Diabetes in numbers

Scully, Tony

doi:10.1038/485s2a

Cited by 274 publications

(227 citation statements)

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“…Sub-Saharan Africa is not excluded from this rapid rise in prevalence, which is predicted to double within the next 20 years. (1,2) In addition to these factors, the sub-Saharan region suffers from high mortality from infectious diseases such as HIV infection, tuberculosis and malaria. It is, however, predicted that by 2020 the mortality from non-communicable diseases will overtake that of infections as the major source of mortality.…”

Section: Introductionmentioning

confidence: 99%

Diabetes care and complications in primary care in the Tshwane district of South Africa

Webb

Rheeder

Zyl

2015

Primary Care Diabetes

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Aims: To describe the diabetic population receiving primary care from the Tshwane district public health services and to assess the quality of care of members of this population, their level of disease control and the extent of their complications. Methods:A cluster-randomised trial was conducted in 12 primary care clinics in Tshwane district. A total of 599 diabetic patients attending these clinics for review were consecutively interviewed and clinically examined. Data on the care received was also obtained from their clinical records for the previous 12 months. Patients randomised to the active arm of the study were screened for complications. Results:The mean age was 58 years and 80.5% had a body mass index (BMI) ≥ 25kg/m 2 . Sixty-eight percent of patients were female. Acceptable glycaemic control and LDL-cholesterol were found for only 27% and 33% of patients respectively (HbA1c<7%; LDL <2.5 mmol/l). Despite more than 79% of patients reporting to be hypertensive, 68% of patients had a systolic blood pressure above 130 mmHg and 64% had a diastolic blood pressure above 80 mmHg. Evaluating patient records of the preceding year, screening for eye complications was only reported in 8.2%, feet complications in 6.5%, kidney complications in 21.4% and cardiovascular complications in 7.8%. The screening prevalences found were 29% for retinopathy, 22% for maculopathy, 5% for neuropathy (neurothesiometer), 7% for nephropathy (eGFR stage3-5), 17% for possible infarction (Rose questionnaire) and 36% for severe erectile dysfunction (SHIM questionnaire). Conclusion:Diabetes care and screening for complications at primary care level in the Tshwane district were found to be sub-optimal. Measures should be taken to address this.

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Section: Introductionmentioning

confidence: 99%

Diabetes care and complications in primary care in the Tshwane district of South Africa

Webb

Rheeder

Zyl

2015

Primary Care Diabetes

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“…1,2 In 2008, World Health Organization estimated the number of overweight and obese adults worldwide to be 1 billion and 500 million, respectively. In 2009−2010, more than one-third of the American population was classified as obese.…”

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confidence: 99%

Potent DGAT1 Inhibitors in the Benzimidazole Class with a Pyridyl-oxy-cyclohexanecarboxylic Acid Moiety

Hong

Lai

et al. 2013

ACS Med. Chem. Lett.

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We report the design and synthesis of a series of novel DGAT1 inhibitors in the benzimidazole class with a pyridyl-oxy-cyclohexanecarboxylic acid moiety. In particular, compound 11A is a potent DGAT1 inhibitor with excellent selectivity against ACAT1. Compound 11A significantly reduces triglyceride excursion in lipid tolerance tests (LTT) in both mice and dogs at low plasma exposure. An in vivo study in mice with des-fluoro analogue 10A indicates that this series of compounds appears to distribute in intestine preferentially over plasma. The propensity to target intestine over plasma could be advantageous in reducing potential side effects since lower circulating levels of drug are required for efficacy. However, in the preclinical species, compound 11A undergoes cis/trans epimerization in vivo, which could complicate further development due to the presence of an active metabolite. KEYWORDS: DGAT1, inhibitor, benzimidazole, ACAT1, cyclohexanecarboxylic acid, lipid tolerance test, epimerization, metabolite T ype II diabetes mellitus (T2DM) and obesity, two interlinked disease conditions, have emerged as the major threats to human health globally. 1,2 In 2008, World Health Organization estimated the number of overweight and obese adults worldwide to be 1 billion and 500 million, respectively. In 2009−2010, more than one-third of the American population was classified as obese. 3 Meanwhile, a recent estimate indicates that there are about 371 million people worldwide living with diabetes. 4 Current drugs available to treat diabetes and obesity have limitations in terms of longterm efficacy and/or side effects. 5−7 The unmet need prompts significant research efforts in this area.Inhibition of DGAT1 (diglyceride acyltransferase 1) has emerged as a potential mechanism for the treatment of T2DM and obesity. 8,9 The DGAT family (diglyce diglyceride acyltransferase 1 and 2) catalyzes the formation of triglyceride (TG) from diacylglycerol and acyl-CoA, the terminal and committed step in TG synthesis. 10 DGAT1 shares only limited sequence homology with DGAT2, the other known isoform. 11 In contrast, DGAT1 has more sequence homology to acyl CoA:cholesterol acyltransferase (ACAT1 and ACAT2). ACAT plays an important role in cholesterol homeostasis. 12 The strong interest in DGAT1 started after the reports on DGAT1 knockout mouse phenotyping studies. DGAT1 knockout mice were shown to be viable and resistant to diet-induced obesity. 13 Furthermore, these mice appeared to have increased sensitivity to insulin and leptin. 14 This compelling data set has inspired major efforts in identifying small molecule DGAT1 inhibitors for potential treatment of diabetes and obesity (Figure 1

