Continuous intraperitoneal insulin infusion in the treatment of type 1 diabetes mellitus:Glycaemia and beyond

Continuous intraperitoneal insulin infusion (CIPII) with an implantable pump is a last-resort treatment option for selected patients with type 1 diabetes mellitus (T1DM). As compared to the most commonly used forms of insulin administration -injections and an externally placed pump- which deliver insulin in the subcutaneous (SC) tissue, CIPII delivers the insulin in the intraperitoneal space. CIPII using an implantable pump is an unique treatment which has been available for more than 30 years and is nowadays used in very few patients around the world. In The Netherlands, the Isala hospital in Zwolle is the only center providing this treatment. Aim of this thesis was to provide an update and extension about the knowledge of CIPII in the management of T1DM by investigating several important and relative new aspects of this treatment modality. It was demonstrated that CIPII is a safe and effective therapy for selected patients with T1DM. The predominant effect of CIPII, also as compared to SC insulin therapy administration, is a reduction of the number of hypoglycaemic (low blood glucose concentrations) episodes. Furthermore, treatment satisfaction is high among patients treated with CIPII using an implantable pump. Finally, this thesis demonstrated that the effects of CIPII reach beyond glycaemia by demonstrating restoration of the altered ‘growth-hormone – insulin-like growth factor 1 axis’ with CIPII

Scheduling deliveries under uncertainty

Quite often transportation companies face two types of jobs, ones which they can plan themselves and ones which have to be done on call. In this paper we study the scheduling of these jobs, while we assume that job durations are known beforehand as well as windows in which the jobs need to be done. We develop several heuristics to solve the problem at hand. The most successful are based on defining an appropriate buffer. The methods are assessed in extensive experiments on two aspects, viz. efficiency, in the sense that they carry out many jobs and certainty, in the sense that they provide information beforehand about which jobs they will execute

Plasma Citrate Levels Are Associated with an Increased Risk of Cardiovascular Mortality in Patients with Type 2 Diabetes (Zodiac-64)

Circulating citrate may represent a proxy of mitochondrial dysfunction which plays a role in the development of vascular complications in type 2 diabetes (T2D). Here, we determined the associations between plasma citrate levels and cardiovascular (CV) mortality in T2D patients. In this prospective cohort study, 601 patients were included who participated in the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC). Plasma citrate levels were measured by nuclear magnetic resonance spectroscopy. Cox proportional hazards regression models were used to evaluate the associations between plasma citrate and the risk of CV mortality. Over a median follow-up of 11.4 years, 119 (19.8%) of the 601 patients died from a CV cause. In multivariable Cox proportional hazards regression models, adjusting for conventional risk factors, plasma citrate was associated with an increased risk of CV mortality (the hazard ratio (HR) per 1-SD increment was 1.19 (95%CI: 1.00–1.40), p = 0.048). This association was prominent in males (n = 49 with CV mortality) (HR 1.52 (95%CI: 1.14–2.03), p = 0.005), but not in females (n = 70 with CV mortality) (HR 1.11 (95%CI: 0.90–1.37), p = 0.319) (age-adjusted Pinteraction = 0.044). In conclusion, higher plasma citrate levels are associated with an increased risk of CV mortality in patients with established T2D. Future studies are warranted to unravel the potential role of citrate-related pathways in the pathogenesis of T2D-related vascular complications

The Role of Gasotransmitters in Gut Peptide Actions

Although gasotransmitters nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H(2)S) receive a bad connotation; in low concentrations these play a major governing role in local and systemic blood flow, stomach acid release, smooth muscles relaxations, anti-inflammatory behavior, protective effect and more. Many of these physiological processes are upstream regulated by gut peptides, for instance gastrin, cholecystokinin, secretin, motilin, ghrelin, glucagon-like peptide 1 and 2. The relationship between gasotransmitters and gut hormones is poorly understood. In this review, we discuss the role of NO, CO and H(2)S on gut peptide release and functioning, and whether manipulation by gasotransmitter substrates or specific blockers leads to physiological alterations

Course of body weight before and after the initiation of insulin therapy in type 2 diabetes mellitus:Retrospective inception cohort study (ZODIAC 58)

Aims: The aim of this study was to explore the effect of insulin treatment initiation on weight by taking weight change prior to initiation into account. Materials and methods: We performed an observational retrospective inception cohort study, concerning Dutch primary care. We identified all patients that initiated insulin treatment (n = 7967) and individually matched patients with a reference patient (n = 5213 pairs). We obtained estimated mean weight changes in the five years prior to five years post insulin therapy. We applied linear regression analysis on weight change in the first year after insulin therapy (T0 to T+1), with matched group as primary determinant adjusted for pre-insulin weight change and additional covariates. Results: Estimated mean weight increased in the five consecutive years prior to insulin therapy (-0.23 kg in year T-5 to T-4, 0.01 kg in year T-4 to T-3, 0.07 kg in year T-3 to T-2, 0.24 kg in year T-2 to T-1, and 0.46 kg in year T-1 to T0) and continued to increase in the first year after, that is T0 to T+1, at a slightly lower rate (0.31 ± 3.9 kg). Pre-insulin weight change had the highest explained variance and was inversely and independently associated with weight change (p < .001). Starting insulin was associated with weight increase, independent of pre-insulin weight change (β-adjusted 1.228, p < .001). Stratification revealed that despite having a more or less similar baseline BMI, patients with substantial weight increase showed higher estimated mean BMI's followed by weight loss pre-insulin. In matched references, estimated mean weight changes were negative in all years concerning the study period, indicating consistent weight loss. Conclusions: Initiation of insulin therapy was independently associated with weight increase; however, overall effect on weight was small and subject to substantial variation. Pre-insulin weight change is identified as a relatively strong inverse determinant of weight change after insulin initiation

