| 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. |
- 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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| 4. |
- 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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| 5. |
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| 6. |
- 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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| 7. |
- 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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| 8. |
- 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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| 9. |
- 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
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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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| 10. |
- Ahrén, Bo
(författare)
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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
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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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