Biomedical subjects

Jens Juul Holst

Publications and source records attributed to Jens Juul Holst.

At least 19 recordsLinked to original sources

PubMed2006

Effects of PYY1-36 and PYY3-36 on appetite, energy intake, energy expenditure, glucose and fat metabolism in obese and lean subjects.

Peptide YY (PYY)(3-36) has been shown to produce dramatic reductions in energy intake (EI), but no human data exist regarding energy expenditure (EE), glucose and fat metabolism. Nothing is known regarding PYY1-36. To compare effects of PYY(1-36) and PYY(3-36) on appetite, EI, EE, insulin, glucose and free fatty acids (FFA) concentrations, 12 lean and 12 obese males participated in a blinded, randomized, crossover study with 90-min infusions of saline, 0.8 pmol x kg(-1) x min(-1) PYY(1-36) and PYY(3-36). Only four participants completed PYY(3-36) infusions because of nausea. Subsequently, six lean and eight obese participants completed 0.2 pmol x kg(-1) x min(-1) PYY(3-36) and 1.6 pmol x kg(-1) x min(-1) PYY(1-36) infusions. PYY(3-36) [corrected] produced [corrected] lower ratings of well-being and [corrected] increases in heart rate, [corrected] FFA, and [corrected] postprandial [corrected] insulin concentrations. Furthermore, high-dose [corrected] PYY(3-36) (0.8 [corrected] pmol x kg(-1) x min(-1)) produced decreased [corrected] EI and increased postprandial [corrected] glucose concentrations and tendency to reduced EE [corrected]

Adult↗

PubMed2006

The elimination rates of intact GIP as well as its primary metabolite, GIP 3-42, are similar in type 2 diabetic patients and healthy subjects.

UNLABELLED: The incretin hormone, glucose-dependent insulinotropic polypeptide (GIP, previously known as gastric inhibitory polypeptide), is rapidly degraded to the biologically inactive metabolite GIP (3-42) in the circulation, but little is known about the kinetics of the intact hormone and the metabolite and whether differences exist between patients with type 2 diabetes mellitus and healthy subjects. We examined eight type 2 diabetic patients (six men, two women); mean (range) age: 59 (48-69) years; BMI: 31.6 (26.0-37.7) kg/m2; HbA1C: 9.0 (8.2-13.2) %; fasting plasma glucose (FPG): 10.0 (8.3-13.2) mmol/l and 8 healthy subjects matched for age, gender and BMI. An intravenous bolus injection of GIP (7.5 nmol) was given and venous blood samples were drawn the following 45 minutes. Peak concentrations of total GIP (intact+metabolite, mean+/-SEM) and intact GIP (in brackets) were 920+/-91 (442+/-52) pmol/l in the type 2 diabetic patients and 775+/-68 (424+/-30) pmol/l in the healthy subjects (NS). GIP was eliminated rapidly with the clearance rate for intact GIP being 2.3+/-0.2 l/min in the type 2 diabetic patients and 2.4+/-0.2 l/min in the healthy subjects (NS). The volumes of distributions were similar in the two groups and ranged from 8 to 21 l per subject. The primary metabolite, GIP 3-42, generated through the action of dipeptidyl peptidase IV (DPP-IV), was eliminated with a mean half-life of 17.5 and 20.5 min in patients and healthy subjects (NS). CONCLUSION: Elimination of GIP is similar in obese type 2 diabetic patients and matched healthy subjects. Differences in elimination of GIP and its primary metabolite, therefore, do not seem to contribute to the defective insulinotropic effect of GIP in type 2 diabetes.

Aged↗

PubMed2006

Inhibitory effect of GLP-1 on gastric motility persists after vagal deafferentation in pigs.

