Food-induced thermogenesis is generally reported to be higher in the morning, although contrasting results exist because of differences in experimental settings related to the preceding fasting, ...exercise, sleeping and dieting. To definitively answer to this issue, we compared the calorimetric and metabolic responses to identical meals consumed at 0800 hours and at 2000 hours by healthy volunteers, after standardized diet, physical activity, duration of fast and resting.
Twenty subjects (age range 20-35 years, body mass index=19-26 kg m(-)(2)) were enrolled to a randomized cross-over trial. They randomly received the same standard meal in the morning and, 7 days after, in the evening, or vice versa. A 30-min basal calorimetry was performed; a further 60-min calorimetry was done 120-min after the beginning of the meal. Blood samples were drawn every 30-min for 180-min. General linear models, adjusted for period and carry-over, were used to evaluate the 'morning effect', that is, the difference of morning delta (after-meal minus fasting values) minus evening delta (after-meal minus fasting values) of the variables.
Fasting resting metabolic rate (RMR) did not change from morning to evening; after-meal RMR values were significantly higher after the morning meal (1916; 95% confidence interval (CI)=1792, 2041 vs 1756; 1648, 1863 kcal; P<0.001). RMR was significantly increased after the morning meal (90.5; 95% CI=40.4, 140.6 kcal; P<0.001), whereas differences in areas-under-the-curve for glucose (-1800; -2564,-1036 mg dl(-1) × h, P<0.001), log-insulin (-0.19; -0.30,-0.07 μU ml(-1) × h; P=0.001) and fatty free acid concentrations (-16.1;-30.0,-2.09 mmol l(-1) × h; P=0.024) were significantly lower. Delayed and larger increases in glucose and insulin concentrations were found after the evening meals.
The same meal consumed in the evening determined a lower RMR, and increased glycemic/insulinemic responses, suggesting circadian variations in the energy expenditure and metabolic pattern of healthy individuals. The timing of meals should probably be considered when nutritional recommendations are given.
Purpose
Few and contradictory data suggest changes in taste perception in type 2 diabetes (T2DM), potentially altering food choices. We, therefore, analyzed taste recognition thresholds in T2DM ...patients with good metabolic control and free of conditions potentially impacting on taste, compared with age-, body mass index-, and sex-matched normoglycemic controls.
Methods
An ascending-concentration method was used, employing sucrose (sweet), sodium chloride (salty), citric acid (sour), and quinine hydrochloride (bitter), diluted in increasing concentration solutions. The recognition threshold was the lowest concentration of correct taste identification.
Results
The recognition thresholds for the four tastes were higher in T2DM patients. In a multiple regression model, T2DM
β
= 0.95; 95% CI 0.32–1.58;
p
= 0.004 (salty);
β
= 0.61; 0.19–1.03;
p
= 0.006 (sweet);
β
= 0.78; 0.15–1.40;
p
= 0.016 (sour);
β
= 0.74; 0.22–1.25;
p
= 0.006 (bitter) and waist circumference
β
= 0.05; 0.01–0.08;
p
= 0.012 (salty);
β
= 0.03; 0.01–0.05;
p
= 0.020 (sweet);
β
= 0.04; 0.01–0.08;
p
= 0.020 (sour);
β
= 0.04; 0.01–0.07;
p
= 0.007 (bitter) were associated with the recognition thresholds. Age was associated with salty (
β
= 0.06; 0.01–0.12;
p
= 0.027) and BMI with sweet thresholds (
β
= 0.06; 0.01–0.11;
p
= 0.019).
Conclusions
Taste recognition thresholds were higher in uncomplicated T2DM, and central obesity was significantly associated with this impairment. Hypogeusia may be an early sign of diabetic neuropathy and be implicated in the poor compliance of these patients to dietary recommendations.
