Anna Erzsébet Körei

Diabetes-Related Dysfunction of the Small Intestine and the Colon: Focus on Motility

In contrast to gastric dysfunction, diabetes-related functional impairments of the small and large intestine have been studied less intensively. The gastrointestinal tract accomplishes several functions, such as mixing and propulsion of luminal content, absorption and secretion of ions, water, and nutrients, defense against pathogens, and elimination of waste products. Diverse functions of the gut are regulated by complex interactions among its functional elements, including gut microbiota. The network-forming tissues, the enteric nervous system) and the interstitial cells of Cajal, are definitely impaired in diabetic patients, and their loss of function is closely related to the symptoms in diabetes, but changes of other elements could also play a role in the development of diabetes mellitus-related motility disorders. The development of our understanding over the recent years of the diabetes-induced dysfunctions in the small and large intestine are reviewed in this article.

Autonomic dysfunction and circadian blood pressure variations in people with impaired glucose tolerance

To assess circadian blood pressure variability in people with impaired glucose tolerance and a healthy control population.

Heart rate variability is severely impaired among type 2 diabetic patients with hypertension

The aim of our study was to evaluate the relative effect of diabetes and hypertension on heart rate variability.

Small-Fiber Neuropathy: A Diabetic Microvascular Complication of Special Clinical, Diagnostic, and Prognostic Importance.

Damage of small nerve fibers may lead to a large variety of clinical symptoms. Small-fiber neuropathy underlies the symptoms of painful diabetic neuropathy, which may decrease quality of life. It also contributes to the poor prognosis of diabetic neuropathy because it plays a key role in the pathogenesis of foot ulceration and autonomic neuropathy. Impairment of small nerve fibers is considered the earliest alteration in the course of diabetic neuropathy. Therefore, assessment of functional and morphological abnormalities of small nerve fibers may enable timely diagnosis. The definition, symptoms, and clinical significance of small-fiber neuropathy are considered in the present review. An apparently more complex interaction between small-fiber impairment and microcirculation is extensively discussed. Diagnostic modalities include morphometric and functional methods. Corneal confocal microscopy and punch skin biopsy are considered gold standards, but noninvasive functional tests are also diagnostically useful. However, in routine clinical practice, small-fiber neuropathy is diagnosed by its typical clinical presentation. Finally, prompt treatment should be initiated following diagnosis.

Is there an association between diabetic neuropathy and low vitamin D levels

In the past few years, the effects of vitamin D that go beyond its relationship with bone metabolism have come into the focus of scientific attention. Research concerning diabetes and its complications has become a public health priority. An increasing number of reports link vitamin D deficiency to diabetes; however, so far, there has only been limited and contradictory data available on the correlation between diabetic peripheral neuropathy and vitamin D. Studies of people with type 2 diabetes confirmed the relationship between vitamin D deficiency and neuropathy incidence as well as the severity of the symptoms caused by neuropathy. The latest studies are also suggesting a relationship between the incidence of plantar ulcers and vitamin D deficiency.

Gastrointestinal autonomic neuropathy in diabetes: the unattended borderline between diabetology and gastroenterology.

‘Autonomic dysfunction is often perceived as a black box of nebulous disorders, often not easily differentiated from variants of normality’ [1]. On the one hand, this sentence is still absolutely valid: most consequences of autonomic neuropathy are mild and silent. However, on the other hand, at the tip of the iceberg, there are very severe manifestations of autonomic dysfunction, such as sudden death and gastroparesis. In addition to cardiovascular autonomic dysfunction, gastrointestinal manifestations of autonomic neuropathy are common and relevant [2]. There are multiple levels of regulation in the gastrointestinal tract: the central, autonomic and enteric nervous systems and the interstitial cells of Cajal (mainly ‘pacemaker cells’). The gut microbiota are also important. Moreover, many other factors probably affect gastrointestinal motility, including duration of diabetes, hyperand hypoglycaemia, electrolyte disturbances, malnutrition and medications such as metformin, acarbose and glucagon-like peptide-1 analogues. The companion piece in this issue by Fernando Azpiroz and Carolina Malagelada discusses these aspects in more detail [3]. Data on the prevalence of gastrointestinal symptoms are inconsistent, but symptoms are generally very common, especially in women with diabetes. Differences in methodology may partly explain the conflicting results. Overall, the relationship between symptoms and altered gastrointestinal motility is relatively weak [4]. The frequency of symptoms is much higher, often 100%, when data are reported by a gastroenterologist, but much lower if reported by a diabetologist. Fluctuating glucose levels and poor quality of life are the main consequences of impaired gastrointestinal function. Altered pharmacokinetics of drugs, insufficient or very variable absorption of important nutrients (potentially leading to malnutrition), impaired postprandial regulation of blood pressure, increased risk of gallstone formation and higher prevalence of gastrointestinal infections are other important consequences. The paradox of dissociation of neuropathic gastrointestinal symptoms from objective evidence of neuropathic dysfunction is common. On the one hand, the absence of symptoms in patients with demonstrable markedly disordered gastric emptying may reflect an afferent nerve defect due to neuropathy. On the other hand, patients with symptoms have good evidence of visceral hypersensitivity, even though abnormalities of gastric emptying are not demonstrated on formal testing. Moreover, actual ambient glucose levels might influence the perception of gastrointestinal symptoms in central neuronal structures. These important facts contribute to the dissociation between subjective symptoms and objective motility findings. Up to 50% of diabetic patients have some disorder of oesophagus motility. Reflux is frequently observed as a result of decreased tone of the lower oesophageal sphincter. The * Péter Kempler kempler.peter@med.semmelweis-univ.hu

Vitamin D and neuropathy

Diabetes is a widespread disease and, therefore, studies dealing with diabetes and its complications are very important for public health. Numerous reports link vitamin D deficiency to the increased risk of diabetes mellitus and complications such as neuropathy. However, there are limited and conflicting data available on vitamin D deficiency in patients with diabetic peripheral neuropathy. Studies in type 2 diabetics confirmed the relationship between vitamin D deficiency and incidence of neuropathy. Recent reports suggest a relationship between the incidence of plantar ulcers and vitamin D deficiency.

