N. Ejskjaer - Academia.edu (original) (raw)

Papers by N. Ejskjaer

Research paper thumbnail of Gastrointestinal function in diabetes is affected regardless of asymptomatic appearance

Journal of Internal Medicine

Research paper thumbnail of PDB16 The Cost-Effectiveness of Empagliflozin in Type 2 Diabetes in Denmark, Incorporating Cardiovascular Outcomes

Research paper thumbnail of Diffusion tensor imaging MR Neurography detects polyneuropathy in type 2 diabetes

Journal of Diabetes and its Complications

AIM To evaluate if diffusion-tensor-imaging MR-Neurography (DTI-MRN) can detect lesions of periph... more 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.

Research paper thumbnail of 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

Current Diabetes Reports

Purpose of ReviewIn recent years, the recommendation for and use of patient-reported outcome meas... more Purpose of ReviewIn 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 FindingsRecent 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.SummaryWe 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.

Research paper thumbnail of Euglycemic ketosis in patients with type 2 diabetes on SGLT2-inhibitor therapy—an emerging problem and solutions offered by diabetes technology

Endocrine

Diabetic ketoacidosis is an infrequent but life-threatening acute complication of diabetes, affec... more 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.

Research paper thumbnail of Magnetic Resonance Imaging May Be Used for Early Evaluation of Diabetic Peripheral Polyneuropathy

Journal of Diabetes Science and Technology, 2014

Research paper thumbnail of Prevalence of auto-antibodies against nervous tissue structures in a population of insulin dependent diabetic patients

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

Neurogastroenterology & Motility, 2013

TZP-102, a potent, oral, ghrelin receptor agonist, improved diabetic gastroparesis symptoms in Ph... more TZP-102, a potent, oral, ghrelin receptor agonist, improved diabetic gastroparesis symptoms in Phase 2a. 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. 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). 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).

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

Neurogastroenterology & Motility, 2010

Research paper thumbnail of Self-Monitoring of Cardiac Autonomic Function at Home is Feasible

Journal of Diabetes Science and Technology, 2011

Research paper thumbnail of Screening for Diabetic Cardiac Autonomic Neuropathy Using a New Handheld Device

Journal of Diabetes Science and Technology, 2012

Abbreviations: (ADA) American Diabetes Association, (BMI) body mass index, (CAN) cardiac autonomi... more Abbreviations: (ADA) American Diabetes Association, (BMI) body mass index, (CAN) cardiac autonomic neuropathy, (HbA1c) hemoglobin A1c, (HRV) heart rate variability, (T1DM) type 1 diabetes mellitus, (T2DM) type 2 diabetes mellitus

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

Research paper thumbnail of 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

Diabetologia, 2013

Aims/hypothesis There is limited evidence on how multifactorial treatment improves outcomes of di... more 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 clusterrandomised 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, n0910; RC, n0623) 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 followup the level of medication was also high in the RC group.

Research paper thumbnail of Prevalence of autoantibodies to autonomic nervous tissue structures in Type 1 diabetes mellitus

Diabetic Medicine, 1999

The pathogenesis of diabetic autonomic neuropathy is multifactorial, but recent studies have sugg... more 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. 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. 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 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 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). 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.

Research paper thumbnail of Autoimmunity in diabetic autonomic neuropathy: does the immune system get on your nerves?

Diabetic Medicine, 1998

Symptomatic autonomic neuropathy is a devastating occasional complication of diabetes mellitus, e... more 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.

Research paper thumbnail of Dissociated sensory loss in diabetic autonomic neuropathy

Diabetic Medicine, 2000

Aims Clinical observation has led to the idea that there might be a distinctive form of selective... more 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 > 2 autonomic symptoms; age 39.3 6 10.2 years; duration of disease 25.6 6 10.5 years). For comparison, 19 Type 1 diabetic patients with neuropathic foot ulcers (age 44.5 6 6.6 years; duration of disease 26.7 6 9.2 years), 14 clinically uncomplicated Type 1 diabetic patients (age 39.9 6 5.6 years; duration of disease 22.9 6 9.3 years) and 16 non-diabetic healthy people as controls (age 39.3 6 10.7 years) were also examined. Results The large ®bre 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 6 15.0 V and 40.5 6 7.9 V, respectively (P < 0.002) with some of the Type 1-DAN patients in the normal range. In contrast, the small ®bre modalities, thermal perception and autonomic function, were grossly abnormal in both groups (hot thermal perception 14.1 6 2.5°C and 12.6 6 3.7°C; cold thermal perception 13.8 6 2.7°C and 10.9 6 4.7°C; heart rate variation 2.9 6 1.5 beats/min and 4.8 6 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 ®bre sensory and autonomic loss with relatively preserved large ®bre sensory modalities. Diabet. Med. 17, 457±462 (2000) Keywords autonomic neuropathy, small ®bre polyneuropathy, Type 1 diabetes Abbreviations LT, light touch; TPT, temperature perception threshold; Type 1-controls, patients with Type 1 diabetes and no complications; Type 1-DAN, patients with Type 1 diabetes and autonomic neuropathy; Type 1-foot ulcers, patients with Type 1 diabetes and neuropathic (non-ischaemic) foot ulcers; VPT, vibration perception threshold

