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Type 2 diabetes mellitus has become an epidemic, and virtually no physician is without patients who have the disease. Diabetes mellitus has reached epidemic proportions and affects more than 170 million individuals worldwide.
The medical and socioeconomic burden of the disease is caused by the associated complications,7-9 which impose enormous strains on health-care systems. Although lifestyle and overeating seem to be the triggering pathogenic factors, genetic elements are also involved in the pathogenesis of type 2 diabetes. Since dizygotic twins share the environment (both intrauterine and extrauterine) but only 50% of their genes, concordance rates in monozygotic twins in excess of those in dizygotic twins have been used to distinguish genetic from non-genetic contributions. Nevertheless, concordance rates in monozygotic twins might produce an underestimate of genetic effects, because the monochorionic intrauterine nutrition of monozygotic twins has been shown to result in growth retardation compared with dizygotic twins.32 And low birthweight itself is associated with increased risk of type 2 diabetes later in life.
To understand the cellular and molecular mechanisms responsible for type 2 diabetes it is necessary to conceptualise the framework within which glycaemia is controlled.
In people with normal glucose tolerance (NGT) a quasi-hyperbolic relation exists between ß-cell function and insulin sensitivity. However, not only deviation from but also progression along the hyperbola affects glycaemia.
Insulin resistance is said to be present when the biological effects of insulin are less than expected for both glucose disposal in skeletal muscle and suppression of endogenous glucose production primarily in the liver.38 In the fasting state, however, muscle accounts for only a small proportion of glucose disposal (less than 20%) whereas endogenous glucose production is responsible for all the glucose entering the plasma. Insulin secretion from the pancreas normally reduces glucose output by the liver, enhances glucose uptake by skeletal muscle, and suppresses fatty acid release from fat tissue.
Insulin resistance is strongly associated with obesity and physical inactivity, and several mechanisms mediating this interaction have been identified.
To understand the contribution of insulin resistance in a particular tissue to whole body glucose homoeostasis, conditional knockouts of the insulin receptor have been created using the Cre-lox system. In states of insulin resistance, one or more of the following molecular mechanisms to block insulin signalling are likely to be involved.
Insulin signalling involves binding of insulin to its receptor followed by a cascade of intracellular events, depicted as activation pathways.
A close connection between insulin resistance and classic inflammatory signalling pathways has also recently been identified. In ß cells, oxidative glucose metabolism will always lead to production of reactive oxygen species, normally detoxified by catalase and superoxide dismutase. Islet amyloid consists of deposits of islet amyloid polypeptide, also known as amylin, which is co-secreted with insulin at a more than tenfold lower rate.
It is possible that early in the disease, increased demands of insulin secretion lead to islet amyloid polypeptide aggregates, especially in the presence of raised concentrations of NEFA. Although there is little doubt as to the importance of genetic factors in type 2 diabetes (table 2), it should be borne in mind that this disease is very heterogeneous. The candidate gene approach examines specific genes with a plausible role in the disease process.
The candidate gene approach in attempts to identify a causative factor among the obvious biological candidates for insulin resistance has been largely disappointing (table 4). Among the many candidate genes for insulin secretory dysfunction, those encoding SUR1 and KIR6·2 have been most extensively studied.
Genes involved in embryonic ß-cell development, such as components of the insulin-like growth factor pathways, have also been studied. Several findings of positive associations of genomic regions with type 2 diabetes have been replicated in one or more studies (1q21-24, 1q31-q42, 9q21, 10q23, 11p15, 11q13-14, 12q12, 19q13, and 20q11-q13 ).114 Generally, such findings are followed by positional cloning of the causative gene, which to date has not been successful for most regions.
A peculiar possibility is the relation of diabetes to imprinted genes--ie, genes for which expression varies depending on the sex of the transmitting parent.
