Faculty of Medicine and Surgery
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Item Genetic Association of Adrenergic Receptor Alpha 2a with Obesity and Type 2 Diabetes(Original Article EPIDEMIOLOGY/GENETICS, 2013) La ̊ ngberg,Ewa-Carin; Ahmed,Mohammed Seed; Efendic,Suad; Gu,Harvest F; Ostenson,Claes-GoranObjective: The sympathetic nervous system (SNS) is linked to glucose, lipid, and protein metabolism. The a2A-adrenergic receptor (ADRA2A) is involved in the SNS and mediates inhibition of insulin secretion and lipolysis. The association of ADRA2A single-nucleotide polymorphisms (SNPs) with obesity and/or type 2 diabetes (T2D) was investigated. Design and Methods: Genotyping was performed in a case–control study of 1,177 Swedish individuals, including lean and obese subjects with normal glucose tolerance (NGT) and T2D patients. ADRA2A mRNA expression was measured in pancreatic islets isolated from T2D patients and nondiabetic subjects. Results: SNP rs553668 was associated with T2D in men (odds ratio [OR] 1⁄4 1.47; 95% confidence interval [CI] 1⁄4 1.08–2.01; P 1⁄4 0.015) but this association was lost after adjusting for age and for body mass index (BMI). Associations were also detected when comparing obese NGT and lean NGT subjects (OR 1⁄4 1.49; 95% CI 1⁄4 1.07–2.07; P 1⁄4 0.017), and in obese (OR 1⁄4 1.62; 95% CI 1⁄4 1.06–2.49; P 1⁄4 0.026), but not in lean T2D. In women, multiple logistic regression regarding SNP rs521674 demonstrated an increased OR of 7.61 (95% CI 1⁄4 1.70–34.17; P 1⁄4 0.008) for T2D when including age as a covariant. Correcting for BMI removed the significant association. When age was included in the model, association also found when obese T2D patients were compared with lean NGT subjects (P 1⁄4 0.041). ADRA2A mRNA expression in human pancreatic islets was detectable, but with no statistically significant difference between the diabetic and the control groups. Conclusions: ADRA2A genetic polymorphisms are mainly associated with obesity and possibly with T2D in a Swedish population.Item Expression of Protein Kinase C Isoforms in Pancreatic Islets and Liver of Male Goto- Kakizaki Rats, a Model of Type 2 Diabetes(PLOS ONE journal, 2015) Ahmed,Mohammed Seed; Pelletier,Julien; Leumann,Hannes; Gu,Harvest F; Östenson,Claes-GöranProtein kinase C (PKC) is a family of protein kinases controlling protein phosphorylation and playing important roles in the regulation of metabolism. We have investigated expres- sion levels of PKC isoforms in pancreatic islets and liver of diabetic Goto-Kakizaki (GK) rats with and without insulin treatment to evaluate their association with glucose homeostasis. mRNA and protein expression levels of PKC isoforms were assessed in pancreatic islets and liver of Wistar rats and GK rats with or without insulin treatment. PKCα and PKCζ mRNA expressions were down-regulated in islets of GK compared with Wistar rats. PKCα and phosphorylated PKCα (p-PKCα) protein expressions were decreased in islets of GK compared with insulin-treated GK and Wistar rats. PKCζ protein expression in islets was reduced in GK and insulin-treated GK compared with Wistar rats, but p-PKCζ was decreased only in GK rats. Islet PKCε mRNA and protein expressions were lower in GK compared with insulin-treated GK and Wistar rats. In liver, PKCδ and PKCζ mRNA expres- sions were decreased in both GK and insulin-treated GK compared with Wistar rats. Hepatic PKCζ protein expression was diminished in both GK rats with and without insulin treatment compared with Wistar rats. Hepatic PKCε mRNA expression was down-regulated in insulin- treated GK compared with GK and Wistar rats. PKCα, PKCε, and p-PKCζ expressions were secondary to hyperglycaemia in GK rat islets. Hepatic PKCδ and PKCζ mRNA expressions were primarily linked to hyperglycaemia. Additionally, hepatic PKCε mRNA expression could be under control of insulin.Item Increased expression of adenylyl cyclase 3 in pancreatic islets and central nervous system of diabetic Goto-Kakizaki rats(Journaltandfonline, 2012) Ahmed,Mohammed Seed; Kovoor,Abraham; Nordman,Sofia; Abu Seman,Norhashimah; Gu,Tianwei; Efendic,Suad; Brismar,Kerstin; Östenson,Claes-Göran; Gu,Harvest FAdenylyl cyclase 3 (AC3) is expressed in pancreatic islets of the Goto-Kakizaki (GK) rat, a spontaneous animal model of type 2 diabetes (T2D), and also exerts genetic effects on the regulation of body weight in man. In addition to pancreatic islets, the central nervous system (CNS) plays an important role in the pathogenesis of T2D and obesity by regulating feeding behavior, body weight and glucose metabolism. In the present study, we have investigated AC3 expression in pancreatic islets, striatum and hypothalamus of GK rats to evaluate its role in the regulation of glucose homeostasis. GK and Wistar rats at the age of 2.5 mo were used. A group of GK rats were implanted with sustained insulin release chips for 15 d. Plasma glucose and serum insulin levels were measured. AC3 gene expression levels in pancreatic islets, striatum and hypothalamus were determined by using real-time RT-PCR. Results indicated that plasma glucose levels in Wistar rats were found to be similar to insulin-treated GK rats, and significantly lower compared with non-treated GK rats. AC3 expression levels in pancreatic islets, striatum and hypothalamus of GK rats were higher compared with Wistar rats, while the levels were intermediate in insulin-treated GK rats. The AC3 expression display patterns between pancreatic islets and striatum-hypothalamus were similar. The present study thus provides the first evidence that AC3 is overexpressed in the regions of striatum and hypothalamus of brain, and similarly in pancreatic islets of GK rats suggesting that AC3 plays a role in regulation of glucose homeostasis via CNS and insulin secretion.