Foreword

This issue on diabetic complications provides discussion of both basic pathophysiology and practical treatment for both researchers and clinicians. The next issue will focus on conditions closely associated with diabetes. Given the epidemic of obesity and type 2 diabetes, these are most timely topics for Endocrinology and Metabolism Clinics of North America.

Hypoglycemia is one of the major acute complications that diabetic individuals have to deal with, especially those on sulphonylureas and insulin therapy. The risk is further increased when renal function is compromised. The normal counterregulatory response to hypoglycemia may be impaired, leading to an even more dangerous situation with increased morbidity and mortality. As Drs Alsahli and Gerich discuss, episodes of hypoglycemia can be reduced in severity and occurrence with intensive education of patients.

Drs Maletkovic and Drexler describe the effect of poorly controlled diabetes, namely diabetic ketoacidotic (DKA) and hyperosmolar states (HHS). Despite the widespread use of insulin in type 1 patients as well as a panoply of oral agents for type 2 patients, these acute conditions are still prevalent today. Both conditions present with hyperglycemia and dehydration; however, the complete absence of insulin in type 1 patients leads to excess lipolysis and ketoacidosis. Often the cause is an intermittent stressful condition. DKA is often more rapid in onset, whereas HHS is more insidious. There are established protocols for fluid, insulin, and electrolyte replacement, and while most patients recover, this is unfortunately not always the outcome.

Drs Vlassara and Striker discuss the role of advanced glycosylation end products (AGEs) in the chronic complications of diabetes, both type 1 and type 2. The source of AGEs, pro-oxidant molecules, is primarily from the diet, particularly from so-called “fast-food” meals and heat-processed foods. AGEs function via their receptors on the cell called RAGE, whose activation causes an increase in oxidative stress and increased cellular inflammation. The authors consider this process to be the major pathogenic mechanism for diabetic vascular complications, both microvascular and macrovascular.

Another important microvascular complication is retinopathy, a leading cause of new blindness in the United States. Dr Rosberger reminds us of the various trials demonstrating that tight glycemic control in both type 1 (DCCT) and in type 2 diabetic patients (eg, UKPDS) controls retinopathy progression. Two serious conditions, the macular edema and proliferative retinopathy, are treated using laser photocoagulation that can save the patient’s eyesight.

Diabetic neuropathy, especially peripheral neuropathy, is a very common and extremely troublesome complication of diabetes. There is both a vascular and a metabolic component in the pathogenesis. Painful neuropathy can be treated with agents like pregabalin and/or duloxetine, but the relief of pain is incomplete in many patients. Drs Vinik, Nevoret, Casellini, and Parson detail the pathophysiology, symptomatology, and clinical signs in detail and also stress that autonomic neuropathy often coexists and should be screened for in all these cases. Furthermore, they detail the various agents that have been tested for the condition and proven to be essentially ineffective. The mainstay of prevention and even reversal of early peripheral neuropathy remains tight glycemic control.

The connection of the cardiovascular system and the kidney in the development of diabetic complications such as impaired renal function and end-stage renal disease is now well described as the cardio-renal syndrome. It posits that elements of the cardiovascular system, such as hypertension and the lack of nocturnal blood pressure “dipping,” are risk factors for the development and progression of renal disease. In their article, Drs Jindal, Garcia-Touza, Jindal, Whaley-Connell, and Sowers discuss the importance of controlling both blood pressure and blood glucose levels to retard the early renal complications seen in diabetes.

Gastrointestinal complications are quite common in diabetic patients with the most troublesome being due to autonomic neuropathy as well as those caused by medications. Some of the conditions include esophageal motility dysfunction, reflux, esophageal candidiasis, and gastroparesis. As Drs Boland, Edelman, and Wolosin discuss, in addition to the symptomatology there is also the problem of glycemic control that is affected by the GI complications, in both type 1 and type 2 diabetes. Furthermore, autoimmune disorders such as celiac disease are increased in type 1 patients. In obese and type 2 patients non-alcoholic fatty liver disease (NAFLD) has been recognized as a major complication and, if left untreated, may progress to steatohepatitis and cirrhosis; the incidence or detection of NALFD has increased recently and has become a major health concern.

