Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Immunology, Endocrine and Metabolic Agents) - Volume 7, Issue 1, 2007

Management of diabetes is a rapidly expanding area. A few decades ago diabetes therapy mainly consisted of diet, sulfonylurea derivatives in type 2 and insulin in type 1 diabetes. However, at the same time exciting new concepts were discovered involving the interactions between lipid and glucose metabolism, on the biochemical and haemodynamic pathways involved in the development of vascular complications, etc. But the gap between science and practise was too large. This issue of CMC-IEMA is dedicated to new insights in the pathophysiology and treatment of diabetes and its complications. These articles clearly show that science is reaching practise. Diabetes therapy is currently based on 5 pillars: stimulation of self-management, restoration of the metabolic imbalances associated with the diabetic state, aggressive treatment of cardiovascular risk factors, measures to prevent microvascular disease and treatment of diabetic complications. The development of hyperglycaemia in type 2 diabetes is currently seen as the consequence of interplay of several cell types and four major players seem to be involved: adipose tissue, liver, muscle and pancreas. In summary, during fasting insulin levels are low and the liver is responsible for maintaining blood glucose levels at a sufficient level to enable survival. During fasting, free fatty acids (FFAs), derived from the breakdown of fat in adipose tissue, are converted to glucose by the liver. After a meal there is an influx of nutrients, and glucose levels rise which is accompanied by a rapid increase in insulin secretion by the pancreas. The elevated insulin levels inhibit glucose production by the liver and release of FFAs by adipose tissue; moreover insulin stimulates the uptake of glucose by insulin sensitive tissues such as muscle, liver and adipose tissue. In addition, insulin facilitates the uptake of FFAs. In type 2 diabetes these finely tuned processes are clearly deranged. Muscle, liver and fat cells are less sensitive to insulin, resulting in enhanced glucose and FFA production by the liver and fat cells, respectively. After a meal, nutrients are cleared more slowly due the combination of insulin resistance and impaired insulin secretion by the pancreas. As discussed by Hesselink et al, the close interaction between fat and muscle cells could help to explain the development of insulin resistance (Ref Hesselink). Overflow of fat from adipose tissue to muscle could be one of the important mechanisms in the development of insulin resistance in obesity, “lipotoxicity”. Recent studies indicate that intramyocellular accumulation of fat results in mitochondrial dysfunction with impaired fatty acid oxidation and impaired insulin signalling as a consequence. A drastic reduction in nutrient intake, as discussed by Nijhuis et al, results in a rapid improvement in insulin sensitivity in obese type 2 diabetic patients and bariatric surgery can be a very effective treatment in morbid obese type diabetic patients (Ref Nijhuis). Blaak describes in her article the relationship between dietary fat, FFAs and insulin resistance (Ref Blaak). These insights could be the basis for new dietary interventions in which not the absolute amount of fat intake is changed to reduce caloric intake but in which the type of fat intake is modulated to improve insulin sensitivity. In the article of Van Loon another dietary strategy is explored (Ref van Loon). Specific amino acids/ proteins have been shown in short term experiments to stimulate insulin secretion and to reduce muscle proteolysis and/or to stimulate protein synthesis, which could have beneficial effects on insulin sensitivity. Supplementation with specific amino acids/ proteins in combination with an exercise programme seems therefore an attractive intervention for sedentary type 2 diabetic patients, which remains to be tested. Insulin secretion is not only influenced by nutrients but also by several gut hormones (incretins) and several lines of evidence suggest that one of these incretins, glucagon like peptide-1 (GLP-1), could be an attractive new therapeutic modality (Ref Holst). As discussed by Holst GLP-1 has several pancreatic and extra-pancreatic actions, which might be beneficial for patients with type 2 diabetes. Aggressive treatment of hyperglycaemia is one of the cornerstones in the prevention of diabetic complications. Unfortunately, most patients do not succeed in maintaining a normal glucose level day after day. As described by Schalkwijk, this chronic hyperglycaemia results in the formation of advanced glycation end products (AGEs), which could be one of the pivotal steps in the development of diabetic micro- and macroangiopathy (Ref Schalkwijk).......