ObjectiveTo clarify the metabolic effects of an overnight i.v. infusion of unacylated ghrelin (UAG) in humans. UAG exerts relevant metabolic actions, likely mediated by a still unknown ghrelin ...receptor subtype, including effects on β-cell viability and function, insulin secretion and sensitivity, and glucose and lipid metabolism.DesignWe studied the effects of a 16-h infusion (from 2100 to 1300 h) of UAG (1.0 μg/kg per h) or saline in eight normal subjects (age (mean±s.e.m.), 29.6±2.4 years; body mass index (BMI), 22.4±1.7 kg/m2), who were served, at 2100 and 0800 h respectively, with isocaloric balanced dinner and breakfast. Glucose, insulin, and free fatty acid (FFA) levels were measured every 20 min.ResultsIn comparison with saline, UAG induced significant (P<0.05) changes in glucose, insulin, and FFA profiles. UAG infusion decreased glucose area under the curve (AUC) values by 10% (UAG0–960 min: 79.0±1.7×103 mg/dl per min vs saline0–960 min: 87.5±3.8×103 mg/dl per min) and the AUC at night by 14% (UAG180–660 min: 28.4±0.5×103 mg/dl per min vs saline180–660 min: 33.2±1.1×103 mg/dl per min). The overall insulin AUC was not significantly modified by UAG infusion; however, insulin AUC observed after meals was significantly increased under the exposure to UAG with respect to saline at either dinner or breakfast. The FFA AUC values were decreased by 52% under the exposure to UAG in comparison with saline (UAG0–960 min: 0.3±0.02×103 mEq/l per min vs saline0–960 min: 0.6±0.05×103 mEq/l per min).ConclusionsExposure to the i.v. administration of UAG improves glucose metabolism and inhibits lipolysis in healthy volunteers. Thus, in contrast to the diabetogenic action of AG, UAG displays hypoglycemic properties.
Aim
Oral semaglutide, an innovative orally administered GLP-1 receptor agonist for type 2 diabetes (T2D) management was herein evaluated for its effectiveness in a multi-center retrospective ...real-world study.
Methods
We included new-users of oral semaglutide from 18 specialist care centres and collected retrospective data on baseline clinical characteristics. Updated values of HbA1c and body weight were analyzed using the mixed model for repeated measures.
Results
The study included 166 individuals with T2D, predominantly men (64.5%), with a mean age of 64.4 years and a mean diabetes duration of 10.1 years. In the majority of patients (68.3%) oral semaglutide was used as a second-line drug, mostly with metformin. At baseline, mean BMI was 28.9 kg/m
2
and HbA1c was 7.5%. During the 18-month observation period, oral semaglutide demonstrated significant reductions in HbA1c, with a maximum change of − 0.9%, and 42.1% of patients achieved HbA1c values below 7.0%. Additionally, there was a substantial reduction in body weight, with an estimated change of − 3.4 kg at 18 months, and 30.3% of patients experienced a 5% or greater reduction in baseline body weight. Only 24.2% of patients reached the 14 mg dose. Subgroup analysis revealed that baseline HbA1c > 7%, persistence on drug, not being on a prior therapy with DPP-4 inhibitors, and loosing 5% or more the initial body weight were associated with greater HbA1c reductions.
Conclusion
This study supports oral semaglutide as an effective option for T2D treatment, offering improved glucose control and weight management in a real-world setting.
Summary
Ghrelin, an acylated peptide produced predominantly by the stomach, has been discovered to be a natural ligand of the growth hormone secretagogue receptor type 1a (GHS‐R1a). Ghrelin has ...recently attracted considerable interest as a new orexigenic factor. However, ghrelin exerts several other neuroendocrine, metabolic and also nonendocrine actions that are explained by the widespread distribution of ghrelin and GHS‐R expression. The likely existence of GHS‐R subtypes and evidence that the neuroendocrine actions, but not all the other actions, of ghrelin depend on its acylation in serine‐3 revealed a system whose complexity had not been completely explored by studying synthetic GHS. Ghrelin secretion is mainly regulated by metabolic signals and, in turn, the modulatory action of ghrelin on the control of food intake and energy metabolism seems to be among its most important biological actions. However, according to a recent study, ghrelin‐null mice are neither anorectics nor dwarfs and this evidence clearly depicts a remarkable difference from leptin null mice. Nevertheless, the original and fascinating story of ghrelin, as well as its potential pathophysiological implications in endocrinology and internal medicine, is not definitively cancelled by these data as GHS‐R1a null aged mice show significant alterations in body composition and growth, in glucose metabolism, cardiac function and contextual memory. Besides potential clinical implications for natural or synthetic ghrelin analogues acting as agonists or antagonists, there are several open questions awaiting an answer. How many ghrelin receptor subtypes exist? Is ghrelin ‘the’ or just ‘a’ GHS‐R ligand? That is, are there other natural GHS‐R ligands? Is there a functional balance between acylated and unacylated ghrelin forms, potentially with different actions? Within the next few years suitable answers to these questions will probably be found, making it possible to gain a better knowledge of ghrelin's potential clinical perspectives.
