Persistent C-peptide is associated with reduced hypoglycaemia but not HbA1c in adults with longstanding Type 1 diabetes: evidence for lack of intensive treatment in UK clinical practice?

AIMS: Most people with Type 1 diabetes have low levels of persistent endogenous insulin production. The Diabetes Control and Complications Trial showed that close to diagnosis preserved endogenous insulin was associated with lower HbA1c , hypoglycaemia and complication rates, when intensively treated. We aimed to assess the clinical impact of persistent C-peptide on rate of hypoglycaemia and HbA1c in those with long duration (> 5 years) Type 1 diabetes. METHODS: We conducted a cross-sectional case-control study of 221 people (median age 24 years) with Type 1 diabetes. We confirmed ongoing endogenous insulin secretion by measuring C-peptide after a mixed-meal tolerance test. We compared self-reported hypoglycaemia (n = 160), HbA1c , insulin dose and microvascular complications (n = 140) in those with preserved and low C-peptide. RESULTS: Stimulated median (IQR) C-peptide was 114 (43, 273) pmol/l and < 3 (< 3, < 3) pmol/l in those with preserved and low C-peptide respectively. Participants with preserved C-peptide had lower reported monthly rates of hypoglycaemia, with 21% fewer symptomatic episodes, 5.9 vs. 7.5 [incidence rate ratio (IRR) 0.79, P = 0.001], and 65% fewer asymptomatic episodes, 1.0 vs. 2.9 (IRR 0.35, P < 0.001). Those with preserved C-peptide had a lower insulin dose (0.68 vs. 0.81 units/kg, P = 0.01) but similar HbA1c (preserved 69 vs. low 67 mmol/mol, P = 0.06). CONCLUSIONS: Adults with Type 1 diabetes and preserved endogenous insulin production receiving usual care in the UK have lower daily insulin doses and fewer self-reported hypoglycaemic episodes, but no difference in HbA1c . This is consistent with non-intensive treatment in previous studies, and suggests a need to consider therapy intensification to gain full benefit of preserved endogenous insulin.

Random non-fasting C-peptide: bringing robust assessment of endogenous insulin secretion to the clinic.

BACKGROUND: Measuring endogenous insulin secretion using C-peptide can assist diabetes management, but standard stimulation tests are impractical for clinical use. Random non-fasting C-peptide assessment would allow testing when a patient is seen in clinic. METHODS: We compared C-peptide at 90 min in the mixed meal tolerance test (sCP) with random non-fasting blood C-peptide (rCP) and random non-fasting urine C-peptide creatinine ratio (rUCPCR) in 41 participants with insulin-treated diabetes [median age 72 (interquartile range 68-78); diabetes duration 21 (14-31) years]. We assessed sensitivity and specificity for previously reported optimal mixed meal test thresholds for severe insulin deficiency (sCP < 200 pmol//l) and Type 1 diabetes/inability to withdraw insulin (< 600 pmol//l), and assessed the impact of concurrent glucose. RESULTS: rCP and sCP levels were similar (median 546 and 487 pmol//l, P = 0.92). rCP was highly correlated with sCP, r = 0.91, P < 0.0001, improving to r = 0.96 when excluding samples with concurrent glucose < 8 mmol//l. An rCP cut-off of 200 pmol//l gave 100% sensitivity and 93% specificity for detecting severe insulin deficiency, with area under the receiver operating characteristic curve of 0.99. rCP < 600 pmol//l gave 87% sensitivity and 83% specificity to detect sCP < 600 pmol//l. Specificity improved to 100% when excluding samples with concurrent glucose < 8 mmol//l. rUCPCR (0.52 nmol/mmol) was also well-correlated with sCP, r = 0.82, P < 0.0001. A rUCPCR cut-off of < 0.2 nmol/ mmol gave sensitivity and specificity of 83% and 93% to detect severe insulin deficiency, with area under the receiver operating characteristic curve of 0.98. CONCLUSIONS: Random non-fasting C-peptide measures are strongly correlated with mixed meal C-peptide, and have high sensitivity and specificity for identifying clinically relevant thresholds. These tests allow assessment of C-peptide at the point patients are seen for clinical care.

