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51.
  • Ahrén, Bo (författare)
  • Glucagon-early breakthroughs and recent discoveries.
  • 2015
  • Ingår i: Peptides. - : Elsevier BV. - 1873-5169 .- 0196-9781. ; 67, s. 74-81
  • Forskningsöversikt (refereegranskat)abstract
    • Glucagon was discovered in 1922 as a hyperglycemic factor in the pancreas. During its early history up to 1970, glucagon was shown to increase circulating glucose through stimulating glycogenolysis in the liver. It was also shown to be a constituent of islet non-ß cells and to signal through G protein coupled receptors and cyclic AMP. Furthermore, its chemical characteristics, including amino acid sequence, and its processing from the preproglucagon gene had been established. During the modern research during the last 40 years, glucagon has been established as a key hormone in the regulation of glucose homeostasis, including a key role for the glucose counterregulation to hypoglycemia and for development of type 2 diabetes, and today glucagon is a potential target for treatment of the disease. Glucagon has also been shown to be a key factor beyond glucose control and involved in many processes. For the coming, future research, studies will be focused on α-cell biology beyond glucagon, hyperglucagonemia in other conditions than diabetes, its involvement in the regulation of body weight and energy expenditure and the potential of glucagon as a target for other diseases than type 2 diabetes, such as type 1 diabetes and obesity. This review summarizes the more than 90 years history of this important hormone as well as discusses potential future research regarding glucagon.
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52.
  • Ahrén, Bo (författare)
  • Glucagon-like peptide-1 and beta cell glucose sensitivity - a glucose ramp study in mice
  • 2021
  • Ingår i: Peptides. - : Elsevier BV. - 0196-9781. ; 146
  • Tidskriftsartikel (refereegranskat)abstract
    • The incretin glucagon-like peptide-1 (GLP-1) is a gut hormone but also locally produced in pancreatic islets. We evaluated effects of GLP-1 on the insulin response to a gradual increase in glucose in mice within physiological levels. We initially developed a glucose ramp technique in mice. Glucose levels were slowly increased by 0.2 mmol/l/min for 40 min under control conditions, during intravenous infusion of GLP-1 and in GLP-1 receptor knockout mice. In control mice, glucose levels increased from 8.5 ± 0.3 to 16.1 ± 0.3 mmol/l over the 40 min, i.e., by 0.22 ± 0.01 mmol/l/min. This resulted in a slow increase in insulin levels by 96 ± 38 pmol/l from the baseline of 319 ± 53 pmol/l. GLP-1 at 0.5 nmol/kg as bolus plus 0.3 nmol/kg/min over 40 min progressively increased this insulin response by 100-fold, to 9.5 ± 0.2 nmol/l (P < 0.001). Higher doses of GLP-1 enhanced the insulin response similarly (1.0 or 3.0 nmol/kg bolus followed by 0.4 or 1.2 nmol/kg/min), whereas a lower dose (0.3 nmol/kg bolus plus 0.15 nmol/kg/min) had no significant effect compared to controls. Moreover, there was no significant difference in insulin responses between controls and GLP-1 receptor knockout mice. Since the increase in glucose levels were standardized, there was no significant difference in glucose levels between the experimental groups. We conclude that the glucose ramp technique is a tool for studies on insulin responses to slow changes in circulating glucose levels in mice. We also conclude that GLP-1 is extraordinarily potent in enhancing the insulin response to a slow increase in glucose levels.
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53.
  • Ahrén, Bo (författare)
  • Glucagon-like peptide-1 receptor agonists for type 2 diabetes : A rational drug development
  • 2019
  • Ingår i: Journal of Diabetes Investigation. - : Wiley. - 2040-1116. ; 10:2, s. 196-201
  • Tidskriftsartikel (refereegranskat)abstract
    • Today, glucagon-like peptide-1 (GLP-1) receptor agonists are established glucose-lowering drugs used in the management of type 2 diabetes. Their development emerged from the understanding that a combined islet dysfunction comprising of impaired insulin secretion and exaggerated glucagon secretion is the key defect of hyperglycemia. GLP-1 was shown to target these defects, and after the discovery that dipeptidyl peptidase-4 inactivates native GLP-1, several different dipeptidyl peptidase-4-resistant GLP-1 receptor agonists have been developed. They are administered subcutaneously, but show differences in molecular structure, molecular size and pharmacokinetics, the latter allowing twice-daily, once-daily or once-weekly administration. They have been shown to be efficient in reducing both glycated hemoglobin and bodyweight, and to be safe and highly tolerable. Cardiovascular outcomes trials have shown them to be neutral or beneficial. GLP-1 receptor agonists are positioned as add-ons to metformin alone or in combination with oral agents in the clinical paradigm. They are also efficient when combined with insulin, and fixed dose combinations with long-acting insulin have been developed. Recent development includes a very long administration schedule and oral availability. The research from the first demonstration of the antidiabetic action of GLP-1 in the early 1990s to the enormously accumulated data today represents a successful and rational development, which has been characterized by focused perseverance to establish this therapy in the management of type 2 diabetes.
