Current Diabetes Reviews - Volume 6, Issue 5, 2010

Impaired glucose tolerance and diabetes mellitus are a manifestation of several well recognised endocrine disorders. Hyperglycaemia subsides upon removal of the underlying cause in these conditions - usually a hormone secreting tumour. We describe two subjects who were cured of their poorly controlled diabetes mellitus following surgical removal of a phaeochromocytoma and a cortisol secreting adrenal adenoma and review the mechanisms underlying glucose intolerance in endocrine disorders. The reported incidence of diabetes is variable in these conditions and may range between 2- 95%. The severity is also variable as some affected individuals have only minor glucose intolerance while others have frank symptomatic diabetes mellitus which forms a major manifestation of their illness. The mechanisms causing hyperglycaemia are (a) insulin resistance, (b) increased hepatic glucose production and output, (c) decreased insulin production and release and (d) increased intestinal glucose absorption. Multiple intermediate mechanisms which include electrolyte perturbations and hormone receptor and post receptor mediated effects are responsible for these abnormalities. An understsanding of these mechanisms and diagnostic strategies is important as these may be used to advantage in managing these patients. We describe some of these in greater detail below.

Pancreatic islet transplantation is a promising treatment option for Type 1 Diabetics, offering improved glycaemic control through restoration of insulin production and freedom from life-threatening hypoglycaemic episodes. Implementation of the Edmonton protocol in 2000, a glucocorticoid-free immunosuppressive regimen has led to improved islet transplantation success. >50% of islets are lost post-transplantation primarily through cytokine-mediated apoptosis, ischemia and hypoxia. Gene therapy presents a novel strategy to modify islets for improved survival post-transplantation. Current islet gene therapy approaches aim to improve islet function, block apoptosis and inhibit rejection. Gene transfer vectors include adenoviral, adeno-associated virus, herpes simplex virus vectors, retroviral vectors (including lentiviral vectors) and non-viral vectors. Adeno-associated virus is currently the best islet gene therapy vector, due to the vectors minimal immunogenicity and high safety profile. In animal models, using viral vectors to deliver genes conferring local immunoregulation, anti-apoptotic genes or angiogenic genes to islets can significantly improve islet survival in the early post-transplant period and influence long term engraftment. With recent improvements in gene delivery and increased understanding of the mechanisms underlying graft failure, gene therapy for islet transplantation has the potential to move closer to the clinic as a treatment for patients with Type 1 Diabetes.

Insulin resistance of glucose transport and metabolism in insulin-sensitive tissues is a primary defect leading to the development of type 2 diabetes. While the etiology of insulin resistance is multifactorial, one factor associated with reduced insulin action is enhanced activity of the serine/threonine kinase glycogen synthase kinase-3 (GSK-3) in skeletal muscle, liver, and adipose tissue. GSK-3 is involved in numerous cellular functions, including glycogen synthesis, protein synthesis, gene transcription, and cell differentiation. Evidence from muscle and fat cell lines and in skeletal muscle from a variety of obese rodent models and from type 2 diabetic humans supports a role of GSK-3 overactivity in the development of insulin resistance of glucose transport and glycogenesis. Studies utilizing highly selective GSK-3 inhibitors indicate that GSK-3 overactivity in obesity is associated with enhanced IRS-1 serine phosphorylation and defective IRS-1- dependent signaling, ultimately resulting in reduced GLUT-4 translocation and glucose transport activity in skeletal muscle. A role of GSK-3 overactivity in the exaggerated hepatic glucose production of type 2 diabetes has also been reported. Recent studies have demonstrated that oxidative stress, resulting from enhanced exposure to oxidants, causes impaired insulin signaling and insulin resistance of skeletal muscle glucose transport, in part due to reduced suppression of GSK-3 activity and increased IRS-1 Ser307 phosphorylation. The evidence to date supports an important role of GSK-3 dysfunction in the multifactorial etiology of insulin resistance in skeletal muscle. GSK-3 remains an important target for interventions designed to improve insulin action in obesity-associated insulin resistance and type 2 diabetes.