Determinants of excessive weight gain after the initiation of insulin therapy in type 2 diabetes mellitus:Retrospective inception cohort study (ZODIAC 60)

AIMS: To explore determinants of excessive weight gain after initiation of insulin therapy in type 2 diabetes mellitus (T2DM), in particular variables identified in the pre-insulin phase.METHODS: We performed a retrospective observational intervention cohort study, by means of a new user design/ inception cohort concerning n = 5086 patients. We studied determinants of excessive weight gain (5 kg or more) in the first year after initiation of insulin therapy, using both visualization and logistic regression analysis with subsequent receiver operation characteristic (ROC) analyses. Potential determinants pre-, at- and post-insulin initiation were included.RESULTS: One out of 10 patients (10.0%) gained 5 kg weight or more. The earliest determinants of excessive weight gain were weight change (inversely) and HbA1c change in the two years prior to insulin therapy (p &lt; 0.001). Patients that lost weight parallel with HbA1c rise in the two-years pre-insulin, showed the most pronounced weight gain. Of these patients, roughly one out of five (20.3%) gained 5 kg weight or more.CONCLUSIONS: Clinicians and patients should be alert for excessive weight gain after initiation of insulin, in the case of weight loss prior to insulin therapy initiation, particularly with increasing and prolonged high HbA1c at (and after) insulin initiation.</p

Incidence and determinants of hypophosphatemia in diabetic ketoacidosis:an observational study

Introduction Diabetic ketoacidosis (DKA) is a life-threatening complication of type 1 diabetes mellitus (T1DM) characterized by hyperglycemia and metabolic acidosis. Hypophosphatemia in DKA often occurs during hospital admittance for DKA. Literature on the magnitude, determinants and consequences of hypophosphatemia in DKA is scarce. Primary aim of this study was to investigate the incidence and consequences of hypophosphatemia during hospitalisation for DKA. Research design and methods Cohort study among individuals with T1DM who were admitted for DKA between 2005 and 2020 in an academic and a non-academic hospital. Multivariate regression models were performed to investigate determinants of the lowest phosphate during the treatment of DKA. Results A total of 127 episodes of DKA among 80 individuals were identified. Age at DKA presentation was 28 (22-46) years, 45% of the cases was female, diabetes duration was 13.2 (8.9-25.5) years with glycosylated hemoglobin levels of 91.9 +/- 26.2 mmol/mol. In 9% of all cases, DKA was the first presentation of T1DM. Lowest phosphate levelss reported during the treatment phase were 0.54 (0.32-0.83) mmol/L and hypophosphatemia was present in 74% (62/84). The time to lowest phosphate was 16 (8-23) hours. In multivariate analysis, baseline bicarbonate and hemoglobin at admission were significantly associated with the lowest phosphate level reported. No adverse effects of hypophosphatemia on hospital stay duration, morbidity or mortality were found, even if left untreated. Conclusions Hypophosphatemia during DKA is common and increases with severe acidosis. However, in this study it was not related to adverse outcomes. Although limitations of this retrospective study should be taken into account, the routine and repeated measurement of phosphate levels in DKA could be reconsidered, provided that possible symptoms related to hypophosphatemia are monitored

Type 2 diabetes seems not to be a risk factor for the carpal tunnel syndrome:a case control study

BACKGROUND: Previous studies have shown that the carpal tunnel syndrome seems to occur more frequently in patients with diabetes mellitus and might be associated with the duration of diabetes mellitus, microvascular complications and degree of glycaemic control. Primary aim was to determine if type 2 diabetes can be identified as a risk factor for carpal tunnel syndrome after adjusting for possible confounders. Furthermore, the influence of duration of diabetes mellitus, microvascular complications and glycaemic control on the development of carpal tunnel syndrome was investigated. METHODS: Retrospective, case-control study using data from electronic patient charts from the Isala (Zwolle, the Netherlands). All patients diagnosed with carpal tunnel syndrome in the period from January 2011 to July 2012 were included and compared with a control group of herniated nucleus pulposus patients. RESULTS: A total of 997 patients with carpal tunnel syndrome and 594 controls were included. Prevalence of type 2 diabetes was 11.5% in the carpal tunnel syndrome group versus 7.2% in the control group (Odds Ratio 1.67 (95% confidence interval 1.16-2.41)). In multivariate analyses adjusting for gender, age and body mass index, type 2 diabetes was not associated with carpal tunnel syndrome (OR 0.99 (95% CI 0.66-1.47)). No differences in duration of diabetes mellitus, microvascular complications or glycaemic control between groups were detected. CONCLUSION: Although type 2 diabetes was more frequently diagnosed among patients with carpal tunnel syndrome, it could not be identified as an independent risk factor