Psychiatric morbidity in children with KCNJ11 neonatal diabetes.

AIMS: Mutations in the KCNJ11 gene, which encodes the Kir6.2 subunit of the pancreatic KATP channel, cause neonatal diabetes. KCNJ11 is also expressed in the brain, and ~ 20% of those affected have neurological features, which may include features suggestive of psychiatric disorder. No previous studies have systematically characterized the psychiatric morbidity in people with KCNJ11 neonatal diabetes. We aimed to characterize the types of psychiatric disorders present in children with KCNJ11 mutations, and explore their impact on families. METHODS: The parents and teachers of 10 children with neonatal diabetes due to KCNJ11 mutations completed the Strengths and Difficulties Questionnaire and the Development and Wellbeing Assessment. Strengths and Difficulties Questionnaire scores were compared with normative data. Diagnoses from the Development and Wellbeing Assessment were compared with known clinical diagnoses. RESULTS: Strengths and Difficulties Questionnaire scores indicated high levels of psychopathology and impact. Psychiatric disorder(s) were present in all six children with the V59M or R201C mutation, and the presence of more than one psychiatric disorder was common. Only two children had received a formal clinical diagnosis, with a further one awaiting assessment, and the coexistence of more than one psychiatric disorder had been missed. Neurodevelopmental (attention deficit hyperactivity disorder and autism) and anxiety disorders predominated. CONCLUSIONS: Systematic assessment using standardized validated questionnaires reveals a range of psychiatric morbidity in children with KCNJ11 neonatal diabetes. This is under-recognized clinically and has a significant impact on affected children and their families. An integrated collaborative approach to clinical care is needed to manage the complex needs of people with KCNJ11 neonatal diabetes.

Urinary C-peptide creatinine ratio detects absolute insulin deficiency in Type 2 diabetes.

AIMS: To determine the prevalence and clinical characteristics of absolute insulin deficiency in long-standing Type 2 diabetes, using a strategy based on home urinary C-peptide creatinine ratio measurement. METHODS: We assessed the urinary C-peptide creatinine ratios, from urine samples taken at home 2 h after the largest meal of the day, in 191 insulin-treated subjects with Type 2 diabetes (diagnosis age ≥45 years, no insulin in the first year). If the initial urinary C-peptide creatinine ratio was ≤0.2 nmol/mmol (representing absolute insulin deficiency), the assessment was repeated. A standardized mixed-meal tolerance test with 90-min stimulated serum C-peptide measurement was performed in nine subjects with a urinary C-peptide creatinine ratio ≤ 0.2 nmol/mmol (and in nine controls with a urinary C-peptide creatinine ratio >0.2 nmol/mmol) to confirm absolute insulin deficiency. RESULTS: A total of 2.7% of participants had absolute insulin deficiency confirmed by a mixed-meal tolerance test. They were identified initially using urinary C-peptide creatinine ratio: 11/191 subjects (5.8%) had two consistent urinary C-peptide creatinine ratios ≤ 0.2 nmol/mmol; 9 of these 11 subjects completed a mixed-meal tolerance test and had a median stimulated serum C-peptide of 0.18 nmol/l. Five of these 9 had stimulated serum C-peptide <0.2 nmol/l and 9/9 subjects with urinary C-peptide creatinine ratio >0.2 had endogenous insulin secretion confirmed by the mixed-meal tolerance test. Compared with subjects with a urinary C-peptide creatinine ratio >0.2 nmol/mmol, those with confirmed absolute insulin deficiency had a shorter time to insulin treatment (median 2.5 vs. 6 years, P=0.005) and lower BMI (25.1 vs. 29.1 kg/m(2) , P=0.04). Two out of the five patients with absolute insulin deficiency were glutamic acid decarboxylase autoantibody-positive. CONCLUSIONS: Absolute insulin deficiency may occur in long-standing Type 2 diabetes, and cannot be reliably predicted by clinical features or autoantibodies. Absolute insulin deficiency in Type 2 diabetes may increase the risk of hypoglycaemia and ketoacidosis, as in Type 1 diabetes. Its recognition should help guide treatment, education and management. The urinary C-peptide creatinine ratio is a practical non-invasive method to aid detection of absolute insulin deficiency, with a urinary C-peptide creatinine ratio > 0.2 nmol/mmol being a reliable indicator of retained endogenous insulin secretion.

