Reviews

Rev Diabet Stud, 2009, 6(4):237-246 DOI 10.1900/RDS.2009.6.237

Mitochondrial DNA Variants in the Pathogenesis of Type 2 Diabetes - Relevance of Asian Population Studies

Pei-Wen Wang1, Tsu-Kung Lin2, Shao-Wen Weng1, Chia-Wei Liou2

1Department of Internal Medicine, Chang Gung University College of Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Kaohsiung, Taiwan 83305
2Department of Neurology, Chang Gung University College of Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Kaohsiung, Taiwan 83305
Address correspondence to: Chia-Wei Liou, e-mail: cwliou@adm.cgmh.org.tw

Abstract

Mitochondrial dysfunction involves defective insulin secretion by pancreatic beta-cells, and insulin resistance in insulin-sensitive tissues such as muscle and adipose tissue. Mitochondria are recognized as the most important cellular source of energy, and the major generator of intracellular reactive oxygen species (ROS). Intracellular antioxidative systems have been developed to cope with increased oxidative damage. In case of minor oxidative stress, the cells may increase the number of mitochondria to produce more energy. A mechanism called mitochondrial biogenesis, involving several transcription factors and regulators, controls the quantity of mitochondria. When oxidative damage is advanced beyond the repair capacity of antioxidative systems, then oxidative stress can lead to cell death. Therefore, this organelle is central to cell life or death. Available evidence increasingly shows genetic linkage between mitochondrial DNA (mtDNA) alterations and type 2 diabetes (T2D). Based on previous studies, the mtDNA 16189 variant is associated with metabolic syndrome, higher fasting insulin concentration, insulin resistance index and lacunar cerebral infarction. These data support the involvement of mitochondrial genetic variation in the pathogenesis of T2D. Importantly, phylogeographic studies of the human mtDNAs have revealed that the human mtDNA tree is rooted in Africa and radiates into different geographic regions and can be grouped as haplogroups. The Asian populations carry very different mtDNA haplogroups as compared to European populations. Therefore, it is critically important to determine the role of mtDNA polymorphisms in T2D.

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Rev Diabet Stud, 2009, 6(4):247-259 DOI 10.1900/RDS.2009.6.247

Preclinical and Clinical Data on Extraglycemic Effects of GLP-1 Receptor Agonists

Baptist Gallwitz

Department of Medicine IV, Universitätsklinikum Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany

Abstract

The diverse actions of the incretin hormone glucagon-like peptide (GLP)-1 include insulinotropic, beta-cell preservative, cardioprotective and vasodilatory effects. This spectrum makes GLP-1 an appealing therapeutic option for patients with type 2 diabetes. However, its rapid metabolism by the enzyme dipeptidyl peptidase (DPP)-4 renders it impractical. Incretin-based analogues have been developed to extend endogenous GLP-1 action (GLP-1 receptor agonists) and to hamper its degradation (DPP-4 inhibitors). Evidence suggests that GLP-1 receptor agonists and DPP-4 inhibitors have different pharmacodynamic and pharmacokinetic effects. For example, GLP-1 receptor agonists deliver supraphysiologic levels of GLP-1 analogues designed to resist inactivation by DPP-4, whereas DPP-4 inhibition conserves native GLP-1 resulting in concentrations within the physiologic range. Furthermore, GLP-1 receptor agonists induce glucose-dependent insulin secretion, beta-cell protection, and other extraglycemic benefits such as weight loss and improvement in markers of cardiovascular risk. In contrast, DPP-4 inhibitors are weight neutral and have modest effects on glucose control. DPP-4 inhibition is dependent on the availability of endogenous GLP-1, which appears to be adversely affected by type 2 diabetes and its progression. Therefore, DPP-4 inhibitors may be better suited for patients with mild hyperglycemia without comorbidities. This review examines the present understanding of the pancreatic effects of endogenous GLP-1, and the extrapancreatic actions it exerts on human bodily systems. Also, it analyzes available preclinical and clinical data on incretin therapies with respect to glycemia, lipids, blood pressure, and weight.

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