Effects of intraperitoneal insulin versus subcutaneous insulin administration on sex hormone-binding globulin concentrations in patients with type 1 diabetes mellitus.

AIMS: Elevated sex hormone-binding globulin (SHBG) concentrations have been described in patients with type 1 diabetes mellitus (T1DM), probably due to low portal insulin concentrations. We aimed to investigate whether the route of insulin administration, continuous intraperitoneal insulin infusion (CIPII), or subcutaneous (SC), influences SHBG concentrations among T1DM patients. METHODS: Post hoc analysis of SHBG in samples derived from a randomized, open-labeled crossover trial was carried out in 20 T1DM patients: 50% males, mean age 43 (±13) years, diabetes duration 23 (±11) years, and hemoglobin A1c (HbA1c) 8.7 (±1.1) (72 (±12) mmol/mol). As secondary outcomes, testosterone, 17-ß-estradiol, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were analyzed. RESULTS: Estimated mean change in SHBG was -10.3nmol/L (95% CI: -17.4, -3.2) during CIPII and 3.7nmol/L (95% CI: -12.0, 4.6) during SC insulin treatment. Taking the effect of treatment order into account, the difference in SHBG between therapies was -6.6nmol/L (95% CI: -17.5, 4.3); -12.7nmol/L (95% CI: -25.1, -0.4) for males and -1.7nmol/L (95% CI: -24.6, 21.1) for females, respectively. Among males, SHBG and testosterone concentrations changed significantly during CIPII; -15.8nmol/L (95% CI: -24.2, -7.5) and -8.3nmol/L (95% CI: -14.4, -2.2), respectively. The difference between CIPII and SC insulin treatment was also significant for change in FSH 1.2U/L (95% CI: 0.1, 2.2) among males. CONCLUSIONS: SHBG concentrations decreased significantly during CIPII treatment. Moreover, the difference in change between CIPII and SC insulin therapy was significant for SHBG and FSH among males. These findings support the hypothesis that portal insulin administration influences circulating SHBG and sex steroids.

Intraperitoneal versus subcutaneous insulin therapy in the treatment of type 1 diabetes mellitus.

BACKGROUND: Continuous intraperitoneal insulin infusion (CIPII), a last-resort type 1 diabetes mellitus (T1DM) treatment, has only been investigated in small or controlled studies. We aimed to investigate glycaemia and quality of life (QoL) with CIPII versus subcutaneous (SC) insulin therapy during usual T1DM care. METHODS: A prospective, observational case-control study. CIPII-treated cases were matched to SC controls. The primary endpoint was a non-inferiority assessment (pre-defined margin of -5.5 mmol÷mol) of the baseline adjusted difference in HbA1c between groups during a 26-week follow-up. Secondary outcomes included QoL, clinical and biochemical measurements. RESULTS: In total, 183 patients were analysed (CIPII n = 39 and SC n = 144). The HbA1c difference between treatment groups was -3.0 mmol÷mol (95% CI -5.0, -1.0), being lower in the SC group. Patients using SC insulin therapy spent less percentage of time in hyperglycaemia (-9.3% (95% CI -15.8, -2.8)) and more in euglycaemia (6.9% (95% CI 1.2, 12.5) as compared with CIPII-treated patients. Besides a 3.6 U÷l (95% CI 1.2, 6.0) lower concentration of alanine aminotransferase with CIPII, no biochemical and clinical differences were present. Most QoL scores were lower at baseline among CIPII-treated patients. However, besides lower health status, there were no differences in the baseline-adjusted general and diabetes-specific QoL and treatment satisfaction. CONCLUSION: Although patients using CIPII had a higher glycaemic profile compared with patients using SC insulin therapy, the HbA1c difference was non-inferior. Overall, health status was lower among CIPII-treated patients, although diabetes-specific QoL and treatment satisfaction was similar to subcutaneously treated patients.

Report of a 7 year case-control study of continuous intraperitoneal insulin infusion and subcutaneous insulin therapy among patients with poorly controlled type 1 diabetes mellitus: favourable effects on hypoglycaemic episodes.

