Prediction of glucose excursions under uncertain parameters and food intake in intensive insulin therapy for type 1 diabetes mellitus

Considering the difficulty in the insulin dosage selection and the problem of hyper- and hypoglycaemia episodes in type 1 diabetes, dosage-aid systems appear as tremendously helpful for these patients. A model-based approach to this problem must unavoidably consider uncertainty sources such as the large intra-patient variability and food intake. This work addresses the prediction of glycaemia for a given insulin therapy face to parametric and input uncertainty, by means of modal interval analysis. As result, a band containing all possible glucose excursions suffered by the patient for the given uncertainty is obtained. From it, a safer prediction of possible hyper- and hypoglycaemia episodes can be calculated

Prediction of postprandial blood glucose under intra-patient variability and uncertainty and its use in the design of insulin dosing strategies for type 1 diabetic patients

In this thesis I propose a novel method to estimate the dose and injection-to-meal time for low-risk intensive insulin therapy. This dosage-aid system uses an optimization algorithm to determine the insulin dose and injection-to-meal time that minimizes the risk of postprandial hyper- and hypoglycaemia in type 1 diabetic patients. To this end, the algorithm applies a methodology that quantifies the risk of experiencing different grades of hypo- or hyperglycaemia in the postprandial state induced by insulin therapy according to an individual patient’s parameters. This methodology is based on modal interval analysis (MIA). Applying MIA, the postprandial glucose level is predicted with consideration of intra-patient variability and other sources of uncertainty. A worst-case approach is then used to calculate the risk index. In this way, a safer prediction of possible hyper- and hypoglycaemic episodes induced by the insulin therapy tested can be calculated in terms of these uncertainties.

Psychometric properties of the Swedish version of the Fear of Complications Questionnaire

Objectives: To translate and evaluate the psychometric properties of the Swedish version of the Fear of Complications Questionnaire. Design: Cross-sectional study design and scale development. Settings: Totally, 469 adults (response rate 63.5%) with Type 1 diabetes completed the questionnaires. Participants were recruited from two university hospitals in Sweden. Participants: Eligible patients were those who met the following inclusion criteria: diagnosed with Type 1 diabetes, diabetes duration of at least 1 year and aged at least 18 years. Methods: The Fear of Complications Questionnaire was translated using the forward-backward translation method. Factor analyses of the questionnaire were performed in two steps using both exploratory and confirmatory factor analysis. Convergent validity was examined using the Hospital Anxiety and Depression Scale and the Fear of Hypoglycaemia Fear Survey. Internal consistency was estimated using Cronbach’s alpha.Results: Exploratory factor analysis supported a two-factor solution. One factor contained three items having to do with fear of kidney-related complications and one factor included the rest of items concerning fear of other diabetes-related complications, as well as fear of complications in general. Internal consistency was high Cronbach’s alpha 0.96. The findings also gave support for convergent validity, with significant positive correlations between measures (r = 0.51 to 0.54). Conclusion: The clinical relevance of the identified two-factor model with a structure of one dominant subdomain may be considered. We suggest, however a one-factor model covering all the items as a relevant basis to assess fear of complications among people with Type 1 diabetes.

Pre-exercise carbohydrate and fat ingestion : effects on metabolism and performance

A key goal of pre-exercise nutritional strategies is to maximize carbohydrate stores, thereby minimizing the ergolytic effects of carbohydrate depletion. Increased dietary carbohydrate intake in the days before competition increases muscle glycogen levels and enhances exercise performance in endurance events lasting 90 min or more. Ingestion of carbohydrate 3-4 h before exercise increases liver and muscle glycogen and enhances subsequent endurance exercise performance. The effects of carbohydrate ingestion on blood glucose and free fatty acid concentrations and carbohydrate oxidation during exercise persist for at least 6 h. Although an increase in plasma insulin following carbohydrate ingestion in the hour before exercise inhibits lipolysis and liver glucose output, and can lead to transient hypoglycaemia during subsequent exercise in susceptible individuals, there is no convincing evidence that this is always associated with impaired exercise performance. However, individual experience should inform individual practice. Interventions to increase fat availability before exercise have been shown to reduce carbohydrate utilization during exercise, but do not appear to have ergogenic benefits.

