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Biomedical subjects

J J Holst

Publications and source records attributed to J J Holst.

At least 19 recordsLinked to original sources
PubMed2007

Inappropriate suppression of glucagon during OGTT but not during isoglycaemic i.v. glucose infusion contributes to the reduced incretin effect in type 2 diabetes mellitus.

AIMS/HYPOTHESIS: We investigated glucagon responses during OGTT and isoglycaemic i.v. glucose infusion, respectively, to further elucidate the mechanisms behind the glucose intolerance in patients with type 2 diabetes. MATERIALS AND METHODS: Ten patients (eight men) with type 2 diabetes (age: 64 [51-80] years; BMI: 23 [21-26] kg/m(2); HbA(1c): 6.9 [6.2-8.7]%, values mean [range]) and ten control subjects matched for sex, age and BMI were studied. Blood was sampled on two separate days following a 4-h 50-g OGTT and an isoglycaemic i.v. glucose infusion, respectively. RESULTS: Isoglycaemia during the 2 days was obtained in both groups. In the control subjects no difference in glucagon suppression during the first 45 min of OGTT and isoglycaemic i.v. glucose infusion (-36 +/- 12 vs -64 +/- 23 mmol/l x 45 min; p = NS) was observed, whereas in the group of patients with type 2 diabetes significant glucagon suppression only occurred following isoglycaemic i.v. glucose infusion (-63 +/- 21 vs 10 +/- 16 mmol/l x 45 min; p = 0.002). The incretin effect was significantly reduced in patients with type 2 diabetes compared with control subjects, but no significant differences in the secretion of glucagon-like peptide-1 or glucose-dependent insulinotropic polypeptide between the two groups during OGTT or isoglycaemic i.v. glucose infusion, respectively, could explain this. CONCLUSIONS/INTERPRETATION: Attenuated and delayed glucagon suppression in patients with type 2 diabetes occurs after oral ingestion of glucose, while isoglycaemic i.v. administration of glucose results in normal suppression of glucagon. We suggest that this phenomenon contributes both to the glucose intolerance and to the reduced incretin effect observed in patients with type 2 diabetes.

Adult↗
PubMed2007

Gastric emptying of glucose solution and associated plasma concentrations of GLP-1, GIP, and PYY before and after fundoplication.

BACKGROUND: This study was designed to assess the relationship between gastric emptying of glucose solution and the ensuing plasma concentrations of glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and glucose-dependent insulinotropic polypeptide (GIP) in patients having undergone fundoplication for gastroesophageal reflux (GERD). SUBJECTS AND METHODS: In 10 male patients the emptying of 50% glucose solution was determined scintigraphically and its relationship with plasma glucose, GLP-1, PYY, and GIP concentrations was studied before and 3 months after fundoplication. RESULTS: In the first 30 min after glucose ingestion, emptying was significantly (p = 0.048) faster after fundoplication than before. Emptying and GLP-1 and GIP correlated: the faster the emptying during the first 30 min the greater the concentrations integrated over that period (p = 0.04; p = 0.01; p = 0.02). Emptying and PYY concentrations were unrelated. In the 120-180 min. period, blood glucose concentrations were lower the faster the emptying in the initial 30 min (p = 0.06) and the entire 50-min recording period (p = 0.03) had been. The GLP-1 concentrations integrated over the first 30 min correlated inversely with the integrated plasma glucose during the third hour after ingestion (p = 0.004). CONCLUSIONS: After fundoplication, gastric emptying may, if accelerated in its initial phases, give rise to greater and earlier increases in plasma glucose, GLP-1, and GIP concentrations and thus to reactive hypoglycemia.

Adult↗
PubMed2006

Ghrelin stimulates gastric emptying and hunger in normal-weight humans.

