Clinical and Metabolic Consequences of Type 1 and 2 Diabetes - Dissertation Example

Current research in and the clinical and metabolic consequences of type and 2 diabetes Diabetes mellitus is a metabolic disease which essentially is associated with a hyperglycemic state and carbohydrate intolerance. The general classification of diabetes comprises of 2 large clinical groups, type 1 and type 2. The hallmark of both types of diabetes is decreased functional β-cell mass (Donath and Ehses, 2006). In type 1 diabetes, which is commonly encountered in children, a complete loss of insulin production occurs due to infiltration of the pancreas by autoreactive T cells and autoimmune destruction of pancreatic beta cells. Type 2 diabetes manifests most commonly in adults as impaired fasting glucose on account of progressive beta-cell failure. The range of characteristics of type 2 diabetes have been described as “predominantly insulin resistance with relative insulin deficiency to predominantly an insulin secretory defect with insulin resistance” (American Diabetes Association, 2006). Some studies have suggested an associated reduction in β cell mass due to increased apoptosis in type 2 diabetes (Butler et al., 2003). However, both types of diabetes are believed to share a common genetic aetiology, and clinical evidence also indicates a marked overlap between these two diabetic conditions. For instance, anti-islet cell antibodies, elevated circulating cytokines and chemokines typically associated with type 1 diabetes have been observed in many patients with type 2 diabetes. Similarly, obesity, which is commonly linked to insulin resistance and type 2 diabetes, has been seen to correlate strongly with type 1 diabetes as well (Donath and Halban, 2004). Worldwide, type 2 diabetes has assumed epidemic proportions. The projected estimate of increase is 221 million diabetic people in 2010 from the 151 million diagnosed with diabetes in 2000, and expected to rise further to 324 million by 2025 (Zimmet et al., 2001) . Type 2 diabetes and Metabolic Syndrome Type 2 diabetes is generally associated with a condition known as metabolic syndrome. The Adult Treatment Panel III (ATP III, 2001) Report guidelines have suggested the working definition of the metabolic syndrome as the presence of at least 3 of the following features: abdominal obesity, atherogenic dyslipidemia or elevated triglycerides, reduced levels of HDL cholesterol, small low-density lipoprotein [LDL] particles, high blood pressure, insulin resistance and high fasting glucose, and prothrombotic and proinflammatory states (Reaven, 1988). The presence of high glucose in blood in diabetes leads to both micro and macro vascular damages. Impairment in large vessels can result in stroke and cardiovascular complications, while vascular damage in the extremities, kidneys and eyes could lead to amputation, blindness and kidney failure. The risk of macrovascular events in patients with type 2 diabetes is usually enhanced because of many other comorbid conditions. A central feature of the metabolic syndrome is abdominal obesity. An increase in the prevalence of the metabolic syndrome in persons aged 20 and above has been reported in the U.S. (Ford et al., 2004). Whether the syndrome is a disease or simply an assemblage of risk factors is a matter of debate (Reaven, 2002). But it is agreed that the metabolic syndrome provides a set of diagnostic indications to identify people with high relative risk of developing cardiovascular disease although it does not provide a measure of absolute risk A lot of effort is being directed towards diabetes research because the disease in particular, type 2 diabetes is assuming pandemic proportions. A multi-pronged research approach encompassing immunological, biochemical, and nutritional studies is currently being pursued which is evident from the large number of research reports being published. Immunological research related to diabetes Autoantibodies against pancreatic islet cell proteins are being intensively studied. A 64K protein with GAD activity and identified as the isoform GAD65 has been recognised as one of the unique islet autoantigens (Bækkeskov et al., 1990). Interestingly, GAD65 is a major autoantigen in type I diabetes, whereas the closely related isoform, GAD67, is not antigenic probably due to its structural features. Other islet cell antibodies (ICA) including insulinoma-antigen 2 (i.e., insulinoma-associated tyrosine phosphatase IA-2) antibody (IA-2A), and insulin autoantibodies (IAAs) were discovered subsequently as markers of islet autoimmunity in patients of type 1 diabetes (Bækkeskov et al., 1990). High levels of IA-2A in combination with ICA or GAD65 is an indicator of β-cell failure while the presence of low concentrations of GAD65 alone indicates a slowly progressive β-cell dysfunction especially during the first 5 years after diagnosis (Borg et al., 2001). According to Yoon et al. (1999), the suppression of GAD expression in nonobese diabetic mice prevents autoimmune diabetes thereby confirming that glutamic acid decarboxylase