AIMS: Continuous intraperitoneal insulin infusion (CIPII) is a last-resort treatment option for patients with type 1 diabetes mellitus (T1DM) who fail to reach adequate glycaemic control with subcutaneous (SC) insulin therapy. Aim was to compare the long-term effects of CIPII and SC insulin therapy among patients with T1DM in poor glycaemic control. METHODS: Patients in which CIPII was initiated in 2006 were compared with a control group of T1DM patients who continued SC therapy. Linear mixed models were used to calculate differences between the baseline (2006) and final (2013) measurements within and between groups. RESULTS: A total of 95 patients of which 21 were using CIPII and 74 using SC insulin were included. Within the CIPII group, the number of hypoglycaemic episodes decreased with -5 (95% CI -8 to -3) per 2 weeks while it remained stable among SC patients. Over time, only the number of hypoglycaemic episodes decreased more with CIPII as compared to SC insulin treatment (difference: -6 (95% CI -9 to -4)). There were no differences between treatment groups regarding clinical parameters and quality of life scores over time. Pump or catheter dysfunction led to ketoacidosis in 6 patients: 2 using CIPII and 4 SC insulin. CONCLUSIONS: After 7 years of follow-up, there is a persistent decline of hypoglycaemic events among CIPII treated T1DM patients. Besides less hypoglycaemic episodes with CIPII therapy, there are no differences between long-term CIPII and SC insulin therapy.

Intraperitoneal insulin infusion: treatment option for type 1 diabetes resulting in beneficial endocrine effects beyond glycaemia.

Continuous intraperitoneal insulin infusion (CIPII) is a treatment option for patients with type 1 diabetes mellitus who fail to reach adequate glycaemic control despite intensive subcutaneous (SC) insulin therapy. CIPII has clear advantages over SC insulin administration in terms of pharmacokinetic and pharmacodynamic properties and has been shown to improve glycaemic regulation. Due to the delivery of insulin predominantly in the portal vein, as opposed to systemically, CIPII offers a unique research model to investigate the effects of insulin on endocrine and metabolic parameters in vivo. The aim of the present article is to provide an overview of the literature with respect to the effects of CIPII on glucose management, quality of life, complications and costs, with additional focus on metabolic and endocrine aspects. Finally, future use and research objectives are discussed.

Effect of i.p. insulin administration on IGF1 and IGFBP1 in type 1 diabetes.

In type 1 diabetes mellitus (T1DM), low concentrations of IGF1 and high concentrations of IGF-binding protein 1 (IGFBP1) have been reported. It has been suggested that these abnormalities in the GH-IGF1 axis are due to low insulin concentrations in the portal vein. We hypothesized that the i.p. route of insulin administration increases IGF1 concentrations when compared with the s.c. route of insulin administration. IGF1 and IGFBP1 concentrations in samples derived from an open-label, randomized cross-over trial comparing the effects of s.c. and i.p. insulin delivery on glycaemia were determined. T1DM patients were randomized to receive either 6 months of continuous i.p. insulin infusion (CIPII) through an implantable pump (MIP 2007C, Medtronic) followed by 6 months of s.c. insulin infusion or vice versa with a washout phase in between. Data from 16 patients who had complete measurements during both treatment phases were analysed. The change in IGF1 concentrations during CIPII treatment was 10.4 µg/l (95% CI -0.94, 21.7 µg/l; P=0.06) and during s.c. insulin treatment was -2.2 µg/l (95% CI -13.5, 9.2 µg/l; P=0.69). When taking the effect of treatment order into account, the estimated change in IGF1 concentrations was found to be 12.6 µg/l (95% CI -3.1, 28.5 µg/l; P=0.11) with CIPII treatment compared with that with s.c. insulin treatment. IGFBP1 concentrations decreased to -100.7 µg/l (95% CI -143.0, -58.3 µg/l; P<0.01) with CIPII treatment. During CIPII treatment, parts of the GH-IGF1 axis changed compared with that observed during s.c. insulin treatment. This supports the hypothesis that the i.p. route of insulin administration is of importance in the IGF1 system.

Self-monitoring of blood glucose in tablet-treated type 2 diabetic patients (ZODIAC).