Herb-drug interactions: a literature review

Herbs are often administered in combination with therapeutic drugs, raising the potential of herb-drug interactions. An extensive review of the literature identified reported herb-drug interactions with clinical significance, many of which are from case reports and limited clinical observations.
Cases have been published reporting enhanced anticoagulation and bleeding when patients on long-term warfarin therapy also took Salvia miltiorrhiza (danshen). Allium sativum (garlic) decreased the area under the plasma concentration-time curve (AUC) and maximum plasma concentration of saquinavir, but not ritonavir and paracetamol (acetaminophen), in volunteers. A. sativum increased the clotting time and international normalised ratio of warfarin and caused hypoglycaemia when taken with chlorpropamide. Ginkgo biloba (ginkgo) caused bleeding when combined with warfarin or aspirin (acetylsalicylic acid), raised blood pressure when combined with a thiazide diuretic and even caused coma when combined with trazodone in patients. Panax ginseng (ginseng) reduced the blood concentrations of alcohol (ethanol) and warfarin, and induced mania when used concomitantly with phenelzine, but ginseng increased the efficacy of influenza vaccination. Scutellaria baicalensis (huangqin) ameliorated irinotecan-induced gastrointestinal toxicity in cancer patients.
Piper methysticum (kava) increased the 'off' periods in patients with parkinsonism taking levodopa and induced a semicomatose state when given concomitantly with alprazolam. Kava enhanced the hypnotic effect of alcohol in mice, but this was not observed in humans. Silybum marianum (milk thistle) decreased the trough concentrations of indinavir in humans. Piperine from black (Piper nigrum Linn) and long (P. longum Linn) peppers increased the AUC of phenytoin, propranolol and theophylline in healthy volunteers and plasma concentrations of rifamipicin (rifampin) in patients with pulmonary tuberculosis. Eleutheroccus senticosus (Siberian ginseng) increased the serum concentration of digoxin, but did not alter the pharmacokinetics of dextromethorphan and alprazolam in humans. Hypericum perforatum (hypericum; St John's wort) decreased the blood concentrations of ciclosporin (cyclosporin), midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline, but did not alter the pharmacokinetics of carbamazepine, pravastatin, mycophenolate mofetil and dextromethorphan. Cases have been reported where decreased ciclosporin concentrations led to organ rejection. Hypericum also caused breakthrough bleeding and unplanned pregnancies when used concomitantly with oral contraceptives. It also caused serotonin syndrome when used in combination with selective serotonin reuptake inhibitors (e.g. sertraline and paroxetine).
In conclusion, interactions between herbal medicines and prescribed drugs can occur and may lead to serious clinical consequences. There are other theoretical interactions indicated by preclinical data. Both pharmacokinetic and/or pharmacodynamic mechanisms have been considered to play a role in these interactions, although the underlying mechanisms for the altered drug effects and/or concentrations by concomitant herbal medicines are yet to be determined. The clinical importance of herb-drug interactions depends on many factors associated with the particular herb, drug and patient. Herbs should be appropriately labeled to alert consumers to potential interactions when concomitantly used with drugs, and to recommend a consultation with their general practitioners and other medical carers.

Metabolic and cardiac outcomes after acute myocardial infarction

The original DIGAMI protocol recommended using intravenous insulin to manage myocardial infarction from first presentation followed by subcutaneous insulin for 3 months in patients with diabetes. This paper describes the metabolic and cardiac outcomes and barriers to implementing a protocol designed to match the DIGAMI principles across our emergency and cardiology departments. Patients managed using the revised DIGAMI protocol achieved better blood glucose control and had fewer reinfarcts than those managed without insulin. The major barrier to using the protocol appeared to be staff fear of causing hypoglycaemia.