CONTEXT: Ghrelin is produced primarily by enteroendocrine cells in the gastric mucosa and increases gastric emptying in patients with gastroparesis. MAIN OBJECTIVE: The objective of the study was to evaluate the effect of ghrelin on gastric emptying, appetite, and postprandial hormone secretion in normal volunteers. DESIGN: This was a randomized, double-blind, crossover study. SUBJECTS: Subjects included normal human volunteers and patients with GH deficiency. INTERVENTION: Intervention included saline or ghrelin (10 pmol/kg.min) infusion for 180 min after intake of a radioactively labeled omelette (310 kcal) or GH substitution in GH-deficient patients. MAIN OUTCOME MEASURES: Measures consisted of gastric empty-ing parameters and postprandial plasma levels of ghrelin, cholecystokinin, glucagon-like peptide-1, peptide YY, and motilin. RESULTS: The emptying rate was significantly faster for ghrelin (1.26 +/- 0.1% per minute), compared with saline (0.83% per minute) (P < 0.001). The lag phase (16.2 +/- 2.2 and 26.5 +/- 3.8 min) and half-emptying time (49.4 +/- 3.9 and 75.6 +/- 4.9 min) of solid gastric emptying were shorter during ghrelin infusion, compared with infusion of saline (P < 0.001). The postprandial peak in plasma concentration for cholecystokinin and glucagon-like peptide-1 occurred earlier and was higher during ghrelin infusion. There was no significant effect of ghrelin on plasma motilin or peptide YY. There was no difference in gastric emptying before and after GH substitution. CONCLUSION: Our results demonstrate that ghrelin increases the gastric emptying rate in normal humans. The effect does not seem to be mediated via GH or motilin but may be mediated by the vagal nerve or directly on ghrelin receptors in the stomach. Ghrelin receptor agonists may have a role as prokinetic agents.

Adult↗
PubMed2006

Possible role of adiponectin and insulin sensitivity in mediating the favorable effects of lower body fat mass on blood lipids.

AIMS: The objective of this study was to investigate the role of insulin sensitivity and serum adiponectin concentration as determinants, in middle-aged men, of the relationship between lower body fat and blood lipids after truncal fat has been accounted for. METHODS: Men (443) aged 39-65 yr, body mass index 18-43 kg/m(2), participated in the study. The following variables were measured: regional body fat distribution as assessed by dual-energy x-ray absorptiometry, maximal oxygen uptake, physical activity, fasting levels of serum adiponectin, triglycerides, and high-density lipoprotein- and total cholesterol. Plasma glucose and serum insulin were measured in the fasting state and after an oral glucose load. RESULTS: Lower body fat mass was inversely associated with serum triglycerides and total cholesterol and positively with serum high-density lipoprotein-cholesterol after adjustment for age, lean tissue mass, truncal fat mass, weight history, maximal oxygen uptake, and the level of physical activity (P < 0.0005). Serum adiponectin level and Matsudas insulin sensitivity index were positively intercorrelated, and both were positively correlated to lower body fat mass. When including adiponectin and insulin sensitivity in the analyses, the relationships between lower body fat mass and serum lipids were partly explained. CONCLUSION: For a given level of truncal fat mass, a large lower body fat mass is associated with an advantageous blood lipid profile, which may be partially mediated by the relationships to both insulin sensitivity and serum adiponectin level.

Absorptiometry, Photon↗
PubMed2006

Glucagon-like peptide 1 abolishes the postprandial rise in triglyceride concentrations and lowers levels of non-esterified fatty acids in humans.

AIMS/HYPOTHESIS: Diabetic dyslipidaemia contributes to the excess morbidity and mortality in patients with type 2 diabetes. Exogenous glucagon-like peptide 1 (GLP-1) lowers postprandial glycaemia predominantly by slowing gastric emptying. Therefore, the effects of GLP-1 on postprandial lipid levels and gastric emptying were assessed. METHODS: 14 healthy male volunteers were studied with an i.v. infusion of GLP-1 (1.2 pmol kg(-1) min(-1)) or placebo over 390 min in the fasting state. A solid test meal was served and gastric emptying was determined using a (13)C-labelled sodium octanoate breath test. Venous blood was drawn frequently for measurement of glucose, insulin, C-peptide, glucagon, GLP-1, triglycerides and NEFA. RESULTS: GLP-1 administration lowered fasting and postprandial glycaemia (p<0.0001). Gastric emptying was delayed by GLP-1 compared with placebo (p<0.0001). During GLP-1 administration, insulin secretory responses were higher in the fasting state but lower after meal ingestion. After meal ingestion, triglyceride plasma levels increased by 0.33+/-0.14 mmol/l in the placebo experiments (p<0.0001). In contrast, the postprandial increase in triglyceride levels was completely abolished by GLP-1 (change in triglycerides, -0.023+/-0.045 mmol/l; p<0.05). During GLP-1 infusion, plasma concentrations of NEFA were suppressed by 39% in the fasting state (p<0.01) and by 31+/-5% after meal ingestion (p<0.01). CONCLUSIONS/INTERPRETATION: GLP-1 improves postprandial lipidaemia, presumably as a result of delayed gastric emptying and insulin-mediated inhibition of lipolysis. Thus, by lowering both glucose and lipid concentrations, GLP-1 administration may reduce the cardiovascular risk in patients with type 2 diabetes.

