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Diabetes |
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Diabetes mellitus (hereafter referred to as diabetes) is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both (Saltiel, 2001;Kahn, 2003;Notkins, 2002;Marx, 2002). Type 2 diabetes is quickly reaching epidemic proportions in Canada and worldwide. According to the Canadian Diabetes Association (CDA; www.diabetes.ca, accessed January 15, 2004) there are about 2 million diabetic patients in Canada and this is costing the healthcare system an estimated $9 billion (USD) annually. Glucose homeostasis in the body depends on the balance between glucose production and glucose utilization. Glucose production occurs predominantly in liver, whereas glucose utilization occurs in insulin-dependent tissues, such as the muscle and adipose, and in insulin-independent tissues such as the brain, kidney and red blood cells (Kahn, 1994;Bergman, 1989). Although there are a number of other factors involved in glucose homeostasis, it is primarily regulated by the pancreatic islet β-cells, which secrete insulin, and a-cells, which secrete glucagon. Maintenance of glucose homeostasis relies on three important events: 1) during changes in glycemia, the body needs to secrete the appropriate amounts of insulin and glucagon in response to a given glycemic level and to maintain these responses until basal glucose is reached; 2) once secreted both insulin and glucagon must be able to act on their target tissues; and 3) glucose needs to enter cells independent of insulin’s action (often referred to as “glucose sensitivity” or “glucose effectiveness”) (Bergman, 1989;Bergman et al., 1992). Defects anywhere along the insulin secretion to insulin action pathway can result in hyperglycemia. At the clinical level there two major forms of diabetes, type 1 diabetes and type 2 diabetes. In the next few sections I will discuss both forms of diabetes and then discuss current treatments in combating diabetes with a focus on type 2 diabetes. Type 1 Diabetes
Type 1 diabetes is a result of a near or complete lack of insulin producing β-cells in the pancreas. Type 1 diabetes is primarily an autoimmune disease that attacks insulin-producing β-cells and affects 0.3% of the worlds population (Berkow & Fletcher, 1992;Notkins, 2002). There are three lines of evidence that type 1 diabetes has an autoimmune component; 1) the presence of inflammatory infiltrates (insulitis) in pancreatic islets; 2) the strong linkage between type 1 diabetes and certain alleles of the major histocompatability complex (MHC) and 3) the presence of autoantibodies against islet cell antigens called islet cell autoantibodies (ICA) (Notkins, 2002).
There is a strong association between certain HLA class II alleles or combinations of alleles (haplotypes) and the development of type 1 diabetes. Binding of antigenic peptides to pockets within the groove of certain HLA class II molecules is associated with autoimmune type 1 diabetes. HLA typing is one means in screening to identify individuals at high risk for type 1 diabetes (Notkins, 2002).
The major cause of type 1 diabetes appears to be due to autoaggressive T cells that infiltrate the pancreas and destroy insulin-producing b-cells, leading to a rise in basal blood glucose levels in the body. The target antigen of the autoaggressive T cells has long been debated, but current research suggests that there are three major autoantigens present in β-cells including glutamic acid decarboxylase (GAD65), islet associated antigen-2 (IA-2 or ICA512) and insulin (Notkins, 2002). It appears that the autoaggressive T cells promote the production of autoantibodies against these pancreatic antigens. GAD65 may be involved in the initial developmental steps leading to type 1 diabetes (Yoon et al., 1999) (Baekkeskov et al., 1990). The function of GAD65 in the pancreatic β-cell is not known but between 60 and 80% of newly diagnosed type 1 diabetic patients have autoantibodies to it (Baekkeskov et al., 1990).
The islet IA-2 antigen is a transmembrane protein found in the secretory vesicles of both endocrine and neuronal cells. Its function in β-cells is not known but it may play a role in insulin secretion (Solimena et al., 1996). Of newly diagnosed type 1 diabetic patients, 60-70% have autoantibodies to this antigen.
