Cerebral dysfunction in type 1 diabetes: effects of insulin, vascular risk factors and blood-glucose levels

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Abstract

Type 1 diabetes can lead to several well-described complications such as retinopathy, nephropathy and peripheral neuropathy. Evidence is accumulating that it is also associated with gradually developing end-organ damage in the central nervous system. This relatively unknown complication can be referred to as ‘diabetic encephalopathy’ and is characterised by electrophysiological and neuroradiological changes, such as delayed latencies of evoked potentials, modest cerebral atrophy and (periventricular) white matter lesions. Furthermore, individuals with type 1 diabetes may show performance deficits in a wide range of cognitive domains. The exact mechanisms underlying this diabetic encephalopathy are only partially known. Chronic metabolic and vascular changes appear to play an important role. Interestingly, the differences in the ‘cognitive profile’ between type 1 and type 2 diabetes also suggest a critical role for disturbances of insulin action in the central nervous system.

Introduction

Diabetes mellitus is a common metabolic disease. Prevalence of diabetes in adults was estimated to be 4% in 1995 and is expected to rise to over 5% by the year 2025 worldwide (King et al., 1998). This implies an increase of the number of adults with diabetes from 135 million in 1995 to 300 million in 2025 (King et al., 1998). Diabetes is characterised by hyperglycaemia due to defects in the secretion of, or resistance to insulin, or both (American Diabetes Association, 2002). The most common form is type 2 diabetes, in which resistance to insulin is accompanied by an inadequate compensation in the secretion of insulin. Type 1 diabetes is caused by an absolute shortage in the production of insulin due to the destruction of pancreatic β cells (American Diabetes Association, 2002). This type of diabetes, which was previously defined as Insulin Dependent Diabetes Mellitus, is not as common as type 2 diabetes; only 5–10% of the patients with diabetes has type 1 diabetes.

Patients with type 1 diabetes are treated with exogenous insulin. Unfortunately, even with repeated injections, or subcutaneously implanted insulin pumps, these treatments cannot fully compensate for the tightly regulated insulin secretions of a normally functioning pancreas. Therefore, individuals with type 1 diabetes may experience fluctuations in blood glucose levels throughout the day, ranging from low blood glucose levels (i.e. hypoglycaemia) to high blood glucose levels (i.e. hyperglycaemia). These fluctuations depend upon the timing, type, dose of insulin administration, the quantity and nutritional content of food ingested, and the amount of physical activity. Since normal cerebral functioning is dependent upon sufficient levels of continuous circulating glucose, these fluctuations can affect functioning of the brain.

It is well known that both type 1 and type 2 diabetes can lead to several complications, such as retinopathy, nephropathy and peripheral neuropathy, and the characteristic clinical signs and symptoms as well as the techniques to diagnose these complications are well established (American Diabetes Association, 2002). Already in 1922, it was recognised that diabetes may also affect cognition (Miles and Root, 1922). Today, there is substantial evidence that acute hypo- and hyperglycaemia have disruptive effects on the central nervous system (CNS) (Weinger and Jacobson, 1998), although relatively less is known about the slowly developing end-organ damage to the CNS that may present itself by electrophysiological and structural changes and impairment of cognitive functioning. These cerebral complications of both type 1 and type 2 diabetes may be referred to as ‘diabetic encephalopathy’, a concept introduced several decades ago (Reske-Nielsen et al., 1965). Since then many different features of these complications have been identified and important leads into the pathophysiology are emerging. However, the clinical characteristics remain heterogeneous. In this review, we will provide an overview of the available data and the questions that remain to be answered. First, we will look into the clinical characteristics and the risk factors that have been implicated in altered CNS functioning in type 1 diabetes. In the last sections, we will explore the possible mechanisms that may underlie diabetic encephalopathy.

Section snippets

Neurophysiological changes

Evoked potentials are frequently used to evaluate CNS physiology. The electrophysiological response of specific CNS structures to visual, auditory or somatosensory stimuli are called visual evoked potentials, brainstem auditory evoked potentials and somatosensory evoked potentials respectively (Di Mario et al., 1995). In the brainstem auditory evoked potentials, five waves can be distinguished (I–V). The latency of wave I is determined by the peripheral components of the acoustic system and the

Possible underlying mechanisms

Multiple pathogenic factors appear to be involved in the pathogenesis of cerebral dysfunctioning in type 1 diabetes. The relative contribution of different factors will vary between individuals, depending on characteristics such as age, sex, amount of glycaemic control and co-morbidity.

Conclusions and directions for future research

Type 1 diabetes can lead to slowly developing end-organ damage resulting in cerebral dysfunction. Diabetic encephalopathy seems to be a heterogeneous disorder characterised by cognitive impairments, electrophysiological and structural changes, and depression or anxiety disorders. A reliable diagnosis of diabetic encephalopathy in individual patients, however, is to date very difficult. There are no specific diagnostic criteria available yet, and the level of cognitive decline might be

Acknowledgements

The research of Ineke Brands is partially supported by grant 2001.00.023 from the Dutch Diabetes Foundation. The research of Geert Jan Biessels is supported by grant 2001.00.023 from the Dutch Diabetes Foundation and grant 2000D030 from the Dutch Heart Association.

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