The prevalence of pre-diabetes and type 2 diabetes increases alarmingly the last few decades and estimates indicate this rise will continue the forthcoming decades. Transition of the pre-diabetic to the diabetic state is a slow but inevitable process. It is therefore of importance to intervene in this transition period in order to prevent overt type 2 diabetes to occur. While the focus of research towards type 2 diabetes has long been glucocentric, over the last decade the focus has shifted to a more lipocentric view. Thus, subnormal fat oxidative capacity, increased mitochondrial damage (lipotoxicity) and decrease mitochondrial function and biogenesis have been identified as factors associated with type 2 diabetes. Within a mitocentric framework, we aim to evaluate the available literature on lipotoxicity and mitochondrial dysfunction and its contribution to the development of insulin resistance and finally type 2 diabetes. In addition, putative targets of intervention will be identified and the modes of action of currently available anti-diabetic agents will be reviewed. In the majority of this review the organ of interest will be the skeletal muscle, as this is the major site of insulin resistance.

Morbid obesity is associated with serious co-morbidities as cardiovascular disease, insulin resistance (IR) and type 2 diabetes (T2DM). Conventional therapy for T2DM consists of weight loss and pharmacotherapy. Recently, surgery was suggested to be the best treatment for T2DM in morbid obese patients. This review will focus on the effects of bariatric surgery on T2DM. The outcomes of different bariatric techniques will be discussed. Moreover, the question why weight loss is advantageous in treating T2DM will be addressed. In this view, the effect of decreased nutrient intake, decreased intracellular fatty acid accumulation as well as decreased body fat mass on T2DM are discussed.

A high dietary fat intake is associated with an increased risk for the development of obesity. Obesity, in a particular abdominal obesity, is one of the major risk factors for the development of insulin resistance and type 2 diabetes mellitus. There are indications for a direct relation between dietary fat and insulin sensitivity, independent of body weight, which may be mainly mediated by dietary fat quality. Cross sectional studies in humans show a clear relationship between dietary fat quality and markers of insulin sensitivity. Also, the composition of fatty acids in serum lipids and tissues (muscle, adipose tissue), partly reflecting dietary fatty acid intake, show that insulin resistance is related to a specific pattern of fatty acids with a high content of SFAs (mainly palmitic acid) and a low concentration of PUFAs (mainly n-3 and n-6 PUFAs). There is increased evidence that lipid overflow to non-adipose tissues (lipotoxicity) may interfer with insulinmediated glucose uptake through an accumulaton of intramyocellar lipids. PUFAs may regulate fuel partitioning within the muscle cell through effects on membrane phospholipid composition and intramuscular fat storage mediated by changes in membrane fluidity, intracellular signaling molecules and gene expression. The relationship between dietary fat and insulin sensitivity needs additional confirmation in well-controlled human dietary intervention trials

Evidence is accumulating showing amino acids to play a key regulatory role in numerous metabolic processes. Amino acids, and leucine in particular, can be applied as potent insulin secretagogues. These stimulating properties are not restricted to healthy humans, but are also effective in long-term diagnosed type 2 diabetes patients. Co-ingestion of amino acid/protein with carbohydrate substantially augments endogenous insulin release, accelerates blood glucose disposal, and improves post-prandial glucose homeostasis. Besides their function as precursors for protein synthesis, some amino acids are also able to stimulate protein anabolism in an insulin-independent manner. Branched chain amino acids (BCAA), and leucine in particular, are capable of activating the mRNA translational machinery through the mammalian target of rapamycin (mTOR), which represents an interesting molecular target for the prevention or reduction of elevated muscle proteolysis in uncontrolled type 2 diabetes. Protein and/or specific amino acid supplementation could help to reduce muscle proteolysis and/or to stimulate protein synthesis, leading to an improved muscle protein balance, which augments whole-body blood glucose disposal capacity. Besides the potential benefits of protein and/or amino acid supplementation, there is evidence showing hyperaminoacidemia to impair skeletal muscle insulin signaling. Understanding the mechanisms by which different amino acids can alter metabolic signaling will be of great value for the development of effective nutritional and/or pharmacological interventions to prevent and/or treat insulin resistance and/or type 2 diabetes. Studies investigating the benefits of long-term amino acid and/or protein supplementation in type 2 diabetes patients are warranted.