Validation of a single-sample urinary C-peptide creatinine ratio as a reproducible alternative to serum C-peptide in patients with Type 2 diabetes.

AIMS: Serum C-peptide can be used in Type 2 diabetes as a measure of endogenous insulin secretion, but practicalities of collection limit its routine clinical use. Urine C-peptide creatinine ratio is a non-invasive alternative that is stable for at least 3 days at room temperature in boric acid preservative. We aimed to assess the utility of urine C-peptide creatinine ratio in individuals with Type 2 diabetes as an alternative to serum C-peptide. METHODS: We assessed, in 77 individuals with Type 2 diabetes, the reproducibility of, and correlations between, fasting and postprandial urine C-peptide creatinine ratio and serum C-peptide, and the impact of renal impairment (estimated glomerular filtration rate < 60 ml min(-1) 1.73 m(-2)) on these correlations. RESULTS: Urine C-peptide creatinine ratio was at least as reproducible as serum C-peptide [fasting coefficient of variation mean (95% CI): 28 (21-35)% vs. 38 (26-59)% and 2-h post-meal 26 (18-33)% vs. 27 (20-34)%. Urine C-peptide creatinine ratio 2 h post-meal was correlated with stimulated serum C-peptide, both the 2-h value (r = 0.64, P < 0.001) and the 2-h area under the C-peptide curve (r = 0.63, P < 0.001). The association seen was similar in patients with and without moderate renal impairment (P = 0.6). CONCLUSIONS: In patients with Type 2 diabetes, a single urine C-peptide creatinine ratio is a stable, reproducible measure that is well correlated with serum C-peptide following meal stimulation, even if there is moderate renal impairment. Urine C-peptide creatinine ratio therefore has potential for use in clinical practice in the assessment of Type 2 diabetes.

The impact of insulin administration during the mixed meal tolerance test.

AIMS: The mixed meal tolerance test is the gold standard measure of endogenous insulin secretion. Practical issues limit the routine clinical use of this test, including omitting insulin prior to the ingestion of a high-carbohydrate liquid mixed meal, which can result in marked hyperglycaemia. We aimed to assess whether insulin omission is necessary during the mixed meal tolerance test and whether fasting C-peptide was a practical alternative to the test. METHODS: Ninety-one adults with insulin-treated diabetes (Type 1 n = 56, Type 2 n = 35) underwent two mixed meal tolerance tests; one standard without insulin and one with the patient's usual morning insulin. RESULTS: The 90-min serum C-peptide was highly correlated in the standard mixed meal tolerance test and the test with insulin (r = 0.98, P < 0.0001). There was a 20% reduction in the peak C-peptide value when insulin was given {test with insulin [0.39 (0.01-1.16) vs. test without insulin 0.48 (0.01-1.36) nmol/l, P = 0.001]}, but the original serum C-peptide cut-off for significant endogenous insulin secretion (≥ 0.2 nmol/l) still correctly classified 90/91 patients (98% sensitivity/100% specificity). Fasting serum C-peptide was highly correlated to 90-min serum C-peptide during the test (r = 0.97, P < 0.0001). A fasting serum C-peptide ≥ 0.07 nmol/l was the optimal cut-off (100% sensitivity and 97% specificity) for significant endogenous insulin secretion (defined as 90-min stimulated serum C-peptide ≥ 0.2 nmol/l). CONCLUSIONS: Insulin omission may not always be necessary during a mixed meal tolerance test and fasting serum C-peptide may offer a practical alternative in insulin-treated patients.

