Physiological role of cytokines in the regulation of mammalian metabolism.

The innate cytokine system is involved in the response to excessive food intake. In this review, we highlight recent advances in our understanding of the physiological role of three prominent cytokines, interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF), in mammalian metabolic regulation. This recent research highlights the pleiotropic and context-dependent functions in the immune-metabolic interplay. IL-1ß is activated in response to overloaded mitochondrial metabolism, stimulates insulin secretion, and allocates energy to immune cells. IL-6 is released by contracting skeletal muscle and adipose tissue and directs energy from storing tissues to consuming tissues. TNF induces insulin resistance and prevents ketogenesis. Additionally, the therapeutic potential of modulating the activity of each cytokine is discussed.

Glucose turnover at whole-body and skeletal muscle level in response to parenteral nutrition in male patients with alcoholic liver cirrhosis.

BACKGROUND & AIMS: Cirrhosis is associated with insulin resistance and impaired glucose tolerance, which may be caused by impairments at different tissue levels (liver, skeletal muscle, and/or beta cell). METHODS: Here, glucose kinetics at whole-body and skeletal muscle level in patients with cirrhosis (Child-Pugh A and B) were studied during parenteral nutrition using the isotope dilution technique and arteriovenous balance approach across the leg. As opposed to the euglycemic hyperinsulinemic clamp or glucose tolerance tests applied in previous studies, this approach provides a nutrient composition more similar to a normal meal while circumventing any possible portal-systemic shunting, impaired hepatic uptake and incretin effect. RESULTS: We confirmed the presence of hepatic and peripheral insulin resistance in our patient population. Endogenous glucose production was less suppressed in response to parenteral nutrition. However, glucose uptake in skeletal muscle was increased. CONCLUSION: Our results suggests that in our study participants with cirrhosis, the hepatic and peripheral insulin resistance is compensated for by increased insulin secretion and thus, increased glucose uptake in muscle. Hereby, glucose homeostasis is maintained.

Effects of different doses of exercise and diet-induced weight loss on beta-cell function in type 2 diabetes (DOSE-EX): a randomized clinical trial.

Diet-induced weight loss is associated with improved beta-cell function in people with type 2 diabetes (T2D) with remaining secretory capacity. It is unknown if adding exercise to diet-induced weight loss improves beta-cell function and if exercise volume is important for improving beta-cell function in this context. Here, we carried out a four-armed randomized trial with a total of 82 persons (35% females, mean age (s.d.) of 58.2 years (9.8)) with newly diagnosed T2D (<7 years). Participants were randomly allocated to standard care (n = 20), calorie restriction (25% energy reduction; n = 21), calorie restriction and exercise three times per week (n = 20), or calorie restriction and exercise six times per week (n = 21) for 16 weeks. The primary outcome was beta-cell function as indicated by the late-phase disposition index (insulin secretion multiplied by insulin sensitivity) at steady-state hyperglycemia during a hyperglycemic clamp. Secondary outcomes included glucose-stimulated insulin secretion and sensitivity as well as the disposition, insulin sensitivity, and secretion indices derived from a liquid mixed meal tolerance test. We show that the late-phase disposition index during the clamp increases more in all three intervention groups than in standard care (diet control group, 58%; 95% confidence interval (CI), 16 to 116; moderate exercise dose group, 105%; 95% CI, 49 to 182; high exercise dose group, 137%; 95% CI, 73 to 225) and follows a linear dose-response relationship (P > 0.001 for trend). We report three serious adverse events (two in the control group and one in the diet control group), as well as adverse events in two participants in the diet control group, and five participants each in the moderate and high exercise dose groups. Overall, adding an exercise intervention to diet-induced weight loss improves glucose-stimulated beta-cell function in people with newly diagnosed T2D in an exercise dose-dependent manner (NCT03769883).

Amino Acid Metabolism and Protein Turnover in Lean and Obese Humans During Exercise-Effect of IL-6 Receptor Blockade.

