| 1. |
- Ahren, Jonatan, et al.
(författare)
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Increased beta-cell volume in mice fed a high-fat diet A dynamic study over 12 months
- 2010
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Ingår i: Islets. - : Informa UK Limited. - 1938-2022 .- 1938-2014. ; 2:6, s. 353-356
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Tidskriftsartikel (refereegranskat)abstract
- As we previously demonstrated, there is an adaptive increase in insulin secretion in insulin resistance in the model of high-fat fed female mice. Since it is assumed that islets also adapt to insulin resistance with beta-cell expansion, we have now examined beta-cell volume in this experimental model. Female C57BL/6JBomTac mice were therefore fed a high-fat diet (60% fat from lard) for three, six or twelve months and beta-cell volume was estimated as beta-cell area per islet, individual beta-cell size and beta-cell number per islet. Control animals were fed a normal chow (11% fat). We found that beta-cell area per islet and total number of beta-cells per islet were increased already after three months of high-fat feeding and that this increase was sustained throughout the twelve month study period. In contrast, individual beta-cell size showed a dynamic pattern with a reduction after three months followed by increase after six and twelve months. The number of apoptosis (caspase-3) positive beta-cells was reduced after three months, whereas there was no difference in proliferation (Ki-67) positive cells, although these were generally rarely observed. Thus, we conclude that insulin resistance accompanying high-fat feeding in mice is followed by progressive beta-cell expansion as evident by early increased islet beta-cell volume and total number of beta-cells, whereas individual beta-cell size showed a dynamic response. The model is also associated with an early reduced apoptosis, which may contribute to the increased beta-cell volume.
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| 2. |
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| 3. |
- Bülow, Birgitta, et al.
(författare)
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Adrenal incidentaloma - follow-up results from a Swedish prospective study
- 2006
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Ingår i: European journal of endocrinology / European Federation of Endocrine Societies. - : Oxford University Press (OUP). - 0804-4643 .- 1479-683X. ; 154:3, s. 419-23
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To examine the risk of developing adrenal carcinomas and clinically overt hypersecreting tumours during short-term follow-up in patients with adrenal incidentalomas. DESIGN: 229 (98 males and 131 females) patients with adrenal incidentalomas were investigated in a prospective follow-up study (median time 25 months; range 3-108 months). The patients were registered between January 1996 and July 2001 and followed until December 2004. Twenty-seven Swedish hospitals contributed with follow-up results. METHODS: Diagnostic procedures were undertaken according to a protocol including reinvestigation with computed tomography scans after 3-6 months, 15-18 months and 27-30 months, as well as hormonal evaluation at baseline and after 27-30 months of follow-up. Operation was recommended when the incidentaloma size increased or if there was a suspicion of a hypersecreting tumour. RESULTS: The median age at diagnosis of the 229 patients included in the follow-up study was 64 years (range 28-84 years) and the median size of the adrenal incidentalomas when discovered was 2.5 cm (range 1-8 cm). During the follow-up period, an increase in incidentaloma size of > or =0.5 cm was reported in 17 (7.4%) and of > or =1.0 cm was reported in 12 (5.2%) of the 229 patients. A decrease in size was seen in 12 patients (5.2%). A hypersecreting tumour was found in 2% of the hormonally investigated patients: Cushing's syndrome (n = 2) and phaeochromocytoma (n = 1). Eleven patients underwent adrenalectomy, but no cases of primary adrenal malignancy were observed. CONCLUSIONS: Patients with adrenal incidentaloma had a low risk of developing malignancy or hormonal hypersecretion during a short-term follow-up period.
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| 4. |
- Dencker, Magnus, et al.
(författare)
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Body fat related to daily physical activity and insulin concentrations in non-diabetic children.
- 2008
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Ingår i: Clinical Physiology and Functional Imaging. - 1475-0961. ; 28, s. 211-215
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Tidskriftsartikel (refereegranskat)abstract
- This study explored the associations between body fat versus daily physical activity and insulin concentrations in non-diabetic young children in a cross-sectional study of 172 children (93 boys and 79 girls) aged 8-11 years. Blood samples were analysed for serum insulin and daily physical activity was measured by accelerometers. Time spent performing vigorous activity was estimated from accelerometer data by using established cut-off points. Dual-energy x-ray absorptiometry (DXA) was used to quantify abdominal fat mass (AFM) and total body fat (TBF), also calculated as percentage of body weight (BF%). Body fat distribution was calculated as AFM/TBF. Body fat distribution was independently linked to both insulin concentrations and physical activity. In contrast, TBF, AFM, and BF% were linked to physical activity only and not to insulin concentrations. In conclusion in this population of non-diabetic children, body fat distribution was independently associated with increased concentrations of insulin and deceased amount of vigorous activity per day. Also, AFM, TBF, and BF% were independently related to minutes of vigorous activity per day.
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| 5. |
- Pacini, Giovanni, et al.
(författare)
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Reappraisal of the intravenous glucose tolerance index for a simple assessment of insulin sensitivity in mice
- 2009
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Ingår i: American Journal of Physiology: Regulatory, Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 296:5, s. 1316-1324
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Tidskriftsartikel (refereegranskat)abstract
- Pacini G, Ahren M, Ahren B. Reappraisal of the intravenous glucose tolerance index for a simple assessment of insulin sensitivity in mice. Am J Physiol Regul Integr Comp Physiol 296: R1316-R1324, 2009. First published February 11, 2009; doi: 10.1152/ajpregu.90575.2008.- Mice are increasingly used in studies where measuring insulin sensitivity (IS) is a common procedure. The glucose clamp is labor intensive, cannot be used in large numbers of animals, cannot be repeated in the same mouse, and has been questioned as a valid tool for IS in mice; thus, the minimal model with 50-min intravenous glucose tolerance test (IVGTT) data was adapted for studies in mice. However, specific software and particular ability was needed. The aim of this study was to establish a simple procedure for evaluating IS during IVGTT in mice (CSI). IVGTTs (n = 520) were performed in NMRI and C57BL/6J mice (20-25g). After glucose injection (1 g/kg), seven samples were collected for 50 min for glucose and insulin measurements, analyzed with a minimal model that provided the validated reference IS (S-perpendicular to). By using the regression CS perpendicular to = alpha(1) + alpha(2) x K-G/AUC(D), where K-G is intravenous glucose tolerance index and AUC(D) is the dynamic area under the curve, IS was calculated in 134 control animals randomly selected (regression CSI vs. S-I: r = 0.66, P < 0.0001) and yielded alpha(1) = 1.93 and alpha(2) = 0.24. KG is the slope of log (glucose(5-20)) and AUCD is the mean dynamic area under insulin curve in the IVGTT. By keeping fixed alpha(1) and alpha(2), CSI was validated in 143 control mice (4.7 +/- 0.2 min . mu U- . ml(-1), virtually identical to S-I: 4.7 +/- 0.3, r = 0.89, P < 0.0001); and in 123 mice in different conditions: transgenic, addition of neuropeptides, incretins, and insulin (CSI: 6.0 +/- 0.4 vs. SI: 6.1 +/- 0.4, r = 0.94, P < 0.0001). In the other 120 animals, CSI revealed its ability to segregate different categories, as does S-I. This easily usable formula for calculating CSI overcomes many experimental obstacles and may be a simple alternative to more complex procedures when large numbers of mice or repeated experiments in the same animals are required.
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| 6. |
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| 7. |
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| 8. |
- Abdelgadir, M, et al.
(författare)
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Reduced leptin concentrations in subjects with type 2 diabetes mellitus in Sudan.