The third autoantigen is insulin, which appear in the prediabetic state in very young children and occurs in 30-50% of type 1 diabetic patients (Atkinson & Eisenbarth, 2001). Most autoantibodies recognize epitopes on the B chain of insulin. Autoantibodies to insulin are commonly the first to appear in prediabetic individuals. The detection of two or more of the autoantibodies (GAD65, IA2 or insulin) in relatives of patients with type 1 diabetes has a positive predictive value exceeding 90%.
Type 2 Diabetes
Type 2 diabetes accounts for approximately 90% of all diabetic cases and it results from an interaction of both a subject’s genetic make-up and environmental cues (Saltiel, 2001;Kahn, 2003). In general, type 2 diabetes is characterized by two pathological defects: 1) peripheral insulin resistance (Himsworth & Kerr, 1942;Kahn, 1978;Olefsky, 1981;Reaven, 1988;Kahn et al., 1988;Leahy et al., 1992;Kolterman et al., 1981;Saltiel, 2001); and 2) an inability of pancreatic b-cells to secrete the appropriate amount of insulin for a given glycemic state (Porte, Jr., 1991;Leahy et al., 1992;Turner et al., 1992;Kahn, 2003). In the prediabetic state an individual can have mild insulin resistance but maintain normal glycemia by increasing their insulin output. However, once hyperglycemia develops, both insulin resistance and β-cell dysfunction are present but which of these two come first is still debated (McGarry, 2002). Several groups suggest that insulin resistance is the earliest detectable defect in type 2 diabetes (Kruszynska & Olefsky, 1996;DeFronzo & Ferrannini, 1991). However, others have suggested that β-cell dysfunction develops before insulin resistance and is a prerequisite for the progression from normal glucose tolerance to hyperglycemia (Porte, Jr., 1991;Mitrakou et al., 1992;Kahn, 2001).
Insulin resistance is an impairment in the body’s ability to respond to insulin (Kahn, 1994;DeFronzo et al., 1992;Järvinen, 1995;Saltiel, 2001;Shulman, 2000). Glucose homeostasis is primarily regulated by insulin actions on the liver and skeletal muscle. Insulin resistance can occur in liver, skeletal muscle and to a lesser extent in adipose tissue (Saltiel & Kahn, 2001). In the early stages of type 2 diabetes, liver insulin resistance results in normal or even increased hepatic glucose output in the postabsorptive state even though insulin levels are elevated. In the later stages of type 2 diabetes, the ability of endogenous insulin to suppress glucose production in the liver degrades further and insulin-dependent glucose uptake in the skeletal muscle is reduced (Saltiel, 2001). The increased glucose production and output by the liver is largely due to gluconeogenesis (Saltiel & Kahn, 2001).
The defects in insulin action on skeletal muscle are the primary reasons for the decreased whole body glucose uptake; some of these defects may be due to impaired insulin-receptor tyrosine kinase activity, diminished glucose phosphorylation (via hexokinase) and transport (via glucose transporter-4), and reduced glycogen synthase and pyruvate dehydrogenase activities (Perseghin et al., 2003;Petersen & Shulman, 2002). The defects in these pathways account for all three common disturbances seen in the insulin-resistant skeletal muscle (e.g. glucose disposal, glycogen synthesis and glucose oxidation) (DeFronzo et al., 1992;Perseghin et al., 2003;Petersen & Shulman, 2002).
What initiates the development of type 2 diabetes in unknown however it likely involves a multitude of defects including genetic and environmental factors (Kahn, 1994;DeMeyts, 1993;Kahn & Reynet, 1995;Marx, 2002). The genetic factors can be classified into primary and secondary subsets. Primary genetic factors, or “diabetogenic factors”, are factors that initiate the diabetic process (Kahn, 1994;Kahn & Reynet, 1995;Marx, 2002). Secondary factors are those that are diabetes-related and result from changes in gene expression due to hyperglycemia and hyperlipidemia. They are not usually unique to type 2 diabetes and may also occur in type 1 diabetes (Kahn & Reynet, 1995;Saltiel, 2001). Environmental factors include: over consumption of glucose, fatty foods, or a combination of both of these, activity level, and possibly environmental toxins, all of which may be interacting with the genetic factors to promote the progression of type 2 diabetes (DeFronzo et al., 1992;Kahn, 1994;Kahn, 2003;Saltiel, 2001).
