Elevated levels of interleukin-12/23p40 may serve as a potential indicator of dysfunctional heart rate variability in type 2 diabetes.

BACKGROUND: Systemic inflammatory processes plausibly contribute to the development of cardiovascular complications, causing increased morbidity and mortality in type 2 diabetes. Circulating inflammatory markers, i.e., interleukin (IL)-6 and tumour necrosis factor-α, are associated with neurocardiac measures. We examined a broad panel of various inflammatory and inflammation-related serum markers to obtain more detailed insight into the possible neuro-immune interaction between cardiovascular regulation and systemic level of inflammation. METHODS: Serum samples from 100 participants with type 2 diabetes were analysed. Heart rate variability, cardiovascular autonomic reflex tests, and cardiac vagal tone tests were performed based on electrocardiographic readings. Data regarding covariates (demographic-, diabetes-, and cardiovascular risk factors) were registered. RESULTS: Increased serum levels of IL-12/IL-23p40 (p < 0.01) and intercellular adhesion molecule (ICAM)-1 (p < 0.007) were associated with diminished heart rate variability measures. After all adjustments, the associations between IL-12/23p40, SDANN and VLF persisted (p = 0.001). Additionally, serum levels of vascular endothelial growth factor (VEGF)-C were associated with response to standing (p = 0.005). DISCUSSION: The few but robust associations between neurocardiac regulation and serum markers found in this study suggest systemic changes in proinflammatory, endothelial, and lymphatic function, which collectively impacts the systemic cardiovascular function. Our results warrant further exploration of IL-12/IL-23p40, ICAM-1, and VEGF-C as possible cardiovascular biomarkers in T2D that may support future decisions regarding treatment strategies for improved patient care.

Twenty years with diabetes and amputations: a retrospective population-based cohort study.

AIM: To investigate the trends in non-traumatic lower limb amputation in people with and without diabetes. METHODS: From the Danish National Patient Register, all people with either type 1 or type 2 diabetes (n = 462 743) as well as a group of people without diabetes from the general population (n = 1 388 886) were identified and separated into three groups based on diabetes type. Among these, 17 265 amputations were identified between 1997 and 2017 and stratified into trans-femoral amputations, trans-tibial amputations and amputations below the ankle using surgical codes. Annual changes were described using least-squares linear regression. RESULTS: The yearly mean decrease in incidence rate of amputation per 1000 person-years was -0.032 [95% CI: -0.062, -0.001], -0.022 [-0.032, -0.012] and -0.006 [-0.009, -0.003] for trans-femoral amputation, -0.072 [-0.093, -0.052], -0.090 [-0.102, -0.078] and -0.015 [-0.016, -0.013] for trans-tibial amputation, and -0.055 [-0.080, -0.020], -0.075 [-0.090, -0.060] and -0.011 [-0.014, -0.007] for amputation below the ankle in people with type 1 diabetes, people with type 2 diabetes and people without diabetes, respectively. CONCLUSIONS: Over recent decades, the incidence of amputation has decreased significantly in people with diabetes and in the general population without diabetes.

Diffusion tensor imaging MR Neurography detects polyneuropathy in type 2 diabetes.

AIM: To evaluate if diffusion-tensor-imaging MR-Neurography (DTI-MRN) can detect lesions of peripheral nerves due to polyneuropathy in patients with type 2 diabetes. METHODS: Ten patients with type 2 diabetes with polyneuropathy (DPN), 10 patients with type 2 diabetes without polyneuropathy (nDPN) as well as 20 healthy controls (HC) were included. DTI-MRN covered proximal (sciatic nerve) and distal regions (tibial nerve) of the lower extremity. Fractional-anisotropy (FA) and diffusivity (mean (MD), axial (AD) and radial (RD)) were calculated and compared to neuropathy severity. Conventional T2-relaxation-time and proton-spin-density data were obtained from a multi-echo SE sequence. Furthermore, we evaluated sensitivity and specificity of DTI-MRN from receiver operating characteristics (ROC). RESULTS: The proximal and distal FA was lowest in patients with DPN compared with nDPN and HC (p < 0.01). Likewise, proximal and distal RD was highest in patients with DPN (p < 0.01). MD and AD were also significantly different though less pronounced. ROC curve analyses of DTI separated nDPN and DPN with area-under-the-curve values ranging from 0.65 to 0.98. T2-relaxation-time and proton-spin-density could not differentiate between nDPN and DPN. CONCLUSION: DTI-MRN accurately detects DPN by lower nerve FA and higher RD. These alterations are likely to reflect both proximal and distal nerve fiber pathology in patients with type 2 diabetes.