CONTEXT: Interleukin-6 (IL-6) is implicated in skeletal muscle wasting and in regulating skeletal muscle hypertrophy in the healthy state. OBJECTIVE: This work aimed to determine the role of IL-6 in regulating systemic protein and amino acid metabolism during rest, exercise, and recovery in lean and obese humans. METHODS: In a nonrandomized, single-blind design, 12 lean and 9 obese individuals were infused first with 0.9% saline (Saline), secondly with the IL-6 receptor antibody tocilizumab (Acute IL-6R ab), and 21 days later with saline while still under tocilizumab influence (Chronic IL-6R ab). Outcome measures were determined before, during, and after 90 minutes of exercise at 40% Wattmax by isotope dilution technique, using primed continuous infusion of L-[ring-D5]phenylalanine and L-[D2]tyrosine. Main outcomes measures included systemic protein turnover and plasma amino acid concentrations. RESULTS: We saw no effect of acute or chronic IL-6 receptor blockade on protein turnover. In lean individuals, chronic IL-6 receptor blockade increased plasma concentrations of total amino acids (rest Δ + 186 µmol/L; 95% CI, 40-332; recovery Δ + 201 µmol/L; 95% CI, 55-347) and essential amino acids (rest Δ + 43 µmol/L; 95% CI, 12-76; recovery Δ + 45 µmol/L; 95% CI, 13-77) independently of exercise but had no such effect in obese individuals (total amino acids rest Δ + 63 µmol/L; 95% CI, -170 to 295, recovery Δ - 23 µmol/L, 95% CI, -256 to 210; essential amino acids rest Δ + 26 µmol/L; 95% CI, -21 to 73, recovery Δ + 11 µmol/L; 95% CI, -36 to 58). CONCLUSION: IL-6 receptor blockade has no effect on protein turnover in fasting lean and obese humans during rest, exercise, and recovery. Chronic IL-6 receptor blockade increases total and essential amino acid concentrations only in lean individuals.

Endurance Training Improves GLP-1 Sensitivity and Glucose Tolerance in Overweight Women.

Context and objective: Obesity and inactivity are risk factors for developing impaired glucose tolerance characterized by insulin resistance and reduced beta-cell function. The stimulatory effect of glucagon-like peptide 1 (GLP-1) on insulin secretion is also impaired in obese, inactive individuals. The aim of this study was to investigate whether endurance training influences beta-cell sensitivity to GLP-1. Participants and intervention: Twenty-four female participants, age 46 ±â€…2 years, body mass index 32.4 ±â€…0.9 kg/m2, and maximal oxygen consumption 24.7 ±â€…0.8 mL/kg/min participated in a 10-week exercise training study. Methods: Beta-cell sensitivity to GLP-1 was assessed in a subset of participants (n = 6) during a 120-minute hyperglycemic glucose clamp (8.5 mM) including a 1-hour GLP-1 (7-36 amide) infusion (0.4 pmol/kg/min). Changes in glucose tolerance, body composition, and cardiorespiratory fitness were assessed by oral glucose tolerance tests (OGTTs), dual-energy X-ray absorptiometry scans, magnetic resonance scans, and maximal oxygen consumption (VO2max) tests, respectively. Results: The c-peptide response to infusion of GLP-1 increased 28 ±â€…3% (P < 0.05) toward the end of the hyperglycemic clamp. The insulin response remained unchanged. Training improved glucose tolerance and reduced GLP-1, insulin, and glucagon levels during the OGTTs. Training increased VO2max (from 24.7 ±â€…0.8 to 27.0 ±â€…0.7 mL/kg/min; P < 0.05) and reduced visceral fat volume (from 4176 ±â€…265 to 3888 ±â€…266 cm3; P < 0.01). Conclusion: Along with improved glycemic control, endurance training improved beta-cell sensitivity to GLP-1 in overweight women. The study was deemed not to constitute a clinical trial and was not registered as such.

The mTOR-inhibitor everolimus reduces hypervolemia in patients with primary aldosteronism.

