Regulation of Insulin Secretion in Relation to Nitric Oxide, Carbon Monoxide and Acid alpha-Glucoside Hydrolase Activities

Henrik Mosén

Forskningsoutput: AvhandlingDoktorsavhandling (sammanläggning)

156 Nedladdningar (Pure)

Sammanfattning

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.
Originalspråkengelska
KvalifikationDoktor
Tilldelande institution
  • Klinisk fysiologi, Lund
Handledare
  • Salehi, S Albert, handledare
  • Lundquist, Ingmar, handledare
Tilldelningsdatum2005 nov. 11
Förlag
ISBN (tryckt)91-85439-97-5
StatusPublished - 2005

Bibliografisk information

Defence details

Date: 2005-11-11
Time: 09:15
Place: Segerfalk lecture hall, BMC, Sölvegatan 17, Lund, Sweden

External reviewer(s)

Name: Jansson, Leif
Title: Professor
Affiliation: Department of Medical Cell Biology, Uppsala University, Sweden

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<div class="article_info">A Salehi, H Mosén and I Lundquist. <span class="article_issue_date">1998</span>. <a href="javascript:downloadFile(545541)" class="article_link">Insulin release transduction mechanism through acid glucan-1,4-alpha-glucosidase activation is Ca2+ regulated.</a> <span class="journal_series_title">American Journal of Physiology</span>, <span class="journal_volume">vol 274</span> <span class="journal_pages">pp E459-E468</span>. <span class="journal_distributor">(Used with permission)</span></div>
<div class="article_info">A Salehi, R Henningsson, H Mosén, C-G Östenson, S Efendic and I Lundquist. <span class="article_issue_date">1999</span>. <a href="javascript:downloadFile(545542)" class="article_link">Dysfunction of the islet lysosomal system conveys impairment of glucoseinduced insulin release in the diabetic GK rat.</a> <span class="journal_series_title">Endocrinology</span>, <span class="journal_volume">vol 140</span> <span class="journal_pages">pp 3045-3053</span>. <span class="journal_distributor">The Endocrine Society (Copyright 1999, The Endocrine Society)</span></div>
<div class="article_info">H Mosén, A Salehi and I Lundquist. <span class="article_issue_date">2000</span>. <a href="javascript:downloadFile(545543)" class="article_link">Nitric oxide, islet acid glucan-1,4-alpha-glucosidase activity and nutrient-stimulated insulin secretion.</a> <span class="journal_series_title">Journal of Endocrinology</span>, <span class="journal_volume">vol 165</span> <span class="journal_pages">pp 293-300</span>. <span class="journal_distributor">(Copyright Society for Endocrinology 2000, Reproduced by permission)</span></div>
<div class="article_info">H Mosén, A Salehi, P Alm, R Henningsson, J Jimenez-Feltström, CG Östenson, S Efendic and I Lundquist. <span class="article_issue_date">2005</span>. <a href="javascript:downloadFile(545544)" class="article_link">Defective glucose-stimulated insulin release in the diabetic Goto-Kakizaki (GK) rat coincides with reduced activity of the islet carbon monoxide signaling pathway.</a> <span class="journal_series_title">Endocrinology</span>, <span class="journal_volume">vol 146</span> <span class="journal_pages">pp 1553-1558</span>. <span class="journal_distributor">The Endocrine Society (Copyright 2005, The Endocrine Society)</span></div>
<div class="article_info">H Mosén, CG Östenson, I Lundquist, P Alm, R Henningsson, J Jimenez-Feltström, A Guenifi, S Efendic and A Salehi. <span class="article_issue_date">2005</span>. <span class="article_title">Impaired glucose-stimulated insulin secretion in the GK rat is associated with abnormalities in islet nitric oxide production.</span> (manuscript)</div>
<div class="article_info">H Mosén, A Salehi, R Henningsson and I Lundquist. <span class="article_issue_date">2005</span>. <span class="article_title">Nitric oxide inhibits, and carbon monoxide activates, islet acid alpha-glucoside hydrolase activities in parallel with glucose-stimulated insulin secretion.</span> (manuscript)</div>

Ämnesklassifikation (UKÄ)

  • Medicinska grundvetenskaper

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