Can the Routine Use of Patient-Reported Outcome Measures Improve the Delivery of Person-Centered Diabetes Care? A Review of Recent Developments and a Case Study.

PURPOSE OF REVIEW: In recent years, the recommendation for and use of patient-reported outcome measures (PROMs) in routine diabetes care has significantly increased. We review recent evidence and highlight key opportunities and challenges related to the active clinical use of PROMs to support person-centered diabetes care and focus areas for future research in the area. RECENT FINDINGS: Recent pragmatic studies support that integration of multi-dimensional PROMs for diabetes in clinical care as part of a care improvement strategy can be acceptable for and valued by people with diabetes (PWD) and healthcare professionals (HCPs) and may improve multiple aspects of quality of care, including screening, medical care monitoring and decision support, individualization of self-management support and goal-setting, and broader benefits related to active patient participation and person-centred diabetes care. We identify multiple intervention, individual, and care setting characteristics, which influence acceptability, feasibility, implementation, and effectiveness of PROMs in routine care. Recent clinical PROM studies highlight the value of mixed methods research and systematic involvement of PWD, clinicians, and other stakeholders in the design and implementation of questionnaires for patient input in routine diabetes care. We identified a new significant trend towards participatory development of multi-dimensional PROMs with the aim of IT-enabled integration into routine diabetes care to facilitate multiple components of person-centered diabetes care and better clinical, quality of life, and cost outcomes. While results from large-scale randomized controlled studies are still limited, a growing number of pragmatic implementation studies support that user-centric PROM interventions have the potential to facilitate significant improvements in care for PWD.

Euglycemic ketosis in patients with type 2 diabetes on SGLT2-inhibitor therapy-an emerging problem and solutions offered by diabetes technology.

Diabetic ketoacidosis is an infrequent but life-threatening acute complication of diabetes, affecting predominantly patients with type 1 diabetes, children, and pregnant women, where ketosis is usually associated with marked hyperglycemia. Recently, an increasing number of cases have been reported of euglycemic diabetic ketoacidosis in patients with type 2 diabetes receiving sodium-glucose cotransporter 2 inhibitor treatment in routine practice. There is a minor, but not negligible diabetic ketoacidosis risk associated with this drug class, which was not seen in randomized clinical trials. However, sodium-glucose cotransporter2 inhibitors increase the risk of ketosis by increasing glucagon secretion in the pancreas and decreasing the renal excretion of 3-hydroxybutyrate and acetoacetate. When used in addition to insulin, any insulin dose reduction required to avoid hypoglycemia may lead to insufficient suppression of lipolysis and ketogenesis. sodium-glucose cotransporter2 inhibitor-induced loss of urinary glucose encourages euglycemia. Normo-glycemic or near-normoglycemic diabetic ketoacidosis represents a major threat to the health and well-being of a patient, because it may occur undetected and without any indicative hyperglycemia. In consequence, patients on sodium-glucose cotransporter2 inhibitors are recommended to perform regular blood ketone tests since they are not alerted to incipient diabetic ketoacidosis by glucose testing alone. This option is offered by several blood glucose meters that can also measure ketones with a separate ketone strip or in one case by an automatic parallel ketone assessment from the same strip. The need for extra testing and the associated costs may be a barrier to patient acceptance of this risk mitigation procedure. However, patients who are at risk for euglycemic diabetic ketoacidosis when being treated with sodium-glucose cotransporter2 inhibitors should be specially advised to monitor blood ketone levels on a regular basis.

Phase 2b, randomized, double-blind 12-week studies of TZP-102, a ghrelin receptor agonist for diabetic gastroparesis.