BACKGROUND: Glucagon-like peptide 1 (GLP-1) is an intestinal hormone that is secreted in response to meal ingestion. GLP-1 inhibits gastric emptying and reduces postprandial gastric secretion and may play a physiological regulatory role in controlling appetite and energy intake in humans. The GLP-1 receptors have been identified in several organs including the stomach, brain and pancreas. The GLP-1 mechanism of action on insulin secretion is at least partly mediated via receptors on the pancreatic islet, but the mechanism by which GLP-1 retards gastric emptying is not known and may involve neural interactions, although GLP-1 has no effect on vagally stimulated motor activity of the isolated porcine antrum. MATERIAL AND METHODS: Previously, an experimental model was developed with centrally (insulin hypoglycaemia) induced vagally mediated stimulation of antral motility, recorded by force transducers, in anaesthetized pigs. This model has now been developed further to include vagal deafferentation to determine the role of the afferent vagus in mediating the inhibitory effect of GLP-1 on gastric motility. RESULTS: Intravenous infusion of GLP-1 resulting in slightly supraphysiological plasma levels inhibited the antral contractile force, with the amplitude falling from 29.9+/-5.7 mm to 14.6+/-3.5 mm (p<0.001). After vagal deafferentation GLP-1 still inhibited antral motility (from 36.6+/-6.4 mm to 25+/-4.4 mm (p<0.019). The decrease in amplitude was the same before and after deafferentation. CONCLUSIONS: GLP-1 significantly inhibited centrally induced antral motility and the inhibitory effect of GLP-1 on gastric motility persisted after vagal deafferentation, supporting the hypothesis that the inhibitory effect results from direct interaction of GLP with receptors in the CNS, which in turn reduce vagal efferent output.

Animals↗

PubMed2006

Immunoneutralization of endogenous glucagon reduces hepatic glucose output and improves long-term glycemic control in diabetic ob/ob mice.

In type 2 diabetes, glucagon levels are elevated in relation to the prevailing insulin and glucose levels. The relative hyperglucagonemia is linked to increased hepatic glucose output (HGO) and hyperglycemia. Antagonizing the effects of glucagon is therefore considered an attractive target for treatment of type 2 diabetes. In the current study, effects of eliminating glucagon signaling with a glucagon monoclonal antibody (mAb) were investigated in the diabetic ob/ob mouse. Acute effects of inhibiting glucagon action were studied by an oral glucose tolerance test (OGTT) and by measurement of HGO. In addition, the effects of subchronic (5 and 14 days) glucagon mAb treatment on plasma glucose, insulin, triglycerides, and HbA1c (A1C) levels were investigated. Glucagon mAb treatment reduced the area under the curve for glucose after an OGTT, reduced HGO, and increased the rate of hepatic glycogen synthesis. Glucagon mAb treatment for 5 days lowered plasma glucose and triglyceride levels, whereas 14 days of glucagon mAb treatment reduced A1C. In conclusion, acute and subchronic neutralization of endogenous glucagon improves glycemic control, thus supporting the contention that glucagon antagonism may represent a beneficial treatment of diabetes.

Animals↗

PubMed2005

Inhibition of human pancreatic and biliary output but not intestinal motility by physiological intraileal lipid loads.

Lipid perfusion into the distal ileal lumen at supraphysiological loads inhibits pancreatic exocrine secretion and gastrointestinal motility in humans. In the present study, we sought to determine the effects of physiological postprandial intraileal lipid concentrations on endogenously stimulated pancreaticobiliary secretion, intestinal motility, and release of regulatory mediators. Eight healthy volunteers were intubated with an oroileal multilumen tube for continuous duodenal perfusion of essential amino acids (450 mumol/min), ileal perfusion of graded doses of lipids (0, 50 and 100 mg/min, each dose for 90-120 min), aspiration of duodenal and ileal chyme, and intestinal manometry. Venous blood samples were obtained for measurement of GLP-1 and PYY. Ileal lipid perfusion dose dependently decreased endogenously stimulated trypsin [262 +/- 59 vs. 154 +/- 42 vs. 92 +/- 20 U/min (P < 0.05)] and bile acid output [18.6 +/- 1.9 vs. 8.4 +/- 2.8 vs. 3.0 +/- 1.0 micromol/min (P < 0.05)]. Duodenal motor activity was not inhibited by either lipid dose. Trypsin and bile acid output correlated inversely with the release of GLP-1 and PYY (absolute value of R > 0.84; P < 0.05), whereas the motility index did not. Physiological postprandial ileal lipid concentrations dose dependently inhibited human digestive pancreatic protease and bile acid output, but not intestinal motor activity. Thus physiological postprandial ileal nutrient exposure may be of importance for the termination of digestive secretory responses. Ileocolonic release of GLP-1 and PYY appears to participate in mediating these effects.

