Impact of Acutely Increased Endogenous- and Exogenous Ketone Bodies on FGF21 Levels in Humans.

PURPOSE: Fibroblast growth factor (FGF) 21 is a circulating hormone with metabolic regulatory importance. In mice, FGF21 increases in response to a ketogenic diet and fasting. In humans, a similar increase is only observed after prolonged starvation. We aim to study the acute effects of ketone bodies on circulating FGF21 levels in humans. METHODS: Participants from three randomized, placebo-controlled crossover studies, with increased endogenous or exogenous ketone bodies, were included. Study 1: patients with type 1 diabetes (T1D) (n = 9) were investigated after a) insulin deprivation and lipopolysaccharide (LPS) injection and b) insulin-controlled euglycemia. Study 2: patients with T1D (n = 9) were investigated after a) total insulin deprivation for 9 hours and b) insulin-controlled euglycemia. Study 3: Healthy adults (n = 9) were examined during a) 3-hydroxybutyrate (OHB) infusion and b) saline infusion. Plasma FGF21 was measured with immunoassay in serial samples. RESULTS: Circulating OHB levels were significantly increased to 1.3, 1.5, and 5.5 mmol/l in the three studies, but no correlations with FGF21 levels were found. Also, no correlations between FGF21, insulin, or glucagon were found. Insulin deprivation and LPS injection resulted in increased plasma FGF21 levels at t = 120 min (p = .005) which normalized at t = 240 min. CONCLUSION: We found no correlation between circulating FGF21 levels and levels of ketone bodies. This suggests that it is not ketosis per se which controls FGF21 production, but instead a rather more complex regulatory mechanism. TRIAL REGISTRATION: clinicaltrials.gov ID number: Study 1: NCT02157155 (5/6-2014), study 2: NCT02077348 (4/3-2014), and study 3: NCT02357550 (6/2-2015).

Increased lipolysis after infusion of acylated ghrelin: a randomized, double-blinded placebo-controlled trial in hypopituitary patients.

CONTEXT: Acylated ghrelin increases growth hormone (GH) and adrenocorticotrophic hormone (ACTH) secretion from the anterior pituitary gland. Additionally, it increases free fatty acid levels independently of GH and ACTH, but the impact of ghrelin on fatty acid turnover has not been determined. This study was designed to test whether acylated ghrelin directly increases the turnover rate of fatty acids. DESIGN: Eight hypopituitary patients on stable replacement with GH and hydrocortisone were included in a randomized, double-blinded, placebo-controlled crossover study including two study days: (a) infusion of acylated ghrelin and (b) infusion of saline. The study day comprised a basal period (t = 0-120 minutes) and a hyperinsulinaemic-euglycemic clamp period (t = 120-300 minutes). Whole-body lipolysis was estimated at t = 90-120 and t = 270-300 minutes with a palmitate isotope dilution technique. RESULTS: Infusion of acylated ghrelin resulted in 10 times increased total ghrelin area under the curve (AUC) levels in the basal period and 15 times increased AUC levels in the clamp period compared with saline infusion (P < .001). GHAUC levels were largely unaffected by ghrelin compared to saline infusion during both the basal and clamp period, but cortisolAUC levels increased by 15% after ghrelin compared to saline infusion in the basal period (P = .03). Palmitate turnover was increased by 43% in the basal period (difference: 77 (20) µmol/min, P = .01) and unchanged in the clamp period (difference 0.9 (17) µmol/min, P = 1.0) after ghrelin compared to saline infusion. CONCLUSIONS: Our results support the hypothesis that pharmacological levels of acylated ghrelin directly activate lipolysis at the whole-body level.

Unmeasurable low vitamin D levels caused by a novel, homozygote loss-of-function variant in the group-specific component gene.

A 29-year-old female, born to consanguineous parents, was found with unmeasurable levels of vitamin D (<10 nmol/L) after routine biochemical screening during her first pregnancy. She did not respond to either oral or intramuscular vitamin D supplementation and was an otherwise healthy young woman, with no signs of rickets, osteomalacia, osteoporosis, or secondary hyperparathyroidism. Western blot analysis revealed total lack of vitamin D binding protein, and next generation sequencing confirmed a novel, pathogenic homozygote loss-of-function mutation in exon 13 of the group-specific component gene, that encodes the poly A tail for vitamin D binding protein. She was therefore diagnosed with hereditary DBP deficiency, and vitamin D supplementation was diminished to life-long regular vitamin D supplementation (25 µg per day). This case is extremely interesting, as it expands our knowledge of vitamin D physiology and supports the free hormone hypothesis, given that the patient was asymptomatic despite no measurable levels of vitamin D.

Nutrient sensing: LEAP2 concentration in response to fasting, glucose, lactate, and ß-hydroxybutyrate in healthy young males.