BACKGROUND: Whether self-monitoring of blood glucose (SMBG) improves glycaemic control in patients with type 2 diabetes mellitus (T2DM) not using insulin is questionable. Our aim was to investigate the effects of SMBG in patients with T2DM who were in persistent moderate glycaemic control whilst not using insulin. METHODS: Patients were eligible when between 18 and 70 years of age, with an HbA1c between 7 and 8.5%, using one or two oral blood glucose lowering agents. Forty-one of the anticipated 52 patients were randomly assigned to receive either SMBG added to usual care, or to continue with usual care for one year. A fasting glucose value and three postprandial glucose values were measured twice weekly (including a Saturday or a Sunday). The primary efficacy parameter was HbA1c. Furthermore, health-related quality of life and treatment satisfaction were assessed using the Short-form 36 Health Survey Questionnaire (SF-36), the Type 2 Diabetes Symptom Checklist (DSC-r), the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and the WHO -Wellbeing Index (WHO-5). RESULTS: Change in HbA1c between groups was -0.05% (95% CI: -0.51, 0.41; p=0.507). Also, there were no significant changes between groups on the DTSQ , DSC type 2, WHO-5 or SF -36, except for the SF -36 dimension 'health change' which was lower in the SBMG group (mean difference: -12 (95% CI: -20.9, -3.1). CONCLUSION: On top of the absence of a clinical benefit, tablet-treated T2DM patients experienced some worsening of their health perception. We therefore argue that the use of SMBG in this patient group is questionable, and its unlimited use and promotion should be reconsidered.

Modification of diet in renal disease and Cockcroft-Gault formulas do not predict mortality (ZODIAC-6).

AIMS: An inverse relationship between estimates of renal function, with formulas such as the Modification of diet in renal disease (MDRD) study equation or the Cockcroft-Gault formula, and mortality has been suggested. These formulas both contain the variables sex, serum creatinine and age and the latter also contains body weight. We investigated whether these formulas predict mortality better than the variables they contain together in patients with Type 2 diabetes. METHODS: In 1998, 1143 primary care patients with Type 2 diabetes participated in the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) Study, in the Netherlands. Clinical and laboratory data were collected at baseline. Life status was assessed after 6 years. We used Cox proportional hazard modelling to investigate the association between estimates of renal function (continuous data) and the variables they contain and mortality, adjusting for confounders. Both formulas were compared with models consisting of the variables present in the formulas. Predictability was assessed using Bayesian information criterion (BIC) and Harrell's C statistics. RESULTS: At follow-up, 335 patients had died. All variables, except sex, influenced mortality. Predictive capability, indicated by lower BIC values and higher Harrell's C values, was up to 10% better for models containing the separate variables as compared with Cockcroft-Gault or MDRD. CONCLUSIONS: Using estimates of renal function to assess mortality risk decreases predictability as compared with the combination of the risk factors they contain. These formulas, therefore, could be used to estimate renal function; however, they should not be used as a tool to predict mortality risk.

Intensification of therapy and no increase in body mass index with longer disease duration in type 2 diabetes mellitus (ZODIAC-5).

BACKGROUND: Decreased insulin sensitivity and beta-cell failure are the two key components in the pathogenesis of type 2 diabetes mellitus (T2DM). Secondary treatment failure is often attributed to the development of obesity-related insulin resistance in combination with continued loss of beta-cell function. OBJECTIVE: Assess metabolic control, body mass index (BMI) and treatment in relationship to diabetes duration to study these mechanisms. METHODS: Cross-sectional study of 7875 patients with T2DM in primary care in The Netherlands. Clinical data and laboratory results were obtained for the 2005 annual visit. Patients were grouped according to diabetes duration in 2-year intervals. Each step in the traditional treatment sequence was considered as a sign of progression of beta-cell failure. RESULTS: Complete data regarding duration and treatment were available for 6850 patients (87%). After the initial years following diagnosis, treatment with diet alone decreases and oral hypoglycaemic agents (OHA) are prescribed to an increasing percentage of patients. Treatment with OHA diminishes after approximately 10 years following diagnosis and treatment with insulin increases until approximately two-thirds of patients with diabetes duration of more than 20 years are being treated with insulin. BMI does not increase with longer disease duration. CONCLUSION: The concept of beta-cell failure as the primary determinant of the chronic progression of T2DM is supported by these results, whereas a deterioration of obesity-related insulin sensitivity as indicator is not supported.