Adult↗
PubMed2006

Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs.

AIMS/HYPOTHESIS: The insulinotropic hormone, glucagon-like peptide-1 (GLP-1), is rapidly degraded in vivo as a result of the combination of extensive enzymatic degradation and renal extraction. The GLP-1 receptor agonist, exendin-4, has a longer duration of action, and has recently been approved as a new agent for the treatment of type 2 diabetes mellitus. Exendin-4 is less prone to enzymatic degradation, but it is still unclear what other factors contribute to the increased metabolic stability. MATERIALS AND METHODS: The overall metabolism of GLP-1 and exendin-4 was directly compared in anaesthetised pigs (n=9). RESULTS: Metabolism of GLP-1 (C-terminal RIA; t (1/2) 2.0+/-0.2 min, metabolic clearance rate [MCR] 23.2+/-2.8 ml min(-1) kg(-1); N-terminal RIA; t (1/2) 1.5+/-0.2 min, MCR 88.1+/-10.6 ml min(-1) kg(-1)) was significantly faster than the metabolism of exendin-4 (t (1/2) 22.0+/-2.1 min, p<0.0001; MCR 1.7+/-0.3 ml min(-1) kg(-1), p<0.01). Differences in arteriovenous concentrations revealed organ extraction of GLP-1 by the kidneys (C-terminal 56.6+/-2.6%; N-terminal 48.3+/-5.9%), liver (N-terminal 41.4+/-3.8%), and peripheral tissues (C-terminal 42.3+/-6.0%; N-terminal 33.0+/-7.8%), whereas organ extraction of exendin-4 was limited to the kidneys (21.3+/-4.9%). While the renal extraction of exendin-4 (6.9+/-2.5 pmol/min) did not differ significantly from the amount undergoing glomerular filtration (8.4+/-2.0 pmol/min), the renal extraction of C-terminal GLP-1 (9.0+/-1.1 pmol/min), exceeded the amount which could be accounted for by glomerular filtration (4.2+/-0.5 pmol/min, p<0.0005). CONCLUSIONS/INTERPRETATION: In addition to an increased resistance to enzymatic degradation, the increased stability of exendin-4 is the result of reduced differential organ extraction compared to GLP-1. The data suggest that in the anaesthetised pig, extraction occurs only in the kidney and can be fully accounted for by glomerular filtration.

Anesthesia↗
PubMed2006

Glucagon-like peptide-1: from extract to agent. The Claude Bernard Lecture, 2005.

The incretin hormones are intestinal polypeptides that enhance postprandial insulin secretion. Gastric inhibitory polypeptide (GIP) was initially thought to regulate gastric acid secretion, whereas glucagon-like peptide-1 (GLP-1) was discovered as a result of a systematic search for intestinal insulinotropic products of proglucagon gene expression. The incretin effect is markedly impaired or absent in patients with type 2 diabetes because of decreased secretion of GLP-1 and a loss of the insulinotropic effects of GIP. Metabolic control can be restored or greatly improved by administration of exogenous GLP-1, but this peptide is almost immediately degraded by dipeptidyl peptidase IV (DPP-IV), and therefore has little clinical value. DPP-IV-resistant analogues (incretin mimetics) have been identified or developed, and inhibitors of DPP-IV have also proved effective in protecting endogenous GLP-1 (and GIP) from degradation. Both principles have been tested in clinical studies. The incretin mimetics, administered by sc injection, have demonstrated lasting improvement in HbA(1)c in patients insufficiently treated with conventional oral therapy, and their use has been associated with steady weight loss for up to 2 years. The DPP-IV inhibitors, given once or twice daily by mouth, also appear to provide lasting improvement in HbA(1)c, but are weight-neutral. The first incretin mimetic has reached the market in the US, and applications for approval of the first inhibitors are expected to be filed early in 2006.