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54.
  • Ahrén, Bo (författare)
  • Glucagon secretion in relation to insulin sensitivity in healthy subjects.
  • 2006
  • Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 49:1, s. 117-122
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims/hypothesis: The study evaluated whether glucagon secretion is regulated by changes in insulin sensitivity under normal conditions. Materials and methods: A total of 155 healthy women with NGT (aged 53-70 years) underwent a glucose-dependent arginine-stimulation test for evaluation of glucagon secretion. Arginine (5 g) was injected i.v. under fasting conditions (plasma glucose 4.8 +/- 0.1 mmol/l) and after raising blood glucose concentrations to 14.8 +/- 0.1 and 29.8 +/- 0.2 mmol/l. The acute glucagon response (AGR) to arginine during the three glucose levels (AGR(1), AGR(2), AGR(3)) was estimated, as was the suppression of baseline glucagon by the increased glucose. All women also underwent a 2-h euglycaemic-hyperinsulinaemic clamp study for estimation of insulin sensitivity. Results: Insulin sensitivity was normally distributed, with a mean of 73.2 +/- 29.3 (SD) nmol glucose kg(-1) min(-1)/pmol insulin l(-1). When relating the variables obtained from the arginine test to insulin sensitivity, insulin resistance was associated with increased AGR and with increased suppression of glucagon levels by glucose. For example, the regression between insulin sensitivity and AGR(2) was r=-0.38 (p < 0.001) and between insulin sensitivity and suppression of glucagon levels by 14.8 mmol/l glucose r=0.36 (p < 0.001). Insulin sensitivity also correlated negatively with insulin secretion; multivariate analysis revealed that changes in insulin sensitivity and insulin secretion were independently related to changes in glucagon secretion. Conclusions/interpretation: The body adapts to insulin resistance by increasing the glucagon response to arginine and by increasing the suppression of glucagon levels by glucose. Hence, not only the islet beta cells but also the alpha cells seem to undergo compensatory changes during the development of insulin resistance.
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55.
  • Ahrén, Bo (författare)
  • Glucose-dependent insulinotropic polypeptide secretion after oral macronutrient ingestion : The human literature revisited and a systematic study in model experiments in mice
  • 2022
  • Ingår i: Journal of Diabetes Investigation. - : Wiley. - 2040-1116 .- 2040-1124. ; 13:10, s. 1655-1665
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims/Introduction: The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is secreted after meal ingestion. This study explored the relative influence of classes of macronutrients on GIP secretion. Materials and Methods: The human literature was revisited by identifying articles from PubMed using key words GIP, macronutrients, carbohydrates, fat, protein, healthy subjects. In model experiments in anesthetized mice, glucose (25–125 mg), protein (15–120 mg), fat emulsion (6–100 mg) or saline was given orally with determination of GIP levels. Results: The literature survey identified 15 studies in which glucose, protein or fat was administered to healthy subjects. All three classes of macronutrients stimulated GIP secretion with a 30–45 min peak after glucose and protein, and a more prolonged release after fat. Limitations in study designs preclude firm conclusions on the relative potency of the macronutrients. In mice, glucose was more potent to stimulate GIP secretion than fat and protein, with no significant difference between protein and fat. By co-administration of the macronutrients at moderate caloric combinations, a synergistic stimulation of GIP secretion was observed. In contrast, when raising the glucose challenge together with protein and fat, no synergy, but an additive effect, was evident. Conclusions: Glucose, protein and fat all stimulate GIP secretion in humans and mice. In mice, glucose is more potent than fat and protein, and there is also a synergy between the macronutrients on GIP secretion at moderate caloric doses. Further studies are warranted in humans to explore the relative potency of macronutrients.
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56.
  • Ahrén, Bo, et al. (författare)
  • Glucose effectiveness : Lessons from studies on insulin-independent glucose clearance in mice
  • 2021
  • Ingår i: Journal of Diabetes Investigation. - : Wiley. - 2040-1116 .- 2040-1124. ; 12:5, s. 675-685
  • Forskningsöversikt (refereegranskat)abstract
    • Besides insulin-mediated transport of glucose into the cells, an important role is also played by the non-insulin-mediated transport. This latter process is called glucose effectiveness (acronym SG), which is estimated by modeling of glucose and insulin data after an intravenous glucose administration, and accounts for ≈70% of glucose disposal. This review summarizes studies on SG, mainly in humans and rodents with focus on results achieved in model experiments in mice. In humans, SG is reduced in type 2 diabetes, in obesity, in liver cirrhosis and in some elderly populations. In model experiments in mice, SG is independent from glucose levels, but increases when insulin secretion is stimulated, such as after administration of the incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. SG is reduced in insulin resistance induced by high-fat feeding and by exogenous administration of glucagon. Glucose-dependent (insulin-independent) glucose disposal is therefore important for glucose elimination, and it is also well regulated. It might be of pathophysiological relevance for the development of type 2 diabetes, in particular during insulin resistance, and might also be a target for glucose-reducing therapy. Measuring SG is essentially important when carrying out metabolic studies to understand glucose homeostasis.