Care of people with diabetes : a manual of nursing practice

Contents: Diagnosing and classifying diabetes -- Assessment and nursing diagnosis -- Monitoring diabetes mellitus -- Nutritional aspects of caring for people with diabetes -- Medication commonly used in diabetes management -- Hypoglycaemia -- Hyperglycaemia, diabetic ketoacidosis (DKA), hyperosmolar coma and lactic acidosis -- Long term complications of diabetes -- Management during surgical and investigative procedures -- Special situations and unusual conditions related to diabetes -- Diabetes and sexual health -- Diabetes in the older person -- Diabetes in children and adolescents -- Women, pregnancy, and gestational diabetes -- Psychological and quality of life issues related to having diabetes -- Diabetes education -- Discharge planning -- Community and primary care nursing and home-based care -- Complementary therapies and diabetes -- Managing diabetes in the emergency situations.

The ADKnowl: identifying knowledge deficits in diabetes care

Aims To present the ADKnowl measure of diabetes-related knowledge and evaluate its use in identifying the nature and extent of patient and health professional knowledge deficits.

Method The ADKnowl was used in a large-scale study of 789 patients (451 treated with insulin and 338 treated with tablets and/or diet) attending for annual review at one of two hospital out-patient diabetes clinics

Results Knowledge deficits were apparent in the patients. For example, 57% did not recognize the inaccuracy of the statement `fresh fruit can be eaten freely with little effect on blood glucose levels'. Seventy-five percent of patients did not know that it is advisable to trim toenails to the shape of the toe. Knowledge deficits were identified for many other areas of diabetes management, e.g. prevention of hypoglycaemia, avoidance of ketoacidosis. Sixteen health professionals at the clinics answered the same items. Contrary to recommendations, 25% of health professionals thought that fresh fruit could be eaten freely. Seventy-five percent of health professionals did not know the current recommendations for trimming toenails. As expected, HbA1c did correlate with scores from two specific items, while HbA1c did not correlate with summed ADKnowl score.

Conclusions Patient knowledge deficits were identified. Some specific knowledge deficits among health professionals may be the cause of some patient knowledge deficits. The ADKnowl is a useful tool in assessing both patient and health professional knowledge deficits and is available for use in a context of continuing evaluation.

Patient-reported outcomes following islet cell or pancreas transplantation (alone or after kidney) in type 1 diabetes: a systematic review

Aims For selected individuals with complex Type 1 diabetes, pancreatic islet transplantation (IT) offers the potential of excellent glycaemic controlwithout significant hypoglycaemia, balanced by the need for ongoing systemic immunosuppression. Increasingly, patient-reported outcomes (PROs) are considered alongside biomedical outcomes as a measure of transplant success. PROs in IT have not previously been compared directlywith the closest alternate treatment option, pancreas transplant alone (PTA) or pancreas after kidney (PAK).

Methods We used a Population, Intervention, Comparisons, Outcomes (PICO) strategy to search Scopus and screened 314 references for inclusion.

Results Twelve studies [including PRO assessment of PAK, PTA, islet-after kidney (IAK) and islet transplant alone (ITA); n = 7–205] used a total of nine specified and two unspecified PRO measures. Results were mixed but identified some benefits which remained apparent up to 36 months post-transplant, including improvements in fear of hypoglycaemia, as well as some aspects of diabetes-specific quality of life (QoL) and general health status. Negative outcomes included short-term pain associated with the procedure, immunosuppressant side effects and depressed mood associated with loss of graft function.

Conclusions The mixed resultsmay be attributable to limited sample sizes. Also, some PROmeasures may lack sensitivity to detect actual changes, as they exclude issues and domains of life likely to be important forQoL post-transplantation and when patients may no longer perceive themselves to have diabetes. Thus, the full impact of islet ⁄ pancreas transplantation (alone or after kidney) on QoL is unknown. Furthermore, no studies have assessed patient satisfaction, which may highlight further advantages and disadvantages of transplantation.

Training in flexible, intensive insulin management to enable dietary freedom in people with type 1 diabetes : dose adjustment for normal eating (DAFNE) randomised controlled trial

Objectives: To evaluate whether a course teaching flexible intensive insulin treatment combining dietary freedom and insulin adjustment can improve both glycaemic control and quality of life in type 1 diabetes.

Design: Randomised design with participants either attending training immediately (immediate DAFNE) or acting as waiting list controls and attending “delayed DAFNE” training 6 months later.
Setting: Secondary care diabetes clinics in three English health districts.