Blood Glucose↗
PubMed2006

Glucose-stimulated prehepatic insulin secretion is associated with circulating alanine, triglyceride, glucagon, lactate and TNF-alpha in patients with HIV-lipodystrophy.

OBJECTIVES: We examined whether insulin-resistant lipodystrophic HIV-infected patients with known high fasting prehepatic insulin secretion rates (FISRs) displayed alterations in first-phase prehepatic insulin response to intravenous glucose (ISREG0-10 min). METHODS: Eighteen normoglycaemic lipodystrophic HIV-infected (LIPO) patients and 25 normoglycaemic nonlipodystrophic HIV-infected patients (controls) were included in the study. The prehepatic insulin secretion rate was estimated by deconvolution of C-peptide concentrations, and insulin sensitivity (SIRd) was estimated by the glucose clamp technique. The disposition index (Di=ISREG0-10 min x SIRd) was calculated to estimate the beta-cell response relative to insulin sensitivity. RESULTS: FISR was increased by 69% (P<0.001), whereas median Di was decreased by 75% (P<0.01), primarily as a result of a reduction of SI(Rd) by 60% (P<0.001) in LIPO patients compared with controls. Three LIPO groups were identified arbitrarily according to their FISR and ISREG0-10 min values relative to those of controls. Four LIPO patients displayed high FISR [+3 standard deviations (SD), P<0.001], high ISREG0-10 min (+3 SD, P<0.001) and low SIRd (P<0.01), suggesting an intact B-cell capacity to compensate insulin resistance; six LIPO patients exhibited high FISR (+3SD, P<0.001), low ISREG0-10min (-1 SD, P=0.01), and low SIRd (P<0.01), suggesting depletion of readily releasable insulin stores; the remaining eight LIPO patients and controls displayed identical FISR and ISREG0-10 min. Increased concentrations of the nonglucose insulin secretagogues triglyceride (+124%), alanine (+35%) and glucagon (+88%), and also lactate (+96%) and tumour necrosis factor (TNF)-alpha (+62%) were observed in the 10 LIPO patients with aberrations in FISR and ISREG0-10 min compared with the remaining HIV-infected patients (all P<0.05). CONCLUSION: Plasma triglyceride, alanine, glucagon, lactate and TNF-alpha may be associated with alterations in the first-phase prehepatic insulin secretion response to intravenous glucose in normoglycaemic lipodystrophic HIV-infected patients.

Adult↗
PubMed2005

The metabolite generated by dipeptidyl-peptidase 4 metabolism of glucagon-like peptide-1 has no influence on plasma glucose levels in patients with type 2 diabetes.

AIM/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1) is metabolised by the enzyme dipeptidyl-peptidase 4 (DPP-4), generating a metabolite with potential antagonistic properties. This study was conducted to evaluate the effect of that metabolite on plasma glucose levels in patients with type 2 diabetes. MATERIALS AND METHODS: The randomised crossover study consisted of five regimens: (1) i.v. infusion of GLP-1 (1.2 pmol kg(-1) min(-1); IV); (2 and 3) s.c. infusion of GLP-1 (2.4 and 9.6 pmol kg(-1) min(-1); LSC, HSC); (4) s.c. infusion of GLP-1 (2.4 pmol kg(-1) min(-1)) in combination with a DPP-4 inhibitor (IB); and (5) s.c. infusion of saline (154 mmol NaCl/l; SAL). Seven patients with type 2 diabetes participated in all protocols. RESULTS: Plasma levels of intact GLP-1 increased from 7+/-1 (SAL) to 17+/-3 (LSC), 61+/-7 (IB), 62+/-5 (IV) and 94+/-10 (9.6 s.c.) pmol/l, p<0.0001. Plasma concentrations of the metabolite increased from 1+/-3 (SAL) and 2+/-6 (IB) pmol/l to 42+/-4 (LSC), 64+/-8 (IV) and 327+/-16 (HSC) pmol/l, p<0.0001. Mean plasma glucose levels at 6 h decreased from 12.4+/-1.1 (SAL) mmol/l to 10.4+/-1.1 (LSC), 8.6+/-0.6 (IB), 8.8+/-0.8 (IV) and 9.1+/-0.9 (HSC) mmol/l, p<0.0001. CONCLUSIONS/INTERPRETATION: At approximately similar concentrations of intact GLP-1 (IV, IB, HSC), but with widely ranging metabolite concentrations, the effect on plasma glucose levels was equal, indicating that the presence of the metabolite does not antagonise the glucose-lowering effect of GLP-1.

