Obstructive sleep apnea syndrome (OSAS) and obesity go hand in hand in the majority of patients and both are associated with a systemic inflammation, immune disturbance and comorbidities such as ...cardiovascular disease. However, the unambiguous impact of OSAS and obesity on the individual inflammatory microenvironment and the immunological consequences of human monocytes has not been distinguished yet. Therefore, aim of this study was to investigate the impact of OSAS and obesity related factors on the inflammatory microenvironment by performing flow cytometric whole blood measurements of CD14/CD16 monocyte subsets in normal weight OSAS patients, patients with obesity but without OSAS, and patients with OSAS and obesity, compared to healthy donors. Moreover, explicitly OSAS and obesity related plasma levels of inflammatory mediators adiponectin, leptin, lipocalin and metalloproteinase-9 were determined and the influence of different OSAS and obesity related factors on cytokine secretion and expression of different adhesion molecules by THP-1 monocytes was analysed. Our data revealed a significant redistribution of circulating classical and intermediate monocytes in all three patient cohorts, but differential effects in terms of monocytic adhesion molecules CD11a, CD11b, CD11c, CX3CR1, CD29, CD49d, and plasma cytokine levels. These data were reflected by differential effects of OSAS and obesity related factors leptin, TNFα and hypoxia on THP-1 cytokine secretion patterns and expression of adhesion molecules CD11b and CD49d. In summary, our data revealed differential effects of OSAS and obesity, which underlines the need for a customized therapeutic regimen with respect to the individual weighting of these overlapping diseases.
Purpose
About 20–25% of patients experience weight regain (WR) or insufficient weight loss (IWL) after bariatric metabolic surgery (BS). Therefore, we aimed to retrospectively assess the ...effectiveness of adjunct treatment with the GLP-1 receptor agonist semaglutide in non-diabetic patients with WR or IWL after BS.
Materials and Methods
Post-bariatric patients without type 2 diabetes (T2D) with WR or IWL (
n
= 44) were included in the analysis. The primary endpoint was weight loss 3 and 6 months after initiation of adjunct treatment. Secondary endpoints included change in BMI, HbA1c, lipid profile, hs-CRP, and liver enzymes.
Results
Patients started semaglutide 64.7 ± 47.6 months (mean ± SD) after BS. At initiation of semaglutide, WR after post-bariatric weight nadir was 12.3 ± 14.4% (mean ± SD). Total weight loss during semaglutide treatment was − 6.0 ± 4.3% (mean ± SD,
p
< 0.001) after 3 months (3.2 months, IQR 3.0–3.5,
n
= 38) and − 10.3 ± 5.5% (mean ± SD,
p
< 0.001) after 6 months (5.8 months, IQR 5.8–6.4,
n
= 20). At 3 months, categorical weight loss was > 5% in 61% of patients, > 10% in 16% of patients, and > 15% in 2% of patients. Triglycerides (OR = 0.99;
p
< 0.05), ALT (OR = 0.87;
p
= 0.05), and AST (OR = 0.89;
p
< 0.05) at baseline were negatively associated with weight loss of at least 5% at 3 months’ follow-up (
p
< 0.05).
Conclusion
Treatment options to manage post-bariatric excess weight (regain) are scarce. Our results imply a clear benefit of adjunct treatment with semaglutide in post-bariatric patients. However, these results need to be confirmed in a prospective randomized controlled trial to close the gap between lifestyle intervention and revision surgery in patients with IWL or WR after BS.
Graphical abstract
Abstract Complications of diabetes are often attributed to glucose and reactive dicarbonyl metabolites derived from glycolysis or gluconeogenesis, such as methylglyoxal. However, in the CNS, neurons ...and endothelial cells use lactate as energy source in addition to glucose, which does not lead to the formation of methylglyoxal and has previously been considered a safer route of energy consumption than glycolysis. Nevertheless, neurons and endothelial cells are hotspots for the cellular pathology underlying neurological complications in diabetes, suggesting a cause that is distinct from other diabetes complications and independent of methylglyoxal. Here, we show that in clinical and experimental diabetes plasma concentrations of dimethylglyoxal are increased. In a mouse model of diabetes, ilvb acetolactate-synthase-like (ILVBL, HACL2) is the enzyme involved in formation of increased amounts of dimethylglyoxal from lactate-derived pyruvate. Dimethylglyoxal reacts with lysine residues, forms Nε−3-hydroxy-2-butanonelysine (HBL) as an adduct, induces oxidative stress more strongly than other dicarbonyls, causes blood-brain barrier disruption, and can mimic mild cognitive impairment in experimental diabetes. These data suggest dimethylglyoxal formation as a pathway leading to neurological complications in diabetes that is distinct from other complications. Importantly, dimethylglyoxal formation can be reduced using genetic, pharmacological and dietary interventions, offering new strategies for preventing CNS dysfunction in diabetes.