Adult↗

PubMed2005

Glucagon-related peptide 1 (GLP-1): hormone and neurotransmitter.

The interest in glucagon-like petide-1 (GLP-1) and other pre-proglucagon derived peptides has risen almost exponentially since seminal papers in the early 1990s proposed to use GLP-1 agonists as therapeutic agents for treatment of type 2 diabetes. A wealth of interesting studies covering both normal and pathophysiological role of GLP-1 have been published over the last two decades and our understanding of GLP-1 action has widened considerably. In the present review, we have tried to cover our current understanding of GLP-1 actions both as a peripheral hormone and as a central neurotransmitter. From an initial focus on glycaemic control, GLP-1 research has been diverted to study its role in energy homeostasis, neurodegeneration, cognitive functions, anxiety and many more functions. With the upcoming introduction of GLP-1 agonists on the pharmaceutical venue, we have witnessed an outstanding example of how initial ideas from basic science laboratories have paved their way to become a novel therapeutic strategy to fight diabetes.

Diabetes Mellitus, Type 2↗

PubMed2005

Normal secretion and action of the gut incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in young men with low birth weight.

CONTEXT: Low birth weight (LBW) is associated with increased risk of type 2 diabetes mellitus. An impaired incretin effect was reported previously in type 2 diabetic patients. OBJECTIVE: We studied the secretion and action of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in young LBW men (n = 24) and matched normal birth weight controls (NBW) (n = 25). RESULTS: LBW subjects were 5 cm shorter but had a body mass index similar to NBW. LBW subjects had significantly elevated fasting and postprandial plasma glucose, as well as postprandial (standard meal test) plasma insulin and C-peptide concentrations, suggestive of insulin resistance. Insulin secretion in response to changes in glucose concentration ("beta-cell responsiveness") during the meal test was similar in LBW and NBW but inappropriate in LBW relative to insulin sensitivity. Fasting and postprandial plasma GLP-1 and GIP levels were similar in the groups. First- and second-phase insulin responses were similar in LBW and NBW during a hyperglycemic clamp (7 mm) with infusion of GLP-1 or GIP, respectively, demonstrating normal action of these hormones on insulin secretion. CONCLUSION: Reduced secretion or action of GLP-1 or GIP does not explain a relative reduced beta-cell responsiveness to glucose or the slightly elevated plasma glucose concentrations observed in young LBW men.

Adult↗

PubMed2005

GLP-2 stimulates colonic growth via KGF, released by subepithelial myofibroblasts with GLP-2 receptors.

BACKGROUND: Glucagon-like peptide-2 is thought to act as a growth factor for the gut, but the localization of the GLP-2 receptor and mechanism of action on epithelial growth is unclear. METHODS AND RESULTS: We found glucagon-like peptide-2 (GLP-2) receptors mainly on subepithelial myofibroblasts in rat, mouse, marmoset and human small and large intestine by immunohistochemistry and in situ hybridisation. By double labelling we found that these GLP-2 receptor immunoreactive cells also produce smooth muscle actin and keratinocyte growth factor (KGF). By subcutaneous infusion of either GLP-2 alone, GLP-2 plus KGF antibody, KGF antibody alone or saline in mice, we found that KGF antibody abolished the growth promoting effect of GLP-2 in the large intestine, but not in the small intestine. CONCLUSIONS: Our findings suggest that GLP-2 in the gut acts by activating receptors on the subepithelial myofibroblasts, causing the release of growth factors, which in turn stimulate intestinal growth.