Urine C-peptide creatinine ratio is an alternative to stimulated serum C-peptide measurement in late-onset, insulin-treated diabetes.

AIMS: Serum C-peptide measurement can assist clinical management of diabetes, but practicalities of collection limit widespread use. Urine C-peptide creatinine ratio may be a non-invasive practical alternative. The stability of C-peptide in urine allows outpatient or community testing. We aimed to assess how urine C-peptide creatinine ratio compared with serum C-peptide measurement during a mixed-meal tolerance test in individuals with late-onset, insulin-treated diabetes. METHODS: We correlated the gold standard of a stimulated serum C-peptide in a mixed-meal tolerance test with fasting and stimulated (mixed-meal tolerance test, standard home meal and largest home meal) urine C-peptide creatinine ratio in 51 subjects with insulin-treated diabetes (diagnosis after age 30 years, median age 66 years, median age at diagnosis 54, 42 with Type 2 diabetes, estimated glomerular filtration rate > 60 ml min(-1) 1.73 m(-2) ). RESULTS: Ninety-minute mixed-meal tolerance test serum C-peptide is correlated with mixed-meal tolerance test-stimulated urine C-peptide creatinine ratio (r = 0.82), urine C-peptide creatinine ratio after a standard breakfast at home (r = 0.73) and urine C-peptide creatinine ratio after largest home meal (r = 0.71). A stimulated (largest home meal) urine C-peptide creatinine ratio cut-off of 0.3 nmol/mmol had a 100% sensitivity and 96% specificity (area under receiver operating characteristic curve = 0.99) in identifying subjects without clinically significant endogenous insulin secretion (mixed-meal tolerance test-stimulated C-peptide < 0.2 nmol/l). In detecting a proposed serum C-peptide threshold for insulin requirement (stimulated serum C-peptide < 0.6 nmol/l), a stimulated (largest home meal) urine C-peptide creatinine ratio cut-off of 0.6 nmol/mmol had a sensitivity and specificity of 92%. CONCLUSION: In patients with insulin-treated diabetes diagnosed after age 30 years, urine C-peptide creatinine ratio is well correlated with serum C-peptide and may provide a practical alternative measure to detect insulin deficiency for use in routine clinical practice.

Clinical outcomes after increasing bladder outlet resistance without augmentation cystoplasty in neurogenic bladder.

