| 1. |
- Ahrén, Bo, et al.
(författare)
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Characterization of GLP-1 effects on beta-cell function after meal ingestion in humans.
- 2003
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 26:10, s. 2860-2864
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE—Glucagon-like peptide 1 (GLP-1) is an incretin that augments insulin secretion after meal intake and is developed for treatment of type 2 diabetes. As a novel therapeutic agent, characteristics of its β-cell effects are important to establish. Previously, β-cell effects of GLP-1 have been characterized in humans during graded intravenous infusions of glucose, whereas its effects after more physiological stimuli, like meal intake, are not known. RESEARCH DESIGN AND METHODS—Eight women (aged 69 years, fasting glucose 3.7–10.3 mmol/l, BMI 22.4–43.9 kg/m2) who had fasted overnight were served a breakfast (450 kcal) with intravenous infusion of saline or synthetic GLP-1 (0.75 pmol · kg–1 · min–1), and β-cell function was evaluated by estimating the relationship between glucose concentration and insulin secretion (calculated by deconvolution of C-peptide data). RESULTS—GLP-1 markedly augmented insulin secretion, despite lower glucose. Total insulin secretion was 29.7 ± 4.2 nmol/m2 with GLP-1 versus 21.0 ± 1.6 nmol/m2 with saline (P = 0.048). GLP-1 increased the dose-response relationship between glucose concentration and insulin secretion (70 ± 26 with GLP-1 versus 38 ± 16 pmol insulin · min−1 · m2 · mmol−1 glucose · l without, P = 0.037) and augmented the potentiation factor that modulates the dose response (2.71 ± 0.42 with GLP-1 versus 0.97 ± 0.17 without, P = 0.005). The potentiation factor correlated to GLP-1 concentration (r = 0.53, P < 0.001); a 10-fold increase in GLP-1 levels produced a twofold increase in the potentiation factor. These effects of GLP-1 did not correlate with fasting glucose levels or BMI. CONCLUSIONS—Administration of GLP-1 along with ingestion of a meal augments insulin secretion in humans by a dose-dependent potentiation of the dose-response relationship between plasma glucose and insulin secretion.
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| 2. |
- Alsalim, Wathik, et al.
(författare)
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Effect of single-dose DPP-4 inhibitor sitagliptin on β-cell function and incretin hormone secretion after meal ingestion in healthy volunteers and drug-naïve, well-controlled type 2 diabetes subjects
- 2018
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902. ; 20:4, s. 1080-1085
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Tidskriftsartikel (refereegranskat)abstract
- To explore the effects of a single dose of the DPP-4 inhibitor sitagliptin on glucose-standardized insulin secretion and β-cell glucose sensitivity after meal ingestion, 12 healthy and 12 drug-naïve, well-controlled type 2 diabetes (T2D) subjects (mean HbA1c 43mmol/mol, 6.2%) received sitagliptin (100mg) or placebo before a meal (525kcal). β-cell function was measured as the insulin secretory rate at a standardized glucose concentration and the β-cell glucose sensitivity (the slope between glucose and insulin secretory rate). Incretin levels were also monitored. Sitagliptin increased standardized insulin secretion, in both healthy and T2D subjects, compared to placebo, but without increasing β-cell glucose sensitivity. Sitagliptin also increased active glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) and reduced total (reflecting the secretion) GIP, but not total GLP-1 levels. We conclude that a single dose of DPP-4 inhibition induces dissociated effects on different aspects of β-cell function and incretin hormones after meal ingestion in both healthy and well-controlled T2D subjects.
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| 3. |
- Alsalim, Wathik, et al.
(författare)
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Incretin and islet hormone responses to meals of increasing size in healthy subjects.