Research paper thumbnail of Novel surgical treatment and gastric pathology in diabetic gastroparesis

Diabetic Medicine, 1999

Observations are made on four Type 1 diabetic patients with the rare syndrome of intractable vomi... more 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. 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. 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. 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.

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

Diabetic Medicine, 2013

To evaluate physical activity in people with newly diagnosed Type 2 diabetes using objective meas... more To evaluate physical activity in people with newly diagnosed Type 2 diabetes using objective measures. 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. 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 &lt; 0.001). This difference remained significant after correction for differences in BMI between the two groups. Using objective measurements, our findings demonstrate that people with newly diagnosed Type 2 diabetes have a more sedentary lifestyle compared with well-matched controls.

Research paper thumbnail of Gut sensations in diabetic autonomic neuropathy

Pain, 2007

The pathogenesis of gastrointestinal symptoms in diabetes mellitus is complex and multi-factorial... more The pathogenesis of gastrointestinal symptoms in diabetes mellitus is complex and multi-factorial. Diabetes induced peripheral and central changes in the neuronal pain matrix may be of importance and were explored using a new multi-modal and multi-segmental sensory testing approach. The sensitivity to mechanical, thermal and electrical stimulations in the oesophagus and duodenum was assessed in 12 type-1 diabetic patients with proven autonomic neuropathy and severe gastrointestinal symptoms using a comprehensive stimulation device aiming to activate different gut nerves and pain mechanisms. Twelve healthy subjects served as controls. The sensory response and the somatic referred pain areas were recorded. In the diabetic patients an overall hyposensitivity to the combination of all stimulations was found in the oesophagus and duodenum (P=0.02). Post hoc analysis revealed hyposensitivity to mechanical stimulations in the oesophagus (P=0.006) and duodenum (P=0.002), and to thermal (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001) and electrical (P=0.005) stimulations in the oesophagus and duodenum combined. The hyposensitivity in the gut was accompanied by a 46% increase in the somatic referred pain areas (P=0.04) indicating central neuronal changes. The multi-modal and multi-segmental sensory testing approach indicates that the sensory nerves are widely affected in the GI tract and generalized to nerves in all layers of the gut. Changes in the neuronal pain matrix including interactions between peripheral and central pain mechanisms may be involved in the pathogenesis of gastrointestinal symptoms in long-standing diabetes. Future targets in the treatment of gastrointestinal symptoms in diabetic patients with autonomic neuropathy could be based on modulation of the central nervous system excitability.

Research paper thumbnail of Prevalence of Neuropathy and Peripheral Arterial Disease and the Impact of Treatment in People With Screen-Detected Type 2 Diabetes: The ADDITION-Denmark study

Diabetes Care, 2011

OBJECTIVE There is limited evidence on how intensive multifactorial treatment (IT) improves outco... more OBJECTIVE There is limited evidence on how intensive multifactorial treatment (IT) improves outcomes of diabetes when initiated in the lead time between detection by screening and diagnosis in routine clinical practice. We examined the effects of early detection and IT of type 2 diabetes in primary care on the prevalence of diabetic peripheral neuropathy (DPN) and peripheral arterial disease (PAD) 6 years later in a pragmatic, cluster-randomized parallel group trial. RESEARCH DESIGN AND METHODS A stepwise screening program in 190 general practices in Denmark was used to identify 1,533 people with type 2 diabetes. General practices were randomized to deliver either IT or routine care (RC) as recommended through national guidelines. Participants were followed for 6 years and measures of DPN and PAD were applied. RESULTS We found no statistically significant effect of IT on the prevalence of DPN and PAD compared with RC. The prevalence of an ankle brachial index ≤0.9 was 9.1% (95% CI 6...

