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| 2. |
- Ahrén, Bo, et al.
(författare)
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Mechanisms of Action of the DPP-4 Inhibitor Vildagliptin in Man.
- 2011
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902. ; 13:9, s. 775-783
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Forskningsöversikt (refereegranskat)abstract
- Inhibition of dipeptidyl peptidase-4 (DPP-4) by vildagliptin prevents degradation of glucagon-like peptide-1 (GLP-1) and reduces glycemia in type 2 diabetes, with low risk for hypoglycemia and no weight gain. Vildagliptin binds covalently to the catalytic site of DPP-4, eliciting prolonged enzyme inhibition. This raises intact GLP-1 levels, both after meal ingestion and in the fasting state. Vildagliptin has been shown to stimulate insulin secretion and to inhibit glucagon secretion in a glucose-dependent manner. At hypoglycemic levels, the counterregulatory glucagon response is enhanced relative to baseline by vildagliptin. Vildagliptin also inhibits hepatic glucose production, mainly through changes in islet hormone secretion, and improves insulin sensitivity, as determined with a variety of methods. These effects underlie the improved glycemia with low risk for hypoglycemia. Vildagliptin also suppresses postprandial triglyceride-rich lipoprotein levels after ingestion of a fat-rich meal and reduces fasting lipolysis, suggesting inhibition of fat absorption and reduced triglyceride stores in non-fat tissues. The large body of knowledge on vildagliptin regarding enzyme binding, incretin and islet hormone secretion and glucose and lipid metabolism is summarized, with discussion of the integrated mechanisms and comparison with other DPP-4 inhibitors and GLP-1 receptor activators, where appropriate.
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| 3. |
- Esguerra, Jonathan L.S., et al.
(författare)
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MicroRNAs in islet hormone secretion
- 2018
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902. ; 20:Suppl 2, s. 11-19
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Forskningsöversikt (refereegranskat)abstract
- Pancreatic islet hormone secretion is central in the maintenance of blood glucose homeostasis. During development of hyperglycaemia, the β-cell is under pressure to release more insulin to compensate for increased insulin resistance. Failure of the β-cells to secrete enough insulin results in type 2 diabetes (T2D). MicroRNAs (miRNAs) are short non-coding RNA molecules suitable for rapid regulation of the changes in target gene expression needed in β-cell adaptations. Moreover, miRNAs are involved in the maintenance of α-cell and β-cell phenotypic identities via cell-specific, or cell-enriched expression. Although many of the abundant miRNAs are highly expressed in both cell types, recent research has focused on the role of miRNAs in β-cells. It has been shown that highly abundant miRNAs, such as miR-375, are involved in several cellular functions indispensable in maintaining β-cell phenotypic identity, almost acting as “housekeeping genes” in the context of hormone secretion. Despite the abundance and importance of miR-375, it has not been shown to be differentially expressed in T2D islets. On the contrary, the less abundant miRNAs such as miR-212/miR-132, miR-335, miR-130a/b and miR-152 are deregulated in T2D islets, wherein the latter three miRNAs were shown to play key roles in regulating β-cell metabolism. In this review, we focus on β-cell function and describe miRNAs involved in insulin biosynthesis and processing, glucose uptake and metabolism, electrical activity and Ca2+-influx and exocytosis of the insulin granules. We present current status on miRNA regulation in α-cells, and finally we discuss the involvement of miRNAs in β-cell dysfunction underlying T2D pathogenesis.
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| 4. |
- Gylfe, Erik, et al.
(författare)
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Neurotransmitter control of islet hormone pulsatility
- 2014
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Ingår i: Diabetes, obesity and metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 16:S1, s. 102-110
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Forskningsöversikt (refereegranskat)abstract
- Pulsatile secretion is an inherent property of hormone-releasing pancreatic islet cells. This secretory pattern is physiologically important and compromised in diabetes. Neurotransmitters released from islet cells may shape the pulses in auto/paracrine feedback loops. Within islets, glucose-stimulated -cells couple via gap junctions to generate synchronized insulin pulses. In contrast, - and -cells lack gap junctions, and glucagon release from islets stimulated by lack of glucose is non-pulsatile. Increasing glucose concentrations gradually inhibit glucagon secretion by -cell-intrinsic mechanism/s. Further glucose elevation will stimulate pulsatile insulin release and co-secretion of neurotransmitters. Excitatory ATP may synchronize -cells with -cells to generate coinciding pulses of insulin and somatostatin. Inhibitory neurotransmitters from - and -cells can then generate antiphase pulses of glucagon release. Neurotransmitters released from intrapancreatic ganglia are required to synchronize -cells between islets to coordinate insulin pulsatility from the entire pancreas, whereas paracrine intra-islet effects still suffice to explain coordinated pulsatile release of glucagon and somatostatin. The present review discusses how neurotransmitters contribute to the pulsatility at different levels of integration.
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| 5. |
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| 6. |
- Jendle, Johan, 1963-, et al.
