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Effect of fat-derived hormone adiponectin on pancreatic ß cell function in type 2 diabetes

posted on 16.01.2017, 23:49 authored by Rao, Jyothsna Rama
Type 2 diabetes is a growing concern. The World Health Organisation predicts a 114% increase by 2030. Obesity is tightly linked to type 2 diabetes. An increase in adiposity predisposes to type 2 diabetes in which insulin resistance in skeletal muscle, adipocyte and liver gives rise to hyperinsulinemia, in the early stages of the disease. This is later followed by failure of pancreatic β cells to secrete insulin. The reduction in insulin secretion could be due to a decrease in β cell number or a functional loss. Adipose tissue is now recognized as an active endocrine organ, secreting adipokines involved in energy homeostasis. Adiponectin is one of the recently discovered adipokines but, paradoxically, its levels are decreased in obesity. In skeletal muscle, adiponectin suppresses triglyceride accumulation and increases fatty acid oxidation, improving insulin signalling, and it suppresses glucose production in the liver, implicating adiponectin as an insulin sensitiser. The effects of adiponectin on pancreatic β cells are unclear. The aims of the thesis were to investigate the acute (30 min) and the longer term (24 hr) effect of full-length adiponectin on Min6 cells, a murine pancreatic β cell line, in a bid to determine if the hormone improved pancreatic β cell function in conditions of diabetes. The first study (chapter 3) confirmed the presence of adiponectin receptors adipoQRl and adipoQR2 in these cells using real time PCR. The mRNA for adipoQRl was 2-fold greater than adipoQR2. Next, we investigated the regulation of gene expression of adipoQ receptors in conditions of high glucose (25mM), high insulin (10nM) and high fat (l-2mM). Our findings suggest that adipoQR1 is upregulated by 25mM glucose whereas adipoQR2 is downregulated. High insulin downregulated both receptors, while high fat upregulated their gene expression. Exogenous adiponectin upregulated both receptors in high glucose conditions. Our next study (chapter 4) investigated the effect of adiponectin (2µg/ml) on insulin secretion in basal (3mM) glucose. Acute (30min) application of adiponectin increased insulin levels in basal glucose (3mM) that was associated with an immediate (within I min) increase in [Ca2⁺]i. These adiponectin-induced increases in insulin and [Ca2⁺]i were comparable with those evoked by high glucose (25mM)stimulation This increase in [Ca2⁺]i was prevented by nifedipine, a blocker of L-type Ca2⁺ channels, and did not occur in Ca2⁺ free solution. The depolarisation required to achieve opening of the L-type Ca2⁺ channels by adiponectin appeared to be via the activation of C1⁻ channels. Our third study (chapter 5) investigated the effect of adiponectin on AMPK activity in 3mM glucose in 30 min using Western blotting. Adiponectin inhibited the phosphorylation of AMPK which was comparable with that of 25mM glucose. Our fourth study (chapter 6) examined the longer term effect of adiponectin on pancreatic β cell number. Thiazolidinediones are insulin sensitizers and ligands for peroxisome proliferator-activated γ receptors (PPARγ). PPARγ have been demonstrated in ~ cells and their activation promotes β cell survival. We hypothesized that adiponectin activates PPARγ in β cells, promoting survival, in 24 hrs. The aims were to investigate the effect of adiponectin on PPARγ message and protein by real-time PCR and western blotting. We also investigated adiponectin's effect on β cell proliferation by quantitating DNA content and examined glucosestimulated insulin secretion and insulin content via PPARγ using ELISA. Our findings showed that adiponectin significantly activated PPARγ message and strongly tended to increase protein. While PPARγ activation caused a significant increase in insulin content, it had no effect on glucose-stimulated insulin secretion. Furthermore, adiponectin also increased β cell number significantly, but this effect was not via PPARγ. In conclusion, our studies reveal the potential role of adiponectin as a novel therapeutic target in the treatment of diabetes.


Principal supervisor

Helena Cecilia Parkington

Year of Award


Department, School or Centre


Campus location



Doctor of Philosophy

Degree Type



Faculty of Medicine Nursing and Health Sciences