Actins↗

PubMed2005

Young, low-birth-weight men are not more susceptible to the diabetogenic effects of a prolonged free fatty acid exposure than matched controls.

Low birth weight (LBW) is associated with increased risk of developing type 2 diabetes later in life. Progression from normal to impaired glucose tolerance and overt diabetes may depend, to some extent, on elevation of plasma free fatty acids (FFAs). We undertook this study to elucidate whether a prolonged physiological lipid load could unmask or augment existing metabolic defects in otherwise healthy young LBW subjects. Forty 19-year-old men (LBW [n = 20], controls [normal birth weight, NBW] [n = 20]) without a family history of diabetes underwent an intravenous glucose tolerance test (0.3 g kg(-1)), followed by 2-step hyperinsulinemic-euglycemic clamps (2 x 120 minutes: 10 and 40 mU m(-2) min(-1)) in combination with [3-3H]-glucose and indirect calorimetry. The tests were preceded, in randomized order, by a 24-hour continuous intralipid (20%, 0.4 mg mL(-1) h(-1)) or saline infusion. Estimates of cellular glucose metabolism were obtained and a disposition index calculated. Clamp FFA concentrations were 4- to ten-fold higher during lipid infusion. Both groups experienced a similar decrease in insulin-stimulated glucose disposal in response to lipid infusion (approximately 15%; P < .05), which was mainly accounted for by reduced glucose oxidation (approximately 30%; P < .001). Glycolysis, glucose storage, and glucose production were not significantly altered by lipid infusion. Nevertheless, the LBW group had significantly lower insulin-stimulated glycolysis during lipid infusion (approximately 27%; P < .05) than the NBW group. An appropriate increase in insulin secretion matched the decline in insulin sensitivity in both groups. A 24-hour low-grade intralipid infusion has similar effects on whole-body glucose metabolism and first-phase insulin secretion in 19-year-old, healthy, lean, LBW men with normal glucose tolerance and in NBW controls. We reproduced our previous finding of lower insulin-stimulated glycolysis in this population.

Adult↗

PubMed2005

Effect of whey on blood glucose and insulin responses to composite breakfast and lunch meals in type 2 diabetic subjects.

BACKGROUND: Whey proteins have insulinotropic effects and reduce the postprandial glycemia in healthy subjects. The mechanism is not known, but insulinogenic amino acids and the incretin hormones seem to be involved. OBJECTIVE: The aim was to evaluate whether supplementation of meals with a high glycemic index (GI) with whey proteins may increase insulin secretion and improve blood glucose control in type 2 diabetic subjects. DESIGN: Fourteen diet-treated subjects with type 2 diabetes were served a high-GI breakfast (white bread) and subsequent high-GI lunch (mashed potatoes with meatballs). The breakfast and lunch meals were supplemented with whey on one day; whey was exchanged for lean ham and lactose on another day. Venous blood samples were drawn before and during 4 h after breakfast and 3 h after lunch for the measurement of blood glucose, serum insulin, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide 1 (GLP-1). RESULTS: The insulin responses were higher after both breakfast (31%) and lunch (57%) when whey was included in the meal than when whey was not included. After lunch, the blood glucose response was significantly reduced [-21%; 120 min area under the curve (AUC)] after whey ingestion. Postprandial GIP responses were higher after whey ingestion, whereas no differences were found in GLP-1 between the reference and test meals. CONCLUSIONS: It can be concluded that the addition of whey to meals with rapidly digested and absorbed carbohydrates stimulates insulin release and reduces postprandial blood glucose excursion after a lunch meal consisting of mashed potatoes and meatballs in type 2 diabetic subjects.

Adult↗

PubMed2005

Enteral feeding without pancreatic stimulation.

