Current Molecular Medicine - Volume 5, Issue 3, 2005

The world is presently experiencing an epidemic of type 2 diabetes predicting an increase from around 200 million presently afflicted to 300 million by 2025. This epidemic will pose tremendous strains on society, not the least in terms of socio-economic costs. Most industrilized countries are already spending 8- 15% of the national health budgets on diabetes and diabetes-related complication. This epidemic is caused by several factors; earlier onset of the disease, longer life-expectancy with an aging population and, not least, due to the changes in life-style with a sedentary living an escalating obesity. Type 2 diabetes is part of a cluster of abnormalities promoting both microvascular and macrovascular disease. In fact , the macrovascular complications (stroke, myocardial infarction etc) account for most deaths and morbidity in type 2 diabetes. Although type 2 diabetes is a complicated and polygenic disorder, important advances have been made in our understanding of its causes, propensity for vascular complications, treatment and prevention. This issue of the current molecular medicine summarizes the current status of type 2 diabetes as reviewed by a number of international experts in their fields. The comprehensive reviews cover both molecular mechanisms and type 2 diabetes patients as they present themselves in the clinical setting. Although type 2 diabetes has been desceribed as a geneticist's “nightmare” important advances have been made both in terms of genes as well as the molecular mechanisms involved in the pancreas and the key target tissues for insulin action; the liver, skeletal muscles and adipose tissue. Type 2 diabetes is associated with profound changes in the genomics of most cells in the body. This is reflected by the reviews deal with current treatment, focusing on the promising PPARγ ligands, new potential targets for treatment as well as how type 2 diabetes can be prevented. I am grateful to all authors who willingly accepted to contribute to this issue. I am sure that the reader of the Current Molecular Medicine appreciate your contribution as much as I do.

The common forms of abnormal glucose regulation including type 2 diabetes and impaired glucose tolerance with pathological implications on vascular biology have a complex aetiology involving multiple crosstalks between genetic influences and important environmental modifying factors. Due to complexity of the genetics and the clinical heterogeneity of these disorders it has proven difficult to apply the same methodological approaches that have recently given insights into the molecular genetics of several single-gene disorders of glucose metabolism. This review gives some reflections on the challenges posed by the current hypotheses about the genetics of the widespread forms of abnormal glucose regulation as well as on the strengths and limitations of the methodological approaches applied to unravel the genetic components of common disorders. Also, we review recent progress in relation to a model for the pathogenesis of the various stages of abnormal glucose regulation based on the concepts of thrifty genes of metabolism and proinflammation and genes responsible for the appearance of impaired pancreatic b-cell function and insulin signalling under the pressure of a westernised environment.

In nondiabetic subjects, insulin secretion is sufficiently increased as a compensatory adaptation to insulin resistance whereas in subjects with type 2 diabetes, the adaptation is insufficient. Evidences for the islet dysfunction in type 2 diabetes are a)impaired insulin response to various challenges such as glucose, arginine and isoproterenol, b)defective dynamic of insulin secretion resulting in preferential reduction on first phase insulin secretion and irregular oscillations of plasma insulin and c)defective conversion of proinsulin to insulin leading to elevated proinsulin to insulin ratio. In addition, recent studies have also presented evidence of a reduced beta cell mass in diabetes, caused predominantly by enhanced islet apoptosis, although this needs to be confirmed in more studies. These defects may be caused by primary beta cell defects, such as seen in the monogenic diabetes forms of MODY, or by secondary beta cell defects, caused by glucotoxicity, lipotoxicity or islet amyloid aggregation. The defects may also be secondary to defective beta cell stimulation by incretin hormones or the autonomic nerves. The appreciation of islet dysfunction as a key factor underlying the progression from an insulin resistant state into type 2 diabetes has therapeutic implications, since besides improvement of insulin sensitivity, treatment should also aim at improving the islet compensation. This may possibly be achieved by stimulating insulin secretion, supporting islet stimulating mechanisms, removing toxic beta-cell insults and inhibiting beta cell apoptosis.