The incretin hormones, GIP and GLP-1, may be responsible for up to 70% of postprandial insulin secretion. In type 2 diabetes (2DM) the incretin effect is severely reduced. Secretion of GIP is normal, but its effect on insulin is lost. GLP-1 secretion may be impaired, but its actions may restore insulin secretion to near normal levels. Substitution therapy with GLP-1 might therefore be possible. GLP-1 actions include: potentiation of glucose-induced insulin secretion; upregulation of insulin and other β-cell genes; stimulation of β-cell proliferation and neogenesis and inhibition of β-cell apoptosis; inhibition of glucagon secretion; inhibition of gastric emptying; and inhibition of appetite and food intake. It may also have cardio- and neuroprotective actions. These actions make GLP-1 particularly attractive as a therapeutic agent for 2DM but GLP-1 is rapidly destroyed in the body by the enzyme, DPP-IV. Clinical strategies therefore include: 1) the development of metabolically stable activators of the GLP-1 receptor; and 2) inhibition of DPP-IV. Orally active DPP-IV inhibitors are currently undergoing clinical trials and recent clinical studies have provided long term proof of concept. Metabolically stable analogues/activators include the structurally related lizard peptide, exendin-4, or analogues thereof, as well as GLP-1 derived molecules that bind to albumin and thereby assume the pharmacokinetics of albumin. These molecules are effective in animal experimental models of type 2 diabetes, and have been employed successfully in clinical studies of up to 82 weeks' duration, and exendin-4 has just been approved for add-on therapy of 2DM.

It is now well established that the non-enzymatic glycation can have direct and indirect biological effects leading to micro- and macrovascular complications in diabetes. Accumulation of AGEs in the extracellular matrix can cause aberrant cross-linking, resulting in vascular stiffness. AGEs can also bind to AGE-receptors, including RAGE, on different cell types resulting in cell activation. In addition, cellular formation of AGEs may be an important contributor to diabetic vascular complications by modification of growth factors. Because of these deleterious effects, a number of natural or synthetic inhibitors are currently being advanced to reduce the clinical impact of AGEs. These specific inhibitors exhibit three possible modes of action: 1. inhibition of the formation of AGEs, 2. cleavage of existing AGE cross-links, and 3. interference of the binding of AGEs to RAGE or suppression of AGE-RAGE induced signalling pathways. Aminoguanidine was the first compound designed to inhibit AGE formation and has undergone clinical trials. Due to safety concerns and lack of efficacy, aminoguanidine is unlikely to be used for therapeutic purpose. In vitro experiments and animal models have shown the potential of other agents designed to reduce the formation of AGEs such as pyridoxamine. In addition, AGE cross-link breakers such the stable derivative ALT-711 were also reported to be effective in in vitro experiments and in several diabetic animal models. Pyridoxamine and ALT-711 are now in clinical trials. The soluble form of RAGE (sRAGE) was reported to reduce deleterious effects of AGEs. Therefore, blockage of RAGE by sRAGE may be a new target for therapeutic intervention in diabetic disorders. These agents interfering in the glycation pathway offer new potential treatments for glucose-derived vascular complications of diabetes.

New data indicate that proinsulin C-peptide, contrary to previous views, exerts important physiological effects and shows the characteristics of a bioactive peptide. Studies in animal models and in type 1 diabetes patients have demonstrated multifaceted effects. Peripheral nerve function, as evaluated by determination of sensory nerve conduction velocity and quantitative sensory testing, is improved by C-peptide replacement in diabetes type 1 patients with early stage neuropathy. Similarly, autonomic nerve dysfunction is ameliorated following administration of C-peptide for up to 3 months. C-peptide given to type 1 diabetic animals results in improved nerve conduction velocity and reversal or prevention of nerve structural changes. C-peptide corrects diabetes-induced reductions in endoneurial blood flow and in Na+,K+-ATPase activity. In vitro studies demonstrate that C-peptide binds specifically to cell membranes, activating a G-protein coupled receptor as well as Ca2+-, PKC- and MAPK-dependent signaling pathways, resulting in stimulation of Na+,K+-ATPase and endothelial nitric oxide synthase (eNOS). In addition, C-peptide activates transcription factors resulting in augmented eNOS mRNA and protein content of endothelial cells and modulation of neurotrophic factors as well as apoptotic phenomena in neuroblastoma cells. Combined, the results demonstrate that C-peptide is a bioactive peptide, possibly of importance in the treatment of neuropathy in type 1 diabetes.

