| 1. |
- 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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| 2. |
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| 3. |
- 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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| 4. |
- Frid, Anders, et al.
(författare)
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Effect of oral pre-meal administration of betaglucans on glycaemic control and variability in subjects with type 1 diabetes
- 2017
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Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 9:9
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Tidskriftsartikel (refereegranskat)abstract
- We conducted a double-blind placebo-controlled crossover pilot study to investigate the effect of oat betaglucans (β-glucan) on glycaemic control and variability in adults with type 1 diabetes (T1D; n = 14). Stomacol® tablets (1.53 g of β-glucan) or placebo (Plac) were administered three times daily before meals for two weeks. Glucose levels were monitored during the second week by continuous glucose monitoring (CGM). There was an increase in basic measures of glycaemic control (maximal glucose value 341 ± 15 vs. 378 ± 13 mg/dL for Plac and β-glucan, p = 0.004), and average daily risk range (62 ± 5 vs. 79 ± 4 mg/dL for Plac and β-glucan, p = 0.003) favouring Plac over β-glucan, but no increase in the M-value (the weighted average of the glucose values) or other more complex measures. Basic measures of glucose variability were also slightly increased during β-glucan treatment, with no difference in more complex measures. However, glycaemic variability increased between the first and last two CGM days on Plac, but remained unchanged on β-glucan. In conclusion, in this pilot study we were unable to demonstrate a general positive effect of β-glucan before meals on glucose control or variability in T1D.
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| 5. |
- Lindgren, Ola, et al.
(författare)
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Incretin Effect after Oral Amino Acid Ingestion in Humans.
- 2015
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 100:3, s. 1172-1176
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Tidskriftsartikel (refereegranskat)abstract
- Context: The incretin effect is the augmented insulin secretion by oral versus intravenous glucose at matching glucose levels. We previously demonstrated an augmented insulin secretion when fat is given orally rather than intravenously, suggesting an incretin effect also after fat. However, whether there is an incretin effect is also present after amino acid ingestion is not known. Objective: To explore insulin secretion and islet hormones after oral and intravenous amino acid administration at matched total amino acid concentrations in healthy subjects. Design: Amino acid mixture (Vaminolac(R)) was administered orally or intravenously at a rate resulting in matching total amino acid concentrations to twelve male volunteers with age 22.5±1.4 yr and BMI 22.4±1.4 kg/m(2), who had no history of diabetes. Main outcome measures: Area under the 120 min curve (AUC) for insulin, C-peptide, glucagon, intact and total glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and insulin secretory rate and insulin clearance. Results: Insulin, C-peptide and glucagon levels increased after both oral and intravenous administration, but insulin secretion was 25% higher after oral than after intravenous amino acid challenges (P=0.006), whereas there was no significant difference in the glucagon response. Intact and total GIP rose after oral but not after intravenous 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 intravenous amino acid at matching amino acid levels and that this is associated with increased GIP level, suggesting that an incretin effect exists also after oral amino acids, possibly mediated by GIP.
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| 6. |
- Morettini, Micaela, et al.
(författare)
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Hepatic and extrahepatic insulin clearance in mice with double deletion of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors
- 2021
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Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:8
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate whether incretins, at physiological levels, affect hepatic and/or extrahepatic insulin clearance. Hepatic and extrahepatic insulin clearance was studied in 31 double incretin receptor knockout (DIRKO) and 45 wild-type (WT) mice, which underwent an Intravenous Glucose Tolerance Test (IVGTT). A novel methodology based on mathematical modeling was designed to provide two sets of values (FEL-P1, CLP-P1; FEL-P2, CLP-P2 ) accounting for hepatic and extrahepatic clearance in the IVGTT first and second phases, respectively, plus the respective total clearances, CLT-P1 and CLT-P2 . A statistically significant difference between DIRKO and WT was found in CLT-P1 (0.61 [0.48–0.82] vs. 0.51 [0.46–0.65] (median [interquartile range]); p = 0.02), which was reflected in the peripheral component, CLP-P1 (0.18 [0.13–0.27] vs. 0.15 [0.11–0.22]; p = 0.04), but not in the hepatic component, FEL-P1 (29.7 [26.7–34.9] vs. 28.9 [25.7–32.0]; p = 0.18). No difference was detected between DIRKO and WT in CLT-P2 (1.38 [1.13–1.75] vs. 1.69 [1.48–1.87]; p = 0.10), neither in CLP-P2 (0.72 [0.64–0.81] vs. 0.79 [0.69–0.87]; p = 0.27) nor in FEL-P2 (37.8 [35.1–43.1] vs. 39.8 [35.8–44.2]; p = 0.46). In conclusion, our findings suggest that the higher insulin clearance observed in DIRKO compared with WT during the IVGTT first phase may be due to its extrahepatic component.
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| 7. |
- Morettini, Micaela, et al.
