Regulation of Insulin Secretion in Relation to Nitric Oxide, Carbon Monoxide and Acid alpha-Glucoside Hydrolase Activities
(2005) In Lund University Faculty of Medicine Doctoral Dissertation Series- Abstract
- The main stimulus for insulin secretion is elevated blood glucose levels. In this thesis the aim was to study less well-known systems involved in the complex regulation of glucose-stimulated insulin release, emphasizing the role of the lysosomal/vacuolar system and the associated glycogenolytic acid alpha-glucoside hydrolases, but also the HO-CO and NOS-NO systems. We performed studies both in healthy and diabetic animals.
We show that the acid alpha-glucoside hydrolases are dependent on Ca2+ and the activities of these enzymes seems to be coupled to Ca2+-glucose-stimulated insulin release. The effect of Ca2+ is probably elicited through activation of the acidic organelles and not on the enzymes themselves. We also show... (More) - The main stimulus for insulin secretion is elevated blood glucose levels. In this thesis the aim was to study less well-known systems involved in the complex regulation of glucose-stimulated insulin release, emphasizing the role of the lysosomal/vacuolar system and the associated glycogenolytic acid alpha-glucoside hydrolases, but also the HO-CO and NOS-NO systems. We performed studies both in healthy and diabetic animals.
We show that the acid alpha-glucoside hydrolases are dependent on Ca2+ and the activities of these enzymes seems to be coupled to Ca2+-glucose-stimulated insulin release. The effect of Ca2+ is probably elicited through activation of the acidic organelles and not on the enzymes themselves. We also show that the acid alpha-glucoside hydrolases are dependent on the NOS-NO-system and the HO-CO system, where NO inhibits and NOS inhibition amplifies the acid alpha-glucoside hydrolase activities, while CO in contrast stimulates the acid alpha-glucoside hydrolases and glucose-stimulated insulin release in parallel.
In the diabetic GK rat we found several abnormalities that could, at least in part, explain the impaired response to glucose seen in this diabetic animal model. We show that the GK rat has a dysfunctional lysosomal/vacuolar system in the islets of Langerhans, and this seems to prevent the normal function of the glucose-stimulated acid alpha-glucoside hydrolase signalling pathway and insulin release. The GK islets expressed inducible NOS (iNOS) and displayed a marked iNOS activity when incubated at low and high glucose, and NOS inhibition resulted in an amplification of glucose-stimulated insulin release. The HO-CO system on the other hand was suppressed, HO-2 expressed and CO production being decreased. Interestingly, the GK islets expressed inducible HO (HO-1) in islets isolated "ex vivo". The GK islets displayed a decreased glucose-stimulated CO production when incubated in vitro, in parallel with impaired glucose-stimulated insulin release.
In conclusion the results suggest that NO and CO have interacting roles on glucose-stimulated insulin release, and that this regulation is, at least partly, transduced through the activity of the lysosomal/vacuolar system and the associated acid alpha-glucoside hydrolases and cGMP, but also through a direct effect on the cAMP system. NO acts inhibitory and CO stimulatory. In the GK rat we found abnormalities in the lysosomal/vacuolar system, as well as in the HO-CO and NOS-NO systems, and these findings might contribute to the understanding of the impaired insulin response to glucose seen in type 2 diabetes. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/545529
- author
- Mosén, Henrik LU
- supervisor
- opponent
-
- Professor Jansson, Leif, Department of Medical Cell Biology, Uppsala University, Sweden
- organization
- publishing date
- 2005
- type
- Thesis
- publication status
- published
- subject
- keywords
- Endokrinologi, secreting systems, diabetology, Endocrinology, Medicin (människa och djur), Medicine (human and vertebrates), GK rat, insulin secretion, carbon monoxide, acid alpha-glucoside hydrolases, nitric oxide, heme oxygenase, isoforms of nitric oxide synthase, diabetologi, sekretion
- in
- Lund University Faculty of Medicine Doctoral Dissertation Series
- pages
- 130 pages
- publisher
- Department of Experimental Medical Science, Lund Univeristy
- defense location
- Segerfalk lecture hall, BMC, Sölvegatan 17, Lund, Sweden
- defense date
- 2005-11-11 09:15:00
- ISSN
- 1652-8220
- ISBN
- 91-85439-97-5
- language
- English
- LU publication?
