The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are gut peptides which are secreted by endocrine cells in the intestinal mucosa. Their ...plasma concentrations increase quickly following food ingestion, and carbohydrate, fat, and protein have all been shown to stimulate GLP-1 and GIP secretion. Although neural and hormonal mechanisms have also been proposed to regulate incretin hormone secretion, direct stimulation of the enteroendocrine cells by the presence of nutrients in the intestinal lumen is probably the most important factor in humans. The actions of the incretin hormones are crucial for maintaining normal islet function and glucose homeostasis. Furthermore, it is also now being recognized that incretin hormones may have other actions in addition to their glucoregulatory effects. Studies have shown that GLP-1 and GIP levels and actions may be perturbed in disease states, but interpretation of the precise relationship between disease and incretins is difficult. The balance of evidence seems to suggest that alterations in secretion and/or action of incretin hormones arise secondarily to the development of insulin resistance, glucose intolerance, and/or increases in body weight rather than being causative factors. However, these impairments may contribute to the deterioration of glycemic control in diabetic patients.
Abstract The two incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), are secreted from the gastrointestinal tract in response to meals and ...contribute to the regulation of glucose homeostasis by increasing insulin secretion. Assessment of plasma concentrations of GLP-1 and GIP is often an important endpoint in both clinical and preclinical studies and, therefore, accurate measurement of these hormones is important. Here, we provide an overview of current approaches for the measurement of the incretin hormones, with particular focus on immunological methods.
Highlights ► GLP-1 agonists may be useful for diabetes prevention. ► GLP-1 agonists promote significant weight loss. ► Currently, it is impossible to estimate risk of serious adverse effects ...(pancreatitis, cancer) that have been claimed to be associated with GLP-1-based therapies, because they are so rare that they are difficult to distinguish from the spontaneous occurrence rates in the (obese) background population.
Context:
The incretin effect is the augmented insulin secretion by oral vs iv glucose at matching glucose levels. We previously demonstrated an augmented insulin secretion when fat is given orally ...rather than iv, suggesting an incretin effect also after fat. However, whether an incretin effect is also present after amino acid ingestion is not known.
Objective:
The objective of the study was to explore insulin secretion and incretin hormones after oral and iv amino acid administration at matched total amino acid concentrations in healthy subjects.
Design:
An amino acid mixture (Vaminolac) was administered orally or iv at a rate resulting in matching total amino acid concentrations to 12 male volunteers with age 22.5 ± 1.4 years and a body mass index 22.4 ± 1.4 kg/m2, who had no history of diabetes.
Main Outcome Measures:
Main outcome measures were area under the 120-minute curve for insulin, C-peptide, glucagon, intact and total glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), and the insulin secretory rate and insulin clearance.
Results:
Insulin, C-peptide, and glucagon levels increased after both oral and iv administration, but insulin secretion was 25% higher after oral than after iv amino acid challenges (P = .006), whereas there was no significant difference in the glucagon response. Intact and total GIP rose after oral but not after iv amino acid administration, whereas intact and total GLP-1 levels did not change significantly in either test.
Conclusion:
Oral amino acid mixture ingestion elicits a stronger insulin secretory response than iv amino acid at matching amino acid levels and this is associated with increased GIP level, suggesting that an incretin effect exists also after oral amino acids, possibly mediated by GIP.
Abstract Inflammation and endothelial dysfunction are increasingly being recognized as key etiological factors in the development of atherosclerosis and subsequent cardiovascular disease. These ...pro-atherogenic factors are strongly correlated and are often found to co-segregate in patients with type 2 diabetes. The impact of sitagliptin, a selective inhibitor of dipeptidyl peptidase-4, on inflammation and markers of endothelial function remains to be fully characterized. Objective The objective of the present study was to examine the effects of treatment with sitagliptin on the plasma levels of various markers of low-grade inflammation and cell adhesion molecules in patients with type 2 diabetes. Methods and results Thirty-six subjects with type 2 diabetes (30 men/6 postmenopausal women with a mean age of 58.1 ± 6.4 years and a body mass index of 30.7 ± 4.9 kg/m2 ) were recruited into this double-blind, cross-over study using sitagliptin (100 mg/d) or placebo, each for a 6-week period, including a 4-week washout period between the two phases. Blood samples were taken at the end of each phase of treatment. Compared with placebo, treatment with sitagliptin significantly reduced the plasma levels of C-reactive protein (CRP) (44.9%, P = 0.006), interleukin (IL)-6 (24.7%, P = 0.04), IL-18 (7.3%, P = 0.004), secreted phospholipase-A2 (sPLA2 ) (12.9%, P = 0.04), soluble intercellular adhesion molecule-1 (5.3%, P = 0.002), and E-selectin (5.9%, P = 0.005). A significant inverse correlation was found between changes in glucagon-like peptide-1 (GLP-1) and changes in CRP levels (r = 0.41, P = 0.01) following sitagliptin therapy. Sitagliptin therapy had more pronounced effects in subjects with higher levels of inflammatory markers and cell adhesion molecules compared with subjects with lower levels. Conclusions Treatment with sitagliptin for 6 weeks reduced plasma markers of low-grade inflammation and cell adhesion molecules, most likely by increasing plasma GLP-1 levels and improving glucose-insulin homeostasis. These beneficial effects of sitagliptin might represent a further advantage in the management of diabetes and its proatherogenic comorbidities.
