Type 2 diabetes: Pathogenesis and treatment. Lancet, 371(9631), 2153-2156

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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    • "The mechanisms of the genesis and progression of DMII are unclear. Although obesity, high-sugar and fat-rich diets are well established predisposition factors for the disease (Zimmet et al., 2001; Venables and Jeukendrup, 2009), genetic risk factors have also been proposed (Stumvoll et al., 2008; Ridderstrale and Groop, 2009). Noteworthy, association between IDE loss-of-function and DMII has been reported, as human populations with mutations in the IDE locus display increased incidence of this disease (Karamohamed et al., 2003; Rudovich et al., 2009). "
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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.
    Full-text · Article · Jan 2014 · Molecular biology of the cell
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    • "In the present study, diabetic patients had higher insulin resistance, which is in accordance with the current understanding of the pathogenesis of diabetes.[40] However, if we consider a cut-off of 2.6 for HOMA-IR as an indicator of insulin resistance in patients with normoglycemia[41] and 3.8 in patients with diabetes,[42] both groups had evidence of underlying severe insulin resistance. "
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    ABSTRACT: There is an increase in awareness about the role of nutritional factors in chronic non-communicable diseases. We therefore conducted this study with an aim to assess the relationship between nutritional factor (vitamin B12 and homocysteine [Hcy]) and its association with insulin resistance and inflammatory markers, and differences in traditional and non-traditional risk factors among diabetics and non-diabetics in known cases of coronary artery disease (CAD). Three hundred consecutive patients with known coronary disease on coronary angiography, who were >25 years old were included in this study. All cases were interviewed using a questionnaire. Blood samples were analyzed for insulin, vitamin B12, Hcy and inflammatory markers (highly sensitive C-reactive protein [hsCRP], interleukin-6 [IL-6], Tumor necrosis factor-alfa [TNF-α]). Insulin resistance was calculated with homeostasis model assessment of insulin resistance (HOMA-IR). Mean age of the patients was 60.95 ± 12.3 years. Body mass index and waist hip ratio were comparable in both groups. Triglyceride, very low-density lipoprotein and HbA1C were significantly higher and high-density lipoprotein (HDL) was significantly lower in patients with diabetes. Patients with diabetes had significantly high levels of IL-6, hsCRP and TNF-α compared with non-diabetic patients. Insulin resistance was twofold higher in diabetic patients. Serum vitamin B12 levels were significantly lower and Hcy was significantly higher in the diabetic group compared with the non-diabetic patients. HbA1C, HOMA-IR and Hcy levels were positively correlated with inflammatory markers in the total study population and in the non-diabetic patients; but, in diabetic patients, HbA1C and Hcy showed this relation. Vitamin B12 deficiency is common in the diabetic population. Hcy levels were higher in diabetics compared with non-diabetics, and were related to glycemic level and insulin resistance in diabetic patients. Patients with diabetes had higher traditional risk factors than patients without diabetes in known patients with CAD. Glycemic status was associated with insulin resistance and inflammatory markers.
    Full-text · Article · Mar 2013
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    • "Due to changes in food structure and lifestyle, the global incidence of T2DM has become much higher [38]. In addition to insulin resistance and impaired function of pancreatic β-cells in patients with T2DM [39], [40], this study focused on insulin secretion affected by 5-HT2CR, which has been suggested the possibility that an abnormal 5-HT system could also affect regulation of energy metabolism [41]. "
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    ABSTRACT: Type 2 diabetes mellitus (T2DM) describes a group of metabolic disorders characterized by defects in insulin secretion and insulin sensitivity. Insulin secretion from pancreatic β-cells is an important factor in the etiology of T2DM, though the complex regulation and mechanisms of insulin secretion from β-cells remains to be fully elucidated. High plasma levels of serotonin (5-hydroxytryptamine; 5-HT) have been reported in T2DM patients, though the potential effect on insulin secretion is unclear. However, it is known that the 5-HT receptor 2C (5-HT(2C)R) agonist, mCPP, decreases plasma insulin concentration in mice. As such, we aimed to investigate the expression of the 5-HT(2C)R in pancreatic islets of diabetic mice and the role of 5-HT(2C)R signaling in insulin secretion from pancreatic β-cells. We found that 5-HT(2C)R expression was significantly increased in pancreatic islets of db/db mice. Furthermore, treatment with a 5-HT(2C)R antagonist (SB242084) increased insulin secretion from pancreatic islets isolated from db/db mice in a dose-dependent manner, but had no effect in islets from control mice. The effect of a 5-HT(2C)R agonist (mCPP) and antagonist (SB242084) were further studied in isolated pancreatic islets from mice and Min-6 cells. We found that mCPP significantly inhibited insulin secretion in Min-6 cells and isolated islets in a dose-dependent manner, which could be reversed by SB242084 or RNA interference against 5-HT(2C)R. We also treated Min-6 cells with palmitic acid for 24 h, and found that the expression of 5-HT(2C)R increased in a dose-dependent manner; furthermore, the inhibition of insulin secretion in Min-6 cells induced by palmitic acid could be reversed by SB242084 or RNA interference against 5-HT(2C)R. Taken together, our data suggests that increased expression of 5-HT(2C)R in pancreatic β-cells might inhibit insulin secretion. This unique observation increases our understanding of T2DM and suggests new avenues for potential treatment.
    Full-text · Article · Jan 2013 · PLoS ONE
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