Studies of pancreatic islet microcirculation and insulin secretion in normal and diabetic rats
Author: Huang, Zhen
Date: 2007-12-14
Location: Lecturehall Aulan, Södersjukhuset
Time: 09.00
Department: Institutionen för klinisk forskning och utbildning, Södersjukhuset / Department of Clinical Science and Education, Södersjukhuset
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thesis.pdf (841.9Kb)
Abstract
Type 2 diabetes is increasing globally. The disease is characterized not
only by hyperglycemia, but also by insulin resistance with attendant
dyslipidemia, hypertension and endothelial dysfunction. These aberrations
may result in macrovascular disease, and deeply impact the longevity and
quality of life in diabetic patients. Gender differences also exist with
more pronounced negative effects of diabetes on the lipid profile and
blood pressure in women compared with men. To well control all of these
risk factors, diabetic patients frequently need to be treated with a
lipid lowering statin, and an ACE inhibitor or angiotensin receptor
antagonist against hypertension and/or albuminuria. Such drugs reportedly
also decrease the risk of incident diabetes in clinical trials, by
unknown mechanisms. The aim of the present work was to characterize the
effects of vasoactive drugs, free fatty acids and ethanol on islet
microcirculation, in vivo insulin secretion and glucose tolerance in
normal and diabetic rats of both genders. To this end, a microsphere
technique was evaluated and applied for measurements of islet blood flow
in rats. Vasoactive drugs that are frequently given to diabetic patients
were found to increase islet blood flow (IBF), augment insulin secretion
and improve glycemia. This suggests that a local pancreatic RAS plays a
substantial role in the regulation of islet microcirculation, thereby
impacting insulin secretion and glucose tolerance. Qualitative and
quantitative gender-specific differences in responses to such drugs were
noted, which may be due to the vasoactive features of sex hormones or
other influences conferred by gender. Free fatty acids lowered IBF and
may thus worsen hyperglycemia by limiting the supply of insulin needed to
curb hyperglycemia. Alternatively, the decreased IBF could represent a
protective mechanism by which islet exposure to free fatty acid toxicity
can be limited. Ethanol acutely exerted substantial influences on
pancreatic microcirculation by evoking a massive redistribution of
pancreatic blood flow from the exocrine into the endocrine part via
mechanisms mediated by nitric oxide and vagal stimuli, augmenting late
phase insulin secretion, and thereby evoking hypoglycemia. This effect
may in part underlie the well known hypoglycemic properties of alcohol in
diabetic patients or in alcoholics with hepatic failure. Collectively,
these direct islet effects of RAS-interfering drugs, statins, fatty acids
and ethanol may prove valuable in designing different and gender-specific
treatment strategies for diabetic patients or subjects at risk of
developing glucose intolerance. Moreover, vasoactive drugs that are
frequently given to diabetic patients may confer additional treatment
benefits beyond their systemic effects by increasing islet blood flow,
augmenting insulin secretion and improving glycemia.
List of papers:
I. Huang Z, Jansson L, Sjöholm A. (2006). "Pancreatic islet blood flow is selectively enhanced by captopril, irbesartan and pravastatin, and suppressed by palmitate." Biochem Biophys Res Commun 346(1): 26-32
Pubmed
II. Huang Z, Jansson L, Sjöholm A. (2007). "Vasoactive drugs enhance pancreatic islet blood flow, augment insulin secretion and improve glucose tolerance in female rats." Clin Sci (Lond) 112(1): 69-76
Pubmed
III. Huang Z, Sjöholm A. (2007). "Ethanol acutely stimulates islet blood flow, amplifies insulin secretion, and induces hypoglycemia via NO and vagally mediated mechanisms." Endocrinology Oct 4: Epub ahead of print
Pubmed
IV. Huang Z, Jansson L, Sjöholm Å. (1970). "Gender-specific regulation of pancreatic islet blood flow, insulin secretion, and glucose tolerance in spontaneously diabetic Goto-Kakizaki rats." (Manuscript)
I. Huang Z, Jansson L, Sjöholm A. (2006). "Pancreatic islet blood flow is selectively enhanced by captopril, irbesartan and pravastatin, and suppressed by palmitate." Biochem Biophys Res Commun 346(1): 26-32
Pubmed
II. Huang Z, Jansson L, Sjöholm A. (2007). "Vasoactive drugs enhance pancreatic islet blood flow, augment insulin secretion and improve glucose tolerance in female rats." Clin Sci (Lond) 112(1): 69-76
Pubmed
III. Huang Z, Sjöholm A. (2007). "Ethanol acutely stimulates islet blood flow, amplifies insulin secretion, and induces hypoglycemia via NO and vagally mediated mechanisms." Endocrinology Oct 4: Epub ahead of print
Pubmed
IV. Huang Z, Jansson L, Sjöholm Å. (1970). "Gender-specific regulation of pancreatic islet blood flow, insulin secretion, and glucose tolerance in spontaneously diabetic Goto-Kakizaki rats." (Manuscript)
Issue date: 2007-11-23
Rights:
Publication year: 2007
ISBN: 978-91-7357-457-0
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