INTRODUCTION: Patients with neurogenic bladder (NGB) and urinary incontinence (UI) due to low bladder outlet resistance may require bladder neck procedures (BNPs) to achieve continence. These patients may also have reduced bladder capacity and or elevated detrusor storage pressures that require augmentation cystoplasty (AC). AC is not without complications that include risks for bladder rupture, urolithiasis, urinary tract infections and metabolic issues. Avoidance of AC would be helpful in patients with neurogenic urinary incontinence that have safe bladder parameters in the setting of low bladder outlet resistance. OBJECTIVE: To determine if pre-operative urodynamics could select children with NGBs and UI for isolated BNPs without AC. Additionally we sought to determine the safety of BNPs without AC and future need of AC with long-term follow-up. STUDY DESIGN: This is an IRB-approved retrospective analysis of all patients undergoing BNPs for management of neurogenic UI over a 17-year period. We separated these BNP patients into two groups: No AC + BNP (Group 1) vs. AC + BNP (Group 2). Our primary analyses focused on postoperative outcomes for patients in Group 1. Outcomes assessed included additional surgical procedures, urodynamic changes, development of CKD, new hydronephrosis (HDN) and vesicoureteral reflux (VUR). Secondary analysis included the timeline for the development of any bladder deterioration that necessitated AC in Group 1. RESULTS: 93 patients underwent BNP at a mean age of 10.8 years. Thirty did not have AC at the time of surgery (Group 1). These children had larger (p < 0.001) and more compliant (p < 0.001) bladders than Group 2 having simultaneous augmentation. At 6 years mean follow-up in Group 1 patients, three developed new reflux and three had new hydronephrosis. Nine (30%) had additional continence procedures. Twelve required (40%) AC at a mean of 23 months after the initial BNP. No patients had AC after 5 years. Detrusor end filling pressure increased 14.8 cm H2O (p = 0.028) and expected bladder capacity decreased 26.1% (p = 0.005) after isolated BNP. DISCUSSION: We found that from our cohort of patients who had normal bladder compliance and normal/near normal expected capacity preoperatively 40% required subsequent AC. We were unable to find pre-operative clinical parameters which predicted failure or conversion to AC. We found that 43.3% of our BNP without AC patients had no subsequent invasive procedures with mean 6-year follow-up. We found that none of our patients developed any degree of CKD. Finally, we found that the majority of patients that converted to AC after their BNP did so within the first 2 years after their initial BNP and no patients required augmentation 5 years post their initial BNP. This data validates that these patients require very strict follow up, particularly in the first 5 years after surgery. CONCLUSIONS: BNP without AC is safe in only a few selected patients with NGB. Despite preoperative selection, there are significant changes in bladder dynamics and 40% required subsequent augmentation. Bladder deterioration occurs early and generally in the first 2 years. Since there are no apparent reliable pre-operative variables predicting the need for subsequent AC, parents should be counseled regarding vigilant post-operative follow-up.

Quantitative assessment of Langerhans cells in actinic keratosis, Bowen's disease, keratoacanthoma, squamous cell carcinoma and basal cell carcinoma.

The quantitative distribution of Langerhans cells (LC) was studied in a range of pre-neoplastic, in-situ and invasive neoplastic skin lesions using an antibody to S100 protein and the indirect immunoperoxidase technique. LC numbers were increased within the lesions of actinic keratosis, Bowen's disease, keratoacanthoma, squamous cell carcinoma and basal cell carcinoma. In all lesions except actinic keratosis the LC density was also significantly increased in the adjacent non-neoplastic epithelium. The increased LC density in neoplastic epithelium suggests either that LC are being retained within the abnormal epithelium for longer periods of time than normal or that increased numbers of LC are being actively attracted by factors produced by the neoplastic epithelium. While reduction of intraepithelial LC density may allow the initiation of neoplasia the increased density observed in this study suggests that at later stages of tumour growth LC may have a functional role in the host response to cutaneous neoplasia.

Mentors and preceptors in the nursing profession.

Mentoring and precepting are currently receiving attention in Australian nursing. Studies in private industry and corporate organizations reveal a high correlation between professional success and a positive mentoring experience. Frequently confused with preceptor relationships, mentoring differs in subtle and not-so-subtle ways. This discussion paper aims to identify differences and similarities between the various experiences in an effort to appreciate the contribution such relationships can make to the novice nurse as well as to the mentor or preceptor. Nursing can use the concepts of mentoring and precepting in a variety of ways to facilitate the transition from novice to expert as well as career changes.

Carcinogen-induced depletion of cutaneous Langerhans cells.

The chemical carcinogen 7,12-dimethylbenz (a) anthracene (DMBA) is a potent carcinogen which, when applied to the skin of BALB/c mice weekly for 7-8 weeks, causes the induction of macroscopically visible skin tumours. We report that DMBA also depletes Langerhans cells (LC) from treated skin; the number of cutaneous LC is reduced by nearly 50% 3 days after the first application of DMBA, and continues to decrease upon further treatment. After 7-8 weeks of DMBA application, while tumours are becoming macroscopically visible, there is a considerably lower LC density in treated skin. Upon cessation of the DMBA treatment, the LC repopulate the skin, returning to control values within 55-64 days. During this repopulation of the skin by LC, the tumours begin to decrease in size. Since LC function as local cutaneous antigen-presenting cells, and are responsible for initiation of an immune response against antigens in the skin, their depletion during tumour induction may allow DMBA-transformed cells to circumvent the immune system and form tumours. Their reappearance associated with tumour regression suggests that the LC are involved in an immune response against the tumours.