There is evidence that reduced sleep duration increases hunger, appetite, and food intake, leading to metabolic diseases, such as type 2 diabetes and obesity. However, the impact of sleep timing, ...irrespective of its duration and on the regulation of hunger and appetite, is less clear. We aimed to evaluate the impact of sleep loss during the late vs. early part of the night on the regulation of hunger, appetite, and desire for food.
Fifteen normal-weight (mean ± SEM body-mass index: 23.3 ± 0.4 kg/m
) healthy men were studied in a randomized, balanced, crossover design, including two conditions of sleep loss, i.e., 4 h sleep during the first night-half ('late-night sleep loss'), 4 h sleep during the second night-half ('early-night sleep loss'), and a control condition with 8h sleep ('regular sleep'), respectively. Feelings of hunger and appetite were assessed through visual analogue scales, and plasma ghrelin and leptin were measured from blood samples taken before, during, and after night-time sleep.
Ghrelin and feelings of hunger and appetite, as well as the desire for food, were increased after 'late-night sleep loss', but not 'early-night sleep loss', whereas leptin remained unaffected by the timing of sleep loss.
Our data indicate that timing of sleep restriction modulates the effects of acute sleep loss on ghrelin and appetite regulation in healthy men. 'Late-night sleep loss' might be a risk factor for metabolic diseases, such as obesity and type 2 diabetes. Thereby, our findings highlight the metabolic relevance of chronobiological sleep timing.
Aims/hypothesis
Attenuated counterregulation after recurrent hypoglycaemia is a major complication of diabetes treatment. As there is previous evidence for the relevance of sleep in metabolic ...control, we assessed the acute contribution of sleep to the counterregulatory adaptation to recurrent hypoglycaemia.
Methods
Within a balanced crossover design, 15 healthy, normal-weight male participants aged 18–35 years underwent three hyperinsulinaemic–hypoglycaemic clamps with a glucose nadir of 2.5 mmol/l, under two experimental conditions, sleep and sleep deprivation. Participants were exposed to two hypoglycaemic episodes, followed by a third hypoglycaemic clamp after one night of regular 8 h sleep vs sleep deprivation. The counterregulatory response of relevant hormones (glucagon, growth hormone GH, ACTH, cortisol, adrenaline epinephrine and noradrenaline norepinephrine) was measured, and autonomic and neuroglycopenic symptoms were assessed.
Results
Sleep deprivation compared with sleep dampened the adaptation to recurrent hypoglycaemia for adrenaline (
p
=0.004), and this pattern also emerged in an overall analysis including adrenaline, GH and glucagon (
p
=0.064). After regular sleep, the counterregulatory responses of adrenaline (
p
=0.005), GH (
p
=0.029) and glucagon (
p
=0.009) were attenuated during the 3rd clamp compared with the 1st clamp, but were preserved after sleep deprivation (all
p
>0.225). Neuroglycopenic and autonomic symptoms during the 3rd clamp compared with the 1st clamp were likewise reduced after sleep (
p
=0.005 and
p
=0.019, respectively). In sleep deprivation, neuroglycopenic symptoms increased (
p
=0.014) and autonomic symptoms were unchanged (
p
=0.859).
Conclusions/interpretation
The counterregulatory adaptation to recurrent hypoglycaemia is compromised by sleep deprivation between hypoglycaemic episodes, indicating that sleep is essential for the formation of a neurometabolic memory, and may be a potential target of interventions to treat hypoglycaemia unawareness syndrome.
Graphical abstract
Hypoglycemia is a particular problem in people with diabetes while it can also occur in other clinical circumstances. Hypoglycemia unawareness describes a condition in which autonomic and ...neuroglycopenic symptoms of hypoglycemia decrease and hence are hardly perceivable. A failure to recognize hypoglycemia in time can lead to unconsciousness, seizure, and even death. The risk factors include intensive glycemic control, prior episodes of severe hypoglycemia, long duration of diabetes, alcohol consumption, exercise, renal failure, and sepsis. The pathophysiological mechanisms are manifold, but mainly concern altered brain glucose sensing, cerebral adaptations, and an impaired hormonal counterregulation with an attenuated release of glucagon, epinephrine, growth hormone, and other hormones, as well as impaired autonomous and neuroglycopenic symptoms. Physiologically, this counterregulatory response causes blood glucose levels to rise. The impaired hormonal counterregulatory response to recurrent hypoglycemia can lead to a vicious cycle of frequent and poorly recognized hypoglycemic episodes. There is a shift in glycemic threshold to trigger hormonal counterregulation, resulting in hypoglycemia-associated autonomic failure and leading to the clinical syndrome of hypoglycemia unawareness. This clinical syndrome represents a particularly great challenge in diabetes treatment and, thus, prevention of hypoglycemia is crucial in diabetes management. This mini-review provides an overview of hypoglycemia and the associated severe complication of impaired hypoglycemia awareness and its symptoms, pathophysiology, risk factors, consequences, as well as therapeutic strategies.