Blood Glucose↗
PubMed2005

Severe hypoglycaemia post-gastric bypass requiring partial pancreatectomy: evidence for inappropriate insulin secretion and pancreatic islet hyperplasia.

AIMS/HYPOTHESIS: Postprandial hypoglycaemia following gastric bypass for obesity is considered a late manifestation of the dumping syndrome and can usually be managed with dietary modification. We investigated three patients with severe postprandial hypoglycaemia and hyperinsulinaemia unresponsive to diet, octreotide and diazoxide with the aim of elucidating the pathological mechanisms involved. METHODS: Glucose, insulin, and C-peptide were measured in the fasting and postprandial state, and insulin secretion was assessed following selective intra-arterial calcium injection. Pancreas histopathology was assessed in all three patients. RESULTS: All three patients had evidence of severe postprandial hyperinsulinaemia and hypoglycaemia. In one patient, reversal of gastric bypass was ineffective in reversing hypoglycaemia. All three patients ultimately required partial pancreatectomy for control of neuroglycopenia; pancreas pathology of all patients revealed diffuse islet hyperplasia and expansion of beta cell mass. CONCLUSIONS/INTERPRETATION: These findings suggest that gastric bypass-induced weight loss may unmask an underlying beta cell defect or contribute to pathological islet hyperplasia, perhaps via glucagon-like peptide 1-mediated pathways.

Adult↗
PubMed2005

Impact of cereal fibre on glucose-regulating factors.

AIMS/HYPOTHESIS: Insoluble dietary fibre intake is associated, by unknown mechanisms, with a reduced risk of type 2 diabetes. We investigated whether a short-term dietary intervention with purified insoluble fibres influences acute and delayed responses of glucose, insulin, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1. METHODS: Fourteen healthy women with NGT were studied for 300 min on six to eight occasions. Subjects consumed three matched portions of control (C) or fibre-enriched bread (10.4-10.6 g/portion; wheat fibre [WF], oat fibre [OF], and, in a substudy [n=9], resistant starch [RS]) followed by control (C-C, C-WF, C-OF, C-RS) on subsequent days. RESULTS: Fibre enrichment accelerated the early insulin response (fibrextime interaction p=0.026 for WF, p<0.001 for OF, p=0.126 for RS; time of maximal concentration [T(max)], C 57.9+/-5.9, WF 49.3+/-2.5 [p=0.086], OF 46.1+/-2.9 [p=0.026], RS 46.7+/-5.8 min [p=0.029]). It was also associated with an earlier postprandial GIP response after OF (T(max), C 83.6+/-7.2, WF 70.7+/-6.0 [p=0.054], OF 64.3+/-6.9 [p=0.022], RS 60.0+/-5.0 [p>0.15]). Increased fibre intake for 24 h was further associated with a reduced postprandial glucose response on the following day subsequent to ingestion of a control meal (AUC(C-C) 4,140+/-401, AUC(C-WF) 2,850+/-331 [p=0.007], AUC(C-OF) 2,830+/-277 [p=0.011]), with no difference in maximal concentration and T(max) of glucose responses. No differences in insulin responses were observed 24 h after the fibre-enriched diets compared with control (p>0.15). Colonic fermentation was increased only on study days C-OF (p=0.017) and C-RS (p=0.016). CONCLUSIONS/INTERPRETATION: The consumption of highly purified insoluble dietary fibres accelerated the acute GIP and insulin response and was further associated with enhanced postprandial carbohydrate handling the following day upon ingestion of a control meal.

Adult↗
PubMed2005

Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig.