Participants: 169 adults with type 1 diabetes and moderate or poor glycaemic control.

Main outcome measures: Glycated haemoglobin (HbA1c), severe hypoglycaemia, impact of diabetes on quality of life (ADDQoL).

Results: At 6 months, HbA1c was significantly better in immediate DAFNE patients (mean 8.4%) than in delayed DAFNE patients (9.4%) (t=6.1, P<0.0001). The impact of diabetes on dietary freedom was significantly improved in immediate DAFNE patients compared with delayed DAFNE patients (t=−5.4, P<0.0001), as was the impact of diabetes on overall quality of life (t=2.9, P<0.01). General wellbeing and treatment satisfaction were also significantly improved, but severe hypoglycaemia, weight, and lipids remained unchanged. Improvements in “present quality of life” did not reach significance at 6 months but were significant by 1 year.

Conclusion: Skills training promoting dietary freedom improved quality of life and glycaemic control in people with type 1 diabetes without worsening severe hypoglycaemia or cardiovascular risk. This approach has the potential to enable more people to adopt intensive insulin treatment and is worthy of further investigation.

Predicting outcomes in the Dose Adjustment For Normal Eating (DAFNE) trial

Background: In the UK, DAFNE training in flexible intensive insulin therapy significantly reduced the negative impact of diabetes on quality of life (QoL) and improved blood glucose (BG) control without significantly increasing severe hypoglycaemia or body mass index (BMI). Analyses were conducted to predict who would benefit most from the generally highly successful DAFNE training and who might experience undesirable effects (e.g. weight gain).

Methods: Multiple regression was used to predict change in outcomes (6-months post-DAFNE) using baseline data: demographic, biomedical, ADDQoL (measure of the impact of diabetes on QoL), extended DTSQ (Diabetes Treatment Satisfaction Questionnaire), and other psychological measures including diabetes-specific well-being and locus of control.

Findings: Greatest improvement in ADDQoL scores was achieved by those reporting less dietary freedom and less treatment satisfaction at baseline (R2=0.21). BG improvement was predicted by higher baseline BG, lower perceived frequency of hypoglycaemia, greater expectations of DAFNE, and greater BMI (R2=0.30). Increase in BMI was predicted by less dietary freedom, DAFNE training centre, and less ‘satisfaction with insulin’ at baseline (R2=0.23).

Conclusions/Discussion: DAFNE has important benefits to offer. Lifting dietary restrictions had substantial benefits for QoL. BG improvement was predicted by baseline BG but also by expectations (perhaps reflecting greater optimism or determination). Prediction of weight gain was more complex. The influence of training centre will have involved implicit messages conveyed by Educators before and during DAFNE. While DAFNE was successful overall, outcomes are likely to be maximised for individuals if their expectations and personal goals are considered by DAFNE Educators.

Patient-reported outcomes in trials of incretin-based therapies in patients with type 2 diabetes mellitus

Incretin-based therapies have a glucose-dependent mode of action that results in excellent glucose-lowering efficacy with very low risk of hypoglycaemia, and weight neutrality [dipeptidyl peptidase-4 (DPP-4) inhibitors] or weight loss [glucagon-like peptide-1 (GLP-1) receptor agonists], in people with type 2 diabetes mellitus (T2DM). Patient-reported outcomes (PROs) complement physician evaluations of efficacy and tolerability and offer insights into the subjective experience of using modern diabetes treatments. We conducted a systematic search of clinical trials of the GLP-1 receptor agonists liraglutide, exenatide and long-acting exenatide, one of which included the oral DPP-4 inhibitor sitagliptin as a comparator. No other PRO data for DPP-4 inhibitors were identified. This review summarizes PRO data from eight clinical trials, the majority of which used the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and/or Impact of Weight on Quality of Life-Lite (IWQOL-Lite) to evaluate patient experience. People with T2DM were highly satisfied with modern incretin-based therapies compared with traditional therapies. Treatment satisfaction (including perceptions of convenience and flexibility) was high and generally higher with GLP-1 agonists in association with their greater glucose-lowering efficacy and tendency to facilitate weight loss. Weight-related quality of life (QoL) also improved in people using incretin therapies. The glycaemic improvements achieved with GLP-1 receptor agonists, coupled with the low incidence of hypoglycaemia and ability to cause weight loss, seemed to offset potential concern about injections. It is plausible that superior patient-reported benefits found in clinical trials may translate into improved, clinically meaningful, long-term outcomes through increased treatment acceptability. Long-term, prospective data are needed to ascertain whether this is the case in practice.