Increased Short-Term Beat-to-Beat QT Interval Variability in Patients with Impaired Glucose Tolerance

Prediabetic states and diabetes are important risk factors for cardiovascular morbidity and mortality. Determination of short-term QT interval variability (STVQT) is a non-invasive method for assessment of proarrhythmic risk. The aim of the study was to evaluate the STVQT in patients with impaired glucose tolerance (IGT). 18 IGT patients [age: 63 ± 11 years, body mass index (BMI): 31 ± 6 kg/m2, fasting glucose: 6.0 ± 0.4 mmol/l, 120 min postload glucose: 9.0 ± 1.0 mmol/l, hemoglobin A1c (HbA1c): 5.9 ± 0.4%; mean ± SD] and 18 healthy controls (age: 56 ± 9 years, BMI: 27 ± 5 kg/m2, fasting glucose: 5.2 ± 0.4 mmol/l, 120 min postload glucose: 5.5 ± 1.3 mmol/l, HbA1c: 5.4 ± 0.3%) were enrolled into the study. ECGs were recorded, processed, and analyzed off-line. The RR and QT intervals were expressed as the average of 30 consecutive beats, the temporal instability of beat-to-beat repolarization was characterized by calculating STVQT as follows: STVQT = Σ|QTn + 1 − QTn| (30x√2)−1. Autonomic function was assessed by means of standard cardiovascular reflex tests. There were no differences between IGT and control groups in QT (411 ± 43 vs 402 ± 39 ms) and QTc (431 ± 25 vs 424 ± 19 ms) intervals or QT dispersion (44 ± 13 vs 42 ± 17 ms). However, STVQT was significantly higher in IGT patients (5.0 ± 0.7 vs 3.7 ± 0.7, P < 0.0001). The elevated temporal STVQT in patients with IGT may be an early indicator of increased instability of cardiac repolarization during prediabetic conditions.

Olfactory dysfunction in diabetes: A further step in exploring central manifestations of neuropathy?

In this issue of the journal, Gouveri et al report on olfactory dysfunction among patients with type 2 diabetes mellitus (T2DM) and raise the question whether it might be considered as an additional manifestation of microvascular disease. 1 Diagnostic methods to assess olfactory dysfunction are well established and validated: odor-dispensing devices, so-called ‘‘Sniffin’ Sticks,’’ are used and a total threshold–discrimination–identification (TDI) score is calculated. Age was negatively associated with the TDI score. After adjusting for age, gender, various risk factors, and cardiovascular disease, only T2DM and hypertension were associated with the TDI score. Olfactory dysfunction was associated with retinopathy and diabetic peripheral neuropathy. The latter finding should be considered particularly important. We agree with the authors that olfactory dysfunction may develop due to olfactory nerve impairment. This way, it should be regarded as a novel manifestation of central neuropathy. The term ‘‘diabetic neuropathy’’ refers to disorders of the peripheral nervous system due to neuropathy. However, we now know that dysfunction of the central nervous system is also present among diabetic patients. Cognitive impairment, 2 as well as depression, 3 is well recognized in diabetes. Cranial neuropathies are less frequent, most likely often overlooked, but well established manifestations of diabetic neuropathy. The impairment of cranial nerves is defined as a form of mononeuropathy. Cranial neuropathies are more frequent in older patients with long diabetes duration. Most of these patients have several comorbidities and their glycemic control is rather poor. 4 Isolated palsy of the third, fourth, or sixth cranial nerves is a characteristic manifestation of diabetic neuropathy. The presence of multiple, painless cranial nerve palsies in diabetic patients, even without other associated neurological deficits, may represent midbrain ischemia. 5 The incidence of cranial nerve involvement is 1% in diabetic patients. 6 Isolated third nerve palsies account for the majority of patients 4 and 11% of inpatients with third nerve palsy had diabetes. 7 The onset of cranial neuropathy is usually abrupt, with progression

Advances in the management of diabetic neuropathy.

The authors review current advances in the therapy of diabetic neuropathy. The role of glycemic control and management of cardiovascular risk factors in the prevention and treatment of neuropathic complications are discussed. As further options of pathogenetically oriented treatment, recent knowledge on benfotiamine and alpha-lipoic acid is comprehensively reviewed. Alpha-lipoic acid is a powerful antioxidant and clinical trials have proven its efficacy in ameliorating neuropathic signs and symptoms. Benfotiamine acts via the activation of transketolase and thereby inhibits alternative pathways triggered by uncontrolled glucose influx in the cells comprising polyol, hexosamine, protein-kinase-C pathways and formation of advanced glycation end products. Beyond additional forms of causal treatment, choices of symptomatic treatment will be summarized. The latter is mostly represented by the anticonvulsive agents pregabalin and gabapentin as well as duloxetine widely acknowledged as antidepressant. Finally, non-pharmacological therapeutic alternatives are summarized. The authors conclude that combination therapy should be more often suggested to our patients; especially the combination of pathogenetic and symptomatic agents.