Differentially expressed genes associated with obesity and type 2 diabetes

The present invention relates to nucleic acid molecules which encode expression products associated with the modulation of obesity, anorexia, weight maintenance, diabetes and/or metabolic energy levels. The nucleic acid molecules and expression products of the present invention are produced by recombinant means or isolated from natural resources. The subject nucleic acid molecules and expression products and their derivatives, homologs, analogs and mimetics are proposed to be useful as therapeutic and diagnostic agents for obesity, anorexia, weight maintenance, diabetes and/or energy imbalance or as targets for the design and/or identification of modulators of their activity and/or function. The subject nucleic acid molecules and expression products are identified using differential display techniques.

Identification of secreted proteins associated with obesity and type 2 diabetes in Psammomys obesus

Objective: Skeletal muscle produces a variety of secreted proteins that have important roles in intercellular communication and affects processes such as glucose homoeostasis. The objective of this study was to develop a novel Signal Sequence Trap (SST) in conjunction with cDNA microarray technology to identify proteins secreted from skeletal muscle of Psammomys obesus that were associated with obesity and type 2 diabetes (T2D).

Design: Secreted proteins that were differentially expressed between lean, normal glucose tolerant (NGT), overweight and impaired glucose tolerant (IGT) and obese, T2D P. obesus were isolated using SST in conjunction with cDNA microarray technology. Subsequent gene expression was measured in tissues from P. obesus by real-time PCR (RT-PCR).

Results: The SST yielded 1600 positive clones, which were screened for differential expression. A total of 91 (B6%) clones were identified by microarray to be differentially expressed between NGT, IGT and T2D P. obesus. These clones were sequenced to identify 51 genes, of which only 27 were previously known to encode secreted proteins. Three candidate genes not previously associated with obesity or type 2 diabetes, sushi domain containing 2, collagen and calcium-binding EGF domains 1 and periostin (Postn), as well as one gene known to be associated, complement component 1, were shown by RT-PCR to be differentially expressed in  skeletal muscle of P. obesus. Further characterization of the secreted protein Postn revealed it to be predominantly expressed in adipose tissue, with higher expression in visceral compared with subcutaneous adipose depots.

Conclusion: SST in conjunction with cDNA microarray technology is a powerful tool to identify differentially expressed secreted proteins involved in complex diseases such as obesity and type 2 diabetes. Furthermore, a number of candidate genes were identified, in particular, Postn, which may have a role in the development of obesity and type 2 diabetes.

The effectiveness of physical activity interventions for the treatment of overweight and obesity and type 2 diabetes

This review summarises current evidence relating to the effectiveness of physical activity (PA) interventions for treating overweight and obesity and type 2 diabetes. Interventions to increase PA for the treatment of overweight and obesity in both children and adults have primarily consisted of health education and behaviour modification strategies in clinical settings or with selected families or individuals. Although evidence is limited, strategies to reduce sedentary behaviours appear to have potential for reducing obesity among children and adolescents. Among adults, strategies that combine diet and PA are more effective than PA strategies alone. Combined lifestyle strategies are most successful for maintained weight loss, although most programs are unsuccessful in producing long-term changes. There is little evidence about compliance to prescribed behaviour changes or the factors that promote or hinder compliance to lifestyle changes. Limited evidence suggests that continued professional contact and self-help groups can help sustain weight loss. Most of the interventions for the treatment of type 2 diabetes have been conducted in clinical settings and have typically required the use of extensive resources. Evidence suggests that interventions can lead to small but clinically meaningful improvements in glycaemic control, even in the absence of weight loss. A recent study demonstrated that a multifactorial intervention (diet, PA and pharmaceutical) can reduce the risk of diabetes complications in individuals with type 2 diabetes. Nevertheless, there is little evidence about the effectiveness of community-based interventions in producing long-term changes in glycaemic control and reduced mortality in people with type 2 diabetes.