Too much of a good thing : why it is bad to stimulate the beta cell to secrete insulin

In many countries, first- or second-line pharmacological treatment of patients with type 2 diabetes consists of sulfonylureas (such as glibenclamide [known as glyburide in the USA and Canada]), which stimulate the beta cell to secrete insulin. However, emerging evidence suggests that forcing the beta cell to secrete insulin at a time when it is struggling to cope with the demands of obesity and insulin resistance may accelerate its demise. Studies on families with persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI), the primary defect of which is hypersecretion of insulin, have shown that overt diabetes can develop later in life despite normal insulin sensitivity. In addition, in vitro experiments have suggested that reducing insulin secretion from islets isolated from patients with diabetes can restore insulin pulsatility and improve function. This article will explore the hypothesis that forcing the beta cell to hypersecrete insulin may be counterproductive and lead to dysfunction and death via mechanisms that may involve the endoplasmic reticulum and oxidative stress. We suggest that, in diabetes, therapeutic approaches should be targeted towards relieving the demand on the beta cell to secrete insulin.

Safety and efficacy of antenatal milk expressing for women with diabetes in pregnancy: protocol for a randomised controlled trial

Many maternity providers recommend that women with diabetes in pregnancy express and store breast milk in late pregnancy so breast milk is available after birth, given (1) infants of these women are at increased risk of hypoglycaemia in the first 24 h of life; and (2) the delay in lactogenesis II compared with women without diabetes that increases their infant's risk of receiving infant formula. The Diabetes and Antenatal Milk Expressing (DAME) trial will establish whether advising women with diabetes in pregnancy (pre-existing or gestational) to express breast milk from 36 weeks gestation increases the proportion of infants who require admission to special or neonatal intensive care units (SCN/NICU) compared with infants of women receiving standard care. Secondary outcomes include birth gestation, breastfeeding outcomes and economic impact.

Glycaemic control and long-term outcomes following transition from modified intensive insulin therapy to conventional glycaemic control

This retrospective observational cohort study compared glycaemic control and long-term outcomes following transition from a modified intensive insulin therapy (mIIT) regimen to conventional glycaemic control (CGC) in adult patients admitted to a tertiary adult general intensive care unit, during two 24-month periods, before and after the publication of the Normoglycemia in Intensive Care Evaluation and Surviving Using Glucose Algorithm Regulation (NICE-SUGAR) trial. The before NICE-SUGAR cohort received mIIT (target glycaemic ranges 4.4 to 7.0 mmol/l), while the after NICE-SUGAR cohort received CGC (target glycaemic range 7.1 to 9.0 mmol/l). A total of 5202 patients were included in the study. With transition from mIIT to CGC, the mean time-weighted glucose increased from 6.94 mmol/l to 8.2 mmol/l (P <0.0001). A similar increase was observed in other glycaemic indices (mean, highest and lowest glucose values, P <0.0001 for all). The adjusted 90-day odds ratio for mortality decreased by 47% with transition from mIIT to CGC (odds ratio 1.47 (95% confidence interval, 1.22 to 1.78) (P <0.0001). The rate of severe and moderate hypoglycaemia also decreased from 1.2 to 0.4% (P=0.004) and from 23.3 to 5.9% (P <0.0001), respectively. mIIT was associated with an increased risk of moderate and severe hypoglycaemia compared to CGC (odds ratio 3.1 (1.51 to 6.39) (P=0.002), 6.29 (5.1 to 7.75) (P <0.0001)). Changes in recommended glycaemic control were translated into practice, with increased glycaemic indices and decreased rates of severe and moderate hypoglycaemia after the introduction of CGC. The associated decrease in 90-day mortality suggests mIIT was not superior to CGC, despite a lower hypoglycaemia rate than in previous IIT trials. Our findings support the continued use of CGC.