OBJECTIVE: All forms of commonly practiced enteral feeding techniques stimulate pancreatic secretion, and only intravenous feeding avoids it. In this study, we explored the possibility of more distal enteral infusions of tube feeds to see whether activation of the ileal brake mechanism can result in enteral feeding without pancreatic stimulation, with particular reference to trypsin, because the avoidance of trypsin stimulation may optimize enteral feeding in acute pancreatitis. METHODS: The pancreatic secretory responses to feeding were studied in 36 healthy volunteers by standard double-lumen duodenal perfusion/aspiration techniques over 6 hours. Subjects were assigned to no feeding (n = 7), duodenal feeding with a polymeric diet (n = 7) or low-fat elemental diet (n = 6), mid-distal jejunal feeding (n = 11), or intravenous feeding (n = 5). All diets provided 40 kcal/kg ideal body weight/d and 1.5 g protein/kg ideal body weight/d. Plasma gut peptide responses were monitored in 15 subjects. RESULTS: In comparison with basal fasting trypsin secretion rates (mean = 134 [standard error = 22] U/h), duodenal feeding with the polymeric and elemental formulae stimulated trypsin secretion (mean = 408 [standard error = 51] U/h; P < 0.001), whereas intravenous feeding (mean = 171 [standard error = 34] U/h) and mid-distal jejunal (mean = 119 [standard error = 16] U/h) did not. Stimulation was associated with an increase in plasma cholecystokinin, whereas distal jejunal feeding resulted in an increase in plasma glucagon-like peptide-1 and peptide YY concentrations. CONCLUSIONS: Our results suggest that enteral feeding can be given without stimulating pancreatic trypsin secretion provided it is delivered into the mid-distal jejunum. The mechanism may involve activation of the ileal brake mechanism.

Adult↗

PubMed2005

Defective glucose and lipid metabolism in human immunodeficiency virus-infected patients with lipodystrophy involve liver, muscle tissue and pancreatic beta-cells.

OBJECTIVES: Lipodystrophy and insulin resistance are prevalent among human immunodeficiency virus (HIV)-infected patients on combined antiretroviral therapy (HAART). Aiming to provide a detailed description of the metabolic adverse effects of HIV-lipodystrophy, we investigated several aspects of glucose metabolism, lipid metabolism and beta-cell function in lipodystrophic HIV-infected patients. METHODS: [3-3H]glucose was applied during euglycaemic hyperinsulinaemic clamps in association with indirect calorimetry in 43 normoglycaemic HIV-infected patients (18 lipodystrophic patients on HAART (LIPO), 18 patients without lipodystrophy on HAART (NONLIPO) and seven patients who were naive to antiretroviral therapy (NAIVE) respectively). beta-cell function was evaluated by an intravenous glucose tolerance test. RESULTS: Compared with NONLIPO and NAIVE separately, LIPO displayed markedly reduced ratio of limb to trunk fat (RLF; > 34%, P < 0.001), hepatic insulin sensitivity (> 40%, P < 0.03), incremental glucose disposal (>50%, P < 0.001) and incremental exogenous glucose storage (>50%, P < 0.05). Furthermore, LIPO displayed reduced incremental glucose oxidation (P < 0.01), increased clamp free fatty acids (P < 0.05) and attenuated insulin-mediated suppression of lipid oxidation (P < 0.05) compared with NONLIPO. In combined study groups, RLF correlated with hepatic insulin sensitivity (r = 0.69), incremental glucose disposal (r = 0.71) and incremental exogenous glucose storage (r = 0.40), all P < 0.01. Disposition index (i.e. first-phase insulin response to intravenous glucose multiplied by incremental glucose disposal) was reduced by 46% (P = 0.05) in LIPO compared with the combined groups of NONLIPO and NAIVE, indicating an impaired adaptation of beta-cell function to insulin resistance in LIPO. CONCLUSION: Our data suggest that normoglycaemic lipodystrophic HIV-infected patients display impaired glucose and lipid metabolism in multiple pathways involving liver, muscle tissue and beta-cell function.

Adult↗

PubMed2005

Distinct effects of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 on insulin secretion and gut motility.