Aims
Glucose-dependent insulinotropic polypeptide (GIP) confers a variety of metabolic benefits in type 2 diabetes mellitus (T2DM). This meta-analysis was conducted to investigate the impact of ...dipeptidyl peptidase 4 (DPP4) inhibitors on GIP levels in T2DM patients.
Methods
Medline (PubMed), CENTER (Cochrane Library), and Embase (Ovid) were searched and randomized controlled trials (RCTs) evaluating the impact of DPP4 inhibitors on fasting and postprandial GIP levels were obtained. For postprandial GIP, only studies with the data of GIP changes reported as the total area under the curve (AUC
GIP
) using a meal or oral glucose tolerance test were included. A random-effects model was used for data pooling after incorporating heterogeneity.
Results
Overall, 14 RCTs with 541 T2DM patients were included. Compared to placebo/no treatment, the use of DPP4 inhibitors significantly increased the fasting GIP level (standard mean difference SMD: 0.77, 95% confidence interval CI: 0.48–1.05,
P
<0.001;
I
2 =
52%) and postprandial AUC
GIP
(SMD: 1.33, 95% CI: 1.02–1.64,
P
<0.001;
I
2 =
65%). Influence analysis by excluding one dataset at a time showed consistent results. Sensitivity analyses only including studies with radioimmunoassay showed also consistent results (fasting GIP: SMD: 0.75, 95% CI: 0.51–1.00, P<0.001; I
2 =
0%; and postprandial AUC
GIP
: SMD: 1.48, 95% CI: 1.18–1.78,
P
<0.001;
I
2 =
54%). Further subgroup analyses demonstrated that the influence of DPP4 inhibitors on fasting and postprandial GIP levels in T2DM patients was not significantly changed by study characteristics such as study design, patient mean age, baseline glycated hemoglobin (HbA1c) concentration, body mass index (BMI), background treatment, treatment duration, or method for postprandial GIP measurement (all
P
for subgroup effects <0.05).
Conclusion
The use of DPP4 inhibitors effectively increases the fasting and postprandial GIP concentrations in T2DM patients.
Systematic review registration
https://www.crd.york.ac.uk/prospero/
, identifier CRD42022356716.
Aim/hypothesis
Hyperglucagonaemia is a characteristic of several clinical conditions (e.g. end-stage renal disease (ESRD), type 2 diabetes, obesity before and after Roux-en-Y gastric bypass (RYGB) ...and vagotomy with pyloroplasty), but the molecular nature of ‘immunoreactive’ glucagon is poorly characterised. The specific determination of fully processed, intact glucagon requires a ‘sandwich’ assay employing a combination of antibodies directed against both N- and C-termini. We compared a novel assay for intact glucagon with a highly sensitive C-terminal RIA (hitherto considered specific) to determine the extent to which the hyperglucagonaemia measured in clinical samples was caused by authentic glucagon.
Methods
We examined the performance of three commercial glucagon ‘sandwich’ ELISAs. The ELISA with the best overall performance was selected to compare glucagon measurements in clinical samples with an established glucagon RIA.
Results
The first assay performed poorly: there was high cross-reactivity with glicentin (22%) and a lack of sensitivity for glucagon. The second and third assays showed minor cross-reactivity (1–5%) with oxyntomodulin and glicentin; however, the second assay had insufficient sensitivity for glucagon in plasma (>10–20 pmol/l). Thus, only the third assay was suitable for measuring glucagon concentrations in clinical samples. The ELISA and RIA measured similar glucagon levels in healthy individuals. Measurements of samples from individuals with abnormally high (type 2 diabetes or obese) or very elevated (post vagotomy with pyloroplasty, post-RYGB) glucagon levels were also similar in both assays. However, glucagon levels in participants with ESRD were much lower when measured by ELISA than by RIA, indicating that the apparent hyperglucagonaemia is not caused by fully processed intact glucagon.
Conclusions/interpretation
For most purposes, sensitive C-terminal glucagon RIAs are accurate. However, measurements may be spuriously high, at least in patients with renal disease.
Trial Registration
Samples from type 2 diabetic and normoglucose-tolerant patients before and 1 year after RYGB were from a study by Bojsen-Møller et al (trial registration number NCT 01202526). Samples from vagotomised and control individuals were from a study by Plamboeck et al (NCT01176890). Samples from ESRD patients were from a study by Idorn et al (NCT01327378).
Context:
The incretin effect is responsible for the higher insulin response to oral glucose than to iv glucose at matching glucose levels. It is not known whether this effect is restricted to glucose ...only.
Objective:
The aim of the study was to examine whether insulin and incretin hormone responses are higher after oral vs. iv challenge of a lipid emulsion with matching triglyceride levels in humans.