BACKGROUND: TZP-102, a potent, oral, ghrelin receptor agonist, improved diabetic gastroparesis symptoms in Phase 2a. METHODS: Patients with type 1 or 2 diabetes, delayed gastric half-emptying (T(1/2)), and ≥3 months gastroparesis symptoms randomized 1 : 1 : 1 to double-blind placebo, 10-mg, or 20-mg TZP-102 once daily for 12 weeks (Study TZP-102-CL-G003). Study TZP-102-CL-G004 patients randomized 1 : 1 to 10-mg TZP-102:placebo three-times-daily. Primary endpoint was change-from-baseline through Weeks 11-12 in Daily Diary of Gastroparesis Symptoms Questionnaire (GSDD) via electronic Patient Recorded Outcome device: worst severity of nausea, early satiety, bloating, and upper abdominal pain in 24 h (0 = none-to-5 = very severe). GSDD Composite Score for eligibility was ≥2.5 (Day-14-to-baseline). Patient Overall Treatment Evaluation (OTE) provided an anchor-based minimal clinically important difference (MCID) for GSDD Composite Score. KEY RESULTS: Study TZP-102-CL-G003 enrolled 201 outpatients: females 72%; Caucasians 87%; type 2 diabetes 61%; insulin-dependent 65%; age mean ± SD 53 ± 11.3 years; HbA1c 7.8 ± 1.5%; GCSI 3.4 ± 0.7; GSDD Composite 3.6 ± 0.6; gastric T1/2 131 ± 32 min; n = 69 (10-mg), n = 66 (20-mg), n = 66 (placebo). Primary endpoint (GSDD): significant improvement in all arms, although not for TZP-102 vs placebo: mean change-from-baseline -1.7, -1.4, -1.5 (10-mg, 20-mg, placebo); Gastroparesis Cardinal Symptom Index -1.8, -1.6, -1.5, respectively. The OTE (all patients) at Week-12 was: Patient 3.7 ± 3.2 and Physician 3.6 ± 3.0 with median score for both of 5.0 = important on scale of improvement; individual MCID was 1.61 and 0.94 for group analyses, greater than expected. Study TZP-102-CL-G004 with similar demographic/disease characteristics was prematurely terminated for efficacy futility (n = 64 with Week-4 assessments). CONCLUSIONS & INFERENCES: Efficacy of TZP-102 was not demonstrated compared with placebo in diabetic gastroparesis; however, there was substantial symptom improvement in all arms (ClinicalTrials.gov NCT01452815/NCT01664637).

Objective measurements of activity patterns in people with newly diagnosed Type 2 diabetes demonstrate a sedentary lifestyle.

AIMS: To evaluate physical activity in people with newly diagnosed Type 2 diabetes using objective measures. METHODS: We analysed data from a study aimed at assessing carotid femoral pulse wave velocity in which a piezoelectric accelerometer was worn by 100 people with newly diagnosed Type 2 diabetes and by 100 age- and sex-matched control subjects. Differences in physical activity patterns were investigated. RESULTS: Compared with the control group, the people with Type 2 diabetes spent significantly more time engaged in sedentary or lower level activities during the day, with a mean (sd) time of 926 (44) vs 898 (70) min, P < 0.001). This difference remained significant after correction for differences in BMI between the two groups. CONCLUSIONS: Using objective measurements, our findings demonstrate that people with newly diagnosed Type 2 diabetes have a more sedentary lifestyle compared with well-matched controls.

A phase 2a, randomized, double-blind 28-day study of TZP-102 a ghrelin receptor agonist for diabetic gastroparesis.