The
time-of-day' modifies the metabolic response to meals, but less data exist on the diurnal variations in the hedonic drive to eat. In the present paper, we evaluate the effects of meal timing and ...macronutrient composition on metabolic responses and the homeostatic vs. hedonic regulation of appetite. In study 1, 84 young, healthy adults completed an online computer-based task assessing the homeostatic and hedonic drive to eat in the morning and evening. In study 2, 24 healthy, young men received 2 identical (850 kcal each) meals in the morning (8:45 h) and evening (18:00 h), of 2 experimental conditions: (i) regular carbohydrate (CH) meals (regular-CH), and (ii) high carbohydrate (high-CH) meals, containing 50 and 80% of energy from CHs, respectively. Serial blood samples were obtained, and the postprandial feelings of hunger, satiety, wanting and liking were assessed. Study 1 revealed a higher hedonic drive to eat in the evening compared to the morning. Study 2 confirmed this diurnal pattern of hedonic appetite regulation and, moreover, showed increased glucose and insulin responses to the evening meal. Postprandial ghrelin and leptin as well as feelings of hunger and satiety were not different between the mealtimes nor between the macronutrient conditions. In line with this, the homeostatic drive to eat was neither affected by the mealtime nor macronutrient composition. Increased the hedonic drive to eat in the evening may represent a vulnerability to palatable food and, thus, energy overconsumption. Together with lower evening glucose tolerance, these findings reflect an adverse metabolic constellation at the end of the day, especially after the ingestion of CH-rich foods.
Abstract
Obesity is a debilitating disease of global proportions that necessitates refined, concept‐driven therapeutic approaches. Policy makers, the public and even health care professionals, but ...also individuals with obesity harbour many misconceptions regarding this disease, which leads to prejudice, negative attitudes, stigmatization, discrimination, self‐blame, and failure to provide and finance adequate medical care. Decades of intensive, successful scientific research on obesity have only had a very limited effect on this predicament. We propose a science‐based, easy‐to‐understand conceptual model that synthesizes the complex pathogenesis of obesity including biological, psychological, social, economic and environmental aspects with the aim to explain and communicate better the nature of obesity and currently available therapeutic modalities. According to our integrative ‘Behavioral Balance Model’, ‘top‐down cognitive control’ strategies are implemented (often with limited success) to counterbalance the increased ‘bottom‐up drive’ to gain weight, which is triggered by biological, psycho‐social and environmental mechanisms in people with obesity. Besides offering a deeper understanding of obesity, the model also highlights why there is a strong need for multimodal therapeutic approaches that may not only increase top‐down control but also reduce a pathologically increased bottom‐up drive.
Background: Nonalcoholic steatohepatitis (NASH) is considered the hepatic manifestation of insulin resistance. Therefore, we aimed to assess the association between biopsy-proven liver steatosis and ...long-term remission of type 2 diabetes (T2D) 8 years following different bariatric procedures.
Methods: In a retrospective cohort study including 249 patients with and without T2D, the association between biopsy-proven NASH and long-term remission of T2D 8 years following sleeve gastrectomy (SG) and Roux-enY-gastric bypass (RYGB) has been assessed.
Results: Out of 249 patients, 15.3% showed NASH and T2D at the time of surgery. 8 years after surgery, T2D remission was achieved in 44.7% of patients with NASH compared to 76.0% without NASH. Patients with T2D remission were younger, had higher BMI, displayed lower HbA1c and lower preoperative insulin use (p<0.001) . Patients without remission of T2D showed higher steatosis scores (p<0.05) . In a multivariate logistic regression, higher preoperative HbA1c (OR 0.41) , insulin use (OR 0.16) and preexisting liver fibrosis (OR 0.19) decreased the probability of long-term T2D remission (p<0.05) . Liver steatosis, hepatocyte ballooning or lobular inflammation were not significantly associated with T2D remission. Patients without T2D were predominantly female, of younger age (p<0.001) and displayed lower scores of steatosis, hepatocyte ballooning and lobular inflammation (p<0.05) . With regard to type of surgery, there was no significant difference in T2D remission.
Discussion and Conclusion: Our data suggest that long-term remission of T2D after bariatric surgery (BS) is associated with lower preoperative insulin use and lower biopsy-proven steatosis scores in patients with NASH. Furthermore, T2D remission might be less likely in patients with liver fibrosis. Type of surgery did not affect T2D remission. Our results might help identify patients with NAFLD who benefit most from BS with regard to glycemic outcomes long-term.
Disclosure
A.Lautenbach: Advisory Panel; Novo Nordisk, Speaker's Bureau; Boehringer Ingelheim International GmbH, Novo Nordisk. M.Wernecke: None. S.M.Meyhöfer: None. S.Meyhöfer: None. F.D.Stoll: None. J.Aberel: Advisory Panel; Novo Nordisk, Speaker's Bureau; Novo Nordisk.
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