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Biomedical subjects

Susan F Murray

Publications and source records attributed to Susan F Murray.

9 recordsLinked to original sources
PubMed2006

Deficiency of adiponectin receptor 2 reduces diet-induced insulin resistance but promotes type 2 diabetes.

Adiponectin/adiponectin receptors (AdipoR) are involved in energy homeostasis and inflammatory pathways. To investigate the role of AdipoR2 in metabolic control, we studied the lipid and glucose metabolic phenotypes in AdipoR2-deficient mice. AdipoR2 deletion diminished high-fat diet-induced dyslipidemia and insulin resistance yet deteriorated glucose homeostasis as high-fat feeding continued, which resulted from the failure of pancreatic beta-cells to adequately compensate for the moderate insulin resistance. A defect in the AdipoR2 gene may represent a mechanism underlying the etiology of certain subgroups of type 2 diabetic patients who eventually develop overt diabetes, whereas other obese patients do not.

Animals↗
PubMed2006

miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting.

Current understanding of microRNA (miRNA) biology is limited, and antisense oligonucleotide (ASO) inhibition of miRNAs is a powerful technique for their functionalization. To uncover the role of the liver-specific miR-122 in the adult liver, we inhibited it in mice with a 2'-O-methoxyethyl phosphorothioate ASO. miR-122 inhibition in normal mice resulted in reduced plasma cholesterol levels, increased hepatic fatty-acid oxidation, and a decrease in hepatic fatty-acid and cholesterol synthesis rates. Activation of the central metabolic sensor AMPK was also increased. miR-122 inhibition in a diet-induced obesity mouse model resulted in decreased plasma cholesterol levels and a significant improvement in liver steatosis, accompanied by reductions in several lipogenic genes. These results implicate miR-122 as a key regulator of cholesterol and fatty-acid metabolism in the adult liver and suggest that miR-122 may be an attractive therapeutic target for metabolic disease.

AMP-Activated Protein Kinases↗
PubMed2005

Maternity referral systems in developing countries: current knowledge and future research needs.

A functioning referral system is generally considered to be a necessary element of successful Safe Motherhood programmes. This paper draws on a scoping review of available literature to identify key requisites for successful maternity referral systems in developing countries, to highlight knowledge gaps, and to suggest items for a future research agenda. Key online social science, medical and health system bibliographic databases, and websites were searched in July 2004 for evidence relating to referral systems for maternity care. Documentary evidence on implementation is scarce, but it suggests that many healthcare systems in developing countries are failing to optimise women's rapid access to emergency obstetric care, and that the poor and marginalised are affected disproportionately. Likely requisites for successful maternity referral systems include: a referral strategy informed by the assessment of population needs and health system capabilities; an adequately resourced referral centre; active collaboration between referral levels and across sectors; formalised communication and transport arrangements; agreed setting-specific protocols for referrer and receiver; supervision and accountability for providers' performance; affordable service costs; the capacity to monitor effectiveness; and underpinning all of these, policy support. Theoretically informed social and organisational research is required on the referral care needs of the poor and marginalised, on the maternity workforce and organisation, and on the implications of the mixed economy of healthcare for referral networks. Clinical research is required to determine how maternity referral fits within newborn health priorities and where the needs are different. Finally, research is required to determine how and whether a more integrated approach to emergency care systems may benefit women and their communities.

Developing Countries↗
PubMed2005

Postpartum maternal morbidity requiring hospital admission in Lusaka, Zambia - a descriptive study.

BACKGROUND: Information on the extent of postpartum maternal morbidity in developing countries is extremely limited. In many settings, data from hospital-based studies is hard to interpret because of the small proportion of women that have access to medical care. However, in those areas with good uptake of health care, the measurement of the type and incidence of complications severe enough to require hospitalisation may provide useful baseline information on the acute and severe morbidity that women experience in the early weeks following childbirth. An analysis of health services data from Lusaka, Zambia, is presented. METHODS: Six-month retrospective review of hospital registers and 4-week cross-sectional study with prospective identification of postpartum admissions. RESULTS: Both parts of the study identified puerperal sepsis and malaria as, respectively, the leading direct and indirect causes of postpartum morbidity requiring hospital admission. Puerperal sepsis accounted for 34.8% of 365 postpartum admissions in the 6-month period. Malaria and pneumonia together accounted for one-fifth of all postpartum admissions (14.5% & 6% respectively). At least 1.7% of the postpartum population in Lusaka will require hospital-level care for a maternal morbidity. CONCLUSIONS: In developing country urban settings with high public health care usage, meticulous review of hospital registers can provide baseline information on the burden of moderate-to-severe postpartum morbidity.

Journal Article↗
PubMed2005

Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice.