Novel secreted proteins involved in obesity and type 2 diabetes

A signal sequence trap was utilised to identify secreted proteins which were differentially expressed in key metabolic tissues associated with obesity and type 2 diabetes. Decorin and periostin were identified and functionally characterised as novel secreted proteins associated with the pathophysiology of these conditions.

Examination of the effect of mental reinstatement of context acress developmental level, retention interval and type of mnemonic instruction

The effect of mental reinstatement of context was examined using a 4*5*2 factorial design incorporating four age groups (6-year-olds, 8-year-olds, 11-year-olds and adults), two retention intervals (1 day and 2 weeks after the stimulus event) and five interview conditions. The interview conditions included; free recall, mental reinstatement-environment (where the setting was reinstated but no event-related detail was provided in the mnemonic instruction), mental reinstatement-event (where specific event-related content was provided), mental reinstatement-combined (a combination of the two above-mentioned methods) and specific questions. Overall, mental reinstatement (irrespective of the type) was found to enhance correct recall performance compared to free recall and (unlike specific questions) it did not lead to greater number of commission errors. Contrary to our initial predictions, however, there was no evidence of any special benefit of mental reinstatement for children and the effect of the technique did not vary consistently as a function of retention interval.

Metabolic remodelling in obesity and type 2 diabetes: pathological or protective mechanisms in response to nutrient excess?

Altered metabolism in tissues such as the liver, skeletal muscle and adipose tissue is observed in metabolic diseases characterized by nutrient excess and energy imbalance, such as obesity and type 2 diabetes. These alterations in metabolism can include resistance to the hormone insulin, lipid accumulation, mitochondrial dysfunction and transcriptional remodelling of major metabolic pathways. The underlying assumption has been that these same alterations in metabolism are fundamental to the pathogenesis of metabolic diseases. An alternative view is that these alterations in metabolism occur to protect cell and tissue viability in the face of constant positive energy balance. This speculative review presents evidence that many of the metabolic adaptations that occur in metabolic diseases characterized by nutrient excess can be viewed as protective in nature, rather than pathogenic per se for disease progression. Finally, we also briefly discuss the usefulness and potential pitfalls of therapeutic approaches that attempt to correct these same metabolic defects when energy balance is not altered, and the potential links between metabolic survival responses and other chronic diseases such as cancer.

Cancer risk among people with type 1 and type 2 diabetes: disentangling true associations, detection bias, and reverse causation

 OBJECTIVE: Evidence indicates an increased risk of certain cancers among people with type 2 diabetes. Evidence for rarer cancers and for type 1 diabetes is limited. We explored the excess risk of site-specific cancer incidence and mortality among people with type 1 and type 2 diabetes, compared with the general Australian population. RESEARCH DESIGN AND METHODS: Registrants of a national diabetes registry (953,382) between 1997 and 2008 were linked to national death and cancer registries. Standardized incidence and mortality ratios (SIRs/SMRs) are reported. RESULTS: For type 1 diabetes, significant elevated SIRs were observed for pancreas, liver, esophagus, colon and rectum (females only [F]), stomach (F), thyroid (F), brain (F), lung (F), endometrium, and ovary, and decreased SIRs were observed for prostate in males. Significantly increased SMRs were observed for pancreas, liver, and kidney (males only), non-Hodgkin's lymphoma, brain (F), and endometrium. For type 2 diabetes, significant SIRs were observed for almost all site-specific cancers, with highest SIRs observed for liver and pancreas, and decreased risks for prostate and melanoma. Significant SMRs were observed for liver, pancreas, kidney, Hodgkin's lymphoma, gallbladder (F), stomach (F), and non-Hodgkin's lymphoma (F). Cancer risk was significantly elevated throughout follow-up time but was higher in the first 3 months postregistration, suggesting the presence of detection bias and/or reverse causation. CONCLUSIONS: Type 1 and type 2 diabetes are associated with an excess risk of incidence and mortality for overall and a number of site-specific cancers, and this is only partially explained by bias. We suggest that screening for cancers in diabetic patients is important.

Focus on Vitamin D, Inflammation and Type 2 Diabetes

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)