Signs of Glucagon Resistance After a 2-Week Hypercaloric Diet Intervention.

CONTEXT: Hyperglucagonemia is observed in individuals with obesity and contributes to the hyperglycemia of patients with type 2 diabetes. Hyperglucagonemia may develop due to steatosis-induced hepatic glucagon resistance resulting in impaired hepatic amino acid turnover and ensuing elevations of circulating glucagonotropic amino acids. OBJECTIVE: We evaluated whether glucagon resistance could be induced in healthy individuals by a hypercaloric diet intervention designed to increase hepatic fat content. METHODS: We recruited 20 healthy male individuals to follow a hypercaloric diet and a sedentary lifestyle for 2 weeks. Amino acid concentrations in response to infusion of glucagon were assessed during a pancreatic clamp with somatostatin and basal insulin. The reversibility of any metabolic changes was assessed 8 weeks after the intervention. Hepatic steatosis was assessed by magnetic resonance spectroscopy. RESULTS: The intervention led to increased hepatic fat content (382% [206%; 705%], P < .01). Glucagon infusion led to a decrease in the concentration of total amino acids on all experimental days, but the percentage change in total amino acids was reduced (-2.5% ± 0.5% vs -0.2% ± 0.7%, P = .015) and the average slope of the decline in the total amino acid concentration was less steep (-2.0 ± 1.2 vs -1.2 ± 0.3 µM/min, P = .016) after the intervention compared to baseline. The changes were normalized at follow-up. CONCLUSION: Our results indicate that short-term unhealthy behavior, which increases hepatic fat content, causes a reversible resistance to the effect of glucagon on amino acid concentrations in healthy individuals, which may explain the hyperglucagonemia associated with obesity and diabetes.

Hepatic microbiome in healthy lean and obese humans.

BACKGROUND & AIMS: Dysbiosis of the gut microbiota in response to an energy-rich Western diet and the potential leak of bacteria and/or bacterial products from the intestine to the liver is perceived as a potential risk factor for the development of non-alcoholic fatty liver disease (NAFLD). We investigated the microbiome in liver biopsies from healthy lean and obese individuals and compared it with their blood microbiome. METHODS: We examined liver biopsies from 15 healthy lean and 14 obese individuals (BMI of 18.5-25 and 30-40 kg/m2, respectively). Bacterial 16S ribosomal DNA (rDNA) was analysed by quantitative polymerase chain reaction (qPCR) and 16S metagenomic sequencing targeting the hypervariable V3-V4 region. Metagenomic analysis was performed using the linear discriminant analysis effect size (LEfSe) algorithm. Data are medians with IQRs in brackets. RESULTS: Histology revealed hepatic steatosis in 13 obese individuals and in 2 lean individuals. A robust signal from qPCR revealed significantly higher amounts of bacterial rDNA copies in liver samples from obese individuals compared with those from lean individuals (148 [118-167] vs. 77 [62-122] 16S copies/ng DNA, p <0.001). Liver biopsies from the obese group were characterised by lower alpha diversity at the phylum level (Shannon index 0.60 [0.55-0.76] vs. 0.73 [0.62-0.90], p = 0.025), and metagenomic profiling revealed a significantly higher proportion of Proteobacteria in this group (81.0% [73.0-82.4%] vs. 74.3% [68.4-78.4%], p = 0.014). CONCLUSIONS: We provide evidence for the presence of bacterial rDNA in the healthy human liver. Based on differences in the hepatic microbiome between obese individuals and healthy lean individuals, we suggest that changes in the liver microbiome could constitute an additional risk factor for the development of NAFLD. LAY SUMMARY: Non-alcoholic fatty liver disease (NAFLD) has become the most common liver disease globally, and new evidence suggests that obesity is associated with a disturbed gut bacterial composition, which may influence the development of NAFLD. We examined the composition of bacterial DNA in liver biopsies from healthy lean and obese individuals and found a different composition of bacterial DNA in liver biopsies from the obese group. We propose that the increased bacterial DNA load in the livers of obese individuals could constitute an early risk factor for the progression of NAFLD. CLINICAL TRIAL NUMBER: NCT02337660.