Research paper thumbnail of Gastrointestinal function in diabetes is affected regardless of asymptomatic appearance

Journal of Internal Medicine

Research paper thumbnail of PDB16 The Cost-Effectiveness of Empagliflozin in Type 2 Diabetes in Denmark, Incorporating Cardiovascular Outcomes

Research paper thumbnail of Diffusion tensor imaging MR Neurography detects polyneuropathy in type 2 diabetes

Journal of Diabetes and its Complications

AIM To evaluate if diffusion-tensor-imaging MR-Neurography (DTI-MRN) can detect lesions of periph... more 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.

Research paper thumbnail of 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

Current Diabetes Reports

Purpose of ReviewIn recent years, the recommendation for and use of patient-reported outcome meas... more Purpose of ReviewIn 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 FindingsRecent 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.SummaryWe 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.

Research paper thumbnail of Euglycemic ketosis in patients with type 2 diabetes on SGLT2-inhibitor therapy—an emerging problem and solutions offered by diabetes technology

Endocrine

Diabetic ketoacidosis is an infrequent but life-threatening acute complication of diabetes, affec... more 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.

Research paper thumbnail of Magnetic Resonance Imaging May Be Used for Early Evaluation of Diabetic Peripheral Polyneuropathy

Journal of Diabetes Science and Technology, 2014

Research paper thumbnail of Prevalence of auto-antibodies against nervous tissue structures in a population of insulin dependent diabetic patients

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

Neurogastroenterology & Motility, 2013

TZP-102, a potent, oral, ghrelin receptor agonist, improved diabetic gastroparesis symptoms in Ph... more TZP-102, a potent, oral, ghrelin receptor agonist, improved diabetic gastroparesis symptoms in Phase 2a. 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. 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). 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).

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

Neurogastroenterology & Motility, 2010

Research paper thumbnail of Self-Monitoring of Cardiac Autonomic Function at Home is Feasible

Journal of Diabetes Science and Technology, 2011

Research paper thumbnail of Screening for Diabetic Cardiac Autonomic Neuropathy Using a New Handheld Device

Journal of Diabetes Science and Technology, 2012

Abbreviations: (ADA) American Diabetes Association, (BMI) body mass index, (CAN) cardiac autonomi... more Abbreviations: (ADA) American Diabetes Association, (BMI) body mass index, (CAN) cardiac autonomic neuropathy, (HbA1c) hemoglobin A1c, (HRV) heart rate variability, (T1DM) type 1 diabetes mellitus, (T2DM) type 2 diabetes mellitus

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

Research paper thumbnail of 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

Diabetologia, 2013

Aims/hypothesis There is limited evidence on how multifactorial treatment improves outcomes of di... more 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 clusterrandomised 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, n0910; RC, n0623) 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 followup the level of medication was also high in the RC group.

Research paper thumbnail of Prevalence of autoantibodies to autonomic nervous tissue structures in Type 1 diabetes mellitus

Diabetic Medicine, 1999

The pathogenesis of diabetic autonomic neuropathy is multifactorial, but recent studies have sugg... more 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. 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. 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 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 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). 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.

Research paper thumbnail of Autoimmunity in diabetic autonomic neuropathy: does the immune system get on your nerves?

Diabetic Medicine, 1998

Symptomatic autonomic neuropathy is a devastating occasional complication of diabetes mellitus, e... more 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.

Research paper thumbnail of Dissociated sensory loss in diabetic autonomic neuropathy

Diabetic Medicine, 2000

Aims Clinical observation has led to the idea that there might be a distinctive form of selective... more 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 > 2 autonomic symptoms; age 39.3 6 10.2 years; duration of disease 25.6 6 10.5 years). For comparison, 19 Type 1 diabetic patients with neuropathic foot ulcers (age 44.5 6 6.6 years; duration of disease 26.7 6 9.2 years), 14 clinically uncomplicated Type 1 diabetic patients (age 39.9 6 5.6 years; duration of disease 22.9 6 9.3 years) and 16 non-diabetic healthy people as controls (age 39.3 6 10.7 years) were also examined. Results The large ®bre 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 6 15.0 V and 40.5 6 7.9 V, respectively (P < 0.002) with some of the Type 1-DAN patients in the normal range. In contrast, the small ®bre modalities, thermal perception and autonomic function, were grossly abnormal in both groups (hot thermal perception 14.1 6 2.5°C and 12.6 6 3.7°C; cold thermal perception 13.8 6 2.7°C and 10.9 6 4.7°C; heart rate variation 2.9 6 1.5 beats/min and 4.8 6 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 ®bre sensory and autonomic loss with relatively preserved large ®bre sensory modalities. Diabet. Med. 17, 457±462 (2000) Keywords autonomic neuropathy, small ®bre polyneuropathy, Type 1 diabetes Abbreviations LT, light touch; TPT, temperature perception threshold; Type 1-controls, patients with Type 1 diabetes and no complications; Type 1-DAN, patients with Type 1 diabetes and autonomic neuropathy; Type 1-foot ulcers, patients with Type 1 diabetes and neuropathic (non-ischaemic) foot ulcers; VPT, vibration perception threshold