- 2015
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 100:2, s. 561-568
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Tidskriftsartikel (refereegranskat)abstract
- Context: Postprandial glucose homeostasis is regulated through the secretion of glucagon-like peptide 1 (GLP-1) through stimulation of insulin secretion and inhibition of glucagon secretion. However, how these processes dynamically adapt to demands created by caloric challenges achieved during daily life is not known. Objective: To explore adaptation of incretin and islet hormones after mixed meals of increasing size in healthy subjects. Design: Twenty-four healthy lean subjects ingested a standard breakfast after an overnight fast followed, after four hours, by a lunch of different size (511, 743 and 1034 kcal) but with identical nutrient composition together with 1.5g paracetamol. Glucose, insulin, C-peptide, glucagon, intact glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and paracetamol were measured after the meals. Main outcome measure: Area under the 180 min curve (AUC) for insulin, C-peptide, glucagon, GLP-1 and GIP and model- derived ß-cell function and paracetamol appearance. Results: Glucose profiles were similar after the two larger meals whereas after the smaller meal, there was a post-peak reduction below baseline to nadir of 3.8±0.1mmol/l after 75min (p<0.001). AUC for GLP-1, GIP, insulin and C-peptide were significantly higher by increasing the caloric load as was β-cells sensitivity to glucose. In contrast, AUC glucagon was the same for all three meals, although there was an increase in glucagon after the postpeak glucose reduction in the smaller meal. The 0-20 min paracetamol appearance was increased by increasing meal size. Conclusion: Mixed lunch meals of increasing size elicit a caloric dependent insulin response due to increased β-cell secretion achieved by increased GIP and GLP-1 levels. The adaptation at larger meals results in identical glucose excursions, whereas after a lower caloric lunch the insulin response is high resulting in postpeak suppression of glucose below baseline.
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| 4. |
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| 5. |
- Alsalim, Wathik, et al.
(författare)
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Persistent whole day meal effects of three dipeptidyl peptidase-4 inhibitors on glycaemia and hormonal responses in metformin-treated type 2 diabetes
- 2020
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 22:4, s. 590-598
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Dipeptidyl peptidase-4 (DPP-4) inhibition has effects on both fasting and postprandial glucose. However, the extent of this effect over the whole day and whether different DPP-4 inhibitors have the same effects have not been established. We therefore explored the whole day effects of three different DPP-4 inhibitors versus placebo on glucose, islet and incretin hormones after ingestion of breakfast, lunch and dinner in subjects with metformin-treated and well-controlled type 2 diabetes. Methods: The study was single-centre and crossover designed, involving 24 subjects [12 men, 12 women, mean age 63 years, body mass index 31.0 kg/m2, glycated haemoglobin 44.7 mmol/mol (6.2%)], who underwent four test days in random order. Each whole day test included ingestion of standardized breakfast (525 kcal), lunch (780 kcal) and dinner (560 kcal) after intake of sitagliptin (100 mg) or vildagliptin (50 mg twice), or saxagliptin (5 mg) or placebo. Results: Compared with placebo, DPP-4 inhibition reduced glucose levels, increased beta-cell function (insulin secretory rate in relation to glucose), suppressed glucagon, increased intact glucagon-like-peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) but suppressed total GLP-1 and GIP after all three meals. The effects were sustained throughout the daytime period with similar changes after each meal and did not differ between the DPP-4 inhibitors. Conclusions: DPP-4 inhibition has persistent daytime effects on glucose, islet and incretin hormones with no difference between three different DPP-4 inhibitors.
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| 6. |
- Lindgren, Ola, et al.
(författare)
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Differential Islet and Incretin Hormone Responses in Morning vs. Afternoon after Standardized Meal in Healthy Men.
