GLP-1(7-36) amide or its metabolite GLP-1(9-36) amide, reduces the endogenous basal release of this incretin. MATERIALS AND METHODS: We evaluated the endogenous basal release of GLP-1 using two separate study designs. In protocol A we examined the GLP-1(7-36) amide levels during the infusion of GLP-1(9-36) amide. In protocol B, we used PYY and GLP-2 as biomarkers for the endogenous basal release of GLP-1(7-36) amide and assessed the endogenous basal release of these two hormones during the GLP-1(7-36) infusion. Twelve lean and 12 obese subjects were enrolled in protocol A and 10 obese volunteers in protocol B. RESULTS: The plasma levels of GLP-1(7-36) amide in protocol A and PYY and GLP-2 in protocol B remained unchanged during the exogenous infusion of GLP-1(9-36) and GLP-1(7-36) amide, respectively. CONCLUSIONS: The negative feedback control system as described by inhibition of the release of endogenous hormone while infusing it exogenously was not observed for the basal secretion of GLP-1(7-36) amide.

Low neural exosomal levels of cellular survival factors in Alzheimer's disease.

Transcription factors that mediate neuronal defenses against diverse stresses were quantified in plasma neural-derived exosomes of Alzheimer's disease or frontotemporal dementia patients and matched controls. Exosomal levels of low-density lipoprotein receptor-related protein 6, heat-shock factor-1, and repressor element 1-silencing transcription factor all were significantly lower in Alzheimer's disease patients than controls (P < 0.0001). In frontotemporal dementia, the only significant difference was higher levels of repressor element 1-silencing transcription factor than in controls. Exosomal transcription factors were diminished 2-10 years before clinical diagnosis of Alzheimer's disease. Low exosomal levels of survival proteins may explain decreased neuronal resistance to Alzheimer's disease neurotoxic proteins.