Glucose-induced insulin secretion from pancreatic beta-cells depends critically on ATP-sensitive K(+) channel (K(ATP) channel) activity, but it is not known whether K(ATP) channels are involved in the potentiation of insulin secretion by glucose-dependent insulinotropic polypeptide (GIP). In mice lacking K(ATP) channels (Kir6.2(-/-) mice), we found that pretreatment with GIP in vivo failed to blunt the rise in blood glucose levels after oral glucose load. In Kir6.2(-/-) mice, potentiation of insulin secretion by GIP in vivo was markedly attenuated, indicating that K(ATP) channels are essential in the insulinotropic effect of GIP. In contrast, pretreatment with glucagon-like peptide-1 (GLP-1) in Kir6.2(-/-) mice potentiated insulin secretion and blunted the rise in blood glucose levels. We also found that GLP-1 inhibited gut motility whereas GIP did not. Perfusion experiments of Kir6.2(-/-) mice revealed severely impaired potentiation of insulin secretion by 1 nmol/l GIP and substantial potentiation by 1 nmol/l GLP-1. Although both GIP and GLP-1 increase the intracellular cAMP concentration and potentiate insulin secretion, these results demonstrate that the GLP-1 and GIP signaling pathways involve the K(ATP) channel differently.

Animals↗

PubMed2004

Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease.

GLP-1 stimulates insulin secretion, suppresses glucagon secretion, delays gastric emptying, and inhibits small bowel motility, all actions contributing to the anti-diabetogenic peptide effect. Endothelial dysfunction is strongly associated with insulin resistance and type 2 diabetes mellitus and may cause the angiopathy typifying this debilitating disease. Therefore, interventions affecting both endothelial dysfunction and insulin resistance may prove useful in improving survival in type 2 diabetes patients. We investigated GLP-1's effect on endothelial function and insulin sensitivity (S(I)) in two groups: 1) 12 type 2 diabetes patients with stable coronary artery disease and 2) 10 healthy subjects with normal endothelial function and S(I). Subjects underwent infusion of recombinant GLP-1 or saline in a random crossover study. Endothelial function was measured by postischemic FMD of brachial artery, using ultrasonography. S(I) [in (10(-4) dl.kg(-1).min(-1))/(muU/ml)] was measured by hyperinsulinemic isoglycemic clamp technique. In type 2 diabetic subjects, GLP-1 infusion significantly increased relative changes in brachial artery diameter from baseline FMD(%) (3.1 +/- 0.6 vs. 6.6 +/- 1.0%, P < 0.05), with no significant effects on S(I) (4.5 +/- 0.8 vs. 5.2 +/- 0.9, P = NS). In healthy subjects, GLP-1 infusion affected neither FMD(%) (11.9 +/- 0.9 vs. 10.3 +/- 1.0%, P = NS) nor S(I) (14.8 +/- 1.8 vs. 11.6 +/- 2.0, P = NS). We conclude that GLP-1 improves endothelial dysfunction but not insulin resistance in type 2 diabetic patients with coronary heart disease. This beneficial vascular effect of GLP-1 adds yet another salutary property of the peptide useful in diabetes treatment.

Adult↗

PubMed2004

Insulin secretion in lipodystrophic HIV-infected patients is associated with high levels of nonglucose secretagogues and insulin resistance of beta-cells.