- 2002
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Ingår i: Metabolism, Clinical and Experimental. - : Elsevier BV. - 1532-8600. ; 51:3, s. 304-306
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Tidskriftsartikel (refereegranskat)abstract
- Differences have been observed in the relationship between leptin and metabolic perturbations in glucose homeostasis. Because no information is available from indigenous African populations with diabetes, the purpose of this study was to investigate the possible associations between leptin and different clinical and biochemical characteristics of a large group of subjects with type 2 diabetes mellitus in Sudan. A total of 104 (45 men and 59 women) consecutive type 2 diabetes patients and 75 control subjects (34 men and 41 women) were studied. The body mass index (BMI), blood glucose, serum insulin, and proinsulin were measured and related to serum leptin concentrations. Leptin was higher in females than in males and correlated significantly to BMI. The main novel finding was that serum leptin was significantly lower in diabetic subjects compared with controls in both females (P =.0001) and males (P =.019), although BMI did not differ between diabetic and nondiabetic subjects. Diabetic subjects treated with sulphonylurea (n = 81) had lower BMI than those treated with diet alone or other hypoglycemic drugs (n = 23) (P =.0017), but there was no difference in leptin levels between the 2 groups after adjustment for BMI (P =.87). In diabetic subjects, serum leptin correlated positively with the homeostatic assessment (HOMA) of both beta-cell function (P =.018) and insulin resistance (P =.038), whereas in control subjects, leptin correlated with insulin resistance (P =.0016), but not with beta-cell function. Diabetic subjects had higher proinsulin levels (P =.0031) and higher proinsulin to insulin ratio (P =.0003) than nondiabetic subjects. In univariate analysis, proinsulin showed a weak correlation to leptin (P =.049). In conclusion, we show in a large cohort of Sudanese subjects with type 2 diabetes that circulating leptin levels are lower in diabetic subjectss than in controls of similar age and BMI. The lower serum leptin in diabetic subjects may be a consequence of differences in fat distribution.
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| 9. |
- Abels, Mia, et al.
(författare)
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CART is overexpressed in human type 2 diabetic islets and inhibits glucagon secretion and increases insulin secretion
- 2016
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 59:9, s. 1928-1937
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Insufficient insulin release and hyperglucagonaemia are culprits in type 2 diabetes. Cocaine- and amphetamine-regulated transcript (CART, encoded by Cartpt) affects islet hormone secretion and beta cell survival in vitro in rats, and Cart(-/-) mice have diminished insulin secretion. We aimed to test if CART is differentially regulated in human type 2 diabetic islets and if CART affects insulin and glucagon secretion in vitro in humans and in vivo in mice. Methods CART expression was assessed in human type 2 diabetic and non-diabetic control pancreases and rodent models of diabetes. Insulin and glucagon secretion was examined in isolated islets and in vivo in mice. Ca2+ oscillation patterns and exocytosis were studied in mouse islets. Results We report an important role of CART in human islet function and glucose homeostasis in mice. CART was found to be expressed in human alpha and beta cells and in a subpopulation of mouse beta cells. Notably, CART expression was several fold higher in islets of type 2 diabetic humans and rodents. CART increased insulin secretion in vivo in mice and in human and mouse islets. Furthermore, CART increased beta cell exocytosis, altered the glucose-induced Ca2+ signalling pattern in mouse islets from fast to slow oscillations and improved synchronisation of the oscillations between different islet regions. Finally, CART reduced glucagon secretion in human and mouse islets, as well as in vivo in mice via diminished alpha cell exocytosis. Conclusions/interpretation We conclude that CART is a regulator of glucose homeostasis and could play an important role in the pathophysiology of type 2 diabetes. Based on the ability of CART to increase insulin secretion and reduce glucagon secretion, CART-based agents could be a therapeutic modality in type 2 diabetes.
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| 10. |
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| 11. |
- Accili, D., et al.
(författare)
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What ails the beta-cell?
- 2010
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902. ; 12, s. 1-3
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 12. |
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| 13. |
- Agardh, Carl-David, et al.
(författare)
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Long-standing hyperglycemia in C57BL/6J mice does not affect retinal glutathione levels or endothelial/pericyte ratio in retinal capillaries
- 2000
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Ingår i: Journal of Diabetes and its Complications. - 1873-460X. ; 14:3, s. 146-153
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Tidskriftsartikel (refereegranskat)abstract
- Free radicals have been suggested to play a role in the development of diabetic retinopathy. The aim of the present study was to examine whether the metabolic perturbations caused by high-fat feeding of two strains of mice, the C57BL6/J mice and the NMRI mice, interfere with one of the free radical enzyme defense systems in the retina, i. e., glutathione (GSH), and whether morphological changes occur in the retinal vessels. C57BL/6J mice and NMRI mice were fed a high-fat diet (55%) for 18 months. High-fat fed mice of both strains developed overweight, hyperinsulinemia, and hyperlipidemia. In addition, the high-fat fed C57BL/6J mice also developed sustained hyperglycemia for at least 15 months. The C57BL/6J mice had lower retinal GSH levels than the NMRI mice, both when given a normal diet (29.6+/-1.2 vs. 37.1+/-1.4 nmol/mg protein; p<0.01) and when given a high-fat diet (27.0+/-1.6 vs. 34.7+/-2.6 nmol/mg protein; p<0.05). Despite the long-standing hyperglycemia, hyperinsulinemia and hyperlipidemia in the C57BL/6J mice, high-fat feeding did not cause any changes in the retinal tissue levels of GSH (27.0+/-1.6 vs. 29. 6+/-1.2 nmol/mg protein) or cysteine (7.61+/-0.63 vs. 6.80+/-0.59 nmol/mg protein). Similarly, high-fat feeding did not affect retinal GSH or cysteine levels in NMRI mice. No light microscopical retinal vessel changes were seen, either in C57BL/6J or in NMRI mice. The study therefore shows that long-standing metabolic perturbations induced by dietary obesity do not induce signs of retinopathy in two different strains of mice. Further studies are needed to explore whether this is explained by increased expression of protecting systems making these strains of mice resistant to effects of oxidative stress.
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| 14. |
- Agardh, Carl-David, et al.
(författare)
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Switching From High-Fat to Low-Fat Diet Normalizes Glucose Metabolism and Improves Glucose-Stimulated Insulin Secretion and Insulin Sensitivity But Not Body Weight in C57BL/6J Mice.
- 2012
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Ingår i: Pancreas. - 0885-3177. ; 41:2, s. 253-257
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Environmental factors such as a high-fat diet contribute to type 2 diabetes and obesity. This study examined glycemia, insulin sensitivity, and β-cell function after switching from a high-fat diet to a low-fat diet in mice. METHODS: C57BL/6J mice were fed a high-fat diet or low-fat diet for 18 months, after which mice on the high-fat diet either maintained this diet or switched to a low-fat diet for 4 weeks. Body weight and glucose and insulin responses to intraperitoneal glucose were determined. Insulin secretion (insulinogenic index: the 10-minute insulin response divided by the 10-minute glucose level) and insulin sensitivity (1 divided by basal insulin) were determined. RESULTS: After 18 months on a high-fat diet, mice had glucose intolerance, marked hyperinsulinemia, and increased body weight compared to mice on a low-fat diet (P < 0.001). Switching from a high-fat diet to low-fat diet normalized glucose tolerance, reduced but not normalized body weight (P < 0.001), increased insulin secretion (248 ± 39 vs 141 ± 46 pmol/mmol; P = 0.028) and improved but not normalized insulin sensitivity (3.2 ± 0.1 vs 1.0 ± 0.1 [pmol/L]; P = 0.012). CONCLUSION: Switching from a high-fat diet to low-fat diet normalizes glucose tolerance and improves but not normalizes insulin secretion and insulin sensitivity. These effects are more pronounced than the reduced body weight.
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| 15. |
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| 16. |
- Agardh, Carl-David, et al.
(författare)
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Varning för okritisk användning av överviktskirurgi vid typ 2-diabetes
- 2012
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Ingår i: Läkartidningen. - Stockholm : Läkartidningen förlag. - 0023-7205 .- 1652-7518. ; 109:25, s. 1208-1209
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Tidskriftsartikel (refereegranskat)abstract
- Överviktskirurgi diskuteras nu som ett behandlingsalternativ även för patienter med typ 2-diabetes där BMI inte överstiger nuvarande indikationsgräns 35 kg/m2. Artikelförfattarna vill varna för en sådan utveckling i avvaktan på kritisk värdering av denna typ av kirurgi.
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| 17. |
- Ahlkvist, Linda, et al.
(författare)
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Defective insulin secretion by chronic glucagon receptor activation in glucose intolerant mice.