Design, Settings, and Participants:
A lipid emulsion (Intralipid) was administered orally (3 ml/kg) or iv (variable infusion rates to match triglyceride levels after oral ingestion) in healthy lean males (n = 12) at a University Clinical Research Unit. Samples were collected during 300 min.
Main Outcome Measures:
We measured the suprabasal area under the curve for insulin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and the insulin secretory rate based on C-peptide levels by deconvolution.
Results:
Triglyceride levels increased similarly after oral and iv lipid; also, glucose and free fatty acid levels were similar in the two tests. Oral lipid elicited a clear insulin and C-peptide response, whereas no insulin or C-peptide responses were observed during iv lipid. Total and intact GIP and GLP-1 levels both increased after oral lipid administration but were not significantly altered after iv lipid.
Conclusions:
At matching triglyceride levels and with no difference in glucose and free fatty acid levels, oral lipid ingestion but not iv lipid infusion elicits a clear insulin response in association with increased GIP and GLP-1 concentrations. This may suggest that the incretin hormones also contribute to the islet response to noncarbohydrate nutrients.
Cephalic phase secretion of insulin and other enteropancreatic hormones in humans Veedfald, Simon; Plamboeck, Astrid; Deacon, Carolyn F ...
American journal of physiology. Gastrointestinal and liver physiology/American journal of physiology: Gastrointestinal and liver physiology,
2016-Jan-01, 2016-01-01, 20160101, Letnik:
310, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Enteropancreatic hormone secretion is thought to include a cephalic phase, but the evidence in humans is ambiguous. We studied vagally induced gut hormone responses with and without muscarinic ...blockade in 10 glucose-clamped healthy men (age: 24.5 ± 0.6 yr, means ± SE; body mass index: 24.0 ± 0.5 kg/m(2); HbA1c: 5.1 ± 0.1%/31.4 ± 0.5 mmol/mol). Cephalic activation was elicited by modified sham feeding (MSF, aka "chew and spit") with or without atropine (1 mg bolus 45 min before MSF + 80 ng·kg(-1)·min(-1) for 2 h). To mimic incipient prandial glucose excursions, glucose levels were clamped at 6 mmol/l on all days. The meal stimulus for the MSF consisted of an appetizing breakfast. Participants (9/10) also had a 6 mmol/l glucose clamp without MSF. Pancreatic polypeptide (PP) levels rose from 6.3 ± 1.1 to 19.9 ± 6.8 pmol/l (means ± SE) in response to MSF and atropine lowered basal PP levels and abolished the MSF response. Neither insulin, C-peptide, glucose-dependent insulinotropic polypeptide (GIP), nor glucagon-like peptide-1 (GLP-1) levels changed in response to MSF or atropine. Glucagon and ghrelin levels were markedly attenuated by atropine prior to and during the clamp: at t = 105 min on the atropine (ATR) + clamp (CLA) + MSF compared with the saline (SAL) + CLA and SAL + CLA + MSF days; baseline-subtracted glucagon levels were -10.7 ± 1.1 vs. -4.0 ± 1.1 and -4.7 ± 1.9 pmol/l (means ± SE), P < 0.0001, respectively; corresponding baseline-subtracted ghrelin levels were 303 ± 36 vs. 39 ± 38 and 3.7 ± 21 pg/ml (means ± SE), P < 0.0001. Glucagon and ghrelin levels were unaffected by MSF. Despite adequate PP responses, a cephalic phase response was absent for insulin, glucagon, GLP-1, GIP, and ghrelin.
Sodium‐glucose co‐transporter‐2 inhibitors (SGLT2is) lower blood glucose and are used for treatment of type 2 diabetes. However, SGLT2is have been associated with increases in endogenous glucose ...production (EGP) by mechanisms that have been proposed to result from SGLT2i‐mediated increases in circulating glucagon concentrations, but the relative importance of this effect is debated, and mechanisms possibly coupling SGLT2is to increased plasma glucagon are unclear. A direct effect on alpha‐cell activity has been proposed, but data on alpha‐cell SGLT2 expression are inconsistent, and studies investigating the direct effects of SGLT2 inhibition on glucagon secretion are conflicting. By contrast, alpha‐cell sodium‐glucose co‐transporter‐1 (SGLT1) expression has been found more consistently and appears to be more prominent, pointing to an underappreciated role for this transporter. Nevertheless, the selectivity of most SGLT2is does not support interference with SGLT1 during therapy. Paracrine effects mediated by secretion of glucagonotropic/static molecules from beta and/or delta cells have also been suggested to be involved in SGLT2i‐induced increase in plasma glucagon, but studies are few and arrive at different conclusions. It is also possible that the effect on glucagon is secondary to drug‐induced increases in urinary glucose excretion and lowering of blood glucose, as shown in experiments with glucose clamping where SGLT2i‐associated increases in plasma glucagon are prevented. However, regardless of the mechanisms involved, the current balance of evidence does not support that SGLT2 plays a crucial role for alpha‐cell physiology or that SGLT2i‐induced glucagon secretion is important for the associated increased EGP, particularly because the increase in EGP occurs before any rise in plasma glucagon.
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