In making therapeutic choices (figure 7) in the management of type 2 diabetes, the major goal of protecting patients from the long-term complications of the disease must be considered. Drugs that enhance insulin sensitivity are primarily those of the thiazolidinedione class, which not only reduce glycaemia, but also enhance vascular function and ameliorate the dyslipidaemia and inflammatory milieu of type 2 diabetes.131 Thiazolidinediones primarily activate PPARgamma receptors in adipose tissue and alter adipose metabolism and distribution. Unlike metformin, the thiazolidinediones can be used in patients with reduced renal function, and they are better tolerated without significant gastrointestinal side-effects. Metformin is a highly effective antihyperglycaemic drug that works independently of the pancreas, sparing insulin. As inadequate ß-cell insulin secretion is fundamental to the development of hyperglycaemia in diabetes, insulin secretion enhancers also play an important role in control of blood glucose. The mode of action of sulfonylurea derivatives implies that they also act at low concentrations of plasma glucose, which explains the potential of (occasionally severe) hypoglycaemia. The recently introduced class of meglitinides consists of nateglinide, which binds to the same site of sulphonylurea receptor 1 as do the sulfonylurea derivatives, and repaglinide, which binds to a nearby site of the receptor, both leading to insulin release.
Replacing circulating concentrations of insulin is essential to support the clinical effects of metformin and the thiazolidinediones, which are ineffective without adequate insulin availability, and may also have important beneficial effects in reducing inflammatory processes, especially in the vasculature.142 Thus, it is essential to initiate insulin injections when required to achieve glycaemic targets in type 2 diabetes, possibly in combination with oral insulin sensitisers. As specific drug targets are identified through improved understanding of the molecular pathogenesis of diabetes, novel therapeutics will become available in the future. The results of the HOPE study,147 in which use of ramipril was associated with a markedly lower risk of myocardial infarction, stroke, and death, favour use of the ACE inhibitor in diabetic patients with one additional risk factor, even if they do not have hypertension.
The benefit of lipid-lowering drugs has now been firmly established, since the Scandinavian Simvastatin Survival Study showed a reduction in total mortality of 43%.


Fibric acid derivatives might benefit diabetic patients because they raise concentrations of HDL cholesterol and reduce triglyceride levels.
Whether therapy should be given for other risk factors such as hyperhomocysteinaemia (treated with folic acid), and whether antioxidants are of use, is still unclear because of the absence of studies with hard endpoints in patients with type 2 diabetes.
The goal of ultimately reducing the population burden of diabetes by early treatment and prevention is clearly of pivotal importance. A more complete understanding of the molecular mechanisms of diabetes will enable the identification of individuals at highest risk, which could lead to novel pharmacological concepts, risk stratification, and development of more targeted preventive measures. Whereas insulin insensitivity is an early phenomenon partly related to obesity, pancreas ß-cell function declines gradually over time already before the onset of clinical hyperglycaemia. The incremental costs of patients with type 2 diabetes arise not only when the diagnosis is established but at least 8 years earlier.10 The devastating complications of diabetes mellitus are mostly macrovascular and microvascular diseases as a consequence of accelerated atherogenesis. Insulin is the key hormone for regulation of blood glucose and, generally, normoglycaemia is maintained by the balanced interplay between insulin action and insulin secretion. When insulin action decreases (as with increasing obesity) the system usually compensates by increasing ß-cell function.
Endogenous glucose production is accelerated in patients with type 2 diabetes or impaired fasting glucose.39,40 Because this increase occurs in the presence of hyperinsulinaemia, at least in the early and intermediate disease stages, hepatic insulin resistance is the driving force of hyperglycaemia of type 2 diabetes (figure 3).
The various factors shown that contribute to the pathogenesis of type 2 diabetes affect both insulin secretion and insulin action. A number of circulating hormones, cytokines, and metabolic fuels, such as non-esterified (free) fatty acids (NEFA) originate in the adipocyte and modulate insulin action. Among the five conditional insulin receptor knockouts shown in table 3, only liver47 and ß-cell specific knockouts50 became glucose intolerant whereas, unexpectedly, knockout models specific for muscle46 and fat cells48 did not.
Negative modulation of insulin action can be mediated via various pathways leading to insulin resistance: various inhibitory triggers affect their respective signal modulators (partly via transcription factors), which lead through deactivating pathways (tyrosine phosphatases, serine kinases, lipid phosphatases and degradation pathways) to inhibitory actions on insulin signalling (activation pathways). Basal insulin concentrations may be raised to roughly double the usual value, especially in obese hyperglycaemic patients, but this finding is presumably due to increased plasma glucose.
Further degradation leads to formation of pyruvate, which is then taken up in the mitochondria in which further metabolism leads to ATP formation. Generally, in both non-diabetic and diabetic obese patients, NEFA concentrations are raised as a result of enhanced adipocyte lipolysis. The physiological role of islet amyloid polypeptide is unclear, and diverse roles such as inhibition of insulin action, inhibition of insulin secretion, and inhibition of glucagon secretion have been proposed.