- 2016
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Ingår i: Journal of Endocrinology. - 1479-6805. ; 228, s. 171-178
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Tidskriftsartikel (refereegranskat)abstract
- Stimulation of insulin secretion by short-term glucagon receptor (GCGR) activation is well characterized, however, the effect of long-term GCGR activation on beta-cell function is not known, but of interest, since hyperglucagonemia occurs early during development of type 2 diabetes. Therefore, we examined whether chronic GCGR activation affects insulin secretion in glucose intolerant mice. To induce chronic GCGR activation, high-fat diet fed mice were continuously (2wk) infused with the stable glucagon analogue ZP-GA-1 and challenged with oral glucose and intravenous glucose +/- GLP-1. Islets were isolated to evaluate the insulin secretory response to glucose +/- GLP-1 and pancreases were collected for immunohistochemical analysis. Two-week ZP-GA-1 infusion reduced insulin secretion both after oral and intravenous glucose challenges in vivo and in isolated islets. These inhibitory effects were corrected for by GLP-1. Also, we observed increased beta-cell area and islet size. We conclude that induction of chronic ZP-GA-1 levels in glucose intolerant mice markedly reduces insulin secretion, and thus, we suggest that chronic activation of the GCGR may contribute to the failure of beta-cell function during development of type 2 diabetes.
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| 18. |
- Ahlkvist, Linda, et al.
(författare)
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Evidence for neural contribution to islet effects of DPP-4 inhibition in mice
- 2016
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 780, s. 46-52
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Tidskriftsartikel (refereegranskat)abstract
- It has been suggested that neural mechanisms may contribute to effects of the incretin hormones, and, therefore, also to the effects of dipeptidyl peptidase (DPP-4) inhibition. We therefore examined whether muscarinic mechanisms are involved in the stimulation of insulin secretion by DPP-4 inhibition. Fasted, anesthetized mice were given intraperitoneal saline or the muscarinic antagonist atropine (5mg/kg) before duodenal glucose (75mg/mouse), with or without the DPP-4 inhibitor NVPDPP728 (0.095mg/mouse), or before intravenous glucose (0.35g/kg) with or without co-administration with GLP-1 or glucose-dependent insulinotropic polypeptide (GIP) (both 3nmol/kg). Furthermore, isolated islets were incubated (1h) in 2.8 and 11.1mM glucose, with or without GIP or GLP-1 (both 100nM), in the presence or absence of atropine (100µM). Duodenal glucose increased circulating insulin and this effect was potentiated by DPP-4 inhibition. The increase in insulin achieved by DPP-4 inhibition was reduced by atropine by approximately 35%. Duodenal glucose also elicited an increase in circulating intact GLP-1 and GIP and this was augmented by DPP-4 inhibition, but these effects were not affected by atropine. Atropine did also not affect the augmentation by GLP-1 and GIP on glucose-stimulated insulin secretion from isolated islets. Based on these findings, we suggest that muscarinic mechanisms contribute to the stimulation of insulin secretion by DPP-4 inhibition through neural effects induced by GLP-1 and GIP whereas neural effects do not affect the levels of GLP-1 or GIP or the islet effects of the two incretin hormones.
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| 19. |
- Ahlkvist, Linda, et al.
(författare)
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Synergism by individual macronutrients explains the marked early GLP-1 and islet hormone responses to mixed meal challenge in mice
- 2012
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Ingår i: Regulatory Peptides. - : Elsevier. - 0167-0115 .- 1873-1686. ; 178:1-3, s. 29-35
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Tidskriftsartikel (refereegranskat)abstract
- Apart from glucose, proteins and lipids also stimulate incretin and islet hormone secretion. However, the glucoregulatory effect of macronutrients in combination is poorly understood. We therefore developed an oral mixed meal model in mice to 1) explore the glucagon-like peptide-1 (GLP-1) and islet hormone responses to mixed meal versus isocaloric glucose, and 2) characterize the relative contribution of individual macronutrients to these responses. Anesthetized C57BL/6J female mice were orally gavaged with 1) a mixed meal (0.285 kcal; glucose, whey protein and peanut oil; 60/20/20% kcal) versus an isocaloric glucose load (0.285 kcal), and 2) a mixed meal (0.285 kcal) versus glucose, whey protein or peanut oil administered individually in their mixed meal caloric quantity, i.e., 0.171, 0.055 and 0.055 kcal, respectively. Plasma was analyzed for glucose, insulin and intact GLP-1 before and during oral challenges. Plasma glucose was lower after mixed meal versus after isocaloric glucose ingestion. In spite of this, the peak insulin response (P=0.02), the peak intact GLP-1 levels (P=0.006) and the estimated β-cell function (P=0.005) were higher. Furthermore, the peak insulin (P=0.004) and intact GLP-1 (P=0.006) levels were higher after mixed meal ingestion than the sum of responses to individual macronutrients. Compared to glucose alone, we conclude that there is a marked early insulin response to mixed meal ingestion, which emanates from a synergistic, rather than an additive, effect of the individual macronutrients in the mixed meal and is in part likely caused by increased levels of GLP-1.
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| 20. |
- Ahlkvist, Linda, et al.
(författare)
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Upregulated insulin secretion in insulin-resistant mice: evidence of increased islet GLP1 receptor levels and GPR119-activated GLP1 secretion.
- 2013
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Ingår i: Endocrine Connections. - 2049-3614. ; 2:2, s. 69-78
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Tidskriftsartikel (refereegranskat)abstract
- We previously demonstrated that the overall incretin effect and the β-cell responsiveness to glucagon-like peptide-1 (GLP1) are increased in insulin-resistant mice and may contribute to the upregulated β-cell function. Now we examined whether this could, first, be explained by increased islet GLP1 receptor (GLP1R) protein levels and, secondly, be leveraged by G-protein-coupled receptor 119 (GPR119) activation, which stimulates GLP1 secretion. Female C57BL/6J mice, fed a control (CD, 10% fat) or high-fat (HFD, 60% fat) diet for 8 weeks, were anesthetized and orally given a GPR119 receptor agonist (GSK706A; 10 mg/kg) or vehicle, followed after 10 min with gavage with a liquid mixed meal (0.285 kcal). Blood was sampled for determination of glucose, insulin, intact GLP1, and glucagon, and islets were isolated for studies on insulin and glucagon secretion and GLP1R protein levels. In HFD vs CD mice, GPR119 activation augmented the meal-induced increase in the release of both GLP1 (AUCGLP1 81±9.6 vs 37±6.9 pM×min, P=0.002) and insulin (AUCINS 253±29 vs 112±19 nM×min, P<0.001). GPR119 activation also significantly increased glucagon levels in both groups (P<0.01) with, however, no difference between the groups. By contrast, GPR119 activation did not affect islet hormone secretion from isolated islets. Glucose elimination after meal ingestion was significantly increased by GPR119 activation in HFD mice (0.57±0.04 vs 0.43±0.03% per min, P=0.014) but not in control mice. Islet GLP1R protein levels was higher in HFD vs CD mice (0.8±0.1 vs 0.5±0.1, P=0.035). In conclusion, insulin-resistant mice display increased islet GLP1R protein levels and augmented meal-induced GLP1 and insulin responses to GPR119 activation, which results in increased glucose elimination. We suggest that the increased islet GLP1R protein levels together with the increased GLP1 release may contribute to the upregulated β-cell function in insulin resistance.
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| 21. |
- Ahmadi, Shilan Seyed, et al.
(författare)
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Effect of liraglutide on anthropometric measurements, sagittal abdominal diameter and adiponectin levels in people with type 2 diabetes treated with multiple daily insulin injections: evaluations from a randomized trial (MDI-liraglutide study 5)
- 2019
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Ingår i: Obesity Science and Practice. - : Wiley. - 2055-2238. ; 5:2, s. 130-140
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Tidskriftsartikel (refereegranskat)abstract
- Aim Use of the glucagon-like peptide 1 receptor agonist liraglutide has been shown to reduce weight. Different types of anthropometric measurements can be used to measure adiposity. This study evaluated the effect of liraglutide on sagittal abdominal diameter, waist circumference, waist-to-hip ratio and adiponectin levels in people with type 2 diabetes (T2D) treated with multiple daily insulin injections (MDI). Materials and methods In the multicentre, double-blind, placebo-controlled MDI-liraglutide trial, 124 individuals with T2D treated with MDI were randomized to either liraglutide or placebo. Basal values of weight, waist circumference, waist-to-hip ratio, sagittal abdominal diameter and adiponectin were compared with measurements at 12 and 24 weeks after randomization. Results Baseline-adjusted mean weight loss was 3.8 +/- 2.9 kg greater in liraglutide than placebo-treated individuals (p < 0.0001). Waist circumference was reduced by 2.9 +/- 4.3 cm and 0.2 +/- 3.6 cm in the liraglutide and placebo groups, respectively, after 24 weeks (baseline-adjusted mean difference: 2.6 +/- 4.0 cm, p = 0.0005). Corresponding reductions in sagittal abdominal diameter were 1.1 +/- 1.7 cm and 0.0 +/- 1.8 cm (baseline-adjusted mean difference: 1.1 +/- 1.7 cm, p = 0.0008). Hip circumference was reduced in patients randomized to liraglutide (baseline-adjusted mean difference between treatment groups: 2.8 +/- 3.8 cm, p = 0.0001), but there was no significant difference between the groups in either waist-to-hip ratio (baseline-adjusted mean difference: 0.0 +/- 0.04 cm, p = 0.51) or adiponectin levels (baseline-adjusted mean difference: 0.8 +/- 3.3 mg L-1, p = 0.17). Lower HbA1c and mean glucose levels measured by masked continuous glucose monitoring at baseline were associated with greater effects of liraglutide on reductions in waist circumference and sagittal abdominal diameter. Conclusions In patients with T2D, adding liraglutide to MDI may reduce abdominal and hip obesity to a similar extent, suggesting an effect on both visceral and subcutaneous fat. Liraglutide had greater effects on reducing abdominal obesity in patients with less pronounced long-term hyperglycaemia but did not affect adiponectin levels.