BACKGROUND: We recently showed in a proof-of-concept study that treating individuals with primary aldosteronism with the mTOR-inhibitor everolimus decreases home blood pressure and renin suppression overall, and markedly reduces aldosterone levels in a subset of individuals. Based on these findings, the question arose whether the effects of everolimus were also mediated via aldosterone-independent mechanisms. Here, we undertook an exploratory, secondary analysis of above-mentioned study to comprehensively investigate how everolimus impacted the hemodynamic status of the study participants, which in turn could elucidate these mechanisms. METHODS: Hemodynamic parameters were measured in study participants with primary aldosteronism at baseline, after treatment with everolimus 0.75 mg orally twice daily for 2 weeks and after a 2-week wash-out. Of the 14 participants, 10 participants had complete data sets for peripheral and central blood pressure, heart rate and pulse wave velocity, and 7 participants had complete data sets for cardiac index, inotropic state index, left stroke work index and stroke systemic vascular resistance index that could be analyzed. Parameters were acquired by brachial oscillometry (Mobil-o-graph PWA) and thoracic electrical bioimpedance (HOTMAN® System). RESULTS: After treatment with everolimus, peripheral (p = 0.049) and central (p = 0.037) diastolic blood pressure, as well as hypervolemia (p = 0.008) were significantly decreased. Likewise, peripheral (p = 0.073) and central systolic blood pressure (p = 0.166) trended downwards. CONCLUSIONS: Everolimus lowers central and peripheral blood pressure in individuals with primary aldosteronism, possibly by decreasing primary aldosteronism-induced hypervolemia and preload.

Blocking endogenous IL-6 impairs mobilization of free fatty acids during rest and exercise in lean and obese men.

Lack of interleukin-6 (IL-6) leads to expansion of adipose tissue mass in rodents and humans. The exact underlying mechanisms have not been identified. In this placebo-controlled, non-randomized, participant-blinded crossover study, we use the IL-6 receptor antibody tocilizumab to investigate the role of endogenous IL-6 in regulating systemic energy metabolism at rest and during exercise and recovery in lean and obese men using tracer dilution methodology. Tocilizumab reduces fatty acid appearance in the circulation under all conditions in lean and obese individuals, whereas lipolysis (the rate of glycerol appearance into the circulation) is mostly unaffected. The fact that fatty acid oxidation is unaffected by IL-6 receptor blockade suggests increased re-esterification of fatty acids. Glucose kinetics are unaffected. We find that blocking endogenous IL-6 signaling with tocilizumab impairs fat mobilization, which may contribute to expansion of adipose tissue mass and, thus, affect the health of individuals undergoing anti-IL-6 therapy (Clinicaltrials.gov: NCT03967691).

Postprandial Hypoglycemia in Patients after Gastric Bypass Surgery Is Mediated by Glucose-Induced IL-1ß.

Postprandial hypoglycemia is a disabling complication of the treatment of obesity by gastric bypass surgery. So far, no therapy exists, and the underlying mechanisms remain unclear. Here, we hypothesized that glucose-induced IL-1ß leads to an exaggerated insulin response in this condition. Therefore, we conducted a placebo-controlled, randomized, double-blind, crossover study with the SGLT2-inhibitor empagliflozin and the IL-1 receptor antagonist anakinra (clinicaltrials.govNCT03200782; n = 12). Both drugs reduced postprandial insulin release and prevented hypoglycemia (symptomatic events requiring rescue glucose: placebo = 7/12, empagliflozin = 2/12, and anakinra = 2/12, pvallikelihood ratio test (LRT) = 0.013; nadir blood glucose for placebo = 2.4 mmol/L, 95% CI 2.18-2.62, empagliflozin = 2.69 mmol/L, 95% CI 2.31-3.08, and anakinra = 2.99 mmol/L, 95% CI 2.43-3.55, pvalLRT = 0.048). Moreover, analysis of monocytes ex vivo revealed a hyper-reactive inflammatory state that has features of an exaggerated response to a meal. Our study proposes a role for glucose-induced IL-1ß in postprandial hypoglycemia after gastric bypass surgery and suggests that SGLT2-inhibitors and IL-1 antagonism may improve this condition.

Inflammation-induced hypoparathyroidism triggered by combination immune checkpoint blockade for melanoma.