BACKGROUND: Gastroparesis causes significant morbidity and treatment options are limited. TZP-102 a novel, macrocyclic, selective, oral ghrelin receptor agonist, was evaluated in a randomized, double-blind, placebo-controlled trial in patients with diabetic gastroparesis. METHODS: A total of 92 outpatients were randomized to once-daily administrations of 10-mg (n = 22), 20-mg (n = 21), 40-mg (n = 23) TZP-102 or placebo (n = 26). The primary endpoint was the change from baseline in gastric half-emptying time (T(½)) utilizing (13)C-breath test methodology and secondary endpoints included symptom improvement using patient-reported gastroparesis symptom scores (PAGI-SYM questionnaire) and patient and physician overall treatment evaluations (OTE). KEY RESULTS: Gastric T½ changes were not statistically significant between TZP-102 and placebo after 28 days of treatment at any dose. Clinical improvements (-1.0 to -1.4 point mean decrease in symptom severity) occurred in the Gastroparesis Cardinal Symptom Index (GCSI) component of the PAGI-SYM, which was significant vs placebo for all TZP-102 doses combined. Improvements became evident after 1 week of treatment. Significantly, more patients given TZP-102 (any dose) had a 50% reduction in baseline GCSI score (28.8%vs 7.7% placebo). Safety profiles were similar across groups. All TZP-102 doses were well-tolerated with no adverse cardiac, weight, or glucose control outcomes. CONCLUSIONS & INFERENCES: TZP-102 for 28 days, at doses of 10-40 mg once daily, was well-tolerated and resulted in a reduction in symptoms of gastroparesis. The lack of correlation between symptom improvement and gastric emptying change is consistent with previous studies in diabetic gastroparesis, and emphasizes the value of patient-defined outcomes in determining therapeutic benefit.

Impact of early detection and treatment of diabetes on the 6-year prevalence of cardiac autonomic neuropathy in people with screen-detected diabetes: ADDITION-Denmark, a cluster-randomised study.

AIMS/HYPOTHESIS: There is limited evidence on how multifactorial treatment improves outcomes of diabetes when initiated in the lead time between detection by screening and diagnosis in routine clinical practice. Cardiac autonomic neuropathy (CAN) in people with diabetes indicates widespread damage to the autonomic nervous system, which may severely affect health and quality of life. We examined effects of early detection and subsequent intensive treatment of type 2 diabetes in primary care on the prevalence of CAN at the 6-year follow-up examination in a pragmatic cluster-randomised parallel group trial. METHODS: One hundred and ninety general practices were randomised to deliver either intensive multifactorial treatment (IT) or routine care (RC) as recommended by national guidelines to patients with type 2 diabetes, identified through a stepwise screening programme in the primary care setting. 1533 people (IT, n = 910; RC, n = 623) were identified and included. At the 6-year follow-up examination, measures of CAN were applied in an unselected subsample of 777 participants using heart rate variability analysis and standard tests of CAN. RESULTS: At the 6-year follow-up examination, the prevalence of early CAN was 15.1% in the RC group and 15.5% in the IT group, while manifest CAN was present in 7.1% and 7.3%, respectively. We found no statistically significant effect of intensive treatment on the prevalence of CAN compared with routine care. CONCLUSIONS/INTERPRETATION: In the Danish arm of the ADDITION Study, signs of CAN were highly prevalent 6 years after a screening-based diagnosis of type 2 diabetes. Intensive multifactorial treatment did not significantly affect the prevalence of CAN compared with routine care. However, at follow-up the level of medication was also high in the RC group.

Randomised clinical trial: ghrelin agonist TZP-101 relieves gastroparesis associated with severe nausea and vomiting--randomised clinical study subset data.

BACKGROUND: Limited therapeutic options exist for severe gastroparesis, where severe nausea and vomiting can lead to weight loss, dehydration and malnutrition due to inadequate caloric and fluid intake. TZP-101 (ulimorelin) is a ghrelin receptor agonist that accelerates gastric emptying and improves upper gastrointestinal symptoms in diabetic patients with gastroparesis. AIM: To assess effects of TZP-101 in diabetic gastroparesis patients with severe nausea/vomiting and baseline severity scores of ≥3.5 (range: 0-5) on the Gastroparesis Cardinal Symptom Index (GCSI) Nausea/Vomiting subscale. METHODS: Patients were hospitalised and received four single daily 30-min infusions of one of six TZP-101 doses (range 20-600 µg/kg) or placebo. Efficacy was assessed by symptom improvement. RESULTS: At baseline, 23 patients had a mean severity score for GCSI Nausea/Vomiting of 4.45±0.44. Statistically significant improvements over placebo occurred in the 80 µg/kg group for end of treatment changes from baseline in GCSI Nausea/Vomiting subscale (reduction in score of -3.82±0.76, P=0.011) and the GCSI Total score (-3.14±0.78, P=0.016) and were maintained at the 30-day follow-up assessment (-2.02±1.63, P=0.073 and -1.99±1.33, P=0.032 respectively). The proportion of days with vomiting was reduced significantly (P=0.05) in the 80 µg/kg group (mean of 1.2 days of vomiting for four treatment days) compared with placebo (mean of 3.2 days of vomiting across 4 treatment days). CONCLUSIONS: TZP-101 substantially reduced the frequency and severity of nausea and vomiting as well as overall gastroparesis symptoms. The results are consistent with gastrointestinal motility effects of TZP-101, supporting further investigation of TZP-101 in the management of severe gastroparesis.