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| 22. |
- Ahrén, Bo, et al.
(författare)
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A Novel Approach to Assess Insulin Sensitivity Reveals No Increased Insulin Sensitivity in Mice with a Dominant-Negative Mutant Hepatocyte Nuclear Factor-1{alpha}
- 2006
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Ingår i: American Journal of Physiology: Regulatory, Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 291:1, s. 131-137
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Tidskriftsartikel (refereegranskat)abstract
- In phenotype experiments in mice, determination of dynamic insulin sensitivity often uses the insulin tolerance test. However, the interpretation of this test is complicated by the counterregulation occurring at low glucose. To overcome this problem, we determined the dynamic insulin sensitivity after inhibition of endogenous insulin secretion by diazoxide (25 mg/kg) in association with intravenous administration of glucose plus insulin (the DSGIT technique). Estimation of insulin sensitivity index (SI) by this technique showed good correlation to SI from a regular intravenous glucose tolerance test (r = 0.87; P < 0.001; n = 15). With DSGIT, we evaluated dynamic insulin sensitivity in mice with a rat insulin promoter (beta-cell-targeted) dominant-negative mutation of hepatic nuclear factor (HNF)-1{alpha} [RIP-DN HNF-1{alpha} (Tg) mice]. When insulin was administered exogenously at the same dose in Tg and wild-type (WT) mice, plasma insulin levels were higher in WT, indicating an increased insulin clearance in Tg mice. When the diazoxide test was used, different doses of insulin were therefore administered (0.1 and 0.15 U/kg in WT and 0.2 and 0.25 U/kg in Tg) to achieve similar insulin levels in the groups. Minimal model analysis showed that SI was the same in the two groups (0.78 ± 0.21 x 10–4 min·pmol–1·l–1 in WT vs. 0.60 ± 0.11 in Tg; P = 0.45) as was the glucose elimination rate (P = 0.27). We conclude that 1) the DSGIT technique determines the in vivo dynamic insulin action in mice, 2) insulin clearance is increased in Tg mice, and 3) chronic islet dysfunction in RIP-DN HNF-1{alpha} mice is not compensated with increased insulin sensitivity.
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| 23. |
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| 24. |
- Ahrén, Bo, et al.
(författare)
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Albiglutide for the treatment of type 2 diabetes mellitus : An integrated safety analysis of the HARMONY phase 3 trials
- 2017
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Ingår i: Diabetes Research and Clinical Practice. - : Elsevier BV. - 0168-8227. ; 126, s. 230-239
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Tidskriftsartikel (refereegranskat)abstract
- Aims Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) stimulate the incretin system and lower glycaemic parameters in type 2 diabetes mellitus (T2DM). This analysis of clinical studies of up to 3 years evaluated the safety of albiglutide, a GLP-1 RA, in people with T2DM. Methods Integrated safety analysis included seven phase-3 T2DM studies of albiglutide compared with placebo and/or active comparators (a dipeptidyl peptidase-4 inhibitor, GLP-1 RA, insulin, sulphonylurea, and thiazolidinedione). Results Studies of 32 months (HARMONY 7), 1 year (HARMONY 6), and 3 years (HARMONY 1–5), reported similar rates of adverse events (AEs) (84.8%, 82.3%), and serious AEs (13.1%, 12.9%) between albiglutide and all comparators, respectively. AEs that did not differ between the groups included symptomatic or severe hypoglycaemia as well as nausea (12.0%, 11.3%) and vomiting (5.3%, 4.7%) for albiglutide and all comparators, respectively. According to the Medical Dictionary for Regulatory Activities preferred terms, only diarrhoea (13.7%, 9.9%), injection-site reaction (9.0%, 2.0%), and peripheral oedema (4.5%, 6.8%) had at least 2% difference between the albiglutide and all-comparator groups. In a similar integrated analysis, pancreatitis occurred more often with albiglutide (0.3%, 0.1%). Renal and cardiac function did not differ between the two groups. Conclusions In an integrated analysis of seven phase 3 clinical trials, albiglutide-treated patients experienced frequencies of AEs (including cardiovascular and renal) similar to the all-comparators group treated with other T2DM medications or placebo. Albiglutide treatment was associated with higher rates of diarrhoea and injection-site reactions, but not increased nausea and vomiting, versus all comparators.
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| 25. |
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| 26. |
- Ahrén, Bo
(författare)
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Are Sulfonylureas Less Desirable Than DPP-4 Inhibitors as Add-on to Metformin in the Treatment of Type 2 Diabetes?
- 2011
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Ingår i: Current Diabetes Reports. - : Springer Science and Business Media LLC. - 1539-0829 .- 1534-4827. ; 11, s. 83-90
-
Tidskriftsartikel (refereegranskat)abstract
- Sulfonylureas (SUs) are commonly used as add-on to metformin in treatment of type 2 diabetes in patients who are insufficiently controlled by metformin alone. They have good efficacy and have been shown to prevent microvascular complications. However, treatment with SUs is also associated with a high frequency of hypoglycemia, increased body weight, and a high risk of secondary failure. During recent years, dipeptidyl peptidase-4 (DPP-4) inhibitors have emerged as alternatives to SUs. They show similar efficacy as SUs but with lower risk of hypoglycemia, and reduction or no change in body weight, and if confirmed in humans, they may preserve islet function and thereby minimize the risk for secondary failure. Their limitation at present is the lack of long-term (>5 years) experience on durability and safety. Overall, therefore, the conclusion emerges that SUs are less desirable than DPP-4 inhibitors in management of hyperglycemia in type 2 diabetes.
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| 27. |
- Ahrén, Bo
(författare)
-
Avoiding hypoglycemia: a key to success for glucose-lowering therapy in type 2 diabetes.
- 2013
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Ingår i: Vascular Health and Risk Management. - 1178-2048. ; 9, s. 155-163
-
Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes carries a risk for hypoglycemia, particularly in patients on an intensive glucose control plan as a glucose-lowering strategy, where hypoglycemia may be a limitation for the therapy and also a factor underlying clinical inertia. Glucose-lowering medications that increase circulating insulin in a glucose-independent manner, such as insulin and sulfonylurea therapy, are the most common cause of hypoglycemia. However, other factors such as a delayed or missed meal, physical exercise, or drug or alcohol consumption may also contribute. Specific risk factors for development of hypoglycemia are old age, long duration of diabetes, some concomitant medication, renal dysfunction, hypoglycemia unawareness, and cognitive dysfunction. Hypoglycemia is associated with acute short-term symptoms related to either counterregulation, such as tachycardia and sweating, or to neuroglycopenia, such as irritability, confusion, and in severe cases stupor, coma, and even death. However, there are also long-term consequences of hypoglycemia such as reduced working capacity, weight gain, loss of self-confidence with reduced quality of life, and increased risk for cardiovascular diseases. For both the patients, the health care system, and the society at large, hypoglycemia carries a high cost. Strategies to mitigate the risk of hypoglycemia include awareness of the condition; education of patients, relatives, and health care providers; and selecting appropriate glucose-lowering medication that also judges the risk for hypoglycemia to prevent this complication. This article summarizes the current knowledge of hypoglycemia and its consequences with a special emphasis on its consequences for the choice of glucose-lowering therapy.