[Assessment of renal function according to the NHG protocol 'Diabetes mellitus type 2': risk of overestimating the number of diabetes patients with renal dysfunction]. / Bepaling van de nierfunctie volgens de NHG-standaard 'diabetes mellitus type 2': kans op overschatting van het aantal diabetespatiënten met nierfunctieproblemen.

OBJECTIVE: To evaluate the consequences of the new Dutch College of General Practitioners (NHG) protocol 'Diabetes mellitus type 2', which recommends using either the Cockcroft-Gault (CG) formula or the 'Modification of diet in renal disease' (MDRD) study formula to determine the estimated glomerular filtration rate (eGFR) as an indicator of renal function, in a cohort of patients with type-2 diabetes. DESIGN: Inventory. METHOD: The eGFR was calculated using the CG formula, the body-mass index (BMI-)corrected CG formula and the MDRD formula in 6224 patients with type-2 diabetes who entered the 'Zwolle outpatient diabetes project integrating available care' (ZODIAC) study in 2005. RESULTS: Using the CG and MDRD formulas, 31% and 63% of patients, respectively, had an eGFR of 30-59 ml/min (units for MDRD are ml/ min/1.73 m2) for which referral is advisable. In addition, 1% and 11%, respectively, had an eGFR <30 ml/min (reference: >90 ml/min), for which referral is necessary. Most patients aged >70 years (or > 50 years using the BMI-corrected CG formula) had an eGFR <60 ml/min. CONCLUSIONS: Reduced eGFR can be a sign of renal dysfunction but, using these formulas, can also be partly explained by advanced age. Therefore other factors should be considered when interpreting the results ofeGFR before it is concluded that the patient has kidney disease and the associated increased risk of cardiovascular disease.

Glycaemic control, health status and treatment satisfaction with continuous intraperitoneal insulin infusion.

BACKGROUND: Continuous intraperitoneal insulin infusion(CIPI ) has been in use for over 20 years. High costs and technical problems have prevented its widespread use. In the Netherlands, the Isala Clinics in Zwolle is the centre with the most extensive experience with CIPII . Its use is aimed at improving glycaemic control with less hypoglycaemic events, and thus improving quality of life inpatients with poorly controlled diabetes despite intensified insulin treatment. Our aim was to assess glycaemic control,health status and treatment satisfaction in subjects treated with CIPII within the Isala Clinics. METHODS: Retrospective longitudinal analysis of clinical data in 48 patients started on CIPII between 1983 and 2005.HbA1c at baseline, after one year, and at present assessment or at the end of pump use were applicable. Cross-sectional assessment of health status, well-being and treatment satisfaction was carried out. RESULTS: Of 48 patients, 33 were treated with CIPII at the moment of assessment. Five patients died whilston CIPII ; four from diabetes-related causes, none from hypoglycaemia. HbA1c decreased significantly from 9.7 to 8.8% after one year, to 8.6% at long-term follow-up; p<0.01. Less hypoglycaemic events were reported. Short-Form 12-Item Health Survey (SF -12)scores were 37.4 and 47.2 (range 0-100), the Well-Being Index (WHO-5) score was 52.7 (range 0-100) and median treatment satisfaction score was 32 (range 0-36). CONCLUSION: CIPII leads to improved glycaemic control with less self-reported hypoglycaemic events in patients with poorly controlled diabetes. Treatment satisfaction is high. Mental health status and well-being scores are low, however.

[Cinnamon: not suitable for the treatment of diabetes mellitus]. / Kaneel: niet geschikt als behandeling voor diabetes mellitus.

OBJECTIVE: To identify published studies evaluating the effects of cinnamon on glycaemic control. DESIGN: Literature search. METHOD: The Medline database was searched using all possible combinations of the words and medical subject headings (MeSH) 'cinnamon', 'diabetes mellitus', 'HbA1C' and 'glucose'. All human or animal studies in which cinnamon was administered as intervention were included. RESULTS: Several animal studies and 5 randomized placebo-controlled trials in humans were found. Most of the animal studies described beneficial effects of cinnamon on glycaemic control. One placebo-controlled trial in patients with type 2 diabetes found that cinnamon intake was associated with favourable effects on fasting plasma glucose. None of the studies reported an improvement in HbA1C. A study in patients with type 1 diabetes found that cinnamon had no effect. CONCLUSION: Based on the currently available evidence, cinnamon should not be recommended for the improvement ofglycaemic control.