The global diabetes burden is predicted to rise to 380 million by 2025 and would present itself as a major health challenge. However, both Type 1 and Type 2 diabetes increase the risk of developing micro-vascular complications and macro-vascular complications which in turn will have a devastating impact on quality of life of the patients and challenge health services Worldwide. The micro-vascular complications that affect small blood vessels are the leading cause of blindness (diabetic retinopathy) in the people of the working-age, end-stage renal disease (diabetic nephropathy) the most common cause of kidney failure today, and foot amputation (diabetic neuropathy) in patients with Type 1 and Type 2 diabetes. It is accepted that hyperglycemia is a major causative factor for the development of these complications, there is now growing evidence for the role of inflammation. Here we discuss low-grade inflammation as a common retinal-renalnerve pathogenic link in patients with Type 1 and Type 2 diabetes. This review summarizes evidence showing a link between circulating and locally produced inflammatory biomarkers, such as cell adhesion molecules (vascular adhesion cell molecule-1, VCAM-1; intracellular adhesion molecule-1, ICAM- 1), pro-inflammatory cytokines (interleukin-6, IL-6; tumour necrosis factor-alpha, TNF-α; C-reactive protein, CRP) with the development and progression of diabetic micro-vascular complications.

Diabetic retinopathy is considered one of the vision-threatening diseases among working-age population. The pathogenesis of the disease is regarded multifactorial and complex: capillary basement membrane thickening, loss of pericytes, microaneuryms, loss of endothelial cells, blood retinal barrier breakdown and other anatomic lesions might contribute to macular edema and/or neovascularization the two major and sight threatening complications of diabetic retinopathy. A number of proangiogenic, angiogenic and antiangiogenic factors are involved in the pathogenesis and progression of diabetic retinal disease, Vascular Endothelial Growth Factor (VEGF) being one of the most important. Other growth factors, which are known to participate in the pathogenesis of the disease, are: Platelet Derived Growth Factor (PDGF), Fibroblast Growth Factor (FGF), Hepatocyte Growth Factor (HGF), Transforming Growth Factor (TGF), Placental Endothelial Cell Growth Factor (PlGF), Connective Tissue Growth Factor (CTGF). Other molecules that are involved in the disease mechanisms are: intergrins, angiopoietins, protein kinase C (PKC), ephrins, interleukins, leptin, angiotensin, monocyte chemotactic protein (MCP), vascular cell adhesion molecule (VCAM), tissue plasminogen activator (TPA), and extracellular matrix metalloproteinases (ECM-MMPs). However, the intraocular concentration of angiogenic factors is counterbalanced by the ocular synthesis of several antioangiogenic factors such as pigment epithelial derived factor (PEDF), angiostatin, endostatin, thrombospondin, steroids, atrial natriuretic peptide (ANP), inteferon, aptamer, monoclonal antibodies, VEGF receptor blocker, VEGF gene suppressors, intracellular signal transduction inhibitors, and extracellular matrix antagonists. Growth stimulation or inhibition by these factors depends on the state of development and differentiation of the target tissue. The mechanisms of angiogenesis factor action are very different and most factors are multipotential; they stimulate proliferation or differentiation of endothelial cells. This review attempts to briefly outline the knowledge about peptide growth factor involvement in diabetic retinopathy. Further ongoing research may provide better understanding of molecular mechanisms, disease pathogenesis and therapeutic interactions.