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57.
  • Ahrén, Bo (författare)
  • Glucose-lowering action through targeting islet dysfunction in type 2 diabetes : Focus on dipeptidyl peptidase-4 inhibition
  • 2021
  • Ingår i: Journal of Diabetes Investigation. - : Wiley. - 2040-1116 .- 2040-1124. ; 12:7, s. 1128-1135
  • Forskningsöversikt (refereegranskat)abstract
    • Dipeptidyl peptidase-4 (DPP-4) inhibition is a glucose-lowering medication for type 2 diabetes. It works through stimulation of insulin secretion and inhibition of glucagon secretion in a glucose-dependent manner, resulting in lowered fasting and postprandial glycemia with low risk of hypoglycemia. As impaired insulin secretion and augmented glucagon secretion are key factors underlying hyperglycemia in type 2 diabetes, DPP-4 inhibition represents a therapy that targets the underlying mechanisms of the disease. If insufficient in monotherapy, it can preferably be used in combination with metformin, which targets insulin resistance, and also in combination with sodium–glucose cotransporter 2 inhibition, thiazolidinediones and insulin, which target other mechanisms. In individuals of East Asian origin, islet dysfunction is of particular importance for the development of type 2 diabetes. Consequently, it has been shown in several studies that DPP-4 is efficient in these populations. This mini-review highlights the islet mechanisms of DPP-4 inhibition, islet dysfunction as a key factor for hyperglycemia in type 2 diabetes and that, consequently, DPP-4 is of particular value in populations where islet dysfunction is central, such as in individuals of East Asian origin.
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58.
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59.
  • Ahrén, Bo, et al. (författare)
  • HARMONY 3: 104-Week Randomized, Double-Blind, Placebo- and Active-Controlled Trial Assessing the Efficacy and Safety of Albiglutide Compared With Placebo, Sitagliptin, and Glimepiride in Patients With Type 2 Diabetes Taking Metformin.
  • 2014
  • Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 37:8, s. 2141-2148
  • Tidskriftsartikel (refereegranskat)abstract
    • To compare the efficacy and safety of weekly albiglutide with daily sitagliptin, daily glimepiride, and placebo.RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes receiving metformin were randomized to albiglutide (30 mg), sitagliptin (100 mg), glimepiride (2 mg), or placebo. Blinded dose titration for albiglutide (to 50 mg) and glimepiride (to 4 mg) was based on predefined hyperglycemia criteria. The primary end point was change in HbA1c from baseline at week 104. Secondary end points included fasting plasma glucose (FPG), weight, and time to hyperglycemic rescue.RESULTS: Baseline characteristics were similar among the albiglutide (n = 302), glimepiride (n = 307), sitagliptin (n = 302), and placebo (n = 101) groups. Baseline HbA1c was 8.1% (65.0 mmol/mol); mean age was 54.5 years. The mean doses for albiglutide and glimepiride at week 104 were 40.5 and 3.1 mg, respectively. At week 104, albiglutide significantly reduced HbA1c compared with placebo (-0.9% [-9.8 mmol/mol]; P < 0.0001), sitagliptin (-0.4% [-4.4 mmol/mol]; P = 0.0001), and glimepiride (-0.3% [-3.3 mmol/mol]; P = 0.0033). Outcomes for FPG and HbA1c were similar. Weight change from baseline for each were as follows: albiglutide -1.21 kg (95% CI -1.68 to -0.74), placebo -1.00 kg (95% CI -1.81 to -0.20), sitagliptin -0.86 kg (95% CI -1.32 to -0.39), glimepiride 1.17 kg (95% CI 0.70-1.63). The difference between albiglutide and glimepiride was statistically significant (P < 0.0001). Hyperglycemic rescue rate at week 104 was 25.8% for albiglutide compared with 59.2% (P < 0.0001), 36.4% (P = 0.0118), and 32.7% (P = 0.1504) for placebo, sitagliptin, and glimepiride, respectively. Rates of serious adverse events in the albiglutide group were similar to comparison groups. Diarrhea (albiglutide 12.9%, other groups 8.6-10.9%) and nausea (albiglutide 10.3%, other groups 6.2-10.9%) were generally the most frequently reported gastrointestinal events.CONCLUSION: Added to metformin, albiglutide was well-tolerated; produced superior reductions in HbA1c and FPG at week 104 compared with placebo, sitagliptin, and glimepiride; and resulted in weight loss compared with glimepiride.
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60.
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