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| 28. |
- Ahrén, Bo
(författare)
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beta- and alpha-Cell Dysfunction in Subjects Developing Impaired Glucose Tolerance Outcome of a 12-Year Prospective Study in Postmenopausal Caucasian Women
- 2009
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 58:3, s. 726-731
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-This study assessed insulin and glucagon secretion in relation to insulin sensitivity in Caucasian women who develop impaired glucose tolerance (IGT) versus those who maintain normal glucose tolerance (NGT) over a 12-year period. RESEARCH DESIGN AND METHODS-At baseline and after 3, 8, and 12 years, glucose tolerance (75-g oral glucose tolerance test), insulin sensitivity (euglycemic-hyperinsulinemic clamp), and insulin and glucagon secretion (2- to 5-min responses to 5 g arginine i.v. at fasting, 14 and >25 mmol/l glucose) were determined in 53 healthy Caucasian women (aged 58 years at. baseline) who all had NGT at baseline. RESULTS-During the 12-year period, 26 subjects developed IGT, whereas the remaining 27 subjects maintained NGT throughout the 12-year period. Subjects developing IGT had lower insulin sensitivity than those maintaining NGT in the tests preceding diagnosis of IGT (P <= 0.05). When judged in relation to insulin sensitivity, P-cell glucose sensitivity and maximal insulin secretion were lower in those who later developed IGT than in those maintaining NGT at all tests (P : 0.05). Furthermore, subject's who developed IGT had defective suppression of glucagon secretion by glucose in the test preceding diagnosis of IGT when they still had NGT (P : 0.05). CONCLUSIONS-beta- and alpha-cell dysfunction are evident several years before diagnosis of IGT, and islet dysfunction is manifeste as impaired glucose sensitivity of the beta- and (x-cells and reduced maximal insulin secretion. Diabetes 58:726-731, 2009
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| 29. |
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| 30. |
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| 31. |
- Ahrén, Bo, et al.
(författare)
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Changes in Prandial Glucagon Levels after 2-year Treatment with Vildagliptin or Glimepiride in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Metformin Monotherapy.
- 2010
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 33:4, s. 730-732
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Tidskriftsartikel (refereegranskat)abstract
- Objective - To determine if the dipeptidyl peptidase 4 inhibitor vildagliptin more effectively than the sulfonylurea glimepiride inhibits glucagon levels during meal. Research design and methods - Glucagon responses to a standard meal were measured at baseline and study endpoint (mean 1.8 years) in a trial evaluating add-on therapy to metformin with vildagliptin 50 mg bid compared to glimepiride up to 6 mg qd in type 2 diabetes (baseline HbA1c 7.3+/-0.6%). Results - HbA(1c) and prandial glucose AUC(0-2h) were reduced similarly in both groups, while prandial insulin AUC(0-2h) increased to a greater extent by glimepiride. Prandial glucagon AUC(0-2h) (baseline 66.6+/-2.3 pmol.h/l) decreased by 3.4+/-1.6 pmol.h/l by vildagliptin group (n=137) and increased by 3.8+/-1.7 pmolh/l by glimepiride group (n=121). The between-group difference was 7.3+/-2.1 pmol.h/l (p<0.001). Conclusion - Vildagliptin therapy but not glimepiride improves post-prandial alpha-cell function, which persists for at least 2 years.
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| 32. |
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| 33. |
- 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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| 34. |
- Ahrén, Bo, et al.
(författare)
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Clinical evidence and mechanistic basis for vildagliptin's action when added to metformin.
- 2011
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902. ; 13:3, s. 193-203
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Tidskriftsartikel (refereegranskat)abstract
- Several new oral antidiabetic agents, known as 'gliptins' or 'enzyme dipeptidyl peptidase-IV (DPP-4) inhibitors', have been developed for the treatment of type 2 diabetes and a key clinical use of the gliptins is in combination with metformin. There are important differences in the kinetics of the interaction of different gliptins with the catalytic site of DPP-4, which may lead to varying pharmacokinetics, pharmacodynamics and dosing regimens. Therefore, individual gliptins need to be characterized and here we discuss the extensively studied DPP-4 inhibitor vildagliptin, which has binding characteristics that ensure inhibition of the enzyme beyond the presence of detectable drug levels in plasma. As vildagliptin has been used most often at doses of 50 mg once or twice daily, in combination with metformin, this review focuses on these dose regimens. All clinical trials employing vildagliptin (50 mg once or twice daily) as an add-on therapy to metformin (identified by MEDLINE search using keywords vildagliptin and metformin or known by authors to be in press) are reviewed, as is current knowledge of the mechanism of action of vildagliptin. Vildagliptin added to a stable dose of metformin elicits a dose-related decrease in both HbA1c and fasting plasma glucose. The additional efficacy seen with 50 mg twice daily [ΔHbA1c ∼- 1.1% (-12.1 mmol/mol)] relative to 50 mg once daily [ΔHbA1c ∼- 0.7% (-7.7 mmol/mol)] is attributable to an overnight effect of the evening dose of vildagliptin, with prolonged DPP-4 inhibition and elevated fasting levels of the intact and insulinotropic form of glucagon-like peptide-1 (GLP-1). Vildagliptin's therapeutic actions are primarily mediated by GLP-1 and metformin enhances vildagliptin's effect to raise plasma levels of intact GLP-1. Vildagliptin is weight-neutral and has a very low hypoglycaemic potential, explained by its remarkable ability to enhance both α-cell and β-cell sensitivity to glucose. Therefore, vildagliptin offers a clinically important outcome when added to metformin with a twice daily dose regimen, taking advantage of its tight binding and slow dissociation characteristics that lead to a sustained overnight effect.
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| 35. |
- Ahrén, Bo, et al.
(författare)
-
Clinical measures of islet function: usefulness to characterize defects in diabetes.
- 2008
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Ingår i: Current Diabetes Reviews. - 1573-3998. ; 4:2, s. 129-145
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Tidskriftsartikel (refereegranskat)abstract
- In healthy individuals, the ability of the pancreatic islets to sense and respond appropriately to changes in plasma glucose levels maintains plasma glucose levels within a narrow range despite broad fluctuations in nutrient intake and variable "demand" for insulin imposed by changes in insulin sensitivity. This ability of the pancreatic islets is lost in type 2 diabetes (T2DM). For studies on the pathophysiology of T2DM, methods for analyzing islet function are therefore required. Many methods of varying degrees of complexity have been developed and used to measure pancreatic beta-cell function in humans and to characterize the defects existing in patients with T2DM or precursors thereof (impaired fasting glucose [IFG] and impaired glucose tolerance [IGT]). Significant, although perhaps less progress has been made toward development of methods to characterize alpha-cell function. This work presents an overview of clinical measures of islet function, from simple static measures such as HOMA-beta to the more complex dynamic measures such as those utilizing stepped hyperglycemic clamps and acute administration of arginine to obtain more detailed information regarding the interaction of glucose and non-glucose secretagogues. We emphazise the need for accurate measures of alpha-cell function, and we discuss the strengths and limitations of the various methods, highlighting the many aspects of both alpha- and beta-cell function that become impaired during development of T2DM.
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| 36. |
- Ahrén, Bo
(författare)
-
Clinical results of treating type 2 diabetic patients with sitagliptin, vildagliptin or saxagliptin - diabetes control and potential adverse events
- 2009
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Ingår i: Best Practice and Research in Clinical Endocrinology and Metabolism. - : Elsevier BV. - 1521-690X. ; 23:4, s. 487-498
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Tidskriftsartikel (refereegranskat)abstract
- Inhibition of dipeptidyl peptidase-4 (DPP-4) is a novel oral treatment for type 2 diabetes. DPP-4 inhibition increases insulin secretion and reduces glucagon secretion by preventing the inactivation of glucagon-like peptide-1 (GLP-1), thereby lowering glucose levels. Several DPP-4 inhibitors are in clinical development; more studies exist for sitagliptin and vildagliptin. They improve metabolic control in type 2 diabetes in monotherapy and also in combination with metformin, sulphonylurea and thiazolidinediones. HbA(1c) is reduced by approximately 0.6-1.1% in studies up to 52 weeks. Similar, although more limited, results were obtained for saxagliptin. DPP-4 inhibitors are safe and tolerable with no increased risk of adverse events compared to placebo and have a low risk of hypoglycaemia. DPP-4 inhibitors are body weight-neutral. The DPP-4 inhibitors are recommended for use in the early stage of type 2 diabetes, in combination with metformin in subjects with inadequate glycaemic control. DPP-4 inhibition may also be used in combination with sulphonylurea and thiazolidinediones and potentially also in combination with insulin. The durability and long-term safety of DPP-4 inhibitors remain to be established.
