There is increasing evidence that an ongoing cytokine-induced acute-phase response (sometimes called low-grade inflammation, but part of a widespread activation of the innate immune system) is closely involved in the pathogenesis of type 2 diabetes and associated complications such as dyslipidemia and atherosclerosis. Elevated circulating inflammatory markers such as C-reactive protein and interleukin-6 predict the development of type 2 diabetes, and several drugs with anti-inflammatory properties lower both acute-phase reactants and glycemia (aspirin and thiazolidinediones) and possibly decrease the risk of developing type 2 diabetes (statins). Among the risk factors for type 2 diabetes, which are also known to be associated with activated innate immunity, are age, inactivity, certain dietary components, smoking, psychological stress, and low birth weight. Activated immunity may be the common antecedent of both type 2 diabetes and atherosclerosis, which probably develop in parallel. Other features of type 2 diabetes, such as fatigue, sleep disturbance, and depression, are likely to be at least partly due to hypercytokinemia and activated innate immunity. Further research is needed to confirm and clarify the role of innate immunity in type 2 diabetes, particularly the extent to which inflammation in type 2 diabetes is a primary abnormality or partly secondary to hyperglycemia, obesity, atherosclerosis, or other common features of the disease.
The cause of the common type of Type II (non-insulin-dependent) diabetes mellitus, which affects at least 100 million people throughout the world, is not known. One of the foremost challenges we face is to account mechanistically for not only the defining hyperglycaemia but also for the myriad of other biochemical and physiological abnormalities which are characteristic of this disease. For example, it is now clear that Type II diabetes and lesser degrees of glucose intolerance commonly occur together with a collection of clinical and biochemical features which have been called metabolic syndrome X [1, 2].These features include central obesity, hypertension, accelerated atherosclerosis, hypertriglyceridaemia and low serum concentrations of high-density lipoprotein (HDL) cholesterol. Though insulin resistance seems to be a central abnormality, the origin of the impaired insulin action and how it explains the many other abnormalities of Type II diabetes is not known.In recent years, we have been gathering evidence that in Type II diabetes there is a cytokine-associated acute-phase reaction, part of the innate immune response. As an alternative direction for research into the aetiology of Type II diabetes, we propose that it may be helpful to consider whether the mechanisms involved in the acute-phase response can be major contributors to the pathophysiology of many of the features of Type II diabetes and syndrome X, including glucose intolerance, insulin resistance, impair- Diabetologia (1998) Summary Type II (non-insulin-dependent) diabetes mellitus is associated with increased blood concentrations of markers of the acute-phase response, including sialic acid, a-1 acid glycoprotein, serum amyloid A, C-reactive protein and cortisol, and the main cytokine mediator of the response, interleukin-6. The dyslipidaemia common in Type II diabetes (hypertriglyceridaemia and low serum levels of HDL cholesterol) is also a feature of natural and experimental acutephase reactions. We review evidence that a long-term cytokine-mediated acute-phase reaction occurs in Type II diabetes and is part of a wide-ranging innate immune response. Through the action of cytokines on the brain, liver, endothelium, adipose tissue and elsewhere, this process could be a major contributor to the biochemical and clinical features of metabolic syndrome X (glucose intolerance, dyslipidaemia, insulin resistance, hypertension, central obesity, accelerated atherosclerosis) but also provides a mechanism for many other abnormalities seen in Type II diabetes, including those in blood clotting, the reproductive system, metal ion metabolism, psychological behaviour and capillary permeability. In the short-term, the innate immune system restores homeostasis after environmental threats; we suggest that in Type II diabetes and impaired glucose tolerance long-term lifestyle and environmental stimulants, probably in those with an innately hypersensitive acute-phase response, produce disease instead of repair. [Diabetologia (1998
Aims Continuous subcutaneous insulin infusion (CSII) is a recommended treatment for reducing severe hypoglycaemia in Type 1 diabetes, but the change in hypoglycaemia compared with multiple daily insulin injections (MDI) is unclear. We therefore conducted a meta-analysis comparing severe hypoglycaemia and glycaemic control during CSII and MDI.Methods Databases and literature (1996 -2006) were searched for randomized controlled trials (RCTs) and before/after studies of ≥ 6 months' duration CSII and with severe hypoglycaemia frequency > 10 episodes/100 patient years on MDI.Results In 22 studies (21 reports), severe hypoglycaemia during MDI was related to diabetes duration ( P = 0.038) and was greater in adults than children (100 vs. 36 events/100 patient years, P = 0.036). Severe hypoglycaemia was reduced during CSII compared with MDI, with a rate ratio of 2.89 (95% CI 1.45 to 5.76) for RCTs and 4.34 (2.87 to 6.56) for before/after studies [rate ratio 4.19 (2.86 to 6.13) for all studies]. The reduction was greatest in those with the highest initial severe hypoglycaemia rates on MDI ( P < 0.001). The mean difference in glycated haemoglobin (HbA 1c ) between treatments was less for RCTs [0.21% (0.13-0.30%)] than in before/after studies [0.72% (0.55-0.90%)] but strongly related to the initial HbA 1c on MDI ( P < 0.001). ConclusionsThe severe hypoglycaemia rate in Type 1 diabetes was markedly less during CSII than MDI, with the greatest reduction in those with most severe hypoglycaemia on MDI and those with the longest duration of diabetes. The biggest improvement in HbA 1c was in those with the highest HbA 1c on MDI.Diabet. Med. 25, 765-774 (2008)
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