Reduction in murine Langerhans cell ATPase staining following topical but not systemic treatment with steroid and non-steroid immunosuppressants.

The effects on murine Langerhans cells (LC) of steroid and non-steroid immunosuppressive drugs which are commonly used for long-term immunotherapy of human patients were investigated. Hydrocortisone, prednisolone, cyclosporin A or azathioprine was administered daily for 7 consecutive days either topically by application to the skin, or systemically by intraperitoneal injection. LC densities were determined on the day following cessation of treatment by staining for the plasma membrane-bound enzyme adenosine triphosphatase (ATPase). All immunosuppressants caused a significant reduction in ATPase-positive LC when administered topically, but not systemically. The systemically administered drugs, although given in high concentration, may not have penetrated the epidermis in sufficient concentrations to disrupt the LC membrane. These observations are consistent with long term immunosuppressants depleting cutaneous LC by bone marrow suppression rather than by a direct effect on LC.

New methodology for assessment of the Langerhans cell network.

A new procedure is described for staining Langerhans cells (LCs) based on the ability of anti-S-100 antibody to stain both epidermal LCs and melanocytes, while L-Dopa stains only melanocytes. This procedure can be used on paraffin-embedded skin sections and is therefore advantageous for examination of pathological skin specimens. In order to determine how best to quantitate LCs in skin sections the distribution of LCs has been investigated using an improved method for preparation of epidermal sheets from mouse skin. Epidermal LCs stained for their surface membrane-bound enzyme adenosine triphosphatase were observed to link with each other via their dendrites, forming a single cell layer which undulates throughout the epidermis. It is therefore proposed that LCs in skin sections should be enumerated per unit length, after identification in paraffin-embedded sections double stained with anti-S-100 antibody and L-Dopa.

A quality management approach to optimizing delivery and administration of preoperative antibiotics.

OBJECTIVE: To optimize the process for delivering and administering preoperative antibiotics in order to prevent potential adverse patient outcomes. DESIGN: Using a multidisciplinary quality-improvement team, an evaluation of the preoperative medication order and delivery process was conducted. Charts were reviewed by selected time periods, with winter 1994 discharges for orthopedic surgeries (n = 97) and spring 1995 discharges for open heart procedures (n = 50) being used to arrive at baseline data (n = 147). A plan was devised to mainstream the medication-use process so that it would be standardized hospitalwide. A goal of administering preoperative antibiotics within 30 to 60 minutes prior to cut time was established. Following redesign and education, a repeat chart review of orthopedic surgeries (n = 33) and open heart procedures (n = 168) was conducted during April 1997 for discharges from the same diagnosis-related groups to total (n = 201). SETTING: A nearly 1,000-bed tertiary referral center and teaching hospital with three separate campuses. RESULTS: We identified multiple ordering mechanisms, multiple medication sources and delivery sites, multiple administration sites and administering personnel, and other logistical conflicts. Thirty-one percent of cases received antibiotics less than 30 minutes prior to start time, 39% between 30 to 60 minutes, and 30% greater than 60 minutes before start time. Following the multidisciplinary redesign and education, an increase from 39% to 61% receiving preoperative antibiotics between 30 to 60 minutes prior to surgery start time and a decrease from 31% to 18% receiving them in less than 30 minutes was documented. The percentage of patients receiving preoperative antibiotics in 60 minutes or less increased from 70% to 80%. CONCLUSION: A continuous quality-improvement approach that engages all departments involved in patient care is necessary to achieve meaningful change in complicated hospital processes.