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Assessment and Treatment of Impaired Insulin- Secretion and Action in Type 2 Diabetes

Dorkhan, Mozhgan LU (2008) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2008:49.
Abstract
Type 2 diabetes (T2D) is a disease characterised by varying degrees of defect in insulin secretion and insulin sensitivity and associated with increased morbidity and mortality. Optimal glycaemic control reduces the progression of diabetic complications. Over time, there is a steady deterioration of glycaemic control that raises the need for effective therapy targeted at the underlying defects in order to achieve treatment goals. The methods available for assessment of insulin secretion and insulin sensitivity have not been suitable for use in clinical practice. The introduction of thiazolidinediones (TZDs) targeting the insulin resistance component of T2D has been promising but accompanied with some adverse effects, mainly fluid retention... (More)
Type 2 diabetes (T2D) is a disease characterised by varying degrees of defect in insulin secretion and insulin sensitivity and associated with increased morbidity and mortality. Optimal glycaemic control reduces the progression of diabetic complications. Over time, there is a steady deterioration of glycaemic control that raises the need for effective therapy targeted at the underlying defects in order to achieve treatment goals. The methods available for assessment of insulin secretion and insulin sensitivity have not been suitable for use in clinical practice. The introduction of thiazolidinediones (TZDs) targeting the insulin resistance component of T2D has been promising but accompanied with some adverse effects, mainly fluid retention and heart failure. In this thesis, a simple method for independent measurement of β-cell function and insulin sensitivity at the same time (combined glucagon-insulin tolerance test, GITT) has been developed (Paper I). We also evaluated the effect of a TZD (pioglitazone) and a long-acting insulin (glargine) as add-on in the treatment of patients with T2D, not achieving glycaemic goals when treated with classic anti-diabetic agents on glycaemic control, insulin sensitivity, β-cell function and markers of increased cardiovascular load (Papers II &IV). We also investigated the effect of pioglitazone on eye protrusion (Paper III).

GITT showed good reproducibility and the index of insulin sensitivity derived from the GITT showed good correlation with the M-value from the euglycaemic clamp. The test also showed good discriminating capacity between individuals with varying degrees of glucose tolerance (Paper I). Both pioglitazone and insulin glargine were effective in reducing HbA1c levels in combination with other oral glucose lowering agents but pioglitazone caused fluid retention and increased levels of natriuretic peptides suggesting increased cardiac load (Papers II & IV). While pioglitazone improved insulin sensitivity and lipids, insulin glargine resulted in improved β-cell function (Paper IV). Pioglitazone also caused an increase in eye protrusion in a subgroup of patients, probably by causing an increase in retrobulbar adipogenesis (Paper III). Taken together, these results can hopefully help clinicians in the choice of novel add-on treatment and in monitoring of untoward side effects. GITT seems to be a promising tool for assessing insulin secretion and action in clinical practice. (Less)
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author
supervisor
opponent
  • Professor Berne, Christian, Akademiska sjukhuset, Uppsala, Sverige
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Type 2 diabetes, insulin secretion, glucagon test, insulin resistance, insulin glargine, insulin tolerance test, thiazolidinediones, natriuretic peptides, adiponectin, thyroid associated ophthalmopathy, proinsulin
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2008:49
pages
124 pages
publisher
Department of Clinical Sciences, Lund University
defense location
Stora Aulan, Medicinsk Forskningscentrum, Ingång 59, Universitetssjukhuset MAS, Malmö
defense date
2008-05-09 09:00
ISSN
1652-8220
ISBN
978-91-86059-02-6
language
English
LU publication?
yes
id
1ffb02c0-897f-4202-b324-a19babec7c5c (old id 1059375)
date added to LUP
2008-04-18 08:15:23
date last changed
2016-09-19 08:44:52
@phdthesis{1ffb02c0-897f-4202-b324-a19babec7c5c,
  abstract     = {Type 2 diabetes (T2D) is a disease characterised by varying degrees of defect in insulin secretion and insulin sensitivity and associated with increased morbidity and mortality. Optimal glycaemic control reduces the progression of diabetic complications. Over time, there is a steady deterioration of glycaemic control that raises the need for effective therapy targeted at the underlying defects in order to achieve treatment goals. The methods available for assessment of insulin secretion and insulin sensitivity have not been suitable for use in clinical practice. The introduction of thiazolidinediones (TZDs) targeting the insulin resistance component of T2D has been promising but accompanied with some adverse effects, mainly fluid retention and heart failure. In this thesis, a simple method for independent measurement of β-cell function and insulin sensitivity at the same time (combined glucagon-insulin tolerance test, GITT) has been developed (Paper I). We also evaluated the effect of a TZD (pioglitazone) and a long-acting insulin (glargine) as add-on in the treatment of patients with T2D, not achieving glycaemic goals when treated with classic anti-diabetic agents on glycaemic control, insulin sensitivity, β-cell function and markers of increased cardiovascular load (Papers II &amp;IV). We also investigated the effect of pioglitazone on eye protrusion (Paper III).<br/><br>
GITT showed good reproducibility and the index of insulin sensitivity derived from the GITT showed good correlation with the M-value from the euglycaemic clamp. The test also showed good discriminating capacity between individuals with varying degrees of glucose tolerance (Paper I). Both pioglitazone and insulin glargine were effective in reducing HbA1c levels in combination with other oral glucose lowering agents but pioglitazone caused fluid retention and increased levels of natriuretic peptides suggesting increased cardiac load (Papers II &amp; IV). While pioglitazone improved insulin sensitivity and lipids, insulin glargine resulted in improved β-cell function (Paper IV). Pioglitazone also caused an increase in eye protrusion in a subgroup of patients, probably by causing an increase in retrobulbar adipogenesis (Paper III). Taken together, these results can hopefully help clinicians in the choice of novel add-on treatment and in monitoring of untoward side effects. GITT seems to be a promising tool for assessing insulin secretion and action in clinical practice.},
  author       = {Dorkhan, Mozhgan},
  isbn         = {978-91-86059-02-6},
  issn         = {1652-8220},
  keyword      = {Type 2 diabetes,insulin secretion,glucagon test,insulin resistance,insulin glargine,insulin tolerance test,thiazolidinediones,natriuretic peptides,adiponectin,thyroid associated ophthalmopathy,proinsulin},
  language     = {eng},
  pages        = {124},
  publisher    = {Department of Clinical Sciences, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Assessment and Treatment of Impaired Insulin- Secretion and Action in Type 2 Diabetes},
  volume       = {2008:49},
  year         = {2008},
}