(författare)
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Mathematical Model of Glucagon Kinetics for the Assessment of Insulin-Mediated Glucagon Inhibition During an Oral Glucose Tolerance Test
- 2021
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Ingår i: Frontiers in Endocrinology. - : Frontiers Media SA. - 1664-2392. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Glucagon is secreted from the pancreatic alpha cells and plays an important role in the maintenance of glucose homeostasis, by interacting with insulin. The plasma glucose levels determine whether glucagon secretion or insulin secretion is activated or inhibited. Despite its relevance, some aspects of glucagon secretion and kinetics remain unclear. To gain insight into this, we aimed to develop a mathematical model of the glucagon kinetics during an oral glucose tolerance test, which is sufficiently simple to be used in the clinical practice. The proposed model included two first-order differential equations -one describing glucagon and the other describing C-peptide in a compartment remote from plasma - and yielded a parameter of possible clinical relevance (i.e., SGLUCA(t), glucagon-inhibition sensitivity to glucose-induced insulin secretion). Model was validated on mean glucagon data derived from the scientific literature, yielding values for SGLUCA(t) ranging from -15.03 to 2.75 (ng of glucagon·nmol of C-peptide-1). A further validation on a total of 100 virtual subjects provided reliable results (mean residuals between -1.5 and 1.5 ng·L-1) and a negative significant linear correlation (r = -0.74, p < 0.0001, 95% CI: -0.82 – -0.64) between SGLUCA(t) and the ratio between the areas under the curve of suprabasal remote C-peptide and glucagon. Model reliability was also proven by the ability to capture different patterns in glucagon kinetics. In conclusion, the proposed model reliably reproduces glucagon kinetics and is characterized by sufficient simplicity to be possibly used in the clinical practice, for the estimation in the single individual of some glucagon-related parameters.
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| 8. |
- 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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| 9. |
- Pacini, Giovanni, et al.
(författare)
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Assessing the Effect of Incretin Hormones and Other Insulin Secretagogues on Pancreatic Beta-Cell Function : Review on Mathematical Modelling Approaches
- 2022
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Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:5
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Forskningsöversikt (refereegranskat)abstract
- Mathematical modelling in glucose metabolism has proven very useful for different reasons. Several models have allowed deeper understanding of the relevant physiological and pathophysiological aspects and promoted new experimental activity to reach increased knowledge of the biological and physiological systems of interest. Glucose metabolism modelling has also proven useful to identify the parameters with specific physiological meaning in single individuals, this being relevant for clinical applications in terms of precision diagnostics or therapy. Among those model-based physiological parameters, an important role resides in those for the assessment of different functional aspects of the pancreatic beta cell. This study focuses on the mathematical models of incretin hormones and other endogenous substances with known effects on insulin secretion and beta-cell function, mainly amino acids, non-esterified fatty acids, and glucagon. We found that there is a relatively large number of mathematical models for the effects on the beta cells of incretin hormones, both at the cellular/organ level or at the higher, whole-body level. In contrast, very few models were identified for the assessment of the effect of other insulin secretagogues. Given the opportunities offered by mathematical modelling, we believe that novel models in the investigated field are certainly advisable.
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| 10. |
- Tura, Andrea, et al.
(författare)
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Four-Point Preprandial Self-Monitoring of Blood Glucose for the Assessment of Glycemic Control and Variability in Patients with Type 2 Diabetes Treated with Insulin and Vildagliptin.
- 2015
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Ingår i: International Journal of Endocrinology. - : Hindawi Limited. - 1687-8337 .- 1687-8345. ; 2015
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Tidskriftsartikel (refereegranskat)abstract
- The study explored the utility of four-point preprandial glucose self-monitoring to calculate several indices of glycemic control and variability in a study adding the DPP-4 inhibitor vildagliptin to ongoing insulin therapy. This analysis utilized data from a double-blind, randomized, placebo-controlled crossover study in 29 patients with type 2 diabetes treated with vildagliptin or placebo on top of stable insulin dose. During two 4-week treatment periods, self-monitoring of plasma glucose was undertaken at 4 occasions every day. Glucose values were used to assess several indices of glycemic control quality, such as glucose mean, GRADE, M-VALUE, hypoglycemia and hyperglycemia index, and indices of glycemic variability, such as standard deviation, CONGA, J-INDEX, and MAGE. We found that vildagliptin improved the glycemic condition compared to placebo: mean glycemic levels, and both GRADE and M-VALUE, were reduced by vildagliptin (P < 0.01). Indices also showed that vildagliptin reduced glycemia without increasing the risk for hypoglycemia. Almost all indices of glycemic variability showed an improvement of the glycemic condition with vildagliptin (P < 0.02), though more marked differences were shown by the more complex indices. In conclusion, the study shows that four-sample preprandial glucose self-monitoring is sufficient to yield information on the vildagliptin effects on glycemic control and variability.
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