In this study, we investigated the role of acyl-coenzyme A:diacylglycerol acyltransferase 2 (DGAT2) in glucose and lipid metabolism in obese mice by reducing its expression in liver and fat with an optimized antisense oligonucleotide (ASO). High-fat diet-induced obese (DIO) C57BL/6J mice and ob/ob mice were treated with DGAT2 ASO, control ASO, or saline. DGAT2 ASO treatment reduced DGAT2 messenger RNA (mRNA) levels by more than 75% in both liver and fat but did not change DGAT1 mRNA levels in either of these tissues, which resulted in decreased DGAT activity in liver but not in fat. DGAT2 ASO treatment did not cause significant changes in body weight, adiposity, metabolic rate, insulin sensitivity, or skin microstructure. However, DGAT2 ASO treatment caused a marked reduction in hepatic triglyceride content and improved hepatic steatosis in both models, which was consistent with a dramatic decrease in triglyceride synthesis and an increase in fatty acid oxidation observed in primary mouse hepatocytes treated with DGAT2 ASO. In addition, the treatment lowered hepatic triglyceride secretion rate and plasma triglyceride levels, and improved plasma lipoprotein profile in DIO mice. The positive effects of the DGAT2 ASO were accompanied by a reduction in the mRNA levels of several hepatic lipogenic genes, including SCD1, FAS, ACC1, ACC2, ATP-citrate lyase, glycerol kinase, and HMG-CoA reductase. In conclusion, reduction of DGAT2 expression in obese animals can reduce hepatic lipogenesis and hepatic steatosis as well as attenuate hyperlipidemia, thereby leading to an improvement in metabolic syndrome.

Acyltransferases↗
PubMed2005

The promotion of private health insurance and its implications for the social organisation of healthcare: a case study of private sector obstetric practice in Chile.

This paper examines some of the implications of the process of privatisation of a national healthcare system for the delivery, organisation and, ultimately, the outcome of services. Through a case study of obstetric care in Chile, we illuminate the relationships between the macro-level of political decisions, the meso-level of the organisations through which government reforms were enacted, and the micro-level of clinical practice. We show that, for a significant proportion of Chilean women seeking maternity care, privatisation has led to expanded access and to ostensibly highly-personalised relationships with specialists. However, because of the fragmentation of maternity services, the altered work patterns for obstetricians occasioned by changes in healthcare financing and the relatively weak market position of most obstetricians, this personalised care is dependent on highly technologised obstetric practices. By examining the specific organisational arrangements under which private maternity care is conducted in Chile we shed light on the connection between privately-funded maternity care and high caesarean section rates in this setting.

Chile↗
PubMed2002

PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice.

The role of protein-tyrosine phosphatase 1B (PTP1B) in diabetes was investigated using an antisense oligonucleotide in ob/ob and db/db mice. PTP1B antisense oligonucleotide treatment normalized plasma glucose levels, postprandial glucose excursion, and HbA(1C). Hyperinsulinemia was also reduced with improved insulin sensitivity. PTP1B protein and mRNA were reduced in liver and fat with no effect in skeletal muscle. Insulin signaling proteins, insulin receptor substrate 2 and phosphatidylinositol 3 (PI3)-kinase regulatory subunit p50alpha, were increased and PI3-kinase p85alpha expression was decreased in liver and fat. These changes in protein expression correlated with increased insulin-stimulated protein kinase B phosphorylation. The expression of liver gluconeogenic enzymes, phosphoenolpyruvate carboxykinase, and fructose-1,6-bisphosphatase was also down-regulated. These findings suggest that PTP1B modulates insulin signaling in liver and fat, and that therapeutic modalities targeting PTP1B inhibition may have clinical benefit in type 2 diabetes.

Adipose Tissue↗
PubMed2002

Specific inhibition of PTEN expression reverses hyperglycemia in diabetic mice.

Signaling through the phosphatidylinositol 3'-kinase (PI3K) pathway is crucial for metabolic responses to insulin, and defects in PI3K signaling have been demonstrated in type 2 diabetes. PTEN (MMAC1) is a lipid/protein phosphatase that can negatively regulate the PI3K pathway by dephosphorylating phosphatidylinositol (3,4,5)-triphosphate, but it is unclear whether PTEN is physiologically relevant to insulin signaling in vivo. We employed an antisense oligonucleotide (ASO) strategy in an effort to specifically inhibit the expression of PTEN. Transfection of cells in culture with ASO targeting PTEN reduced PTEN mRNA and protein levels and increased insulin-stimulated Akt phosphorylation in alpha-mouse liver-12 (AML12) cells. Systemic administration of PTEN ASO once a week in mice suppressed PTEN mRNA and protein expression in liver and fat by up to 90 and 75%, respectively, and normalized blood glucose concentrations in db/db and ob/ob mice. Inhibition of PTEN expression also dramatically reduced insulin concentrations in ob/ob mice, improved the performance of db/db mice during insulin tolerance tests, and increased Akt phosphorylation in liver in response to insulin. These results suggest that PTEN plays a significant role in regulating glucose metabolism in vivo by negatively regulating insulin signaling.

3T3 Cells↗