Safety and efficacy of ghrelin agonist TZP-101 in relieving symptoms in patients with diabetic gastroparesis: a randomized, placebo-controlled study.

BACKGROUND: 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. METHODS: 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. KEY RESULTS: 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. CONCLUSIONS & INFERENCES: TZP-101 appears to be safe, well-tolerated, and effective at acutely addressing several gastroparesis symptoms.

Ghrelin receptor agonist (TZP-101) accelerates gastric emptying in adults with diabetes and symptomatic gastroparesis.

BACKGROUND: TZP-101 is a synthetic, selective ghrelin agonist in development for gastroparesis. AIM: To assess safety and effects of TZP-101 in diabetes patients with symptomatic gastroparesis. METHODS: Adults with type 1 or type 2 diabetes mellitus received placebo and TZP-101 (80, 160, 320 or 600 microg/kg) infusions in a cross-over manner following a radiolabelled meal. Blood glucose levels were stabilized using a hyperinsulinemic-euglycemic clamp. Primary endpoints were gastric half emptying and latency times. Secondary measures included assessment of gastroparesis symptoms and endocrine responses. RESULTS: Ten patients with type 1 (n = 7) or 2 (n = 3) diabetes, moderate-to-severe gastroparesis symptoms and > or =29% retention 4 h after a radiolabelled solid meal were enrolled. TZP-101 produced significant reductions in solid meal half-emptying (20%, P = 0.043) and latency (34%, P = 0.037) times vs. placebo. Reductions in overall postmeal symptom intensity (24%) and postprandial fullness (37%) following TZP-101 infusion were not statistically significant. Most adverse events were mild and self-limiting and there were no identifiable differences in numbers or types of adverse events between TZP-101 and placebo. CONCLUSIONS: This proof-of-concept study demonstrates that the ghrelin agonist TZP-101 is well-tolerated in diabetes patients with moderate-to-severe chronic gastroparesis and shows statistically significant improvements in gastric emptying.

Accelerated atrophy of lower leg and foot muscles--a follow-up study of long-term diabetic polyneuropathy using magnetic resonance imaging (MRI).

AIMS/HYPOTHESIS: The aim of the study was to determine the loss of muscle volume in the lower leg and foot in long-term diabetic patients in relation to the presence of neuropathy. METHODS: We re-examined 26 type 1 diabetic patients who had participated in magnetic resonance imaging (MRI) studies on muscle volume in the lower leg and foot 9 to 12 years earlier. Re-examination involved MRI, isokinetic dynamometry, clinical examination, electrophysiological studies and quantitative sensory examinations. RESULTS: Annual loss of muscle volume of ankle dorsal and plantar flexors was 4.5 (5.5-3.9)% (median [range]) and 5.0 (7.0-4.2)% in neuropathic patients, 1.9 (3.2-1.0)% and 1.8 (2.6-1.3)% in non-neuropathic patients, and 1.7 (2.8-0.8)% and 1.8 (2.4-0.8)% in controls, respectively (p < 0.01). Annual change of volume and strength correlated for ankle dorsal flexors (r (s) = 0.73, p < 0.01) and for ankle plantar flexors (r (s) = 0.63, p < 0.05) in diabetic patients. In addition, annual change of muscle volume for dorsal and plantar flexors was related to the combined score of all measures of neuropathy (r (s) = -0.68, p < 0.02 and r (s) = -0.73, p < 0.01, respectively). Foot muscle volume declined annually by 3.0 (3.4-1.0)% in neuropathic patients and by 1.1 (4.0-0.2)% in non-neuropathic patients, both values being significantly different from controls (0.2 [-2.5 to 2.4]%). Loss of foot muscle volume was related to severity of neuropathy assessed at clinical evaluation (r (s) = -0.6, p < 0.05). CONCLUSIONS/INTERPRETATION: Muscular atrophy in long-term diabetic neuropathy occurs early in the feet, progresses steadily in the lower legs, relates to severity of neuropathy and leads to weakness at the ankle.