has a role to play in the progression of the disease. In both the types of diabetes, GAD as well as IA-2 antibodies are polyclonal and subclass restricted to IgG1 suggesting that the pathogenesis of antigen-specific antibodies in type 1 and type 2 diabetes is similar (Hawa et al., 2000). Studies are being conducted to localise the type 1 diabetes epitope in the region of the PEVKEK loop of GAD65 and to identify the particular amino acids within the epitope that are recognised by autoimmune diabetes sera (Myers et al., 2003). The pre-clinical stage of diabetes is also characterised by the activation of self-reactive lymphocytes that infiltrate the pancreas and selectively damage the islet β-cells but not the neighbouring α- and δ-cells (Bottazzo et al., 1985). As far as the current understanding of diabetes autoantibodies goes, the β-cell destruction is mediated through T-cells and not caused by the antibodies per se; they only reflect autoimmune activity (Pihoker et al., 2005). Thus, type 1 diabetes is currently a field of study for both endocrinologists and immunologists. The best therapeutic approach is being sought through immune-based interventions. The strategies have been to use either islet antigens such as insulin or glutamic acid decarboxylase or utilise mAbs to induce ß cell-specific tolerance (Phillips et al., 2000). Monoclonal antibodies against T-cell receptors have been tested as therapeutic systems for treatment at the prediabetes stage (Masteller, 2002). Effective immunotherapy of type 1 diabetes involving the modulation of islet autoimmunity in humans after the onset of overt disease is a distinct possibility (Staeva-Vieira et al., 2007). Muscle insulin resistance is an important characteristic of type 2 diabetes. Genomic analysis is a powerful tool to study the pathophysiology of type 2 diabetes at the molecular level which can throw more light on muscle insulin resistance. Using microarray technology it is now possible to examine the transcript profiles of thousands of genes simultaneously. Sreekumar et al. (2002) made a comparative survey of the gene transcripts (i.e., transcriptomes) of diabetic and non-diabetic subjects and found that 11 out of the 6451 genes examined remained altered despite insulin treatment in the diabetic subjects. The genes included those involved in structural and contractile functions (e.g., calmodulin type I, troponin-I [fast and slow twitch], troponin-C [fast twitch], tropomyosin, and skeletal muscle C-protein), heat shock protein 70 kDa with stress response, growth factor [IGFBP-5], NADH dehydrogenase-ubiquinone involved in energy metabolism, and 2 gene transcripts relevant to tissue development. According to Sreekumar et al. (2002), the 11 transcripts so identified are candidate genes involved in the pathogenesis of muscle insulin resistance in people with type 2 diabetes that need to be taken up for more focussed investigations. In another study, Stentz and Kitabchi (2007) analysed the transcriptomes and proteomes (that is, the translated proteins) of muscle tissues and activated CD4(+) and CD8(+) T-cells of normal and type 2 diabetic subjects. Transcriptomes related to insulin receptor (INSR), vitamin D receptor, insulin degrading enzyme, Akt, insulin receptor substrate-1 (IRS-1), IRS-2, glucose transporter 4 (GLUT4), and enzymes of the glycolytic pathway were found downregulated by about 50% in the diabetics as compared to controls. On the other hand, more than 2-fold increase in plasma cell glycoprotein-1, tumor necrosis factor alpha (TNF-α), and gluconeogenic enzymes was apparent in the diabetics compared to non-diabetic controls. Proteome profiles of diabetic patients were also significantly different from those of normal subjects. The variations in the expression of genes and gene products of insulin signalling and glucose metabolism in type 2 diabetes might be the cause of insulin resistance and should attract a deeper study. Studies on diabetic embryopathy Diabetes-induced foetal growth disorder is a subject area that has remained unclear. Activation of apoptosis or suppression of cell proliferation in embryos could lead to foetal growth retardation. However, the transcription factor NF-κB which is involved with apoptosis as well as cell proliferation was found to be lower in embryos of diabetic mice as compared to those in controls (Mammon et al., 2005), leading to the inference that foetal growth retardation on account of maternal diabetes occurs as a result of suppression of NF-κB activity in embryos. NF-κB activity was assessed by measuring the amount of NF-κB (p65) DNA binding as well as the expression of NF-κB (p65), IκBα and phosphorylated (p)-IκBα proteins. Another subject matter of diabetes research is concerning the mechanism of autoantigenicity and autoimmunity in diabetes. These studies involve major histocompatibility complex (MHC) class I molecules expressed on all human cells (except erythrocytes and trophoblasts), and which bind a panel of endogenous peptides of self or foreign origin to activate or deactivate cytotoxic CD8+ T cells (Sia & Weinem, 2005). The major genetic susceptibility factor for type 1 diabetes is supposed to lie within MHC (Wong et al., 2005). The current research approach is concerning polymorphisms in TAP and LMP genes that have a significant impact on antigen-processing pathways. The diversity of proteins produced by these genes are likely to supply the epitopes that cause CD8+ cells to become autoreactive, therefore further studies should determine whether the gene products require a combination of factors to confer disease (Sia & Weinem, 2005). Biochemical approach to diabetes There is a continuing endeavour to understand the basic metabolic perturbations underlying both types of diabetes. The identification of the autoantigenicity of glutamic acid dehydrogenase has been one of the important findings. Since ICA reactivity does not always fully correlate with defined autoantigens, the probable presence of as yet unidentified additional specific autoantigens has become apparent (Mansson et al., 2001). The role played by the proteins belonging to high mobility group (HMG) e.g., HMGA1 in severe human severe insulin resistance is becoming more clear. HMGA1 is a small, basic protein which acts as a specific cofactor for gene activation by binding to adenine-thymine (A-T) rich regions of DNA (Chiefari et al., 2009). However, “HMGA1 by itself has no intrinsic transcriptional activity; rather, it can transactivate promoters through mechanisms that facilitate the assembly and stability of a multicomponent enhancer complex, the so-called enhanceosome, that drives gene transcription” (Chiefari et al., 2009). Foti et al. (2003) found that HMGA1 is required for proper insulin receptor gene transcription, while there is evidence also to show that HMGA1 binds to key sites on the insulin receptor gene (INSR) and adversely affects levels of INSR expression in insulin responsive tissues. Moreover, loss of HMGA1 expression induced in mice by disrupting the HMGA1 gene causes a type 2-like diabetic phenotype (Foti et al., 2005). Restoration of HMGA1 protein expression enhances INSR gene transcription, and restores cell-surface insulin receptor protein expression and insulin-binding capacity. A recent finding is the close relationship between peripheral insulin sensitivity and retinol (vitamin A) metabolism. Insulin resistance in rodents and humans has been shown to be linked to anomalies in the vitamin A signalling pathway (Graham et al., 2006). Studies by these authors showed the release of retinol-binding protein 4 (RBP4) by adipose tissue following reduction in glucose uptake, leading to secondary systemic insulin resistance. This is an important finding which shows that insulin-sensitive tissues communicate with distant tissues such as adipose tissue through secretion of factors. A functional link exists between HMGA1 and RBP4, and abnormalities in RBP4 and/or metabolites of the vitamin A pathway directly affect overall insulin action and peripheral insulin sensitivity (Chiefari et al., 2009). These studies further showed that the cAMP pathway might be important for the maintenance of glucose homeostasis in rodents as well as humans, being responsible for RBP4 activation, and HMGA1 is a participant in the expression of cAMP-induced retinol-binding protein 4 (RBP4) gene and protein. New lines of enquiry need to be directed at understanding the “complex metabolic derangement of HMGA1 deficiency” (Semple, 2009) since HMGA1 is a crucial effector regulating glucose homeostasis, and impaired HMGA1 function as such may contribute to the development of specific forms of diabetes mellitus. Enhanced endogenous glucose synthesis is a common anomaly found in type 2 diabetes which, together with pancreatic insufficiency and reduced glucose disposal exacerbates hyperglycaemia in patients suffering from the disease (DeFronzo et al., 1989). Gluconeogenesis has been observed to cause the overproduction of glucose in fasting type 2 diabetic patients (Basu et al., 2005), whereas in the postprandial state, too, reduced suppression of gluconeogenesis is responsible for impaired glucose tolerance (Singhal et al., 2002). Fructose 1,6-bisphosphatase (FBPase) is a crucial enzyme of gluconeogenesis which catalyses the formation of fructose-6-phosphate from fructose-1,6-biphosphate (Pilkis, & Claus, 1991), and, being a rate-controlling step in the pathway, inhibiting the activity of this enzyme could be expected to reduce gluconeogenesis. The importance of FBPase as a target to control gluconeogenesis is essentially related to its position in the pathway, which is amenable to inhibition from all substrate intermediates of the pathway without affecting glycogenolysis, and glucose metabolism (Erion et al., 2005). Treatment with FBPase inhibitors may, therefore, be an efficacious option against both postprandial and fasting hyperglycaemia in type 2 diabetes (van Poelje et al., 2006). However, such inhibition should be able to circumvent the main drawbacks associated with the inhibition of gluconeogenesis namely, hypoglycaemia, lactic acidosis, and hypertriglyceridaemia