AIMS/HYPOTHESIS: The incretin hormone glucagon-like peptide 1 (GLP-1) has antihyperglycaemic effects, but its therapeutic usefulness is limited by its metabolic instability. Dipeptidyl peptidase IV (DPP-IV) is established as the primary inactivating enzyme, but the roles of other enzymes remain unclear. METHODS: The effect of candoxatril, a selective inhibitor of neutral endopeptidase (NEP) 24.11, on GLP-1 pharmacokinetics/pharmacodynamics with or without DPP-IV inhibition was examined in anaesthetised pigs. RESULTS: During GLP-1 infusion, candoxatril doubled C-terminal immunoreactivity, improving the pharmacokinetics (t(1/2) 2.3+/-0.1 to 8.8+/-1.2 min; metabolic clearance rate [MCR] 20.4+/-3.4 to 4.8+/-0.4 ml.kg(-1). min(-1); p<0.01), but had no effect upon intact GLP-1 (t(1/2) 1.4+/-0.1 to 1.6+/-0.1 min; MCR 47.9+/-8.0 to 38.8+/-5.0 ml.kg(-1).min(-1)). Insulin responses to intravenous glucose were unaffected by candoxatril, but glucose tolerance was improved (DeltaAUC(min 27-87) 118+/-5 to 74+/-14 min.mmol.l(-1); glucose elimination rate [k] 6.6+/-0.5 to 8.6+/-0.5%; p<0.05). When candoxatril was co-administered with valine pyrrolidide (a DPP-IV inhibitor), changes in C-terminal GLP-1 pharmacokinetics mirrored those seen when candoxatril alone was administered (t(1/2) 2.7+/-0.3 and 7.7+/-0.8 min; MCR 17.3+/-2.6 and 6.5+/-0.8 ml.kg(-1).min(-1) for valine pyrrolidide without and with candoxatril, respectively). However, intact GLP-1 pharmacokinetics were improved (t(1/2) 2.8+/-0.3 and 7.5+/-0.6 min; MCR 18.3+/-0.6 and 9.4+/-0.9 ml.kg(-1).min(-1); p<0.02), potentiating the antihyperglycaemic/insulinotropic effects of GLP-1 (glucose deltaAUC(min 27- 87) 103+/-8 to 62+/-14 min.mmol.l(-1); k 6.8+/-0.4 to 11.4+/-1.4%; insulin deltaAUC(min 27-87) 3,680+/-738 to 7,201+/-1,183 min.pmol.l(-1); p<0.05). CONCLUSIONS/INTERPRETATION: This study confirms a role for NEP-24.11 in GLP-1 metabolism in vivo, suggesting that up to 50% of GLP-1 entering the circulation may be degraded by NEP-24.11. Furthermore, combined inhibition of DPP-IV and NEP-24.11 is superior to DPP-IV inhibition alone in preserving intact GLP-1, which raises the possibility that the combination has therapeutic potential.

Animals↗
PubMed2005

Secretion of incretin hormones and the insulinotropic effect of gastric inhibitory polypeptide in women with a history of gestational diabetes.

AIMS/HYPOTHESIS: The insulinotropic effect of gastric inhibitory polypeptide (GIP) is reduced in patients with type 2 diabetes and around 50% of their first-degree relatives under hyperglycaemic conditions. It is unknown whether this is a result of a specific defect in GIP action or of a general reduction in beta cell function. Moreover, impaired secretion of glucagon-like peptide 1 (GLP-1) has been described in patients with type 2 diabetes. Therefore, we studied the insulinotropic effect of GIP in women with previous gestational diabetes (pGDM) under euglycaemic fasting conditions and during a hyperglycaemic clamp experiment. The secretion of GIP and GLP-1 was assessed following oral glucose ingestion. MATERIALS AND METHODS: On separate occasions we performed an OGTT and administered an i.v. bolus of 20 pmol GIP/kg body weight in 20 women with pGDM and 20 control women. An additional hyperglycaemic clamp experiment (140 mg/dl [7.8 mmol/l] over 120 min) with i.v. infusion of GIP (2 pmol kg(-1) min(-1); 30-90 min) was performed in 14 women in each group. Capillary and venous blood samples were drawn for the measurement of glucose (glucose oxidase), insulin, C-peptide, GIP and GLP-1 (specific immunoassays). Indices of insulin sensitivity and beta cell function were calculated. Statistical analyses were carried out using repeated measures ANOVA. RESULTS: Following oral glucose ingestion, plasma glucose, insulin and C-peptide concentrations increased to higher levels in the women with pGDM than in the control women (p<0.05). The women with pGDM were characterised by a higher degree of insulin resistance than the control women (p=0.007 for the Matsuda index), but showed no overt defects in glucose-stimulated insulin secretion (p=0.40 for the insulinogenic index following i.v. glucose). The secretion of GLP-1 and GIP was not different between the groups (p=0.87 and p=0.57, respectively). The insulin secretory response to GIP administration was similar in the two groups both after GIP bolus administration and during the hyperglycaemic clamp experiment (p=0.99 and p=0.88, respectively). A hyperbola-like relationship was found between the degree of insulin sensitivity (Matsuda index) and the insulin secretory response to GIP and i.v. glucose administration. CONCLUSIONS/INTERPRETATION: These results do not support the hypothesis of an early defect in GIP action as a risk factor for subsequent development of diabetes in women with previous gestational diabetes. The inverse relationship between insulin resistance and the insulin secretory response to glucose or GIP suggests that beta cell secretory function in response to different stimuli increases adaptively when insulin sensitivity is diminished.