Diabetic peripheral neuropathy affects up to 50% of older type 2 diabetic patients: at any time, up to 50% of patients will experience painful or uncomfortable symptoms, some of whom will require symptomatic therapy. The first step in management is to exclude other causes of neuropathy and assess the level of glycaemic control. Recent research suggests that neuropathic pain may be exacerbated by erratic blood glucose control: thus the first aim in management should be to optimize and stabilize glycaemic control. A number of symptomatic therapies have been proven to be efficacious in randomized controlled trials. Whereas the tricyclic drugs are still commonly prescribed, their use is limited by troublesome and predictable side effects. The anticonvulsants Gabapentin and Pregabalin are now widely used in the management of neuropathic pain: the adverse events appear to be superior to the tricyclics. Other promising therapies include Duloxetine and Tramadol. There is also increasing evidence that opioids may be efficacious in some severe cases unresponsive to traditional treatments.

Diabetes mellitus is associated with a significant and complex pathology involving a large number of secondary cellular and subcellular changes. Most organ functions are impaired resulting in clinical manifestations such as retinopathy, impaired wound healing, and accelerated atherosclerosis, nephropathy and neuropathy. With regard to vascular changes, the situation seems paradox: There is enhanced angiogenesis, such as in the context of proliferative retinopathy or atherosclerotic plaque angiogenesis. On the other hand, arteriogenesis and collateral artery growth is reduced in diabetes mellitus, which is associated with reduced regional organ perfusion. Likewise, wound healing is impaired in diabetes on the basis of reduced angiogenesis. This coexistence of enhanced and impaired neovascularization in diabetes mellitus is defined as the angiogenic paradox. This review is focusing on the different vascular complications of diabetes mellitus, and presents a unifying hypothesis for explaining the angiogenic paradox: The response to vascular growth factors (lead example: VEGF) is impaired in diabetic conditions, secondary to an impaired responsiveness of their receptor systems. The molecular defect is likely to be located within the signal transduction system either downstream of the receptor (“signal transduction defect”) or at the level of the receptor itself. Under specific pathological circumstances that allow the prolonged accumulation of the ligand (VEGF), such as in the eye or within an atherosclerotic plaque, pathological angiogenesis may be induced.

The development of diabetic foot ulcers is a well-known complication of diabetes. The pathophysiological mechanism is complex, and different clinical presentations are possible, depending on the specific underlying pathology. Diabetic foot ulcers are usually caused by several factors acting in concert, with polyneuropathy, altered biomechanics, inadequate shoes and peripheral arterial disease (PAD) as major factors. Neuropathy is present in most patients with diabetic foot ulcers, while PAD is present in 30 - 50 %; infection can be diagnosed in up to 50% of patients presenting with a foot ulcer. Therefore careful examination of the patient and identification of these specific pathologies is needed before the start of any treatment. Because most patients have lost the natural protective mechanism to relieve pressure from the wound, off-loading of these ulcers is extremely important. For plantar foot ulcers total contact casting is the current standard: with this technique up to 90% of neuropathic ulcers can be healed within two months. The recognition and treatment of infection is equally important. Diagnosing infection is a challenge in these patients because signs and symptoms can be absent. The choice of the initial antimicrobial therapy is usually empiric and based on the severity of the infection, prior antibiotic use and local resistance to most common pathogens. Evaluation of the severity of PAD is indicated in many patients. Patients with critical limb ischemia should undergo revascularisation as soon as possible, and both endovascular treatment and bypass surgery are suitable interventions to improve tissue perfusion. Most other strategies to improve wound healing, such as local application of growth factors, have failed to show significant clinical benefits. Recently, negative pressure wound therapy was shown to improve wound healing in patients with a partial foot amputation in a large randomised trial. Many patients not only have foot problems but also other health problems such as cardiovascular and renal disease and self care problems. Therefore an integrated management programme is needed, in which optimal regulation of diabetes and associated co-morbidity, and regular communication and instruction of the patient and his or her caregivers are taken care of.