which were earlier prominent in inhibitors acting against phosphoenolpyruvate carboxykinase, and glucose 6-phosphatase (Erion et al., 2005). Another aspect that is being actively pursued in diabetes research pertains to obesity-associated rise in hepatic lipogenesis which is believed to be responsible for the characteristic insulin resistance. Lipogenesis is controlled through the transcriptional regulation of lipogenic genes Research aimed at preventing the progression of type 2 diabetes is focussed on glucagon-like peptide (GLP)-1, an incretin hormone which stimulates the glucose-induced insulin secretion in pancreatic β-cells (Mojsov et al., 1987). Besides, GLP-1 leads to increased formation of β-cell mass. Endogenous GLP-1, however, is rather short-lived as it is prone to degradation by the protease, dipeptidyl peptidase (DPP) IV (Ahren et al., 2002). Therefore, preservation of β-cell compensation through inhibition of DPP IV could be an effective way of treating diabetes (Cheng, 2005). Hypoxia signalling and impairment of β cell function A recent study has elucidated the role of the von Hippel-Lindau tumor suppressor protein (VHL) in pancreatic β-cells (Puri et al., 2009). VHL plays a critical role in the cellular response to oxygen sensing. Oxygen homoeostasis is normally regulated by the hypoxia inducible factor (HIFα) which undergoes enzyme catalysed hydroxylation of specific proline residues, and subsequently gets degraded by VHL during normoxia (Ivan et al., 2001). Under conditions of hypoxia, HIFα is stabilised and translocated to the nucleus where it modulates the expression of several genes including those involved in glucose metabolism. The absence of VHL, even when oxygen tension is normal, causes an anomalous rise in HIFα-dependent genes (Puri et al., 2009). Thus, the authors observed that a loss of VHL in β cells leads to severe aberration in glucose homoeostasis in mice. Insulin secretion mechanism The onset of type 2 diabetes is typified by inappropriate glucose-stimulated insulin secretion from pancreatic β cells. Studying HMGN3, a nuclear protein synthesised by β cells, and which binds to nucleosomes and affects chromatin function, Ueda et al. (2009) found evidence to show that HMGN3 modulates insulin secretion in β cells of mice. They observed that a deletion of HMGN3 affects the gene transcripts involved in glucose-stimulated insulin secretion, including the Glut2 glucose transporter. Underexpression of GLUT-2 messenger RNA is known to lower high Km glucose transport in β cells, and thereby impairs glucose-stimulated insulin secretion and prevent correction of hyperglycemia (Johnson et al., 1990). Ueda et al. (2009) concluded that an impaired function of HMGN3 is a contributing factor in the etiology of diabetes, based on the fact that HMGN3 and the transcription factor PDX1 both bind to the chromatin in the promoter of the Glut2 gene, thereby regulating GLUT2 protein levels in pancreatic islets and in β cells. Nutrition in diabetes Historically, the hypothesis pertained to an exclusive involvement of the glucose-insulin axis in type 2 diabetes. In keeping with this view, the nutritional approaches to metabolic syndrome and type 2 diabetes earlier related to carbohydrate restriction. However, the thinking got modified by the report of insulin resistance caused by elevated plasma free fatty acids (FFA) (Boden et al., 1991). The potential mechanism by which elevated FFAs lead to insulin resistance and atherogenesis in human muscle cells was described by Inoguchi et al. (2000). The key initiating event viz., increase in plasma FFA leads to the activation of protein kinase C (PKC) in the muscle which is supposed to interrupt insulin signalling. Modulation of FFA levels by drugs (e.g., PPAR agonists) is a strategy that has been used to treat diabetes (Boden and Laakso, 2004), and currently the nutritional approach to diabetes control also concerns limiting dietary fat. An imbalance between energy intake and physical activity leading to excess body fat is a critical risk factor for type 2 diabetes as it impacts glucose metabolism (Marshall et al., 1991; Colditz et al., 1995). The quantity and quality of dietary fat both affect diabetes risk (Hu et al., 2001). The fatty acid composition of cell membranes has an effect on insulin-mediated signal transduction and insulin action as reported by Feskens et al. (1995). Glucose control and insulin sensitivity are known to be positively affected by mono- and polyunsaturated fatty acids (Parillo et al., 1992; Houtsmuller et al., 1980) while trans fatty acids have a negative effect (Christiansen et al., 1997). Fish consumption is already known to reduce mortality due to coronary heart disease (CHD) (Katan, 1995). The current research interest is in studying the specific action of n-3 (polyunsaturated) fatty acids in relation to diabetes (de Caterina et al., 2007). 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Zimmet, P., Alberti KG & Shaw J 2001, ‘Global and societal implications of the diabetes epidemic’, Nature 414, pp. 782-787. Read More