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| 37. |
- Ahrén, Bo
(författare)
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Contribution of GIP and GLP-1 to the Insulin Response to Oral Administration of Glucose in Female Mice
- 2023
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Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 11:2
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Tidskriftsartikel (refereegranskat)abstract
- It has previously been shown that the incretin effect accounts for ≈50% of the insulin response to oral glucose in normal mice. Now, I have proceeded and studied the contribution of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) to the insulin response to oral glucose in female mice by using receptor antagonists. A specific GIP receptor antagonist (mGIP(3-30); 50 or 500 nmol/kg), a specific GLP-1 receptor antagonist (exendin(9-39); 3 or 30 nmol/kg), the combination of mGIP (500 nmol/kg) and exendin(9-39) (30 nmol/kg), or saline was given intravenously four minutes after administration of glucose (50 mg) through a gastric tube in anesthetized C57/BL6J mice (n = 95) with samples obtained before glucose administration and after 15, 30 and 60 min. The insulinogenic index, determined as the area under the 60 min curve for insulin (AUCinsulin) divided by the AUCglucose, was used to reflect the insulin response. It was found that the insulinogenic index was reduced by 67 ± 4% by mGIP(3-30) (p < 0.001), by 60 ± 14% by exendin(9-39) (p = 0.007) and by 61 ± 14% by the combination of mGIP(3-30) and exendin(9-39) (p = 0.043), both at their highest doses, compared to animals injected with glucose in the same experimental series. It is concluded that both GIP and GLP-1 are required for a normal incretin effect in female mice, that they contribute similarly to the insulin response, and that it is unlikely that there is another incretin hormone in this species.
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| 38. |
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| 39. |
- Ahrén, Bo
(författare)
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Creative use of novel glucose-lowering drugs for type 2 diabetes: where will we head in the next 50 years?
- 2015
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 58:8, s. 1740-1744
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Tidskriftsartikel (refereegranskat)abstract
- Research conducted over the last 50 years has produced discoveries on the importance of glucose control for reducing the risk of diabetic complications, the pathophysiology of type 2 diabetes, the development and validation of mechanistic glucose-lowering targets, and the preclinical and clinical development of individual drugs. This science established the different drug classes that are clinically used today in association with lifestyle changes for lowering glucose in type 2 diabetes. For the next 50 years, we can anticipate that science will explore (1) the use of current drugs and, as they become available, newly developed drugs in early (initial) oral combinations followed by intensification with injectable combinations when glycaemia deteriorates, (2) the validation of novel mechanistic biochemical and physiological targets, including indirect effects of future antiobesity drugs, and (3) the development of true disease-modifying strategies based on knowledge of islet cell biology and replacement. This is one of a series of commentaries under the banner '50 years forward', giving personal opinions on future perspectives in diabetes, to celebrate the 50th anniversary of Diabetologia (1965-2015).
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| 40. |
- Ahrén, Bo, et al.
(författare)
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Differential impairment of glucagon responses to hypoglycemia, neuroglycopenia, arginine, and carbachol in alloxan-diabetic mice.
- 2002
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Ingår i: Metabolism, Clinical and Experimental. - : Elsevier BV. - 1532-8600. ; 51:1, s. 12-19
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Tidskriftsartikel (refereegranskat)abstract
- To gain insight into the mechanisms responsible for the loss of the glucagon response to insulin-induced hypoglycemia in type 1 diabetes, glucagon responses to 4 different stimuli were examined over 3 months of diabetes in alloxan-treated mice. At 1, 6, and 12 weeks after alloxan (60 mg/kg), phloridzin (0.1 g/kg) was administered to overnight fasted diabetic mice to match the glucose levels of those in nondiabetic control mice before administration of the acute stimuli. Despite the elevation of baseline glucagon levels produced by the phloridzin treatment, the glucagon responses to insulin (2 U/kg intraperitoneally [IP])-induced hypoglycemia was not impaired at 1 week. However, the response was reduced by greater than 60% after 6 and 12 weeks of diabetes (P <.05). In contrast, the glucagon response to arginine (0.25 g/kg intravenously [IV]) was not reduced after 1, 6, or 12 weeks of diabetes, ruling out a generalized impairment of the A-cell responses. The glucagon response to the neuroglucopenic agent, 2-deoxyglucose (2-DG; 500 mg/kg IV) was impaired, like that to insulin-induced hypoglycemia, after 6 and 12 weeks of diabetes (P <.05), suggesting that supersensitivity to the potential inhibitory effects of exogenous insulin is not the mechanism responsible for the impairment. Finally, the glucagon response to the cholinergic agonist, carbachol (0.53 micromol/kg IV), was not impaired in the diabetic animals, arguing against a defect in the A-cell's responsiveness to autonomic stimulation. The data suggest that the impairment of the glucagon response to insulin-induced hypoglycemia in alloxan diabetic mice is not due to a generalized impairment of A-cell responsiveness, to desensitization by a suppressive action of insulin, or to impairment of the A-cell response to autonomic stimuli. The remaining mechanisms which are likely to explain the late loss of the glucagon response to insulin-induced hypoglycemia include (1) a defect in the A-cell recognition of glucopenic stimuli, or (2) a defect in the autonomic inputs to the A cell that are known to be activated by glucopenic stimuli.
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| 41. |
- Ahrén, Bo, et al.
(författare)
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Disturbed alpha-cell function in mice with beta-cell specific overexpression of human islet amyloid polypeptide.
- 2008
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Ingår i: Experimental Diabetes Research. - : Hindawi Limited. - 1687-5214 .- 1687-5303. ; 2008
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Tidskriftsartikel (refereegranskat)abstract
- Exogenous administration of islet amyloid polypeptide (IAPP) has been shown to inhibit both insulin and glucagon secretion. This study examined alpha-cell function in mice with beta-cell specific overexpression of human IAPP (hIAPP) after an oral protein gavage (75 mg whey protein/mouse). Baseline glucagon levels were higher in transgenic mice (41 +/- 4.0 pg/mL, n = 6) than in wildtype animals (19 +/- 5.1 pg/mL, n = 5, P = .015). In contrast, the glucagon response to protein was impaired in transgenic animals (21 +/- 2.7 pg/mL in transgenic mice versus 38 +/- 5.7 pg/mL in wildtype mice at 15 minutes; P = .027). Baseline insulin levels did not differ between the groups, while the insulin response, as the glucagon response, was impaired after protein challenge (P = .018). Glucose levels were not different between the groups and did not change significantly after protein gavage. Acetaminophen was given through gavage to the animals (2 mg/mouse) to estimate gastric emptying. The plasma acetaminophen profile was similar in the two groups of mice. We conclude that disturbances in glucagon secretion exist in mice with beta-cell specific overexpression of human IAPP, which are not secondary to changes in gastric emptying. The reduced glucagon response to protein challenge may reflect a direct inhibitory influence of hIAPP on glucagon secretion.
