Ca2+i and the pancreatic α cell – intrinsic regulation and dysfunction in type 2 diabetes
<p>In type 2 diabetes (T2D), elevated plasma glucagon concentration (hyperglucagonaemia) exacerbates hyperglycaemia due to inappropriate insulin secretion. Despite this, very little is known about why glucagon secreting α cells become dysfunctional.</p> <p>In α cells, intracellula...
| Autore principale: | |
|---|---|
| Altri autori: | |
| Natura: | Tesi |
| Lingua: | English |
| Pubblicazione: |
2019
|
| Soggetti: |
| _version_ | 1826316576854376448 |
|---|---|
| author | Kellard, J |
| author2 | Knudsen, JG |
| author_facet | Knudsen, JG Kellard, J |
| author_sort | Kellard, J |
| collection | OXFORD |
| description | <p>In type 2 diabetes (T2D), elevated plasma glucagon concentration (hyperglucagonaemia) exacerbates hyperglycaemia due to inappropriate insulin secretion. Despite this, very little is known about why glucagon secreting α cells become dysfunctional.</p>
<p>In α cells, intracellular Ca<sup>2+</sup> ([Ca<sup>2+</sup>]<sub>i</sub>) oscillations drive glucagon secretion but much of their regulation remains obscure. Here we investigate how [Ca<sup>2+</sup>]<sub>i</sub> oscillations are regulated, and whether α cell [Ca<sup>2+</sup>]<sub>i</sub> dynamics change when mice are fed a high fat diet (to induce a T2D-like state).</p>
<p>Mice expressing the genetically encoded calcium sensor GCaMP3 specifically in α cells were fed a control (10% calories from fat; CTL) or high fat (60% calories from fat; HFD) diet. After 12 weeks, glucose tolerance was impaired in HFD fed mice and plasma glucagon levels were elevated. Plasma glucagon was elevated in HFD mice in vivo during insulin-induced hypoglycaemia and in the perfused pancreas in situ. Glucagon secretion from HFD islets was elevated ex vivo suggesting that intra-islet (intrinsic) effects are involved. While the [Ca<sup>2+</sup>]<sub>i</sub> oscillation frequency in α cells was reduced by high (6-15 mM) glucose in both CTL and HFD islets, the frequency was higher in HFD fed mice. Following HFD, α cell [Ca<sup>2+</sup>]<sub>i</sub> oscillations and glucagon secretion were also less sensitive to inhibition by somatostatin (SST), an effect that correlated with reduced SST secretion from δ cells in mice fed the HFD.</p>
<p>Collectively, these data indicate that altered α cell activity underlies hyperglucagonaemia in HFD. These data provide evidence that α cell dysfunction and altered intra-islet signalling manifests early in T2D. Correcting the glucagon secretion defects may provide therapeutic advantages, highlighting the potential of the α cell as a potential pharmacological target.</p> |
| first_indexed | 2024-03-06T21:48:13Z |
| format | Thesis |
| id | oxford-uuid:4a59c2c1-c93f-4d0c-bea6-7aeb138acde2 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-12-09T03:47:31Z |
| publishDate | 2019 |
| record_format | dspace |
| spelling | oxford-uuid:4a59c2c1-c93f-4d0c-bea6-7aeb138acde22024-12-08T10:14:47ZCa2+i and the pancreatic α cell – intrinsic regulation and dysfunction in type 2 diabetesThesishttp://purl.org/coar/resource_type/c_db06uuid:4a59c2c1-c93f-4d0c-bea6-7aeb138acde2Type 2 diabetesDiabetesPhysiologyEnglishHyrax Deposit2019Kellard, JKnudsen, JGRorsman, PBriant, LHodson, LHodson, D<p>In type 2 diabetes (T2D), elevated plasma glucagon concentration (hyperglucagonaemia) exacerbates hyperglycaemia due to inappropriate insulin secretion. Despite this, very little is known about why glucagon secreting α cells become dysfunctional.</p> <p>In α cells, intracellular Ca<sup>2+</sup> ([Ca<sup>2+</sup>]<sub>i</sub>) oscillations drive glucagon secretion but much of their regulation remains obscure. Here we investigate how [Ca<sup>2+</sup>]<sub>i</sub> oscillations are regulated, and whether α cell [Ca<sup>2+</sup>]<sub>i</sub> dynamics change when mice are fed a high fat diet (to induce a T2D-like state).</p> <p>Mice expressing the genetically encoded calcium sensor GCaMP3 specifically in α cells were fed a control (10% calories from fat; CTL) or high fat (60% calories from fat; HFD) diet. After 12 weeks, glucose tolerance was impaired in HFD fed mice and plasma glucagon levels were elevated. Plasma glucagon was elevated in HFD mice in vivo during insulin-induced hypoglycaemia and in the perfused pancreas in situ. Glucagon secretion from HFD islets was elevated ex vivo suggesting that intra-islet (intrinsic) effects are involved. While the [Ca<sup>2+</sup>]<sub>i</sub> oscillation frequency in α cells was reduced by high (6-15 mM) glucose in both CTL and HFD islets, the frequency was higher in HFD fed mice. Following HFD, α cell [Ca<sup>2+</sup>]<sub>i</sub> oscillations and glucagon secretion were also less sensitive to inhibition by somatostatin (SST), an effect that correlated with reduced SST secretion from δ cells in mice fed the HFD.</p> <p>Collectively, these data indicate that altered α cell activity underlies hyperglucagonaemia in HFD. These data provide evidence that α cell dysfunction and altered intra-islet signalling manifests early in T2D. Correcting the glucagon secretion defects may provide therapeutic advantages, highlighting the potential of the α cell as a potential pharmacological target.</p> |
| spellingShingle | Type 2 diabetes Diabetes Physiology Kellard, J Ca2+i and the pancreatic α cell – intrinsic regulation and dysfunction in type 2 diabetes |
| title | Ca2+i and the pancreatic α cell – intrinsic regulation and dysfunction in type 2 diabetes |
| title_full | Ca2+i and the pancreatic α cell – intrinsic regulation and dysfunction in type 2 diabetes |
| title_fullStr | Ca2+i and the pancreatic α cell – intrinsic regulation and dysfunction in type 2 diabetes |
| title_full_unstemmed | Ca2+i and the pancreatic α cell – intrinsic regulation and dysfunction in type 2 diabetes |
| title_short | Ca2+i and the pancreatic α cell – intrinsic regulation and dysfunction in type 2 diabetes |
| title_sort | ca2 i and the pancreatic α cell intrinsic regulation and dysfunction in type 2 diabetes |
| topic | Type 2 diabetes Diabetes Physiology |
| work_keys_str_mv | AT kellardj ca2iandthepancreaticacellintrinsicregulationanddysfunctionintype2diabetes |