- yes
- additional info
- A Salehi, H Mosén and I Lundquist. 1998. Insulin release transduction mechanism through acid glucan-1,4-alpha-glucosidase activation is Ca2+ regulated. American Journal of Physiology, vol 274 pp E459-E468. (Used with permission)A Salehi, R Henningsson, H Mosén, C-G Östenson, S Efendic and I Lundquist. 1999. Dysfunction of the islet lysosomal system conveys impairment of glucoseinduced insulin release in the diabetic GK rat. Endocrinology, vol 140 pp 3045-3053. The Endocrine Society (Copyright 1999, The Endocrine Society)H Mosén, A Salehi and I Lundquist. 2000. Nitric oxide, islet acid glucan-1,4-alpha-glucosidase activity and nutrient-stimulated insulin secretion. Journal of Endocrinology, vol 165 pp 293-300. (Copyright Society for Endocrinology 2000, Reproduced by permission)H Mosén, A Salehi, P Alm, R Henningsson, J Jimenez-Feltström, CG Östenson, S Efendic and I Lundquist. 2005. Defective glucose-stimulated insulin release in the diabetic Goto-Kakizaki (GK) rat coincides with reduced activity of the islet carbon monoxide signaling pathway. Endocrinology, vol 146 pp 1553-1558. The Endocrine Society (Copyright 2005, The Endocrine Society)H Mosén, CG Östenson, I Lundquist, P Alm, R Henningsson, J Jimenez-Feltström, A Guenifi, S Efendic and A Salehi. 2005. Impaired glucose-stimulated insulin secretion in the GK rat is associated with abnormalities in islet nitric oxide production. (manuscript)H Mosén, A Salehi, R Henningsson and I Lundquist. 2005. Nitric oxide inhibits, and carbon monoxide activates, islet acid alpha-glucoside hydrolase activities in parallel with glucose-stimulated insulin secretion. (manuscript)
- id
- ae465301-4ef6-482e-9f47-72633ba0cf65 (old id 545529)
- date added to LUP
- 2016-04-01 16:17:56
- date last changed
- 2019-05-22 05:54:00
@phdthesis{ae465301-4ef6-482e-9f47-72633ba0cf65, abstract = {{The main stimulus for insulin secretion is elevated blood glucose levels. In this thesis the aim was to study less well-known systems involved in the complex regulation of glucose-stimulated insulin release, emphasizing the role of the lysosomal/vacuolar system and the associated glycogenolytic acid alpha-glucoside hydrolases, but also the HO-CO and NOS-NO systems. We performed studies both in healthy and diabetic animals.<br/><br> <br/><br> We show that the acid alpha-glucoside hydrolases are dependent on Ca2+ and the activities of these enzymes seems to be coupled to Ca2+-glucose-stimulated insulin release. The effect of Ca2+ is probably elicited through activation of the acidic organelles and not on the enzymes themselves. We also show that the acid alpha-glucoside hydrolases are dependent on the NOS-NO-system and the HO-CO system, where NO inhibits and NOS inhibition amplifies the acid alpha-glucoside hydrolase activities, while CO in contrast stimulates the acid alpha-glucoside hydrolases and glucose-stimulated insulin release in parallel.<br/><br> <br/><br> In the diabetic GK rat we found several abnormalities that could, at least in part, explain the impaired response to glucose seen in this diabetic animal model. We show that the GK rat has a dysfunctional lysosomal/vacuolar system in the islets of Langerhans, and this seems to prevent the normal function of the glucose-stimulated acid alpha-glucoside hydrolase signalling pathway and insulin release. The GK islets expressed inducible NOS (iNOS) and displayed a marked iNOS activity when incubated at low and high glucose, and NOS inhibition resulted in an amplification of glucose-stimulated insulin release. The HO-CO system on the other hand was suppressed, HO-2 expressed and CO production being decreased. Interestingly, the GK islets expressed inducible HO (HO-1) in islets isolated "ex vivo". The GK islets displayed a decreased glucose-stimulated CO production when incubated in vitro, in parallel with impaired glucose-stimulated insulin release.<br/><br> <br/><br> In conclusion the results suggest that NO and CO have interacting roles on glucose-stimulated insulin release, and that this regulation is, at least partly, transduced through the activity of the lysosomal/vacuolar system and the associated acid alpha-glucoside hydrolases and cGMP, but also through a direct effect on the cAMP system. NO acts inhibitory and CO stimulatory. In the GK rat we found abnormalities in the lysosomal/vacuolar system, as well as in the HO-CO and NOS-NO systems, and these findings might contribute to the understanding of the impaired insulin response to glucose seen in type 2 diabetes.}}, author = {{Mosén, Henrik}}, isbn = {{91-85439-97-5}}, issn = {{1652-8220}}, keywords = {{Endokrinologi; secreting systems; diabetology; Endocrinology; Medicin (människa och djur); Medicine (human and vertebrates); GK rat; insulin secretion; carbon monoxide; acid alpha-glucoside hydrolases; nitric oxide; heme oxygenase; isoforms of nitric oxide synthase; diabetologi; sekretion}}, language = {{eng}}, publisher = {{Department of Experimental Medical Science, Lund Univeristy}}, school = {{Lund University}}, series = {{Lund University Faculty of Medicine Doctoral Dissertation Series}}, title = {{Regulation of Insulin Secretion in Relation to Nitric Oxide, Carbon Monoxide and Acid alpha-Glucoside Hydrolase Activities}}, url = {{https://lup.lub.lu.se/search/files/4629934/545544.pdf}}, year = {{2005}}, }