Type 2 diabetes: pathogenesis and treatment

Department of Medicine, University of Leipzig, Leipzig, Germany.
The Lancet (Impact Factor: 45.22). 07/2008; 371(9631):2153-6. DOI: 10.1016/S0140-6736(08)60932-0
Source: PubMed
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    ABSTRACT: Mammalian Insulin Degrading Enzyme (IDE) cleaves insulin among other peptidic substrates but its function in insulin signaling remains elusive. We have used the Drosophila system to define the function of IDE in the regulation of growth and metabolism. We found that either loss- or gain of function of Drosophila IDE (dIDE) can restrict growth in a cell autonomous manner by affecting both cell size and cell number. dIDE can modulate dILP2 levels, thereby restricting activation of the PI3K pathway and promoting activation of FOXO. Larvae reared in high sucrose exhibit delayed developmental timing due to insulin resistance. We found that dIDE loss of function exacerbates these phenotypes and that mutants display increased levels of circulating sugar, along with augmented expression of a lipid biosynthesis marker. We propose that dIDE is a modulator of insulin signaling, and that its loss of function favors insulin resistance, a hallmark of diabetes mellitus type II.
    Molecular biology of the cell 01/2014; 25(6). DOI:10.1091/mbc.E13-04-0213 · 5.98 Impact Factor
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    ABSTRACT: AIMS/HYPOTHESIS: Glucose metabolism marks health and disease and is causally inferred in the aging process. Ambulant continuous glucose monitoring provides 24-hour glucose rhythms under daily-life conditions. We aimed to describe ambulant 24-hour glucose rhythms measured under daily-life condition in relation to calendar and biological age in apparently healthy individuals. METHODS: In the general population and families with propensity for longevity, we studied parameters from 24-hour glucose rhythms; glucose levels and its variability, obtained by continuous glucose monitoring. Participants were 21 young (aged 22 to 37 years), 37 middle-aged (aged 44 to 72 years) individuals from the general population, and 26 middle-aged (aged 52 to 74 years) individuals with propensity for longevity. All were free of diabetes. RESULTS: Compared to young individuals, middle-aged individuals from the general population had higher mean glucose levels (5.3 vs 4.7 mmol/L, p <0.001), both diurnally (p <0.001) and nocturnally (p = 0.002). Glucose variability was higher in the middle-aged compared to the young (standard deviation 0.70 vs 0.57 mmol/L, p = 0.025). Compared to middle-aged individuals from the general population, middle-aged individuals with propensity for longevity had lower overall mean glucose levels (5.2 vs 5.4 mmol/L, p = 0.047), which were more different nocturnally (4.8 vs 5.2 mmol/L, p = 0.003) than diurnally (5.3 vs 5.5 mmol/L, p = 0.14). There were no differences in glucose variability between these groups. Results were independent of body mass index. CONCLUSIONS: Among individuals without diabetes, we observed significantly different 24-hour glucose rhythms depending on calendar and biological age. © 2012 The Authors Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.
    Aging cell 12/2012; DOI:10.1111/acel.12042 · 5.94 Impact Factor
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    ABSTRACT: Type 2 diabetes (T2D) and obesity represent major challenges for global public health. They are at the forefront of international efforts to identify the genetic variation contributing to complex disease susceptibility, and recent years have seen considerable success in identifying common risk-variants. Given the clinical impact of molecular diagnostics in rarer monogenic forms of these diseases, expectations have been high that genetic discoveries will transform the prospects for risk stratification, development of novel therapeutics and personalised medicine. However, so far, clinical translation has been limited. Difficulties in defining the alleles and transcripts mediating association effects have frustrated efforts to gain early biological insights, whilst the fact that variants identified account for only a modest proportion of observed familiarity has limited their value in guiding treatment of individual patients. Ongoing efforts to track causal variants through fine-mapping and to illuminate the biological mechanisms through which they act, as well as sequence-based discovery of lower-frequency alleles (of potentially larger effect), should provide welcome acceleration in the capacity for clinical translation. This review will summarise recent advances in identifying risk alleles for T2D and obesity, and existing contributions to understanding disease pathology. It will consider the progress made in translating genetic knowledge into clinical utility, the challenges remaining, and the realistic potential for further progress.
    Human Genetics 06/2011; 130(1):41-58. DOI:10.1007/s00439-011-1023-8 · 4.52 Impact Factor


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