Purpose
In patients with obesity, micronutrient deficiencies have been reported both before and after bariatric surgery (BS). Obesity is a chronic pro-inflammatory status, and inflammation increases ...the risk of micronutrient malnutrition. Our objective was to assess in pre-BS patients the prevalence of micronutrient deficiencies and their correlation with blood values of C-reactive protein (CRP).
Methods
Anthropometric data, instrumental examinations, and blood variables were centrally measured in the first 200 patients undergoing a pre-BS evaluation at the “Città della Salute e della Scienza” Hospital of Torino, starting from January 2018.
Results
At least one micronutrient deficiency was present in 85.5% of pre-BS patients. Vitamin D deficiency was the most prevalent (74.5%), followed by folate (33.5%), iron (32%), calcium (13%), vitamin B12 (10%), and albumin (5.5%) deficiency. CRP values were high (> 5 mg/L) in 65% of the patients. These individuals showed increased rate of iron, folate, vitamin B12 deficiency, and a higher number of micronutrient deficiencies. In a multiple logistic regression model, increased CRP levels were significantly associated with deficiencies of vitamin B12 (OR = 5.84; 95% CI 1.25–27.2;
p
= 0.024), folate (OR = 4.02; 1.87–8.66;
p
< 0.001), and with the presence of ≥ 2 micronutrient deficiencies (OR = 2.31; 1.21–4.42;
p
= 0.01).
Conclusions
Micronutrient deficiencies are common in patients with severe obesity undergoing BS, especially when inflammation is present. In the presence of increased CRP values before surgery, it might be advisable to search for possible multiple micronutrient deficiencies.
Ghrelin, a 28 amino acid gastric hormone is a natural ligand of the GH Secretagogue (GHS) receptor (GHS-R) and strongly stimulates GH secretion though, like synthetic GHS, it shows other endocrine ...and non-endocrine activities. Aim of the present study was to clarify whether ghrelin administration influences insulin and glucose levels in humans. To this goal, we compared the effects of ghrelin, hexarelin, a synthetic GHS, or placebo on insulin and glucose as well as on GH levels in 11 normal young volunteers (age mean +/- SEM: 28.5 +/- 3.1 yr; BMI: 22.2 +/- 0.9 Kg/m(2)). Ghrelin induced very marked increase in GH secretion (DeltaAUC(0-180): 5777.1 +/- 812.6 microg/l/h; p < 0.01) which was not modified by placebo. Placebo administration did not modify insulin and glucose levels. On the other hand, ghrelin administration induced a prompt increase in glucose levels (DeltaAUC(0-180): 1343.1 +/- 443.5 mg/dl/h; p < 0.01 vs. saline). Absolute glucose levels at +15' were already higher than those at baseline (93.9 +/- 7.1 mg/dl; p < 0.01) and persisted elevated up to 165' (90.3 +/- 5.8 mg/dl; p < 0.01 vs. 0'). Ghrelin administration was also followed by a decrease in serum insulin levels (DeltaAUC(0-180): -207.1 +/- 70.5 mU/l/h; p < 0.05 vs. saline). Absolute insulin levels were significantly reduced from 30' (11.4 +/- 0.9 mU/l, p < 0.1 vs. 0'), showed the nadir at +45' (10.0 +/- 0.6 mU/l, p < 0.01 vs. 0') and then persisted lower (p < 0.01) than baseline up to +105'. Hexarelin administration did not modify glucose and insulin levels despite its marked GH-releasing effect (DeltaAUC(0-180): 4156.8 +/- 1180.3 microg/l/h; p < 0.01 vs. saline) that was slightly lower (p < 0.05) than that of ghrelin. In conclusion, these findings show that, besides stimulating GH secretion, ghrelin is a gastric hormone possessing metabolic actions such as hyperglycemic effect and lowering effect on insulin secretion in humans, at least after acute administration.
We investigated the metabolic actions of ghrelin in humans by examining the effects of acute administration of acylated ghrelin, unacylated ghrelin, and the combination in eight adult-onset ...GH-deficient patients. We followed glucose, insulin, and free fatty acid concentrations before and after lunch and with or without the presence of GH in the circulation.