Physiological and pathophysiological aspects of incretin hormones and glucagon.

Infusion of oxyntomodulin and the separate and combined infusion of GLP-1 and glucagon inhibited food intake similarly in healthy individuals, with no superior effect of combining GLP-1 and glucagon. We confirm the inhibitory effects of oxyntomodulin and GLP-1, respectively, on GE and appetite scores observed previously, but by adding glucagon to the infusion of GLP-1 we found no additive effects. Unexpectedly, glucagon alone had no effect on GE and appetite scores, but inhibited food intake to the same extent as oxyntomodulin, GLP-1 and GLP-1 + glucagon. Both the GLP-1, oxyntomodulin and GLP-1 + glucagon infusions appeared to increase O2 compared to saline but this observation is most likely confounded by a residual meal-induced thermogenesis because the calorimetry was performed relatively soon after the paracetamol peak indicating that a considerable volume still resided in the stomach and a high rate of nutrient absorption probably was still going on compared to the saline infusion. Flint et al previously concluded from a protocol very similar to ours using GLP-1 infusions, that the observed increases in energy expenditure most likely were linked to the meal. In contrast, we observed no significant changes in O2 from baseline in any of the experiments in our study. The lack of a clear effect on O2 is in contrast to recently reported findings regarding infusions of glucagon and GLP-1. But the dose of glucagon used in that particular study was more than 15-fold higher than ours and associated with large changes in glucose and insulin levels. Such levels are likely to influence REE and offer an explanation of the reported additive effect of combinations of GLP-1 and glucagon. Our conclusion is consistent with recent findings showing no increases after short-term native GLP-1 infusions. Long-term treatment with the GLP-1 analogue liraglutide using 24 h chamber calorimetry has so far shown no differences in energy expenditure following the treatment. Surprisingly, the infusion of glucagon did not change gastric emptying. This finding is controversial since glucagon previously has been used to inhibit bowel motility. However, the doses used to inhibit bowel motility were more than 3,000-fold higher than the dose used in the present study and as mentioned above, such doses might activate the GLP-1 receptor pathway. Interestingly, the glucagon infusion did result in decreased food intake to the same extent as the other peptide infusions despite having no impact on gastric emptying and appetite scores. We found a mean 180 kcal (120 g) difference in food intake following infusions of all the peptides compared to saline. This would roughly sum up to a body weight loss of 402 g of fat per week, which is in the range of what previously has been found in overweight and obese humans with the injection of oxyntomodulin.

Effect of Oxyntomodulin, Glucagon, GLP-1, and Combined Glucagon +GLP-1 Infusion on Food Intake, Appetite, and Resting Energy Expenditure.

CONTEXT: The gut hormone, oxyntomodulin, is a proglucagon product with body weight-lowering potential. It binds to both the glucagon-like peptide-1 (GLP-1) receptor and the glucagon receptor; however, the mechanism behind the body weight-lowering effect remains elusive. OBJECTIVE: We wanted to delineate the contributions of separate and combined GLP-1 receptor and glucagon receptor activation to the body weight-reducing mechanisms of oxyntomodulin. DESIGN: This was a double-blinded, randomized, crossover study. SETTING: The study was conducted at a specialized research unit. PARTICIPANTS: Fifteen young healthy male volunteers (aged 22 [range 18-32] y; body mass index 23 [21-26] kg/m(2); fasting plasma glucose 5.1 [4.4-5.4] mmol/L; and glycated hemoglobin A1c 40 (37-42) mmol/mol). INTERVENTIONS: Five 4-hour liquid meal tests during the infusion of saline, GLP-1 (1 pmol × kg(-1) × min(-1)), glucagon (0.86 pmol × kg(-1) × min(-1)), oxyntomodulin (3 pmol × kg(-1) × min(-1)), or glucagon+GLP-1 (same doses). MAIN OUTCOME MEASURES: We evaluated resting energy expenditure (measured as oxygen uptake, gastric emptying (GE), composite appetite scores (CAS), and food intake. RESULTS: Oxyntomodulin, GLP-1, and GLP-1+glucagon slowed GE and reduced CAS, whereas glucagon did not affect GE and CAS. All infusions caused a similar decrease in food intake compared with saline (total intake (g [95% confidence interval]), saline 811 [729, 892], GLP-1 669 [586, 750], glucagon 686 [604, 768], oxyntomodulin 689 [608, 771], and glucagon+GLP-1 688 [606, 769]). Oxygen uptake did not change significantly from baseline in response to any peptide infusion compared with saline. CONCLUSIONS: Oxyntomodulin, GLP-1, and glucagon decreased food intake but with no additional effect of combining GLP-1 and glucagon.