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| 42. |
- Ahrén, Bo
(författare)
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DPP-4 inhibition and islet function
- 2012
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Ingår i: Journal of Diabetes Investigation. - : Wiley. - 2040-1116. ; 3:1, s. 3-10
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Forskningsöversikt (refereegranskat)abstract
- During recent years, dipeptidyl peptidase-4 (DPP-4) inhibition has been included in the clinical management of type 2 diabetes, both as monotherapy and as add-on to several other therapies. DPP-4 inhibition prevents the inactivation of the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). This results in stimulation of insulin secretion and inhibition of glucagon secretion, and there is also a potential beta-cell preservation effect, as judged from rodent studies; that is, it might target the key islet dysfunction in the disease. In type 2 diabetes. This reduces 24-h glucose levels and reduces HbA1c by approximate to 0.81.1% from baseline levels of 7.78.5%. DPP-4 inhibition is safe, with a very low risk for adverse events including hypoglycemia, and it prevents weight gain. The present review summarizes the studies on the influence of DPP-4 inhibition on islet function. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00184.x, 2012)
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| 43. |
- Ahrén, Bo
(författare)
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DPP-4 inhibition and the path to clinical proof
- 2019
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Ingår i: Frontiers in Endocrinology. - : Frontiers Media SA. - 1664-2392. ; 10:JUN
-
Tidskriftsartikel (refereegranskat)abstract
- In the 1990s it was discovered that the enzyme dipeptidyl peptidase-4 (DPP-4) inactivates the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). DPP-4 inhibition results in raised levels of the two incretin hormones which in turn result in lowering of circulating glucose through stimulation of insulin secretion and inhibition of glucagon secretion. Since then, several small orally available molecules have been developed with DPP-4 inhibitory action. Early studies in the 1990s showed that the DPP-4 inhibitors improve glycemia in animals. Subsequent clinical studies during the 2000s showed a glucose-lowering action of DPP-4 inhibitors also in human subjects with type 2 diabetes. This action was seen when DPP-4 inhibitors were used both as monotherapy and as add-on to other therapies, i.e., metformin, sulfonylureas, tiazolidinediones or exogenous insulin. The DPP-4 inhibitors were also found to have a low risk of adverse events, including hypoglycemia. Five of the DPP-4 inhibitors (sitagliptin, vildagliptin, alogliptin, saxagliptin and linagliptin) were approved by regulatory authorities and entered the market between 2006 and 2013. DPP-4 inhibitors have thereafter undergone long-term cardiovascular outcome trials, showing non-inferiority for risk of major acute cardiovascular endpoints. Also the risk of other potential adverse events is low in these long-term studies. DPP-4 inhibitors are at present included in guidelines as a glucose-lowering concept both as monotherapy and in combination therapies. This article summarizes the development of the DPP-4 inhibition concept from its early stages in the 1990s. The article underscores that the development has its basis in scientific studies on pathophysiology of type 2 diabetes and the importance of targeting the islet dysfunction, that the development has been made possible through academic science in collaboration with the research-oriented pharmaceutical industry, and that the development of a novel concept takes time and requires focused efforts, persistence and long-term perserverance.
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| 44. |
- Ahrén, Bo, et al.
(författare)
-
DPP-4 inhibition improves glucose tolerance and increases insulin and GLP-1 responses to gastric glucose in association with normalized islet topography in mice with beta-cell-specific overexpression of human islet amyloid polypeptide.
- 2007
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Ingår i: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 143:1-3, s. 97-103
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Tidskriftsartikel (refereegranskat)abstract
- Inhibition of dipeptidyl peptidase-4 (DPP-4) is currently explored as a novel therapy of type 2 diabetes. The strategy has been shown to improve glycemia in most, but not all, rodent forms of glucose intolerance. In this study, we explored the effects of DPP-4 inhibition in mice with [beta-cell overexpression of human islet amyloid polypeptide (IAPP). We therefore administered the orally active and highly selective DPP-4 inhibitor, vildagliptin (3 pmol/mouse daily) to female mice with [beta-cell overexpression of human IAPP. Controls were given plain water, and a series of untreated wildtype mice was also included. After five weeks, an intravenous glucose tolerance test showed improved glucose disposal and a markedly enhanced insulin response in mice treated with vildagliptin. After eight weeks, a gastric tolerance test showed that vildagliptin improved glucose tolerance and markedly (approximately ten-fold) augmented the insulin response in association with augmented (approximately five-fold) levels of intact glucagon-like peptide-1 (GLP-1). Furthermore, after nine weeks, islets were isolated. Islets from vildagliptin-treated mice showed augmented glucose-stimulated insulin response and a normalization of the islet insulin content, which was reduced by approximately 50% in transgenic controls versus wildtype animals. Double immunostaining of pancreatic islets for insulin and glucagon revealed that transgenic islets displayed severely disturbed intra-islet topography with frequently observed centrally located a-cells. Treatment with vildagliptin restored the islet topography. We therefore conclude that DPP-4 inhibition improves islet function and islet topography in mice with [beta-cell specific transgenic overexpression of human IAPP. (c) 2007 Elsevier B.V. All rights reserved.
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| 45. |
- Ahrén, Bo
(författare)
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DPP-4 inhibitors.
- 2007
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Ingår i: Baillière's Best Practice & Research in Clinical Endocrinology & Metabolism. - : Elsevier BV. - 1521-690X. ; 21:4, s. 517-533
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Tidskriftsartikel (refereegranskat)abstract
- Inhibition of dipeptidyl peptidase 4 (DPP-4) is a novel treatment for type-2 diabetes. DPP-4 inhibition prevents the inactivation of glucagon-like peptide 1 (GLP-1), which increases levels of active GLP-1. This increases insulin secretion and reduces glucagon secretion, thereby lowering glucose levels. Several DPP-4 inhibitors are in clinical development. Most experience so far has been with sitagliptin (Merck; approved by the FDA) and vildagliptin (Novartis; filed). These are orally active compounds with a long duration, allowing once-daily administration. Both sitagliptin and vildagliptin improve metabolic control in type-2 diabetes, both in monotherapy and in combination with metformin and thiazolidinediones. A reduction in HbA(1c) of approximately 1% is seen in studies of DPP-4 inhibition of up to 52 weeks' duration. DPP-4 inhibition is safe and well tolerated, the risk of hypoglycaemia is minimal, and DPP-4 inhibition is body-weight neutral. DPP-4 inhibition is suggested to be a first-line treatment of type-2 diabetes, particularly in its early stages in combination with metformin. However, the durability and long-term safety of DPP-4 inhibition remain to be established.
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| 46. |
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| 47. |
- Ahrén, Bo, et al.
(författare)
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Effects of conjugated linoleic acid plus n-3 polyunsaturated fatty acids on insulin secretion and estimated insulin sensitivity in men.
- 2009
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Ingår i: European Journal of Clinical Nutrition. - : Springer Science and Business Media LLC. - 1476-5640 .- 0954-3007. ; Sep 3, s. 778-786
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Tidskriftsartikel (refereegranskat)abstract
- Background/Objectives:Dietary addition of either conjugated linoleic acid (CLA) or n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs) has been shown to alter adiposity and circulating lipids, risk markers of cardiovascular diseases. However, CLA may decrease insulin sensitivity, an effect that may be reversed by n-3 LC-PUFA. Thus, the potential of CLA plus n-3 LC-PUFA to affect insulin secretion and sensitivity in non-diabetic young and old, lean and obese subjects was tested.Subjects/Methods:CLA (3 g daily) plus n-3 LC-PUFA (3 g daily) or control oil (6 g daily) was given to lean (n=12; BMI 20-26 kg/m(2)) or obese (n=10; BMI 29-35 kg/m(2)) young (20-37 years old) or lean (n=16) or obese (n=11) older men (50-65 years) for 12 weeks. The study had a double-blind, placebo-controlled randomized crossover design, and primary end points were insulin secretion and sensitivity during a standardized meal test, evaluated by modeling glucose, insulin and C-peptide data.Results:The combination was well tolerated. There was no significant difference in fasting levels of glucose, insulin or C-peptide after CLA/n-3 LC-PUFA treatment compared with control oil. Neither insulin secretion nor estimated sensitivity was affected by CLA/n-3 LC-PUFA in lean or obese young subjects or in older lean subjects. However, in older obese subjects, estimated insulin sensitivity was reduced with CLA/n-3 LC-PUFA compared with control (P=0.024).Conclusions:The results do not support beneficial effects of CLA/n-3 LC-PUFA for beta-cell dysfunction or insulin resistance in humans but suggest that insulin sensitivity in older obese subjects is reduced.European Journal of Clinical Nutrition advance online publication, 3 September 2008; doi:10.1038/ejcn.2008.45.
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| 48. |
- Ahren, Bo, et al.