Research paper thumbnail of Novel surgical treatment and gastric pathology in diabetic gastroparesis

Diabetic Medicine, 1999

Observations are made on four Type 1 diabetic patients with the rare syndrome of intractable vomi... more 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. 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. 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. 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.

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

Diabetic Medicine, 2013

To evaluate physical activity in people with newly diagnosed Type 2 diabetes using objective meas... more To evaluate physical activity in people with newly diagnosed Type 2 diabetes using objective measures. 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. 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 &lt; 0.001). This difference remained significant after correction for differences in BMI between the two groups. Using objective measurements, our findings demonstrate that people with newly diagnosed Type 2 diabetes have a more sedentary lifestyle compared with well-matched controls.

Research paper thumbnail of Gut sensations in diabetic autonomic neuropathy

Pain, 2007

The pathogenesis of gastrointestinal symptoms in diabetes mellitus is complex and multi-factorial... more The pathogenesis of gastrointestinal symptoms in diabetes mellitus is complex and multi-factorial. Diabetes induced peripheral and central changes in the neuronal pain matrix may be of importance and were explored using a new multi-modal and multi-segmental sensory testing approach. The sensitivity to mechanical, thermal and electrical stimulations in the oesophagus and duodenum was assessed in 12 type-1 diabetic patients with proven autonomic neuropathy and severe gastrointestinal symptoms using a comprehensive stimulation device aiming to activate different gut nerves and pain mechanisms. Twelve healthy subjects served as controls. The sensory response and the somatic referred pain areas were recorded. In the diabetic patients an overall hyposensitivity to the combination of all stimulations was found in the oesophagus and duodenum (P=0.02). Post hoc analysis revealed hyposensitivity to mechanical stimulations in the oesophagus (P=0.006) and duodenum (P=0.002), and to thermal (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001) and electrical (P=0.005) stimulations in the oesophagus and duodenum combined. The hyposensitivity in the gut was accompanied by a 46% increase in the somatic referred pain areas (P=0.04) indicating central neuronal changes. The multi-modal and multi-segmental sensory testing approach indicates that the sensory nerves are widely affected in the GI tract and generalized to nerves in all layers of the gut. Changes in the neuronal pain matrix including interactions between peripheral and central pain mechanisms may be involved in the pathogenesis of gastrointestinal symptoms in long-standing diabetes. Future targets in the treatment of gastrointestinal symptoms in diabetic patients with autonomic neuropathy could be based on modulation of the central nervous system excitability.

Research paper thumbnail of Prevalence of Neuropathy and Peripheral Arterial Disease and the Impact of Treatment in People With Screen-Detected Type 2 Diabetes: The ADDITION-Denmark study

Diabetes Care, 2011

OBJECTIVE There is limited evidence on how intensive multifactorial treatment (IT) improves outco... more OBJECTIVE There is limited evidence on how intensive multifactorial treatment (IT) improves outcomes of diabetes when initiated in the lead time between detection by screening and diagnosis in routine clinical practice. We examined the effects of early detection and IT of type 2 diabetes in primary care on the prevalence of diabetic peripheral neuropathy (DPN) and peripheral arterial disease (PAD) 6 years later in a pragmatic, cluster-randomized parallel group trial. RESEARCH DESIGN AND METHODS A stepwise screening program in 190 general practices in Denmark was used to identify 1,533 people with type 2 diabetes. General practices were randomized to deliver either IT or routine care (RC) as recommended through national guidelines. Participants were followed for 6 years and measures of DPN and PAD were applied. RESULTS We found no statistically significant effect of IT on the prevalence of DPN and PAD compared with RC. The prevalence of an ankle brachial index ≤0.9 was 9.1% (95% CI 6...