Adult↗
PubMed2005

A role for pancreatic polypeptide in the regulation of gastric emptying and short-term metabolic control.

CONTEXT: Previous studies using pancreatic polypeptide (PP) infusions in humans have failed to show an effect on gastric emptying, glucose metabolism, and insulin secretion. This might be due to the use of nonhuman sequences of the peptide. OBJECTIVE: The objective of this study was to use synthetic human PP to study gastric emptying rates of a solid meal and postprandial hormone secretion and glucose disposal as well as the gastric emptying rate of water. DESIGN: This was a single-blind study. SETTING: The study was performed at a university hospital. PARTICIPANTS: Fourteen healthy adult subjects were studied. INTERVENTIONS: Infusion of saline or PP at 0.75 or 2.25 pmol/kg.min was given to eight subjects (gastric emptying of solid food), and infusion of saline or PP at 2.25 pmol/kg.min was given to six subjects (gastric emptying of water). MAIN OUTCOME MEASURES: The main outcome measures were gastric emptying of solids (scintigraphy), hunger ratings (visual analog scale), and plasma concentrations of PP, insulin, glucagon, somatostatin, glucagon-like peptide 1, glucose, and gastric emptying of plain water (scintigraphy). RESULTS: PP prolonged the lag phase and the half-time of emptying of the solid meal. The change in hunger rating, satiety, desire to eat after the meal, or prospective consumption was not affected. The postprandial rise in plasma glucose was prolonged by PP. The postprandial rise in insulin was also delayed by PP. PP had no significant effect on the emptying of water. CONCLUSIONS: PP inhibits gastric emptying of solid food and delays the postprandial rise in plasma glucose and insulin. PP is suggested to have a physiological role in the pancreatic postprandial counterregulation of gastric emptying and insulin secretion.

Adult↗
PubMed2005

Vildagliptin, a dipeptidyl peptidase-IV inhibitor, improves model-assessed beta-cell function in patients with type 2 diabetes.

AIMS/HYPOTHESIS: The dipeptidyl peptidase IV inhibitor, vildagliptin, increases levels of intact glucagon-like peptide-1 (GLP-1) and improves glycemic control in patients with type 2 diabetes. Although GLP-1 is known to stimulate insulin secretion, vildagliptin does not affect plasma insulin levels in diabetic patients, suggesting that more sophisticated measures are necessary to ascertain the influence of vildagliptin on beta-cell function. METHODS: This study examined the effects of 28-d treatment with vildagliptin (100 mg, twice daily; n = 9) vs. placebo (n = 11) on beta-cell function in diabetic patients using a mathematical model that describes the insulin secretory rate as a function of glucose levels (beta-cell dose response), the change in glucose with time (derivative component), and a potentiation factor, which is a function of time and may reflect the actions of nonglucose secretagogues and other factors. RESULTS: Vildagliptin significantly increased the insulin secretory rate at 7 mmol/liter glucose (secretory tone), calculated from the dose response; the difference in least squares mean (deltaLSM) was 101 +/- 51 pmol.min(-1).m(-2) (P = 0.002). The slope of the beta-cell dose response, the derivative component, and the potentiation factor were not affected. Vildagliptin also significantly decreased mean prandial glucose (deltaLSM, -1.2 +/- 0.4 mmol/liter; P = 0.01) and glucagon (deltaLSM, -10.7 +/- 4.8 ng/liter; P = 0.03) levels and increased plasma levels of intact GLP-1 (deltaLSM, +10.8 +/- 1.6 pmol/liter; P < 0.0001) and gastric inhibitory polypeptide (deltaLSM, +43.4 +/- 9.4 pmol/liter; P < 0.0001) relative to placebo. CONCLUSION: Vildagliptin is an incretin degradation inhibitor that improves beta-cell function in diabetic patients by increasing the insulin secretory tone.