BACKGROUND: Treatment with a combination of PD-1 and CTLA-4 targeted checkpoint inhibition has improved outcome of melanoma patients and led to durable remissions but is also associated with significant toxicities. Endocrinopathies such as thyroiditis and hypophysitis are often seen, but other, rarer disturbances have also been described. Endocrinopathies affecting the parathyroid gland are rarely reported and no clear pathomechanism has been proposed. CASE PRESENTATION: Here, we report a case of severe hypocalcemia due to an antibody-mediated hypoparathyroidism as an immune-related adverse event (irAE) in a patient who was treated with the anti-PD-1 antibody nivolumab and anti-CTLA-4 antibody ipilimumab. Hypocalcemia was rapidly corrected by substitution, but the endogenous serum parathyroid hormone (PTH) remained low. The patient demonstrated a rapid and profound tumor response to the combination immune checkpoint blockade, but developed a severe colitis that required high-dose intravenous corticosteroid and anti-TNFα therapy. During this strong immunosuppression the PTH level normalized and the calcium levels were stable without substitution. However, during tapering of immunosuppressants, the PTH and calcium levels decreased again to a level requiring calcium substitution. CONCLUSION: Our report demonstrates a rare endocrinopathy as a complication of combined PD-1 and CTLA-4 blockade. In addition, it provides evidence from the course of the disease that inflammation within the parathyroid gland is involved in the mechanism.

Exercise and the dipeptidyl-peptidase IV inhibitor sitagliptin do not improve beta-cell function and glucose homeostasis in long-lasting type 1 diabetes-A randomised open-label study.

BACKGROUND: Increasing evidence points to beta-cell regeneration in individuals with type 1 diabetes mellitus (type 1 DM) at all stages of the disease. Exercise and glucagon-like peptide-1 (GLP-1) independently improve beta-cell function and glucose homeostasis in animal studies and in clinical trials in individuals with type 2 diabetes mellitus (type 2 DM). Whether a combination of both, exercise and GLP-1, induces a similar effect in individuals with long-lasting type 1 DM remains to be investigated. METHODS: In an open-label study, participants with long-standing type 1 DM were randomly assigned to oral sitagliptin 100 mg daily for 12 weeks in combination with or without an exercise intervention. The primary end-point was change in the area under the concentration-time curve of C-peptide during a mixed meal tolerance test before and after 12 weeks of intervention. RESULTS: A total of 24 participants were included in the study and treated with sitagliptin, 12 participants were allocated to a 12-week exercise intervention. After 12 weeks, there was no difference in the change of AUC C-peptide between groups (exercise: 0 [-1424 to 1870], no exercise: 2091 [283-17 434]; P = 0.09). HDL improved in the exercise intervention group compared to the group with sitagliptin only (exercise: 0.11 [-0.09 to 0.27]; no exercise: -0.18 [-0.24 to 0.01]; P = 0.04). AUC glucose was numerically slightly lower in the exercise intervention group but this did not translate into changes in HbA1c. CONCLUSION: The combination of exercise and sitagliptin had no effect on beta-cell function in individuals with long-lasting type 1 DM.

Treatment of Primary Aldosteronism With mTORC1 Inhibitors.

CONTEXT: Mammalian target of rapamycin complex 1 (mTORC1) activity is often increased in the adrenal cortex of patients with primary aldosteronism (PA), and mTORC1 inhibition decreases aldosterone production in adrenocortical cells, suggesting the mTORC1 pathway as a target for treatment of PA. OBJECTIVE: To investigate the effect of mTORC1 inhibition on adrenal steroid hormones and hemodynamic parameters in mice and in patients with PA. DESIGN: (i) Plasma aldosterone, corticosterone, and angiotensin II (Ang II) were measured in mice treated for 24 hours with vehicle or rapamycin. (ii) Plasma aldosterone levels after a saline infusion test, plasma renin, and 24-hour urine steroid hormone metabolome and hemodynamic parameters were measured during an open-label study in 12 patients with PA, before and after 2 weeks of treatment with everolimus and after a 2-week washout. MAIN OUTCOME MEASURES: (i) Change in plasma aldosterone levels. (ii) Change in other steroid hormones, renin, Ang II, and hemodynamic parameters. RESULTS: Treatment of mice with rapamycin significantly decreased plasma aldosterone levels (P = 0.007). Overall, treatment of PA patients with everolimus significantly decreased blood pressure (P < 0.05) and increased renin levels (P = 0.001) but did not decrease aldosterone levels significantly. However, prominent reduction of aldosterone levels upon everolimus treatment was observed in four patients. CONCLUSION: In mice, mTORC1 inhibition was associated with reduced plasma aldosterone levels. In patients with PA, mTORC1 inhibition was associated with improved blood pressure and renin suppression. In addition, mTORC1 inhibition appeared to reduce plasma aldosterone in a subset of patients.