Early in the development of type 2 diabetes, the pancreatic β-cell can usually compensate for increasing insulin resistance by secreting more insulin, allowing glycemia to remain at relatively normal levels. As time passes, the β-cell is unable to compensate for the increasing degree of insulin resistance, which leads to the development of impaired glucose tolerance and eventually type 2 diabetes. The exact cause of “β-cell failure” is unknown, but it is likely that an effect of glucose and/or lipid toxicity in genetically predisposed β-cells is likely a major factor (Leahy et al., 1992;Poitout & Robertson, 2002;Unger, 2002). Some of the important characteristics during the development of β-cell failure are the loss of first-phase insulin secretion, altered pulsatility of insulin release, and an enhanced proinsulin to insulin secretory ratio (DeFronzo et al., 1992;Kahn, 2003). β-cell failure in type 2 diabetes may also be due to the accumulation of toxic islet amyloid deposits (Marzban et al., 2003). Islet amyloid polypeptide (IAPP; amylin) is secreted with insulin and is the major component of islet amyloid. However the mechanism of toxicity is still unclear.
For both type 1 and 2 diabetes, once the diabetes has progressed individuals are exposed to long-term hyperglycemia, which can lead to the development of a number of diabetes associated complications including microvascular and macrovascular diseases (Saltiel, 2001;Brownlee, 2001;Reusch, 2003). Microvascular complications involve pathologies in the retina, renal glomerulus and peripheral nerves. The complications of microvascular pathology are a major cause of diabetes related blindness, end-stage renal disease and a variety of debilitating neuropathies. Diabetes associated macrovascular complications include accelerated atherosclerotic disease affecting arteries that supply the heart, brain and lower extremities. As a consequence diabetic patients have a higher incidence of myocardial infarction, stroke and limb amputations.
Treatment of Diabetes
Since most of the long-term complications of diabetes [e.g. macrovascular disease (National Diabetes Data Group, 1995;Hseuh & Anderson, 1992;Fuller, 1985;Sower & Ebstein, 1995), cardiovascular disease (Berkow & Fletcher, 1992), hyperlipidemia (Fontbonne et al., 1989;Koskinen et al., 1992), retinopathy, nephropathy, neuropathy and foot ulcers (Berkow & Fletcher, 1992)] are a result of poor glycemic control, it is very important to maintain normal or near-normal blood glucose levels. In the next two sections current and newly developed treatments of diabetes will be discussed. Treatment of Type 1 Diabetes After the diagnosis of type 1 diabetes (usually at a young age), these individuals are then dependent upon exogenous insulin for the rest of their lives. This is the same treatment for type 1 diabetes for over 80 years with only modifications in the preparation, mode of delivery used and treatment regiment (intensive insulin therapy) over the years. The importance of good glycemic control has been best demonstrated by The Diabetes Control and Complication Trial (DCCT), which was a large randomized, controlled trial performed in type 1 diabetic patients. They showed that by aggressively improving glycemic control one can reduce the long-term complications of microvascular disease and some macrovascular disease (The Diabetes Control and Complications Trials Research Group, 1993;1996b;1996a;2002b;2000). New strategies for therapeutic intervention are currently being developed and tested (Rossini et al., 2001). One focus is to prevent the development of diabetes by suppressing the autoimmune response with immunosuppressive agents (Rossini et al., 2001). Once diabetes is diagnosed the focus is to either replace insulin producing β-cells by transplantation of isolated human islets or to restore insulin production by genetic therapy such as adenoviral or lentiviral approaches to introduce the insulin gene to the liver (Lee et al., 2000). Treatment of Type 2 Diabetes
Similar results to the DCCT have been obtained for type 2 diabetic patients (Klein et al., 1988;Klein et al., 1996;Ohkubo et al., 1995;Turner et al., 1996;2002a) and in larger studies by the United Kingdom Prospective Diabetes Study (UKPDS) group (1998c;1998a;1998b;1998d). The UKPDS is the largest and longest study on type 2 diabetic patients and studied 1) whether intensive insulin therapy can prevent the progression of the disease, 2) whether the commonly used drugs (sulfonylurea drugs, metformin or insulin) have any therapeutic advantages or disadvantages and 3) it also looked at the advantages and disadvantages that drugs that control blood pressure would have on the progression of type 2 diabetes. The UKPDS study showed that good glycemic control could prevent some of the complications of type 2 diabetes including retinopathy, nephropathy and possibly neuropathy. Although UKPDS has not yet shown that intensive therapy has any effect on improving complication of the cardiovascular system it did show that lowering blood pressure could prevent some of the macrovascular complications and visual loss (1998c;1998a;1998b;1998d;2002a). Therefore tight glycemic control appears to be extremely important in preventing the complications of type 2 diabetes.