Diabetic foot complications can be devastating, as they can result in amputation that can further complicate the patient’s metabolic control as well as the effect on lifestyle. Drs Kim and Steinberg describe how peripheral vascular changes and peripheral neuropathy together can lead to lower limb ulceration and, if left untreated, can eventuate in gangrene and amputation. They also describe how the pressure of the lower limb adds to the sensitivity of the tissues to ulceration. Standard therapeutic regimens, including debridement, antibiotics, and foot care, with an emphasis on a team approach, can prevent devastating complications.

A less well-known complication of diabetes is periodontitis. Dr Preshaw discusses how the relationship between periodontal disease and diabetes is bidirectional. Diabetic individuals are three times more at risk for periodontal disease, due in part to poor glycemic control and a tendency to inflammatory processes. Periodontal disease itself makes glycemic control worse probably through the effects of inflammatory cytokines. Indeed, when periodontal disease is treated efficiently, HbA1c levels fall by almost 0.5%. This relationship should be brought to the attention of health care providers and dentists as well as patients.

Drs Murphy-Chutorian and Cohen describe the numerous skin manifestations that are seen in diabetic patients. These include specific conditions, such as necrobiosis lipoidica diabeticorum, generalized granuloma annulare, bullosa diabeticorum, scleredema diabeticorum, acanthosis nigricans, and others. Commonly, the skin conditions are named according to certain observed characteristics and, while in some cases the etiology involves a vascular abnormality, often the underlying cause is unknown. Similarly, therapy can be either specific depending on the known etiologic factors or empiric. Diabetic patients are also prone to infections, both bacterial and fungal, and here the therapy is more directed. In addition, lipodystrophy and lipohypertrophy may present at the sites of insulin injections, the latter probably due to the direct effect of insulin on adipocytes, whereas the former from unknown reasons.

Drs Gaunay, Nagler, and Stember describe the effect of diabetes on male sexual function. The two major complications involve sexual dysfunction and hypogonadism, the former due to vascular changes and neuropathy, while the latter more commonly secondary to hypothalamic-pituitary effects. Erectile dysfunction is the most worrisome problem and the authors describe the multiple methods of treatment, not all being totally successful. Ejaculatory dysfunction may also require medical or surgical interventions. In regard to hypogonadism, testosterone replacement is recommended, again with varying success rates.

Insulin plays an important role in the female reproductive system. Acting via its own cognate receptor insulin stimulates ovarian steroidogenesis, at least partially, by synergizing with gonadotrophins. Other effects of insulin are mediated by its inhibition of sex hormone binding globulin synthesis, thereby increasing the proportion of free sex hormone in the circulation. Similarly it decreases insulin-like growth factor bondingprotein 1 (IGFBP-1) production, freeing IGF-1 to also enhance ovarian steroidogenesis. Drs Nandi and Poretsky explain in their article how these peripheral and central effects of insulin often lead to infertility and especially to polycystic ovarian syndrome; not surprising then, that metformin and thiazolidinediones are effective in this condition.

Drs Corathers, Peavie, and Salehi discuss the various antidiabetic agents used to manage diabetes and to prevent the long-term complications. Their article covers both the known mechanisms of each class of agents and the potential side effects. Thus, metformin has gastrointestinal side effects and may possibly cause lactic acidosis, particularly in patients with renal impairment. Thiazolidinediones cause weight gain, edema, and bone fractures and may precipitate heart failure in susceptible patients. Insulin secretagogues cause weight gain and hypoglycemia. Incretins (GLP-1 mimetics and DPP-IV inhibitors) have recently been described as possibly associated with pancreatitis and pancreatic cancer; however, the...