(författare)
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Efficacy and safety of liraglutide added to capped insulin treatment in subjects with type 1 diabetes : The adjunct two randomized trial
- 2016
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 39:10, s. 1693-1701
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE To investigate the efficacy and safety of liraglutide added to capped insulin doses in subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS A 26-week, placebo-controlled, double-blind, parallel-group trial enrolling 835 subjects randomized 3:1 receiving once-daily subcutaneous liraglutide (1.8, 1.2, and 0.6 mg) or placebo added to an individually capped total daily dose of insulin. RESULTS Mean baseline glycated hemoglobin (HbA1c ) (8.1% [65.0 mmol/mol]) was significantly decreased with liraglutide versus placebo at week 26 (1.8 mg: -0.33% [3.6mmol/mol]; 1.2mg: -0.22% [2.4mmol/mol]; 0.6 mg: -0.23% [2.5mmol/mol]; placebo: 0.01% [0.1 mmol/mol]). Liraglutide significantly reduced mean body weight (-5.1, -4.0, and -2.5 kg for 1.8, 1.2, and 0.6 mg, respectively) versus placebo (-0.2 kg). Significant reductions in daily insulin dose and increases in quality of life were seen with liraglutide versus placebo. There were higher rates of symptomatic hypoglycemia (21.3 vs. 16.6 events/patient/year; P = 0.03) with liraglutide 1.2mg vs. placebo and of hyperglycemia with ketosis >1.5mmol/L with liraglutide 1.8 mg vs. placebo (0.5 vs. 0.1 events/patient/year; P = 0.01). CONCLUSIONS In a broad population of subjects with long-standing type 1 diabetes, liraglutide added to capped insulin reduced HbA1c, body weight, and insulin requirements but with higher rates of hypoglycemia for liraglutide 1.2 mg and hyperglycemia with ketosis for liraglutide 1.8 mg.
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| 49. |
- Ahrén, Bo, et al.
(författare)
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Efficacy and Safety of Lixisenatide Once-Daily Morning or Evening Injections in Type 2 Diabetes Inadequately Controlled on Metformin (GetGoal-M).
- 2013
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 36:9, s. 2543-2550
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVEExamine the efficacy and safety of lixisenatide (20 μg once daily, administered before the morning or evening meal) as add-on therapy in type 2 diabetes patients insufficiently controlled with metformin alone.RESEARCH DESIGN AND METHODSA 24-week, randomized, double-blind, placebo-controlled study in 680 patients with inadequately controlled type 2 diabetes (HbA1c 7-10% [53-86 mmol/mol]). Patients were randomized to lixisenatide morning (n = 255), lixisenatide evening (n = 255), placebo morning (n = 85), or placebo evening (n = 85) injections.RESULTSLixisenatide morning injection significantly reduced mean HbA1c versus combined placebo (mean change -0.9% [9.8 mmol/mol] vs. -0.4% [4.4 mmol/mol]; least squares [LS] mean difference vs. placebo -0.5% [5.5 mmol/mol], P < 0.0001). HbA1c was significantly reduced by lixisenatide evening injection (mean change -0.8% [8.7 mmol/mol] vs. -0.4% [4.4 mmol/mol]; LS mean difference -0.4% [4.4 mmol/mol], P < 0.0001). Lixisenatide morning injection significantly reduced 2-h postprandial glucose versus morning placebo (mean change -5.9 vs. -1.4 mmol/L; LS mean difference -4.5 mmol/L, P < 0.0001). LS mean difference in fasting plasma glucose was significant in both morning (-0.9 mmol/L, P < 0.0001) and evening (-0.6 mmol/L, P = 0.0046) groups versus placebo. Mean body weight decreased to a similar extent in all groups. Rates of adverse events were 69.4% in both lixisenatide groups and 60.0% in the placebo group. Rates for nausea and vomiting were 22.7 and 9.4% for lixisenatide morning and 21.2 and 13.3% for lixisenatide evening versus 7.6 and 2.9% for placebo, respectively. Symptomatic hypoglycemia occurred in 6, 13, and 1 patient for lixisenatide morning, evening, and placebo, respectively, with no severe episodes.CONCLUSIONSIn patients with type 2 diabetes inadequately controlled on metformin, lixisenatide 20 μg once daily administered in the morning or evening significantly improved glycemic control, with a pronounced postprandial effect, and was well tolerated.
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| 50. |
- Ahrén, Bo, et al.
(författare)
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Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2) : a 56-week, double-blind, phase 3a, randomised trial
- 2017
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Ingår i: The Lancet Diabetes and Endocrinology. - 2213-8587. ; 5:5, s. 341-354
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Tidskriftsartikel (refereegranskat)abstract
- Background Semaglutide is a novel glucagon-like peptide-1 (GLP-1) analogue, suitable for once-weekly subcutaneous administration, in development for treatment of type 2 diabetes. We assessed the efficacy and safety of semaglutide versus the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin in patients with type 2 diabetes inadequately controlled on metformin, thiazolidinediones, or both. Methods We did a 56-week, phase 3a, randomised, double-blind, double-dummy, active-controlled, parallel-group, multinational, multicentre trial (SUSTAIN 2) at 128 sites in 18 countries. Eligible patients were aged at least 18 years (or at least 20 years in Japan) and diagnosed with type 2 diabetes, with insufficient glycaemic control (HbA1c 7·0–10·5% [53·0–91·0 mmol/mol]) despite stable treatment with metformin, thiazolidinediones, or both. We randomly assigned participants (2:2:1:1) using an interactive voice or web response system to 56 weeks of treatment with subcutaneous semaglutide 0·5 mg once weekly plus oral sitagliptin placebo once daily, subcutaneous semaglutide 1·0 mg once weekly plus oral sitagliptin placebo once daily, oral sitagliptin 100 mg once daily plus subcutaneous semaglutide placebo 0·5 mg once weekly, or oral sitagliptin 100 mg once daily plus subcutaneous semaglutide placebo 1·0 mg once weekly. The two oral sitagliptin 100 mg groups (with semaglutide placebo 0·5 mg and 1·0 mg) were pooled for the analyses. The primary endpoint was change in HbA1c from baseline to week 56, assessed in the modified intention-to-treat population (all randomly assigned participants who received at least one dose of study drug); change in bodyweight from baseline to week 56 was the confirmatory secondary endpoint. Safety endpoints included adverse events and hypoglycaemic episodes. This trial is registered with ClinicalTrials.gov, number NCT01930188. Findings Between Dec 2, 2013, and Aug 5, 2015, we randomly assigned 1231 participants; of the 1225 included in the modified intention-to-treat analysis, 409 received semaglutide 0·5 mg, 409 received semaglutide 1·0 mg, and 407 received sitagliptin 100 mg. Mean baseline HbA1c was 8·1% (SD 0·93); at week 56, HbA1c was reduced by 1·3% in the semaglutide 0·5 mg group, 1·6% in the semaglutide 1·0 mg group, and 0·5% with sitagliptin (estimated treatment difference vs sitagliptin −0·77% [95% CI −0·92 to −0·62] with semaglutide 0·5 mg and −1·06% [–1·21 to −0·91] with semaglutide 1·0 mg; p<0·0001 for non-inferiority and for superiority, for both semaglutide doses vs sitagliptin). Mean baseline bodyweight was 89·5 kg (SD 20·3); at week 56, bodyweight reduced by 4·3 kg with semaglutide 0·5 mg, 6·1 kg with semaglutide 1·0 mg, and 1·9 kg with sitagliptin (estimated treatment difference vs sitagliptin −2·35 kg [95% CI −3·06 to −1·63] with semaglutide 0·5 mg and −4·20 kg [–4·91 to −3·49] with semaglutide 1·0 mg; p<0·0001 for superiority, for both semaglutide doses vs sitagliptin). The proportion of patients who discontinued treatment because of adverse events was 33 (8%) for semaglutide 0·5 mg, 39 (10%) for semaglutide 1·0 mg, and 12 (3%) for sitagliptin. The most frequently reported adverse events in both semaglutide groups were gastrointestinal in nature: nausea was reported in 73 (18%) who received semaglutide 0·5 mg, 72 (18%) who received semaglutide 1·0 mg, and 30 (7%) who received placebo, and diarrhoea was reported in 54 (13%) who received semaglutide 0·5 mg, 53 (13%) who received semaglutide 1·0 mg, and 29 (7%) who received placebo. Seven (2%) patients in the semaglutide 0·5 mg group, two (<1%) in the semaglutide 1·0 mg group, and five (1%) in the sitagliptin group had blood-glucose confirmed hypoglycaemia. There were six fatal events (two in the semaglutide 0·5 mg group, one in the semaglutide 1·0 mg group, and three in the sitagliptin group); none were considered likely to be related to the trial drugs. Interpretation Once-weekly semaglutide was superior to sitagliptin at improving glycaemic control and reducing bodyweight in participants with type 2 diabetes on metformin, thiazolidinediones, or both, and had a similar safety profile to that of other GLP-1 receptor agonists. Semaglutide seems to be an effective add-on treatment option for this patient population. Funding Novo Nordisk A/S.
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