Adamantane↗
PubMed2005

Effects of soy supplementation on blood lipids and arterial function in hypercholesterolaemic subjects.

BACKGROUND: Studies on soy supplementation suggest a cardioprotective potential. OBJECTIVE: To examine the effects on LDL cholesterol and arterial function as a result of dietary enrichment with soy supplementation. DESIGN: A Randomized, double blind, parallel intervention trial. SETTING: Department of Endocrinology and Metabolism C, Aarhus University Hospital, and Department of Human Nutrition, The Royal Veterinary and Agricultural University, Denmark. SUBJECTS: In all, 100 hypercholesterolaemic but otherwise healthy subjects were included in the study of which 89 completed it. INTERVENTIONS: Subjects were randomly assigned to 24 weeks of daily intake of either a soy supplement, Abalon (30 g soy protein, 9 g cotyledon fibre and 100 mg isoflavones) or placebo (30 g of casein). The soy supplement and placebo were provided in two sachets daily that were stirred in water. Fasting plasma lipids, TNF-alpha, homocysteine, insulin sensitivity, homeostasis model assessment (HOMA-IR), serum insulin, serum glucose, blood pressure as well as Glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) and plasma lipids to a fat-rich meal were recorded before and after the intervention. In a sub study in 32 subjects, arterial dilatory capacity, compliance, and distensibility were recorded before and after the intervention. RESULTS: In the main study, no difference in fasting plasma lipid levels or insulin sensitivity was found between soy-based supplement and placebo. A significant postprandial increase in GIP to the meal test was observed in the soy group (P < 0.05). In a substudy, no difference between the groups in changes in flow-mediated vasodilatation (P = 0.84) was detected, while the soy supplementation caused a reduction in LDL and total cholesterol. CONCLUSIONS: No significant effects on blood lipids were observed in the main study to a soy supplementation in hypercholesterolaemic subjects after 24 weeks. In the substudy, the soy supplementation, however, reduced LDL and total cholesterol but did not influence markers of arterial function.

Anticholesteremic Agents↗
PubMed2005

Lower-body fat mass as an independent marker of insulin sensitivity--the role of adiponectin.

AIMS: To study the association between lower-body fat and estimates of whole-body insulin sensitivity in middle-aged men with and without a history of juvenile onset obesity, and to determine the possible mediating role of fasting serum adiponectin level as an insulin-sensitizing peptide. METHODS: A total of 401 men aged 39-65 y, body mass index 18-54 kg/m2, participated in the study. The following variables were measured on the study participants: regional body fat distribution as assessed by dual energy X-ray absorptiometry, abdominal sagittal diameter, maximal oxygen uptake (VO2max), physical activity, fasting and post-glucose load levels of plasma glucose, serum insulin, and blood non-esterified fatty acid plus fasting levels of serum adiponectin and HbA1c. RESULTS: Lower-body fat mass was positively associated with insulin sensitivity as estimated by Matsudas index also after adjusting for age, lean tissue mass, trunkal fat mass, weight changes since draft board examination, VO2max and the level of physical activity. In a subgroup of men selected for a large lower-body fat mass, fasting serum insulin concentration was 24% lower (P<0.01) and fasting serum adiponectin 33% higher (P<0.005) compared to a subgroup of men with a small lower-body fat mass but with similar trunkal fat mass. CONCLUSION: Lower-body fat mass is positively associated with an estimate of insulin sensitivity independently of trunkal fat mass in both lean and obese middle-aged men and this effect could partly be statistically explained by variations in serum adiponectin levels.

Absorptiometry, Photon↗