Comparison of thrice daily 'high' vs. 'medium' premixed insulin aspart with respect to evening and overnight glycaemic control in patients with type 2 diabetes.

BACKGROUND: The glycaemic control of thrice daily treatment with premixed biphasic insulin aspart (BIAsp) without other antidiabetic therapy was tested in type 2 diabetic patients, in order to compare the glucose control of a 'high' mixture (BIAsp 70) or a 'medium' mixture (BIAsp 50) (70 or 50% soluble IAsp and 30 or 50% protamine-crystallized IAsp, respectively) administered just before dinner. AIM: To compare these regimens to conventional 30 : 70 premixture on a twice a day basis. METHODS: This randomized, double-blind, two-period crossover study included 16 patients with type 2 diabetes. Twenty four-hour serum glucose and insulin profiles were obtained thrice: (1) after a one-week run-in period with biphasic human insulin (BHI) 30/70 twice daily (run-in), (2) after 4 weeks of treatment with thrice daily BIAsp 70 before breakfast, lunch and dinner (Dinner70 regimen) and (3) after 4 weeks of BIAsp 70 before breakfast and lunch and BIAsp 50 before dinner (Dinner50). RESULTS: Daytime average serum glucose was lower with Dinner70 compared to run-in (9.6 +/- 0.39 mmol/l vs. 11.2 +/- 0.61 mmol/l, p < 0.05). Postprandial glucose excursions after breakfast and lunch were lower, but fasting morning glucose was higher during the treatment periods than in the run-in period. Twenty four-hour C-peptide AUC was considerably lower during both treatment periods than in the run-in period (run-in/Dinner50 ratio 1.29 [1.08; 1.54] p < 0.01; run-in/Dinner70 ratio 1.31 [1.08;1.58], p < 0.01). CONCLUSIONS: Switching the dinner dose to BIAsp 50 did not alter overall glucose control significantly from that provided with BIAsp 70. Exploratory analyses between the two active treatment regimens and run-in/BHI indicate that thrice daily BIAsp 70 administration: (1) for optimization of the night-time control, the dinner dose needs adjustment or replacement by a premixed insulin with a larger proportion of basal insulin than BIAsp 50 and (2) none of the premixtures adequately provide for both the evening meal and overnight requirements.

Dissociated sensory loss in diabetic autonomic neuropathy.

AIMS: Clinical observation has led to the idea that there might be a distinctive form of selective sensory and autonomic neuropathy affecting patients with Type 1 diabetic mellitus with severe symptomatic autonomic neuropathy (Type 1-DAN) and this study was conducted to evaluate the presence of such a neuropathy in Type 1-DAN. METHODS: Nineteen Type 1 diabetic patients presenting for treatment of severe symptomatic autonomic neuropathy were examined (all had > or = 2 autonomic symptoms; age 39.3 +/- 10.2 years; duration of disease 25.6 +/- 10.5 years). For comparison, 19 Type 1 diabetic patients with neuropathic foot ulcers (age 44.5 +/- 6.6 years; duration of disease 26.7 +/- 9.2 years), 14 clinically uncomplicated Type 1 diabetic patients (age 39.9 +/- 5.6 years; duration of disease 22.9 +/- 9.3 years) and 16 non-diabetic healthy people as controls (age 39.3 +/- 10.7 years) were also examined. Results The large fibre modalities (light touch and vibration perception) were better preserved in the Type 1-DAN group than in the foot ulcer group. Thus, light touch sensation was normal in 11 out of 19 Type 1-DAN patients compared to only three out of 19 foot ulcer patients (P < 0.01), and vibration perception was 24.9 +/- 15.0 V and 40.5 +/- 7.9 V, respectively (P < 0.002) with some of the Type 1-DAN patients in the normal range. In contrast, the small fibre modalities, thermal perception and autonomic function, were grossly abnormal in both groups (hot thermal perception 14.1 +/- 2.5 degrees C and 12.6 +/- 3.7 degrees C; cold thermal perception 13.8 +/- 2.7 degrees C and 10.9 +/- 4. 7 degrees C; heart rate variation 2.9 +/- 1.5 beats/min and 4.8 +/- 4.0 beats/min, respectively). CONCLUSIONS: There is indeed a subgroup of Type 1 diabetic neuropathy patients who suffer from severe autonomic symptoms associated with a selective small fibre sensory and autonomic loss with relatively preserved large fibre sensory modalities.