Obesity is not necessary to observe insulin resistance in humans since severe insulin resistance also characterizes patients lacking subcutaneous fat such as those with HAART (highlyactive antiretroviral therapy) - associated lipodystrophy. Both the obese and the lipodystrophic patients have, however, an increase in the amount of fat hidden in the liver. Liver fat content can be non-invasively accurately quantified by proton magnetic resonance spectroscopy. It is closely correlated with fasting insulin and direct measures of hepatic insulin sensitivity while the amount of subcutaneous adipose tissue is not. The causes of interindividual variation in liver fat content independent of obesity are largely unknown but could involve differences in signals from adipose tissue such as in the amount of adiponectin produced and differences in fat intake. Adiponectin deficiency characterizes both lipodystrophic and obese insulin resistant individuals, and serum levels correlate with liver fat content. Liver fat content can be decreased by weight loss. In addition, treatment of both lipodystrophic and type 2 diabetic patients with PPARγ agonists but not metformin decreases liver fat and increases adiponectin levels. Markers of liver fat such as serum alanine aminotransferase activity have been shown to predict type 2 diabetes in several studies independent of obesity. The fatty liver thus may help to explain why some but not all obese individuals are insulin resistant and why even lean individuals may be insulin resistant, and thereby at risk of developing type 2 diabetes and cardiovascular disease.

Diabetic dyslipidemia is a cluster of plasma lipid and lipoprotein abnormalities that are metabolically interrelated. The recognition that the elevation of large VLDL 1 particles initiates a sequence of events that leads to the formation of small dense LDL and HDL species has focused the assembly of VLDL particles on the spotlight as a potential culprit of dyslipidemia. Notably dyslipidemia is associated with insulin resistance, visceral obesity and liver fat content. Insulin resistance is associated with excessive flux of substrates for VLDL assembly to the liver as well as the upregulation of the machinery generating large VLDL particles in excess. The regulation of different molecular steps in this cascade of events are complex and so far poorly understood. The disordered crosstalk between adipose tissue and the liver results in an imbalance of the machinery that orchestrates the regulation of VLDL production. A number of studies indicates that adipocytokines in particular adiponectin may be a seminal player in the regulation of fat metabolism in the liver. Future discoveries hopefully will delineate the regulatory steps to allow more targeted treatment of diabetic dyslipidemia.

Type 2 diabetes carries a 2-6-fold increased risk of cardiovascular disease (CVD) and death. Indeed, the risk of major cardiovascular events in Type 2 diabetic patients without history of coronary heart disease (CHD) is equivalent to that observed in non-diabetic subjects with CHD. However, atherosclerosis may also precede the development of diabetes, suggesting that both disorders share common genetic and environmental antecedent factors (“common soil” hypothesis). One such a possible ancestor is insulin resistance which constitutes both a major feature of Type 2 diabetes and an independent risk factor for CHD. It is well documented that inflammatory processes play an important role in the causation of atherosclerotic CVD. Inflammatory mediators play a paramount role in the initiation, progression, and rupture of atherosclerotic plaques. Thus, markers of inflammation and endothelial dysfunction may provide additional information about a patient's risk of developing CVD and may become new targets for treatment. On the other hand, evidence has emerged suggesting that inflammation is also involved in the development of Type 2 diabetes. Prospective studies have demonstrated that increased levels of pro-inflammatory markers such as CRP or reduced levels of anti-inflammatory markers such as adiponectin predict the development of Type 2 diabetes. Thus, there is accumulating evidence suggesting that inflammation is the bridging link between atherosclerosis and the metabolic syndrome. Interventions by lifestyle modification or agents with anti-inflammatory properties may reduce the risk of both conditions. Drugs exerting antiinflammatory and vascular effects have future potential to be used within an array of interventions aimed at reducing the enormous cardiovascular burden associated with Type 2 diabetes.

Insulin resistance is found in around 80-90% of subjects with older onset (type 2) diabetes and in approximately 25% of the general population. Insulin resistance prior to the development of frank type 2 diabetes and type 2 diabetes itself is associated with a significant increase in the risk of atherothrombotic disease, which is due in part to a disruption in the balance of factors regulating coagulation and fibrinolysis. Both insulin resistance and type 2 diabetes are associated with the development of endothelial dysfunction, and enhanced platelet aggregation and activation. Whilst the plasma levels of many clotting factors including fibrinogen, FVII, FVIII, FXII, FXIII b-subunit are elevated, the fibrinolytic system is relatively inhibited as a consequence of an increase in plasminogen activator inhibitor type-1 (PAI-1) levels. These changes favour the development of a hypercoagulable pro-thrombotic state, which may in turn enhance cardiovascular risk by increasing the likelihood of developing an occlusive thrombus within a coronary / cerebral artery, and / or contributing to the development of atherosclerotic lesions. This article reviews the current published evidence of the pro-thrombotic changes that occur in association with type 2 diabetes and insulin resistance, and the putative underlying mechanisms which lead to these changes.

