Review Articles

Improved hygiene has reduced childhood exposure to environmental microbes, a change that could partly explain the increased incidence of autoimmune diseases, such as type 1 diabetes mellitus, now reported in the developed world. Such exposure to microbes seems to promote development of a healthy immune system; in experimental animal models, administration of microbes or their components can inhibit autoimmune diabetes. This finding raises the possibility of a future vaccine against type 1 diabetes mellitus.

Immune therapies that induce or, in the case of established type 1 diabetes mellitus (T1DM), restore immune tolerance to target autoantigens hold potential to cure T1DM whilst avoiding the need for chronic immunosuppression. This Review discusses different immune therapies for T1DM and, in particular, focuses on two promising strategies in clinical development—the use of candidate autoantigens and anti-CD3 monoclonal antibodies—that aim to restore immune tolerance.

Stereotactic radiosurgery can be performed to control tumor growth and hypersecretion of pituitary tumors, which are the most frequent type of intercranial tumors and lead to high rates of morbidity and mortality. Results of long-term studies of this treatment are discussed in this Review, with recommendations for therapeutic management.

Adipocytes store energy and regulate themselves depending on the environment. Clinical studies suggest that excess macronutrient intake may induce cellular lipid loading and promote signs of inflammatory stress, which ultimately leads to metabolic dysfunction. This Review discusses how lipid mediators may act on important immune receptors to induce low-grade tissue inflammation, which leads to adipocyte and metabolic dysfunction in obesity.

Diabetic angiopathy is among the most serious consequences of diabetes mellitus owing to its impact on quality of life, morbidity, mortality and burden to health-care systems. This Review discusses data that support a role of dysregulation of components of the complement system and the tumor necrosis factor superfamily in the development of diabetic angiopathy.

Mounting evidence suggests that gastrointestinal surgical procedures, such as gastric bypass, can induce long-term remission of type 2 diabetes mellitus (T2DM) and other metabolic disorders. Here, Rubino and colleagues provide an overview of the use of 'metabolic surgery' for patients with T2DM and discuss the implications for future research. The authors hypothesize that the gastrointestinal tract might have a key role in the pathophysiology of T2DM and obesity.

Osteomyelitis is one of the most feared complications of ulcers associated with the foot in diabetes mellitus as it greatly increases the risk of a lower-extremity amputation. As no generally agreed protocol exists, the management of this condition is also one of the most controversial. This Review discusses the available data on surgical versus primarily nonsurgical management of osteomyelitis as a complication of the diabetic foot.

Hereditary hemochromatosis is a genetic condition leading to iron overload that can have detrimental effects on glucose metabolism and other organ systems. This review summarizes the epidemiology of hereditary hemochromatosis and iron overload and discusses possible pathophysiologic mechanisms whereby iron excess can have toxic effects on β cells.

Raised levels of aldosterone, but also concentrations within the normal range are associated with elevated blood pressure. The authors of this Review assess evidence for the role of aldosterone in the development and maintenance of hypertension, including experimental and clinical studies, and discuss the genetic and environmental mechanisms that underlie its effects.

Type 2 diabetes mellitus is a complex disease with a heterogeneous genetic and environmental background. Three relatively infrequent polymorphisms in genes of the insulin signaling pathway modulate the risk of type 2 diabetes mellitus and cardiovascular diseases related to insulin resistance in specific subgroups of individuals. This article discusses the role of these variants and demonstrates how difficult it is to ascertain the contribution of relatively infrequent genetic variants on disease susceptibility.

Amiodarone is widely used for treating cardiac arrhythmias, but is associated with various adverse effects. This Review discusses how the treatment can affect thyroid function, leading to amiodarone-induced hypothyroidism or hyperthyroidism. It compares outcomes with dronedarone, a structurally similar anti-arrhythmic drug that does not contain iodine and may have fewer and less serious adverse effects.

Depression, anxiety and diabetes-specific distress are common and serious comorbid health problems in type 2 diabetes mellitus that often remain unrecognized and thus untreated. Widely used guidelines have therefore recommended assessments of emotional well-being in type 2 diabetes mellitus. The present Review discusses whether there is evidence to support this recommendation.

Multiple sclerosis and type 1 diabetes mellitus are seemingly very different autoimmune diseases. However, this Review discusses recent studies in genetics, epidemiology and immunology that have uncovered many features common to both disorders. Overlaps between T1DM and MS might lead to similar strategies in preventing and treating these debilitating conditions.

Estrogen therapy can reduce cognitive decline in aging women. However, the beneficial effects of estrogen on cognition are apparent only when treatment is initiated around the time of menopause; the same effect is not detected when estrogen therapy is started years later. The 'critical period' hypothesis attempts to explain this discrepancy. Here, Barbara Sherwin reviews studies in which the timing of estrogen therapy was provided and asks whether their findings support the critical period hypothesis.

Regulation of systemic phosphate homeostasis is strictly controlled by a limited number of factors, including FGF23 (a bone-derived protein) and Klotho (a membrane-bound protein). Dysregulation of FGF23 and Klotho is associated with altered phosphate turnover in several acquired and genetic human diseases. The endocrine effects of the FGF23–Klotho axis in normal physiology and disease are described by the author of this Review.

The metabolic syndrome is a complex disorder that consists of an accumulation of visceral fat tissue, dyslipidemia, insulin resistance and hypertension, and can lead to type 2 diabetes mellitus and cardiovascular disease. This article reviews the mechanisms that underlie the metabolic syndrome, focusing on the role of testosterone. The potential of testosterone substitution therapy to treat patients with the metabolic syndrome is also discussed.

The global burden of microvascular disease associated with type 2 diabetes mellitus continues to escalate. Furthermore, conventional standards of care do not completely abolish the risk of diabetic retinopathy, nephropathy or neuropathy in affected individuals. In this Review, the authors highlight the issue of residual microvascular risk and discuss intensive treatment with statins and/or fibrates to target atherogenic dyslipidemia, a potential trigger of the microvascular complications that can develop in patients with type 2 diabetes mellitus.

Biochemical control cannot be achieved by the use of somatostatin analogs alone in a large number of patients with acromegaly. Combination therapy with somatostatin analogs and the growth-hormone-receptor antagonist pegvisomant is, however, highly effective at normalizing levels of insulin-like growth factor I. In this Review, the efficacy and safety of somatostatin analog–pegvisomant combination therapy as a potential tool for the medical management of patients with acromegaly is discussed.

The Diabetes Control and Complications Trial (DCCT) was a landmark study that evaluated intensive versus conventional insulin therapy in patients with type 1 diabetes mellitus; the Epidemiology of Diabetes Interventions and Complications (EDIC) study continues to follow the same cohort of patients. Many of the key contributions that the DCCT and EDIC have made to our understanding of type 1 diabetes mellitus are discussed by the authors of this Review.

Early foundations of the metabolic syndrome may be laid as a consequence of changes in dietary supply to the rapidly growing fetus and/or postnatal offspring. This review highlights fetal developmental plasticity in cellular homeostasis that may manifest in adult life as the metabolic syndrome particularly if followed by a period of accelerated postnatal growth.