Outside of lifestyle changes, there are currently five common drugs used to treat type 2 diabetes 1) sulphonylureas which increase b-cell insulin output, 2) biguanides such as metformin which reduces hepatic glucose output and can increase insulin sensitivity particularily in the liver, 3) peroxisome proliferator-activated receptor-g (PPARg) agonists which also improves insulin sensitivity, 4) a-glucosidase inhibitors which interfere with glucose absorption and 5) insulin (Moller, 2001). The first-line of therapy for the prevention of hyperglycemia in type 2 diabetes is diet and exercise (Pavlou et al., 1989;Jenkins et al., 1992;Bertelsen et al., 1993;Ludwig, 2002). When these non-pharmacological methods fail, then the second-line of therapy are oral agents, the most commonly prescribed of which are the sulfonylureas (Gerich, 1989;Moller, 2001). Sulfonylureas, such as glibenclamide and the non-sulphonyureas repaglinide and the related compound nateglinide, act primarily by increasing pancreatic β-cell insulin secretion, but since they do so in a glucose-independent fashion they may cause hypoglycemia and can also cause weight gain (Lebovitz, 1995;Moller, 2001). Biguanides, such as metformin (DeFronzo et al., 1995;Bailey & Turner, 1996;Moller, 2001) are another group of drugs used in the treatment of type 2 diabetes. They lower blood glucose primarily by reducing hepatic glucose output but may also improve peripheral insulin sensitivity, and boost glucose utilization by skeletal muscle tissue (Stumvoll et al., 1995;Moller, 2001). However, metformin has some side effects that include gastrointestinal disturbances and lactic acidosis and like sulfonylureas can’t be used in patients with renal, hepatic or cardiac failure (Moller, 2001). Insulin is also an important drug in the treatment of type 2 diabetes and is absolutely required in the later stages of the disease however it is not well accepted by patients and may be associated with adverse effects including hypoglycemia and weight gain (Moller, 2001). The less commonly used treatment is a-glucosidase inhibitors, such as acarbose (Chiasson et al., 1994;Moller, 2001). Acarbose works by slowing the digestion of carbohydrates thereby delaying the absorption of glucose into the blood stream, but it is associated with gastrointestinal side-effects (Chiasson et al., 1994;Moller, 2001).
Perhaps the biggest recent breakthrough in the treatment of type 2 diabetes has been the discovery of drugs that counter insulin resistance. These drugs were discovered while exploring a cell organelle called peroxisomes. Researchers discovered drugs that activate PPARs in particular PPARg. One class of drugs that activate PPARg, is the thiazolidinediones and includes rosiglitazone (Avandia) and pioglitazone (Actos). Avandia and Actos came on the market for the treatment of type 2 diabetes in 1999 (Moller, 2001). They were designed to enhance the sensitivity of liver, muscle and adipose tissue to insulin (Saltiel & Olefsky, 1996;Moller, 2001). However, these drugs also have been associated with a number of side-effects, including liver function abnormalities, reduced hemoglobin, weight gain, oedema and anaemia (Saltiel & Olefsky, 1996;Kumar et al., 1996;Moller, 2001). Glucagon-like peptide-1 (GLP-1) is a new drug being developed for the treatment of type 2 diabetes and is entering the late stages of clinical trials. GLP-1 is able to stimulate glucose-dependent insulin secretion and promote β-cell survival and growth (Nauck, 1998;Nauck et al., 1997a;Ahrén, 1998;Nauck et al., 1997b).
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