The role of adipocytes as protein secreting cells has been known for almost 15 years. Most of these proteins have known biological activity and are called adipokines. However, only a few of the adipokines have been shown to regulate insulin sensitivity. The latter effects are direct or indirect. The adipokines regulating insulin sensitivity are tumor necrosis factor alpha, adiponectin, interleukin-6, resistin and leptin. This review examines the mechanism how these adipokines influence insulin sensitivity, how the adipocyte production of the adipokines is regulated and if genetic variance in the genes encoding for adipokines is important for the development of type 2 diabetes mellitus.

Skeletal muscle insulin resistance is a hallmark feature of Type 2 diabetes. Physical exercise/muscle contraction elicits an insulin-independent increase in glucose transport and perturbation of this pathway may bypass defective insulin signaling. To date, the exercise-responsive signaling molecules governing glucose metabolism in skeletal muscle are largely unknown. AMPactivated protein kinase (AMPK) has been suggested as one of the exercise-responsive signaling molecules involved in glucose homeostasis and consequently it has been heavily explored as a pharmacological target for the treatment of Type 2 diabetes. AMPK exists in heterotrimeric complexes composed of a catalytic α-subunit and regulatory β- and γ-subunits. The γ3-isoform of AMPK is expressed specifically in skeletal muscle of humans and rodents and this tissue specific expression pattern offers selectivity in AMPK action. Furthermore, mutations in the AMPK γ3-isoform may provide protection from diet-induced insulin resistance by increasing lipid oxidation in the presence of increased lipid supply. This review highlights the current understanding of the role of the regulatory AMPK γ3-isoform in the control of skeletal muscle metabolism.

Insulin resistance is a principal underlying defect in type 2 DM along with beta-cell dysfunction, and this insulin resistance underpins many of the abnormalities associated with the metabolic syndrome. Peroxisome-proliferator-activated receptor gamma agonists (PPARγ agonists), also known as glitazones or thiazolidinediones (TZDs) are powerful insulin sensitisers with recent evidence suggesting that they also have a potential to improve pancreatic beta-cell function. TZDs cause a major redistribution of body fat with a decrease in visceral and hepatic fat content with a resultant increase in insulin sensitivity. The glucose lowering effects of TZDs are similar to those seen with the well-established sulphonylureas and metformin. TZDs have a small reducing effect on blood pressure and have been shown to reduce microalbuminuria independent of their blood glucose lowering effect. Both TZDs in clinical practice, pioglitazone and rosiglitazone, reduce small dense LDLcholesterol and increase HDL-cholesterol levels but pioglitazone would appear to have a more pronounced benefit on these two parameters with a greater reduction in plasma triglycerides. TZDs improved the pro-coagulant state and show benefits in improving endothelial dysfunction and reducing ‘non-traditional’ inflammatory cytokines and increasing adiponectin levels. The greatest benefit for the TZDs is to directly influence atherogenesis itself and the potential that these so-called pleiotrophic effects of TZDs to reduce cardiovascular events in type 2 DM will be tested when the results of outcome trials are published in the next few years. If the results are positive for the reduction in vascular end-points, then TZDs will represent a major advance in improving the prognosis of type 2 DM subjects with the metabolic syndrome.

Changes in the human environment and in human behavior and lifestyle, in conjunction with genetic susceptibility, have resulted in a dramatic increase in the incidence and prevalence of diabetes in the world. The rapid escalation of the number of people with type 2 diabetes (T2DM) and diabetes-related cardiovascular disease demands urgent action on prevention. The Finnish Diabetes Prevention Study and The Diabetes Prevention Program showed that the prevention (or delaying) of T2DM is feasible and effective. Both of these trials led to a reduction of 58% in the conversion to diabetes in subjects with impaired glucose tolerance. Compared to lifestyle changes, drug treatment in the prevention of diabetes in people at high risk for T2DM has been less beneficial. Metformin (31%) or acarbose (25%) treatment obtained only about a half of the reduction in the conversion to diabetes compared to lifestyle changes. These drugs require monitoring, and have significant side-effects. Also the effect of orlistat (37%) did not reach the effect of lifestyle modification. Results of the Troglitazone in Prevention of Diabetes study are suggestive for the prevention, but the trial was too small, and included only one ethnic group (Hispanic) and one gender (women). On the basis of the evidence available, we do not have a definite proof that T2DM is prevented in any of these trials. However, we can safely conclude that the current evidence strongly favors the notion that lifestyle changes are the primary means to tackle the epidemic of T2DM.