We found that acylated ghrelin, which is rapidly cleared from the circulation, induced a rapid rise in glucose and insulin levels. Unacylated ghrelin, however, prevented the acylated ghrelin-induced rise in insulin and glucose when it was coadministered with acylated ghrelin. Surprisingly, the injection of acylated ghrelin induced an acute increase in unacylated ghrelin and therefore total ghrelin levels. Finally, acylated ghrelin decreased insulin sensitivity up to the end of a period of 6 h after administration. This decrease in insulin sensitivity was prevented by coinjection of unacylated ghrelin. This combined administration of acylated and unacylated ghrelin even significantly improved insulin sensitivity, compared with placebo, for at least 6 h, which warrants studies to investigate the long-term efficacy of this combination in the treatment of disorders with disturbed insulin sensitivity.
Ghrelin possesses strong GH-releasing activity but also other
endocrine activities including stimulation of PRL and ACTH secretion,
modulation of insulin secretion and glucose metabolism. It is ...assumed
that the GH secretagogue (GHS) receptor (GHS-R) 1a mediates ghrelin
actins provided its acylation in Serine 3; in fact, acylated ghrelin
only is able to exert endocrine activities. Acylated ghrelin (AG) is
present in serum at a 2.5 fold lower concentration than unacylated
ghrelin (UAG). UAG, however, is not biologically inactive; it shares
with AG some non-endocrine actions like cardiovascular effects,
modulation of cell proliferation and even some influence on
adipogenesis. Thus, these actions are likely to be mediated by GHS-R
subtypes able to bind ghrelin independently of its acylation. In order
to further clarify whether UAG is really devoid of any endocrine
action, we studied the interaction of the combined administration of AG
and UAG (1.0 μg/kg iv) in 6 normal young volunteers (age mean ±
SE: 25.4 ± 1.2 yr; BMI: 22.3 ± 1.0 kg/m2). As expected,
AG induced marked increase (p < 0.01) in circulating GH, PRL, ACTH and
cortisol levels. AG administratioin was also followed by a decrease in
insulin levels (−285.4 ± 64.8 mU∗min/l; p < 0.05) and an increase
in plasma glucose levels (1068.4 ± 390.4 mg*min/dl; p < 0.01). UAG
alone did not induce any change in these parameters. UAG also failed to
modify the GH, PRL, ACTH and cortisol responses to AG. However, when
UAG was co-administered together with AG, no significant change in
insulin (−0.5 ± 40.9 mU*min/l) and glucose levels (455.9 ± 88.3
mg*min/dl) was recorded anymore, indicating that the insulin and
glucose response to AG has been abolished by UAG. In conclusion,
non-acylated ghrelin does not affect the GH, PRL, and ACTH response
to acylated ghrelin but is able to antagonize the effects of acylated
ghrelin on insulin secretion and glucose levels. These findings
indicate that unacylated ghrelin is metabolically active and is likely
to counterbalance the influence of acylated ghrelin on insulin
secretion and glucose metabolism. As GHS-R1a is not bound by unacylated
ghrelin, these findings suggest that GHS receptor subtypes mediate the
metabolic actions of both acylated and unacylated ghrelin.
Aim
To compare effectiveness of dapagliflozin versus DPP-4 inhibitors on individualized HbA1c targets and extra-glycaemic endpoints among elderly patients with type 2 diabetes (T2D).
Methods
This was ...a multicentre retrospective study on patients aged 70–80 years with HbA1c above individualized target and starting dapagliflozin or DPP-4 inhibitors in 2015–2017. The primary outcome was the proportion reaching individualized HbA1c targets. Confounding by indication was addressed by inverse probability of treatment weighting (IPTW), multivariable adjustment (MVA), or propensity score matching (PSM).
Results
Patients initiating dapagliflozin (
n
= 445) differed from those initiating DPP-4i (
n
= 977) and balance between groups was achieved with IPTW or PSM. The median follow-up was 7.5 months and baseline HbA1c was 8.3%. A smaller proportion of patients initiating dapagliflozin attained individualized HbA1c target as compared to those initiating DPP-4 inhibitors (RR 0.73,
p
< 0.0001). IPTW, MVA, and PSM yielded similar results. Between-group difference in the primary outcome was observed among patients with lower eGFR or longer disease duration. Dapagliflozin allowed greater reductions in body weight and blood pressure than DPP-4 inhibitors.
Conclusions
Elderly patients with T2D initiating dapagliflozin had a lower probability of achieving individualized HbA1c targets than those initiating DPP-4 inhibitors but displayed better improvements in extra-glycaemic endpoints.
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