BACKGROUND: The appetite-suppressing potential of liver-expressed antimicrobial peptide 2 (LEAP2), and its antagonistic effects on the hunger-inducing hormone ghrelin have attracted scientific interest. It is unclear how LEAP2 is influenced by fasting and how it responds to specific nutrients. OBJECTIVES: The purpose of this investigation was to assess whether LEAP2 concentration 1) decreases after fasting, 2) increases postprandially, and 3) is regulated by nutrient sensing in the splanchnic bed. METHODS: Plasma LEAP2 concentration was measured in blood samples from 5 clinical cross-over trials, following 1) 36 h of fasting (n = 8), 2) 10 h of fasting (n = 37, baseline data pooled from 4 of the clinical trials), 3) Oral and intravenous glucose administration (n = 11), 4) Oral and intravenous Na-lactate administration (n = 10), and 5) Oral and intravenous Na-ß-hydroxybutyrate (BHB) administration (n = 8). All 5 trials included healthy males. RESULTS: Compared with a 10-h fasting period, the median LEAP2 concentration was 38% lower following 36 h of fasting (P < 0.001). Oral administration of glucose elevated, whereas intravenous glucose administration lowered LEAP2 concentration (intervention x time, P = 0.001), resulting in a mean difference of 9 ng/mL (95% confidence interval [CI]: 1, 17) after 120 min. Oral lactate increased, and intravenous lactate decreased LEAP2 (intervention x time, P = 0.007), with a mean difference between interventions of 10 ng/mL (95% CI: 6, 15) after 120 min. In contrast, oral and intravenous administration of BHB reduced the LEAP2 concentration (main effect of time, P < 0.001). CONCLUSIONS: Our investigations show that LEAP2 concentration was lower after a 36-h fast than an overnight fast and that oral delivery of glucose and lactate elevated LEAP2 concentration compared with intravenous administration, whereas LEAP2 concentrations decreased with both oral and intravenous BHB. This indicates that the LEAP2 concentration is sensitive to intestinal exposure to specific substrates, highlighting the need for future studies exploring the relationship between nutrients and LEAP2. This trial was registered at clinicaltrials.gov as NCT01840098, NCT03204877, NCT04299815, NCT03935841, and NCT01705782.

The Effect of Melatonin on Incretin Hormones: Results From Experimental and Randomized Clinical Studies.

CONTEXT: Glucose homeostasis is under circadian control through both endocrine and intracellular mechanisms, with several lines of evidence suggesting that melatonin affects glucose homeostasis. OBJECTIVE: To evaluate the acute in vivo and in situ effects of melatonin on secretion of the incretin hormones, glucagon-like-peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), and their impact on ß-cell insulin secretion. DESIGN: A human randomized, double-blinded, placebo-controlled crossover study combined with a confirmatory in situ study of perfused rat intestines. SETTING: Aarhus University Hospital. METHODS: Fifteen healthy male participants were examined 2 × 2 times: an oral glucose tolerance test (OGTT) was performed on day 1 and an isoglycemic IV glucose infusion replicating the blood glucose profile of the OGTT day was performed on day 2. These pairs of study days were repeated on treatment with melatonin and placebo, respectively. For the in situ study, 6 rat intestines and 4 rat pancreases were perfused arterially with perfusion buffer ±â€…melatonin. The intestines were concomitantly perfused with glucose through the luminal compartment. RESULTS: In humans, melatonin treatment resulted in reduced GIP secretion compared with placebo (ANOVA P = 0.003), an effect also observed in the perfused rat intestines (ANOVA P = 0.003), in which GLP-1 secretion also was impaired by arterial melatonin infusion (ANOVA P < 0.001). Despite a decrease in GIP levels, the in vivo glucose-stimulated insulin secretion was unaffected by melatonin (P = 0.78). CONCLUSION: Melatonin reduced GIP secretion during an oral glucose challenge in healthy young men but did not affect insulin secretion. Reduced GIP secretion was confirmed in an in situ model of the rat intestine.

[Sodium-glucose-cotransporter 2 inhibitor-associated euglycaemic diabetic ketoacidosis].

This case report describes a 51-year-old man, who had Type 2 diabetes and was being treated with a sodium-glucose-cotransporter 2 inhibitor (SGLT2i). The patient developed euglycaemic diabetic ketoacidosis (DKA) during surgery. A perioperative arterial blood gas analysis revealed meta-bolic acidosis (pH = 7.07), but the euglycaemic component of the DKA resulted in a delayed diagnosis of the DKA by 12 hours. A delayed diagnosis of DKA can be fatal, thus em-phasising the importance of considering DKA as a dif-erential diagnosis in SGLT2i-treated patients with unspecific symp-toms.

[Iliac haematoma as a differential diagnosis to lumbar disc herniation].

After a fall without fracture an 83-year-old man who was treated with warfarin was admitted with severe groin pain on the left hip. A few days later he had reduced strength in hip flexion and knee extension, absent patellar tendon reflex, and decreased sensibility of the anterior thigh and the medial lower leg. A magnetic resonance imaging revealed a large haematoma in the left iliac muscle. Iliac haematoma-induced femoral nerve compression neuropathy is a rare condition but should be considered as a differential diagnosis for L4 root compression in patients, who are receiving anticoagulant therapy.