Diabetic retinopathy (DR) remains the major threat to sight in the working age population. Diabetic macular edema (DME) is a manifestation of DR that produces loss of central vision. Proliferative diabetic retinopathy (PDR) is a major cause of visual loss in diabetic patients. In PDR, the growth of new vessels is thought to occur as a result of vascular endothelial growth factor (VEGF) release into the vitreous cavity as a response to ischemia. Furthermore, VEGF increases vessel permeability leading to deposition of proteins in the interstitium that facilitate the process of angiogenesis and macular edema. This review demonstrates multiple benefits of intravitreal bevacizumab (IVB) on DR including DME and PDR at 24 months of follow up. The results indicate that IVB injections may have a beneficial effect on macular thickness and visual acuity (VA) in diffuse diabetic macular edema. Therefore, in the future this new therapy could replace or complement focal/grid laser photocoagulation in DME. In PDR, this new option could be an adjuvant agent to pan-retina photocoagulation so that more selective therapy may be applied. In addition, we report a series of patients in which tractional retinal detachment developed or progressed after adjuvant preoperative IVB in severe PDR.

The pathogenesis of diabetic late complications (DLC) is multifactorial. Studies of mechanisms leading to early functional microvascular changes in retina and kidneys point towards a disturbance in the metabolism of inorganic phosphate (Pi) in diabetes. Since tissue hypoxia and reduced high energy phosphates may be important factors in the development of DLC, the influence of Pi concentration on the metabolism and function of the erythrocytes and renal tubular cells, as well as the relationship of the concentration of Pi to total oxygen consumption, have been reviewed. While extensive research data in non-diabetic conditions support the suggestion, that the Pi concentration is a determining factor in regulation of metabolism and rate of oxygen consumption, diabetes shows the opposite behavior. In diabetes, the highest oxygen consumption is associated with the lowest concentration of Pi. Many conventionally-treated juvenile diabetic patients respond as if their tissues were in a state of chronic hypoxia. A disturbance in phosphate handling occurs in the kidney tubules, where the excessive sodium-dependent glucose entry in diabetics depolarizes the electrochemical sodium gradient and consequently impairs inorganic phosphate reabsorption. Similar changes may occur in other cells and tissues in which glucose entry is not controlled by insulin, and particularly in poorly-regulated diabetic patients in whom long-term vascular complications are more likely.

The musculoskeletal system can be affected by diabetes in a number of ways. The shoulder is one of the frequently affected sites. One of the rheumatic conditions caused by diabetes is frozen shoulder (adhesive capsulitis), which is characterized by pain and severe limited active and passive range of motion of the glenohumeral joint, particularly external rotation. This disorder has a clinical diagnosis and the treatment is based on physiotherapy, non-steroidal antiinflammatory drugs (NSAIDs), corticosteroid injections and, in refractory cases, surgical resolution. As with adhesive capsulitis, calcific periarthritis of the shoulder causes pain and limited joint mobility, although usually it has a better prognosis than frozen shoulder. Reflex sympathetic dystrophy, also known as shoulder-hand syndrome, is a painful syndrome associated with vasomotor and sudomotor changes in the affected member. Diabetic amyotrophy usually affects the peripheral nerves of lower limbs. However, when symptoms involve the shoulder girdle, it must be considered in the differential diagnosis of shoulder painful conditions. Osteoarthritis is the most common rheumatic condition. There are many risk factors for shoulder osteoarthritis including age, genetics, sex, weight, joint infection, history of shoulder dislocation, and previous injury, in older age patients, diabetes is a risk factor for shoulder OA. Treatment options include acetaminophen, NSAIDs, short term opiate, glucosamine and chondroitin. Corticosteroid injections and/or injections of hyaluronans could also be considered. Patients with continued disabling pain that is not responsive to conservative measures may require surgical referral. The present review will focus on practice points of view about shoulder manifestations in patients with diabetes.

Non-alcoholic fatty liver disease (NAFLD) is strongly associated with insulin resistance, and its prevalence is rising in parallel with worldwide increases in obesity and type 2 diabetes. However, the nature of this relationship remains debatable. In particular, it is unclear whether insulin resistance causes NAFLD or hepatic steatosis per se reduces insulin sensitivity. This review will examine data from recent studies on the link between insulin resistance and NAFLD, focusing on studies that have attempted to dissociate fatty liver and hepatic insulin resistance.