(författare)
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Use of insulin pumps and closed-loop systems among people living with diabetes : A narrative review of clinical and cost-effectiveness to enable access to technology and meet the needs of payers
- 2023
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Ingår i: Diabetes, obesity and metabolism. - : Wiley-Blackwell Publishing Inc.. - 1462-8902 .- 1463-1326. ; 25:Sup. 2, s. 21-32
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Forskningsöversikt (refereegranskat)abstract
- The use of continuous subcutaneous insulin infusion delivery via insulin pumps is today considered standard of care for type 1 diabetes (T1D). Closed-loop systems combining continuous glucose monitoring (CGM) with automated algorithm-driven insulin delivery have been shown to be safe and efficacious in randomized controlled studies and in real-life studies in both pediatric and adult individuals with T1D. Implementation of hybrid closed-loop (HCL) systems have shown incremental effectiveness with further reduction of hypoglycemia and hyperglycemia. Although less extensively studied in type 2 diabetes (T2D), insulin pumps have demonstrated their effectiveness on glucose control together with the reduction in insulin needs and a neutral effect on weight. Recent studies have also shown promising results with the use of HCL in T2D. Cost-effectiveness studies both in T1D and T2D have shown that pump is cost effective in several countries, leading to improvements in quality adjusted life years. Insulin pumps are currently reimbursed for T1D in many European countries, but only in a few for individuals with T2D. HCL systems are to be evaluated in future trials performed in T2D to compare their incremental efficacy and cost effectiveness in comparison with available intensification tools which include multiple daily insulin injections, metformin, SGLT-2 inhibitors and GLP-1 receptor agonists. There is a need for updated guidelines for the use of CSII and HCL in individuals living with T2D based on the emerging evidence, identifying, and recommending for the people who'd benefit the most, which would eventually form a basis for the reimbursement and health policies.
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| 7. |
- Ott, V., et al.
(författare)
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Intranasal administration of insulin to the brain impacts cognitive function and peripheral metabolism
- 2012
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Ingår i: Diabetes, obesity and metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 14:3, s. 214-221
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Forskningsöversikt (refereegranskat)abstract
- In recent years, the central nervous system (CNS) has emerged as a principle site of insulin action. This notion is supported by studies in animals relying on intracerebroventricular insulin infusion and by experiments in humans that make use of the intranasal pathway of insulin administration to the brain. Employing neurobehavioural and metabolic measurements as well as functional imaging techniques, these studies have provided insight into a broad range of central and peripheral effects of brain insulin. The present review focusses on CNS effects of insulin administered via the intranasal route on cognition, in particular memory function, and whole-body energy homeostasis including glucose metabolism. Furthermore, evidence is reviewed that suggests a pathophysiological role of impaired brain insulin signaling in obesity and type 2 diabetes, which are hallmarked by peripheral and possibly central nervous insulin resistance, as well as in conditions such as Alzheimer's disease where CNS insulin resistance might contribute to cognitive dysfunction.
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| 8. |
- Tengholm, Anders, 1971-, et al.
(författare)
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cAMP signalling in insulin and glucagon secretion
- 2017
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Ingår i: Diabetes, obesity and metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 19, s. 42-53
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Forskningsöversikt (refereegranskat)abstract
- The second messenger archetype cAMP is one of the most important cellular signalling molecules with central functions including the regulation of insulin and glucagon secretion from the pancreatic - and -cells, respectively. cAMP is generally considered as an amplifier of insulin secretion triggered by Ca2+ elevation in the -cells. Both messengers are also positive modulators of glucagon release from -cells, but in this case cAMP may be the important regulator and Ca2+ have a more permissive role. The actions of cAMP are mediated by protein kinase A (PKA) and the guanine nucleotide exchange factor Epac. The present review focuses on how cAMP is regulated by nutrients, hormones and neural factors in - and -cells via adenylyl cyclase-catalysed generation and phosphodiesterase-mediated degradation. We will also discuss how PKA and Epac affect ion fluxes and the secretory machinery to transduce the stimulatory effects on insulin and glucagon secretion. Finally, we will briefly describe disturbances of the cAMP system associated with diabetes and how cAMP signalling can be targeted to normalize hypo- and hypersecretion of insulin and glucagon, respectively, in diabetic patients.
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| 9. |
- Wentzel, Parri
(författare)
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Can we prevent diabetic birth defects with micronutrients?
- 2009
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Ingår i: Diabetes, obesity and metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 11:8, s. 770-778
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Forskningsöversikt (refereegranskat)abstract
- Congenital malformations are more common in infants of diabetic women than in children of non-diabetic women. The mechanisms behind diabetes-induced congenital anomalies are not known. Disturbed micronutrient metabolism, in concert with oxidative stress, has been suggested as a cause of diabetes-induced malformations by several studies. In experimental work, administration of inositol, arachidonic acid and several antioxidative compounds, as well as folic acid, to the embryo, has proven to attenuate the teratogenic effects of a diabetic environment. Future therapeutic efforts may include supplementation with antioxidants or micronutrients, such as folic acid, to the pregnant diabetic woman, although exact compounds and doses need to be determined.
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