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“…T ype 2 diabetes (T2D) is an increasing global health problem (1). Although genome-wide association studies (GWAS) have yielded more than 70 loci associated with T2D or related traits (2, 3), they have not provided the expected breakthrough in our understanding of the pathogenesis of the disease.…”

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confidence: 99%

Global genomic and transcriptomic analysis of human pancreatic islets reveals novel genes influencing glucose metabolism

Fadista

Vikman

Laakso

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

425

535

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Genetic variation can modulate gene expression, and thereby phenotypic variation and susceptibility to complex diseases such as type 2 diabetes (T2D). Here we harnessed the potential of DNA and RNA sequencing in human pancreatic islets from 89 deceased donors to identify genes of potential importance in the pathogenesis of T2D. We present a catalog of genetic variants regulating gene expression (eQTL) and exon use (sQTL), including many long noncoding RNAs, which are enriched in known T2D-associated loci. Of 35 eQTL genes, whose expression differed between normoglycemic and hyperglycemic individuals, siRNA of tetraspanin 33 (TSPAN33), 5′-nucleotidase, ecto (NT5E), transmembrane emp24 protein transport domain containing 6 (TMED6), and p21 protein activated kinase 7 (PAK7) in INS1 cells resulted in reduced glucose-stimulated insulin secretion. In addition, we provide a genome-wide catalog of allelic expression imbalance, which is also enriched in known T2D-associated loci. Notably, allelic imbalance in paternally expressed gene 3 (PEG3) was associated with its promoter methylation and T2D status. Finally, RNA editing events were less common in islets than previously suggested in other tissues. Taken together, this study provides new insights into the complexity of gene regulation in human pancreatic islets and better understanding of how genetic variation can influence glucose metabolism.T ype 2 diabetes (T2D) is an increasing global health problem (1). Although genome-wide association studies (GWAS) have yielded more than 70 loci associated with T2D or related traits (2, 3), they have not provided the expected breakthrough in our understanding of the pathogenesis of the disease. They have nonetheless pointed at a central role of the pancreatic islets and β-cell dysfunction in the development of the disease (4, 5). It therefore seems pertinent to focus on human pancreatic islets to obtain insights into the molecular mechanisms causing the disease (6, 7). Given that most SNPs associated with T2D lie in noncoding regions, the majority of causal variants are likely to regulate gene expression rather than protein function per se. Therefore, combination of DNA and RNA sequencing in the same individuals may help to disentangle the role these SNPs play in the pathogenesis of the disease (8). Although the human pancreatic islet transcriptome has been previously described (6, 9-18), using microarrays or RNA sequencing of a limited number of nondiabetic individuals, this has not allowed a more global analysis of the complexity of the islet transcriptome in T2D. Here we combined genotypic imputation, expression microarrays, and exome and RNA sequencing (ExomeSeq and RNA-Seq) in a large number of human pancreatic islets from deceased donors with and without T2D. This study identified a number of novel genes, including long intergenic noncoding RNAs (lincRNAs), whose expression and/or splicing influences insulin secretion and is associated with glycemia. In addition, we provide a catalog of RNA editing and allele-specific expr...

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Diabetes in numbers

Cited by 274 publications

References 2 publications

Diabetes care and complications in primary care in the Tshwane district of South Africa

Diabetes care and complications in primary care in the Tshwane district of South Africa

Potent DGAT1 Inhibitors in the Benzimidazole Class with a Pyridyl-oxy-cyclohexanecarboxylic Acid Moiety

Global genomic and transcriptomic analysis of human pancreatic islets reveals novel genes influencing glucose metabolism

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