Postprandial incretin and islet hormone responses and dipeptidyl-peptidase 4 enzymatic activity in patients with maturity onset diabetes of the young.

OBJECTIVE: The role of the incretin hormones in the pathophysiology of maturity onset diabetes of the young (MODY) is unclear. DESIGN: We studied the postprandial plasma responses of glucagon, incretin hormones (glucagon-like peptide 1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP)) and dipeptidyl-peptidase 4 (DPP4) enzymatic activity in patients with glucokinase (GCK) diabetes (MODY2) and hepatocyte nuclear factor 1α (HNF1A) diabetes (MODY3) as well as in matched healthy individuals (CTRLs). SUBJECTS AND METHODS: Ten patients with MODY2 (mean age ± S.E.M. 43 ± 5 years; BMI 24 ± 2 kg/m(2); fasting plasma glucose (FPG) 7.1 ± 0.3 mmol/l: HbA1c 6.6 ± 0.2%), ten patients with MODY3 (age 31 ± 3 years; BMI 24 ± 1 kg/m(2); FPG 8.9 ± 0.8 mmol/l; HbA1c 7.0 ± 0.3%) and ten CTRLs (age 40 ± 5 years; BMI 24 ± 1 kg/m(2); FPG 5.1 ± 0.1 mmol/l; HbA1c 5.3 ± 0.1%) were examined with a liquid test meal. RESULTS: All of the groups exhibited similar baseline values of glucagon (MODY2: 7 ± 1 pmol/l; MODY3: 6 ± 1 pmol/l; CTRLs: 8 ± 2 pmol/l, P=0.787), but patients with MODY3 exhibited postprandial hyperglucagonaemia (area under the curve (AUC) 838 ± 108 min × pmol/l) as compared to CTRLs (182 ± 176 min × pmol/l, P=0.005) and tended to have a greater response than did patients with MODY2 (410 ± 154 min × pmol/l, P=0.063). Similar peak concentrations and AUCs for plasma GIP and plasma GLP1 were observed across the groups. Increased fasting DPP4 activity was seen in patients with MODY3 (17.7 ± 1.2 mU/ml) vs CTRLs (13.6 ± 0.8 mU/ml, P=0.011), but the amount of activity was similar to that in patients with MODY2 (15.0 ± 0.7 mU/ml, P=0.133). CONCLUSION: The pathophysiology of MODY3 includes exaggerated postprandial glucagon responses and increased fasting DPP4 enzymatic activity but normal postprandial incretin responses both in patients with MODY2 and in patients with MODY3.

[Classification of duties in surgical wards].

INTRODUCTION: Night duties in surgical wards can be demanding physically and mentally. Staffing the emergency room, performing emergency operations and taking care of the admitted patients are only few of surgeons' tasks during these busy duties. Night duties can have different effects on the following day/days tasks, limiting some of the leisure activities and maybe life quality. Literature search, however, shows few studies about the subject. The aim of this study was twofold: to study the effects of night duties on the general health of surgeons and to classify duties according to these effects. METHODS: Retrospective study based on modified Short Form Survey (SF)-12. Questionnaire forms were sent to all surgeons in the surgical department at Hvidovre Hospital. RESULTS: The questionnaire forms were sent to 64 surgeons and 38 answered (59.4%). The highest response rate was in the residents group (71.9%: 23/32), senior residents group (70%: 7/10) and the lowest rate in consultants group (36.4%: 8/22). CONCLUSION: Night duties have no significant effect on surgeons' general health. There is a trend, however, that these duties have an effect on hard physical and/or mental activities in the following day especially for female surgeons. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.