Prevalence of autoantibodies to autonomic nervous tissue structures in Type 1 diabetes mellitus.

AIMS: The pathogenesis of diabetic autonomic neuropathy is multifactorial, but recent studies have suggested a link between the presence of autoantibodies to nervous tissue structures and severe, symptomatic autonomic neuropathy. The present study was designed to examine the true prevalence of these autoantibodies in a large clinic-based population of Type 1 diabetic patients compared to nondiabetic controls. METHODS: The presence of complement fixing autoantibodies to vagus nerve (CF-VN), sympathetic ganglion (CF-SG) and adrenal medulla (CF-ADM) was assessed by immunofluorescence in a large cohort of patients (n = 394) of varying duration of Type 1 DM (median 28 years, range 6 months to 73 years) and 160 age and sex-matched nondiabetic control subjects. RESULTS: All three autoantibodies were frequently detected in Type 1 DM (CF-VN, 22.1%; CF-SG, 30.7%; CF-ADM, 13.2%) but only rarely in healthy control subjects (4.4%, 4.4% and 3.1%, respectively; P < 0.0005 for all). There was no association between any of the autoantibodies and retinopathy (fundoscopy), peripheral somatic neuropathy (biothesiometry) or nephropathy (urinary albumin-creatinine ratio). CONCLUSIONS: Our results on this large cohort establish the extensive presence of autonomic nervous tissue autoantibodies in Type 1 DM. Their role in reflecting, causing or predicting autonomic neuropathy remains to be determined.

Novel surgical treatment and gastric pathology in diabetic gastroparesis.

AIMS: Observations are made on four Type 1 diabetic patients with the rare syndrome of intractable vomiting from confirmed gastroparesis, to determine whether radical surgery would alleviate their symptoms and subsequently to examine in detail the gastric histopathology. METHODS: The surgical approach consisted of an approximate 70% resection of the stomach, including the antrum and pylorus, with closure of the duodenum and restoration of gastrointestinal continuity with a 60-cm Roux-en-Y jejunal loop. Four longstanding Type 1 diabetic patients were examined and treated as described. They were all women in the age range 2741 years with grossly abnormal autonomic function tests in whom other causes for gastric paresis had been excluded. RESULTS: Vomiting episodes leading to multiple hospital admissions (6-8) in the year preceding surgery were eliminated in three of the four patients, while in the fourth initial success was followed by the need for dialysis for renal failure. Gastric histopathology showed evidence of smooth muscle degeneration and fibrosis, with eosinophilic inclusion bodies (M-bodies) which appear to be unique to this condition. The findings suggest the presence of a gastromyopathy. CONCLUSIONS: Satisfactory relief of intractable vomiting from diabetic gastroparesis was achieved by a novel radical surgical procedure. Histopathological findings suggest that gastromyopathy may contribute to the production of this syndrome.

Autoimmunity in diabetic autonomic neuropathy: does the immune system get on your nerves?

Symptomatic autonomic neuropathy is a devastating occasional complication of diabetes mellitus, especially Type 1. Although the full-blown clinical syndrome is not common, dysfunction of the autonomic nerves is detectable in up to 40% of Type 1 diabetic patients but its aetiopathogenesis is poorly understood. There is evidence to suggest that the damage to the autonomic nerves may be immune-mediated. This evidence is reviewed in the following article.