We examined whether plasma concentrations of nonglucose insulin secretagogues are associated with prehepatic insulin secretion rates (ISR) in nondiabetic, insulin-resistant, human immunodeficiency virus (HIV)-infected, lipodystrophic patients (LIPO). Additionally, the negative feedback of insulin on ISR was evaluated. ISR were estimated by deconvolution of plasma C-peptide concentrations during fasting (basal) and during the last 30 min of a 120-min euglycemic insulin clamp (40 mU.m(-2).min(-1)). Eighteen normoglycemic LIPO were compared with 25 normoglycemic HIV-infected patients without lipodystrophy (controls). Thirty minutes before start of the clamp, a bolus of glucose was injected intravenously to stimulate endogenous insulin secretion. Insulin sensitivity index (SiRd) was estimated from glucose tracer analysis. LIPO displayed increased basal ISR (69%), clamp ISR (114%), basal insulin (130%), and clamp insulin (32%), all P < or = 0.001, whereas SiRd was decreased (57%, P < 0.001). In LIPO, ISRbasal correlated significantly with basal insulin, alanine, and glucagon (all r > 0.65, P < 0.01), but not with glucose. In control subjects, ISR(basal) correlated significantly with insulin, glucagon, and glucose (all r > 0.41, P < 0.05), but not with alanine. In LIPO, ISRclamp correlated significantly with clamp free fatty acids (FFA), alanine, triglyceride, and glucagon (all r > 0.51, P < 0.05). In control subjects, ISRclamp correlated with clamp triglyceride (r = 0.45, P < 0.05). Paradoxically, in LIPO, ISRclamp correlated positively with clamp insulin (r = 0.68, P < 0.01), which suggests an absent negative feedback of insulin on ISR. Our data support evidence that lipodystrophic, nondiabetic, HIV-infected patients exhibit increased ISR, which can be partially explained by an impaired negative feedback of insulin on beta-cells and an increased stimulation of ISR by FFA, alanine, triglyceride, and glucagon.

Adipose Tissue↗

PubMed2004

Reduction of nocturnal rise in bone resorption by subcutaneous GLP-2.

We have previously shown that a subcutaneous injection of glucagon-like peptide-2 (GLP-2) at 9 a.m. in fasting postmenopausal women results in a dose-dependent decrease in the serum concentration of fragments derived from the degradation of the C-terminal telopeptide region of collagen type I (s-CTX), a marker of bone resorption. In contrast, GLP-2 was found to have a neutral effect on bone formation, as assessed by serum osteocalcin. Since increased s-CTX levels are normally observed at night, we conducted bedtime studies in healthy postmenopausal women. The objective was to study the effect of GLP-2 injection on bone turnover given at bedtime. A total of 81 postmenopausal women were included in two randomised placebo-controlled studies. In conclusion, we found a dose-related reduction of s-CTX after injection of GLP-2 (P < 0.05) and osteocalcin levels was increased as compared to placebo (P = 0.07) by the treatment, suggestive of a stimulative effect on bone formation. An area under the curve (AUC0-10 h) analysis for s-CTX after GLP-2 injection confirmed the dose-related decrease as compared to placebo (P < 0.05).

Bone Resorption↗

PubMed2004

Glucagon-like peptide 1 and inhibitors of dipeptidyl peptidase IV in the treatment of type 2 diabetes mellitus.

Proof-of-concept for the efficacy of a glucagon-like peptide 1 (GLP-1)-based therapy of patients with type 2 diabetes was provided in 2002 by means of prolonged continuous subcutaneous infusion of native GLP-1. Since then, several long-acting analogues of GLP-1, as well as inhibitors of dipeptidyl peptidase IV, the enzyme that rapidly inactivates endogenous GLP-1, have demonstrated efficacy in long term clinical trials.

Animals↗

PubMed2004

Depletion of mucosal substance P in acute otitis media.

OBJECTIVE: The neuropeptide substance P (SP) is an inducer of neurogenic inflammation and bone resorption in the middle ear. Resorption of the bone tissue structures surrounding the middle ear cavity is a distinct feature of the initial stage of acute otitis media (AOM), which may be due to nerve fiber release of SP. MATERIAL AND METHODS: To investigate possible release of SP in the middle ear mucosa during AOM, we used a well-established rat model of AOM caused by Streptococcus pneumoniae. Following tissue extraction on Days 1, 3 and 6 post-inoculation, the mucosal concentration of SP was measured using a radioimmunoassay. RESULTS: Compared to sham-inoculated control ears, the concentration of SP was significantly reduced on Day 1 and even further reduced on Day 3, whereas partial replenishment was found on Day 6. CONCLUSION: SP seems to be depleted in the rat middle ear mucosa in the hyperacute phase of AOM. This depletion is followed by replenishment and the concentration of SP approaches its normal level 6 days post-inoculation. The release of SP may be the trigger of the concurrent bone resorption and may further augment the inflammatory response to the bacterial colonization.

Acute Disease↗