- 2009
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 94:8, s. 2887-2892
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Tidskriftsartikel (refereegranskat)abstract
- Context: The insulin response to meal ingestion is more rapid in the morning than in the afternoon. Whether this is explained by a corresponding variation in the incretin hormones is not known. Objective: Assess islet and incretin hormones after meal ingestion in the morning versus afternoon. Design, Settings and Participants: Ingestion at 8am and at 5pm of a standardized meal (524 kcal) in healthy lean males (n=12) at a University Clinical Research Unit. Main Outcome Measures: 1)Early (30 min) area under the curve (AUC30) of plasma levels of insulin and intact (i) and total (t) glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) after meal ingestion. 2)Estimation of ss-cell function by model analysis of glucose and C-peptide. Results: Peak glucose was lower in the morning than in the afternoon (6.1+/-0.2 vs. 7.4+/-0.3 mmol/l, P=0.001). AUC30insulin (4.9+/-0.6 vs 2.8+/-0.4 nmol/l*30 min; P=0.012), AUC30tGLP-1 (300+/-40 vs. 160+/-30 pmol/l*30 min, P=0.002), AUC30iGIP (0.7+/-0.1 vs. 0.3+/-0.1 nmol/l* 30 min, P=0.002) and AUC30tGIP (1.1+/-0.1 vs. 0.6+/-0.1nmol/l*min, P=0.007) were all higher in the morning. AUC30iGLP-1 (r=0.68, P=0.021) and AUC39iGIP (r=0.78, P=0.001) both correlated to AUC30insulin. Model analysis of ss-cell function showed a higher first hour potentiation factor in the morning (P=0.009). This correlated negatively with the 60 min glucose level (r=-0.63, P<0.001). Conclusions: The early release of GLP-1 and GIP are more pronounced in the morning than in the afternoon. This may contribute to the more rapid early insulin response, more pronounced potentiation of ss-cell function and lower glucose after the morning meal.
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| 7. |
- Lindgren, Ola, et al.
(författare)
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Incretin Hormone and Insulin Responses to Oral Versus Intravenous Lipid Administration in Humans.
- 2011
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 96, s. 2519-2524
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 8. |
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| 9. |
- Ohlsson, Lena, et al.
(författare)
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Glucose-lowering effect of the DPP-4 inhibitor sitagliptin after glucose and non-glucose macronutrient ingestion in non-diabetic subjects.
- 2013
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902. ; 15:6, s. 531-537
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Tidskriftsartikel (refereegranskat)abstract
- AIM: Recent studies suggest that the incretin concept is not restricted to glucose ingestion but relevant also after non-glucose macronutrient administration. We therefore hypothesized that raising incretin hormones reduces circulating glucose after both glucose and non-glucose macronutrient ingestion in healthy subjects. MATERIAL AND METHODS: Twelve healthy subjects received the dipeptidyl peptidase-4 inhibitor sitagliptin (100mg) or placebo before ingestion of glucose, fat (olive oil) or protein mix in equicaloric amounts (8 kcal/kg) plus paracetamol (1g). The 120-min AUC of intact GLP-1, glucose, insulin, C-peptide, glucagon and paracetamol, and model-derived insulin secretion (ISR), insulin sensitivity, insulin clearance and glucose absorption were measured. RESULTS: The increased plasma intact GLP-1 levels after each macronutrient was augmented by sitagliptin. This was associated with a robust lowering of glucose: glucose excursion after oral glucose was diminished, and glucose fell below baseline after oral fat and protein. In spite of lower glucose, AUC(C) (-peptide) and ISR did not differ significantly between sitagliptin and placebo after any macronutrient. AUC(glucagon) , insulin sensitivity and insulin clearance were also not different between sitagliptin and placebo. Glucose absorption after oral glucose was reduced by sitagliptin, whereas AUC(paracetamol) was not statistically different between sitagliptin and placebo. CONCLUSIONS: Physiological elevation of intact GLP-1 levels after ingestion of glucose and non-glucose macronutrients is robustly glucose-lowering in healthy subjects. Hence, the incretin concept is not restricted to glucose ingestion in normal physiology. The glucose-lowering action of sitagliptin at these low glucose levels in healthy subjects may have complex mechanisms, involving both islet-dependent and islet-independent mechanisms.
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