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ABSTRACT: BACKGROUND & AIMS: Long-term diabetes mellitus (DM) has been associated with neuronal changes in the enteric, peripheral and/or central nervous system. Moreover, abnormal visceral sensation and gastrointestinal (GI) symptoms are seen in up to 75% of patients. To explore the role of diabetic autonomic neuropathy (DAN) in patients with long-standing DM, we investigated psychophysical responses and neuronal activity recorded as evoked brain potentials and dipolar source modelling. METHODS: Fifteen healthy volunteers and 14 type-1 DM patients with DAN were assessed with a symptom score index characterizing upper GI abnormalities. Multichannel (62) electroencephalography was recorded during painful electrical stimulation of the lower oesophagus. Brain activity to painful stimulations was modelled using Brain Electrical Source Analysis (besa). RESULTS: Diabetic patients had higher stimulus intensities to evoke painful sensation (p ≤ 0.001), longer latencies of N2 and P2 components (both p ≤ 0.001), and lower amplitudes of P1-N2 and N2-P2 complexes (p ≤ 0.001; p = 0.02). Inverse modelling of brain sources showed deeper bilateral insular dipolar source localization (p = 0.002). Symptom score index was negatively correlated with the depth of insular activity (p = 0.004) and positively correlated with insular dipole strength (p = 0.03). CONCLUSION: DM patients show peripheral and central neuroplastic changes. Moreover, the role of abnormal insular processing may explain the appearance and persistence of GI symptoms related to DAN. This enhanced understanding of DAN may have future clinical and therapeutical implications.
European journal of pain (London, England) 12/2012; · 3.37 Impact Factor
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ABSTRACT: Gastrointestinal symptoms such as pain, bloating, nausea and vomiting are more frequent in pre-diabetic states as well as established diabetes, compared to healthy individuals. The mechanisms behind these symptoms are multi-factorial and complex. Furthermore, the effect of isolated hyperinsulinaemia on visceral and peripheral sensory function is poorly understood. Thus, the current study aimed to evaluate effects of acute hyperinsulinaemia on sensory function in healthy adults.
The sensitivity to electrical oesophageal and median nerve stimulation was assessed in 15 healthy volunteers together with recording of evoked brain potentials. All subjects were studied both fasting and using a euglycaemic hyperinsulinaemic clamp.
There was on average a 15% increased sensitivity to oesophageal electrical stimulation during hyperinsulinaemia compared to fasting state (P<0.05), but the sensation after median nerve stimulation remained stable (P=0.58). No significant changes in latencies and amplitudes of evoked brain potentials were observed after oesophageal or median nerve stimulation (all P>0.05).
This study suggests that acute isolated hyperinsulinaemia increases visceral sensitivity, but does not influence the somatic sensory function. The lack of changes in the evoked brain potentials may indicate that hyperinsulinaemia affects the visceral sensory system at a peripheral level. Our result suggests distinct functions of insulin in the various parts of the nervous system, and yields further clues to the significance of insulin as a satiety signal.
Experimental and Clinical Endocrinology & Diabetes 11/2011; 119(10):604-9. · 1.69 Impact Factor
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N Ejskjaer,
G Dimcevski,
J Wo,
P M Hellström,
L C Gormsen,
I Sarosiek, E Søfteland,
T Nowak,
J C Pezzullo,
L Shaughnessy,
G Kosutic,
R McCallum
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ABSTRACT: Gastroparesis, a chronic disorder of abnormal gastric motility, is common in patients with diabetes mellitus. A synthetic, selective ghrelin receptor agonist, TZP-101, is in clinical development for treatment of gastroparesis. This double-blind, randomized, placebo-controlled study evaluated the safety and efficacy of multiple TZP-101 doses in patients with moderate to severe symptomatic diabetic gastroparesis.
Patients were admitted to the hospital and adaptively randomized to receive a single 30-min intravenous infusion of 20, 40, 80, 160, 320, or 600 μg kg(-1) TZP-101, (n = 57) or placebo, (n = 19) for four consecutive days. Symptoms were evaluated daily with the patient-rated Gastroparesis Cardinal Symptom Index (GCSI) and Gastroparesis Symptom Assessment (GSA). Clinicians rated gastroparesis symptoms on treatment day 4.
The 80 μg kg(-1) dose was identified as the most effective dose. On day 4, there was statistically significant improvement compared with placebo in the severity of GCSI Loss of Appetite and Vomiting scores for that dose group (P = 0.034 and P = 0.006). In addition, at the 80 μg kg(-1) dose, the proportion of patients with at least 50% improvement in vomiting score was significantly different (P = 0.019) compared with placebo. Meal-related GSA scores for Postprandial fullness were significantly improved in the 80 μg kg(-1) TZP-101 group compared with placebo (P = 0.012). Clinicians rated the 80 μg kg(-1) group better improved than placebo for overall symptom assessment (P = 0.047). Safety profiles were similar in the placebo and TZP-101 groups and all doses were well-tolerated.
TZP-101 appears to be safe, well-tolerated, and effective at acutely addressing several gastroparesis symptoms.
Neurogastroenterology and Motility 10/2010; 22(10):1069-e281. · 3.41 Impact Factor
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ABSTRACT: Oral glucose tolerance tests (OGTTs) have detected a pathologic glucose metabolism in up to 60% of patients with acute coronary syndromes. Only one-third of these were previously diagnosed. The purpose of this study was to determine the prevalence of abnormal glucose metabolism among vascular surgery patients.
Between October 2006 and September 2007, 465 consecutive patients admitted to the vascular surgery unit were asked to participate in the study; however, 121 declined. Among the patients included, 68 had previously known diabetes. A total of 276 patients performed an oral glucose tolerance test (OGTT). We categorised the findings based on fasting and 2-h plasma glucose levels into four groups: diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting glucose (IFG) and normal glucose metabolism. Information regarding the affected vascular bed and relevant medical history was also registered.
Of the 276 patients who underwent OGTT, 66 (24%) had IGT, 23 (8%) had IFG and 33 (12%) had diabetes. As many as 17 of the 33 patients with newly diagnosed diabetes would have fulfilled the criteria for diagnosis based only on their fasting glucose levels. Including the patients with previously known diabetes, the prevalence of dysglycaemia was 55% and that of diabetes 29%.
Total prevalence of dysglycaemia in vascular surgery patients corresponds well to that of acute coronary syndromes. The prevalence of unknown pathological glucose metabolism was 44% in our OGTT material. The use of fasting glucose as the sole diagnostic tool for diabetes would have resulted in the correct diagnosis in only half of the patients tested. OGTT should be considered as a routine investigation in non-diabetic vascular surgery patients. It remains to be seen whether early diagnosis and treatment of dysglycaemia in this patient group will influence the surgical treatment and outcome.
European journal of vascular and endovascular surgery: the official journal of the European Society for Vascular Surgery 02/2010; 39(4):447-51. · 2.92 Impact Factor