The finding that first-degree relatives of patients with type 2 diabetes have decreased islet amyloid polypeptide (and insulin) responses to intravenous glucose, however, challenges this speculation.96 Also, amyloid is not observed in middle-aged insulin-resistant individuals. For this purpose the statistical association of a given allele and a phenotype (eg, type 2 diabetes, or insulin resistance) is tested in unrelated individuals. The two genes--ABCC8 and KCNJ11, respectively--are adjacent to one another on chromosome 11.
Genetic variation near or in the P2-promoter of the MODY-1 gene HNF4A gene (chromosome 20q) has been proposed to relate to common type 2 diabetes,128 but this finding requires independent confirmation.
The class III allele of the variable number tandem repeat near the insulin gene (chromosome 11p15) might relate to type 2 diabetes.129 The class III allele is associated with decreased amounts of insulin mRNA. Because insulin resistance plays a fundamental role in the pathogenesis of type 2 diabetes and especially its adverse cardiovascular outcomes, interventions should initially be aimed towards improvement in tissue insulin sensitivity. The redistribution of tissue triglyceride from visceral stores reduces levels of circulating NEFA apparently by sequestration in a less lipolytic subcutaneous compartment.132 Thiazolidinediones also reduce circulating concentrations of pro-inflammatory cytokines that promote insulin resistance (eg, TNFalpha and interleukin 6) and at the same time increase concentrations of adiponectin, which has insulin-sensitising and anti-inflammatory properties. A major adverse effect associated with clinical use of the thiazolidinediones is weight gain, which seems to be coupled to the effects of the drugs on adipose cell differentiation and triglyceride storage. It decreases hepatic glucose output and has been shown to have a beneficial effect on cardiovascular outcomes.136-138 Metformin has less robust effects on insulin resistance, inflammatory markers, and vascular function compared with the thiazolidinediones, but its benefit in abrogating some of the weight gain commonly observed with insulin-sensitisers and insulin secretion enhancers adds important value to this drug. Sulfonylurea derivatives act by closing pancreatic cell potassium channels, which leads to enhanced insulin secretion.
These agents cannot further stimulate insulin release in patients on maximal doses of sulfonylurea derivatives. However, combined use of insulin and thiazolidinediones seems to infer an increased risk of oedema and cardiac failure. This incretin hormone has potent glucose-dependent insulinotropic properties, trophic effects on ß cells, and inhibitory effects on intestinal motility, all of which reduce plasma glucose. Conversely, increasing adiponectin secretion or administration of an adiponectin receptor agonist would probably enhance glucose metabolism in skeletal muscle and liver and also confer beneficial effects in the endothelium. The benefit of antihypertensive therapy is larger in diabetic than in non-diabetic hypertensive patients. They can decrease endothelial cell activation possibly because of their capacity for binding PPARalpha. A number of studies have shown that diabetes can be delayed or prevented in individuals at high risk undergoing an intensive diet and exercise programme, and intervention with medications including metformin, acarbose or thiazolidinediones has also shown to be effective (table 5).
A long-term goal is to develop drugs that restore normoglycaemia by targeting specific pathogenic defects. Several mechanisms have been proposed, including increased non-esterified fatty acids, inflammatory cytokines, adipokines, and mitochondrial dysfunction for insulin resistance, and glucotoxicity, lipotoxicity, and amyloid formation for ß-cell dysfunction. Importantly, the normal pancreatic ßcell can adapt to changes in insulin action--ie, a decrease in insulin action is accompanied by upregulation of insulin secretion (and vice versa).


An increased mass of stored triglyceride, especially in visceral or deep subcutaneous adipose depots, leads to large adipocytes that are themselves resistant to the ability of insulin to suppress lipolysis.
These findings clearly support a central role of hepatic insulin resistance in the pathogenesis of type 2 diabetes, and suggest that an adequate insulin signal in the pancreatic ß cell is needed to maintain its function. Adiponectin has an ameliorating function on glucose metabolism apart from insulin signalling.
Similarly, after a meal, concentrations of insulin in plasma can appear higher than normal, because of substantially raised plasma glucose. ATP is necessary for the delivery of energy needed for the release of insulin, but it is also involved in the cell membrane depolarisation. Fatty acids lead to enhanced insulin secretion in acute studies, but after 24 h they actually inhibit insulin secretion.
