| 1. |
- 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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| 2. |
- 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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| 3. |
- 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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| 4. |
- 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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| 5. |
- 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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| 6. |
- 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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| 7. |
- 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
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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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| 8. |
- 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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| 9. |
- 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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| 10. |
- Ahrén, Bo, et al.
(författare)
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Estimation of the Relative Contribution of Postprandial Glucose Exposure to Average Total Glucose Exposure in Subjects with Type 2 Diabetes
- 2016
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Ingår i: International Journal of Endocrinology. - : Hindawi Limited. - 1687-8337 .- 1687-8345. ; 2016
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Tidskriftsartikel (refereegranskat)abstract
- We hypothesized that the relative contribution of fasting plasma glucose (FPG) versus postprandial plasma glucose (PPG) to glycated haemoglobin (HbA1c) could be calculated using an algorithm developed by the A1c-Derived Average Glucose (ADAG) study group to make HbA1c values more clinically relevant to patients. The algorithm estimates average glucose (eAG) exposure, which can be used to calculate apparent PPG (aPPG) by subtracting FPG. The hypothesis was tested in a large dataset (comprising 17 studies) from the vildagliptin clinical trial programme. We found that 24 weeks of treatment with vildagliptin monotherapy (n = 2523) reduced the relative contribution of aPPG to eAG from 8.12% to 2.95% (by 64%, p < 0.001). In contrast, when vildagliptin was added to metformin (n = 2752), the relative contribution of aPPG to eAG insignificantly increased from 1.59% to 2.56%. In conclusion, glucose peaks, which are often prominent in patients with type 2 diabetes, provide a small contribution to the total glucose exposure assessed by HbA1c, and the ADAG algorithm is not robust enough to assess this small relative contribution in patients receiving combination therapy.
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