It has been suggested that small aggregates are cytotoxic,94 possibly related to radical production. Thus, the role of amyloid deposits (a post-mortem finding) in pancreatic islets in the pathophysiology of type 2 diabetes remains unclear.
In general, two methods are used for studying genetic factors involved in a specific disease: the so-called candidate gene approach and the genome-wide scan approach. The genome-wide scan or linkage approach is not based on assumptions but locates genes through their genomic position and is based on the rationale that family members sharing a specific phenotype will also share chromosomal regions surrounding the gene involved. This often involves lifestyle intervention, with modest exercise and weight loss, which clearly reduces the risk of progression of impaired glucose tolerance to overt diabetes12,13 and can improve many of the cardiovascular risk parameters of the metabolic syndrome. Fluid retention is also linked to the PPARgamma-agonist activity of the thiazolidinediones, leading to peripheral oedema and a mild haemodilution in some patients.
The results of the UK Prospective Diabetes Study8 showed a clear risk reduction for the occurrence of microvascular complications by the use of sulfonylurea derivatives, while the risk reduction of macrovascular disease was around 16%. However, because circulating glucagon-like peptide 1 is immediately inactivated by dipeptidyl peptidase IV, it is therapeutically impractical.
Recent evidence for amelioration of insulin resistance by salicylates by favourable interference with the inflammatory kinase cascade in insulin signalling might lead to entirely novel therapeutic approaches. The interesting observation that improvement in one or more major pathogenic factors offsets the progression of impaired glucose tolerance to diabetes underscores the contribution of each of these factors to the development of the disease, including insulin sensitivity, ß-cell function, and actual glucose excursions. One example would be to advance the thiazolidinedione concept to design compounds that could restore defects in individuals with a defective PPARgamma regulatory system. Thus, even with (theoretically) unlimited ß-cell reserve, insulin resistance paves the way for hyperglycaemia and type 2 diabetes.
Insulin resistance pathways affect the action of insulin in each of the major target tissues, leading to increased circulating fatty acids and the hyperglycaemia of diabetes. Additionally, reactive oxygen species are known to enhance NFkappaB activity, which potentially induces ß-cell apoptosis.
Fortunately, congestive heart failure is quite rare with use of thiazolidinediones, but remains a serious concern that requires caution in selection of patients to receive these agents.135 The ability of thiazolidinediones to ameliorate risk of atherosclerotic events is being assessed in several large outcomes studies.
Thus, careful attention needs to be applied to determine appropriate public interventions for the varied populations of the world. Management includes not only diet and exercise, but also combinations of anti-hyperglycaemic drug treatment with lipid-lowering, antihypertensive, and anti platelet therapy.
Thus, ß-cell dysfunction is a critical component in the pathogenesis of type 2 diabetes.
In turn, the raised concentrations of glucose and fatty acids in the bloodstream will feed back to worsen both insulin secretion and insulin resistance. The closure of the potassium channels will alter the membrane potential and open calcium channels, which triggers the release of preformed insulin-containing granules (figure 5). However, long-chain acyl coenzyme A itself can also diminish the insulin secretory process by opening ß-cell potassium channels (figure 6). Combined management with both sulfonylurea derivatives and antihypertensives improves the risk reduction even more. Lifestyle modification has been difficult to maintain over a long term, and has costs associated with regular visits to various health-care professionals and lifestyle coaches. Antisense inhibition of PTP1B, a tyrosine phosphatase, currently undergoing phase II trials, could become the treatment of choice for patients with a genetic variant in PTP1B.156 Generally, with an optimised risk-benefit ratio, patients who respond to treatment may also benefit from specific drugs in a preventive approach. A second mechanism might be increased expression of uncoupling protein-2, which would lead to reduced ATP formation and, hence, decreased insulin secretion.
Until that day, diet and exercise remain the pillars of prevention and treatment of type 2 diabetes. A third mechanism might involve apoptosis of ß cells, possibly via fatty acid or triglyceride-induced ceramide synthesis or generation of nitric oxide.
Further clinical trials comparing these and newer medications that may affect diabetes pathogenesis (such as glucagon-like peptide 1 analogues) are needed to balance safety and efficacy with the costs of these different agents in various regions. The implementation and sensible use of the available pharmacological agents, including insulin, and the management of other cardiovascular risk factors, remain the practical challenge to the clinician.



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