Glycemic Variability in T1DM: Insulin Infusion vs Injections
Glycemic Variability in T1DM: Insulin Infusion vs Injections
High glycaemic variability is a common feature in patients with diabetes and has been accused to be the main responsible factor for co-morbidities, e. g. diabetic nephropathy and retinopathy. In general, self-monitoring of glucose two-to-four times per day with concomitant adjustment of insulin dosages and carbohydrate intake is used to ensure glucose homeostasis, whereas HbA1c is used as an established marker of long-term metabolic control. It is still a matter of discussion whether or not the additional costs related to CSII are justified from a medical point of view, i.e. whether CSII is superior to MDI in terms of metabolic control and prevention of glycaemic excursions. Instead of individual glucose measurements several hours apart, CGM appears to be ideally suited to detect "automatically" otherwise unheralded extremes and fluctuations of glucose concentrations during a reasonable period of times, i.e. to record glucose concentrations every one or five minutes for at least 72 h. Despite being a very appealing approach and necessary step towards the development of closed loop systems, one ends with huge amounts of data. The latter requires additional tools and algorithms to separate out and highlight information relevant to answer the question at hand. Several indices and statistical tools have been suggested for this purpose. Among these, the mean and standard deviation of the glucose concentration during the entire observation period are fairly direct characteristics, whereas MODD and CONGAn as marker of inter- and intraday glycaemic variation are more sophisticated ones. Both MODD and CONGAn were quite similar in children on MDI and CSII therapy respectively. This may at least in part simply be due to the fact that our patients used CGM under conditions of everyday life rather than during an artificial hospital setting with highly standardized meals and activities. Furthermore, it highlights the inherent danger of data reduction, as those parameters directly calculated from the entire set of data indicate significant differences between groups (see below).
While our data for MODD are well in line with those reported earlier for smaller groups of adult (n = 28) and paediatric (n = 10) patients with type 1 diabetes, the CONGA values in our study were about one-third of those described earlier. The latter may be due to the fact that activities and meals during everyday life in children are quite homogeneous compared with adults. Furthermore, none of the aforementioned studies was conducted to decipher differences related to the mode of therapy, but rather to compare patients and healthy controls. There is one recent report indicating that CONGA-4 values are lower only in adults with type 1 diabetes on CSII therapy with already good metabolic control (HbA1c ≤ 58 mmol/mol (≤ 7·5%)). In those with poor metabolic control (HbA1c > 77 mmol/mol (> 9·2%)), the results for patients on CSII therapy were even worse compared with those on MDI therapy. In our patients, averaged and actual HbA1c values indicate neither good nor poor metabolic control and even did not differ between groups. In this regard, our findings are well in line with the data reported by Lepore et al.
In contrast to MODD and CONGAn, the mean amplitude of glycaemic excursions (MAGE) as an individually standardized index of glucose fluctuations differed significantly between patients on MDI and CSII therapy respectively. The "glucose pentagon" has been suggested as a model to integrate different parameters related to acute glycaemic variability (CGM data) and long-term metabolic control (HbA1c). Although all values entered into this model only tended to be higher in patients on MDI therapy, the GRP was significantly worse in patients on MDI therapy compared with both healthy controls and patients using CSII therapy. This result is remarkable, in that i) the duration of disease tended to be longer in patients on CSII therapy and that ii) apparently all patients in our study group were started on MDI and a subgroup was switched to CSII later. Keeping this in mind, the glucose pentagons and the derived GRP indicate that on average two years of CSII are sufficient to significantly reduce, but not normalize, the GRP. In other words, switching from MDI to CSII therapy several years after onset of disease has only limited potential to normalize the GRP and this might be especially valid for those patients showing initially poor glycaemic control with MDI therapy.
Another parameter to be considered when speculating on glycaemic risk and complications of diabetes is oxidative stress. A strong linear relationship between urinary 8-iso PGF2 has been described in a recent study with adults suffering from type 2 diabetes and being treated with oral anti-diabetic agents rather than insulin. By contrast, we and others were unable to show any association between glycaemic variability and urinary excretion of PGF2 or FISO in paediatric and adult patients with type 1 diabetes. But perhaps even more impressive is the notion that our patients had approximately 100-fold higher urinary creatinine normalized PGF2 and FISO excretion than adults with either form of diabetes. First of all, methodological problems related to the quantitative determination of individual isoforms of the PGF2 family of prostaglandins have to be considered. While a combination of solid-phase extraction and enzyme-immunoassay was used by Monnier et al., we and Wentholt et al. applied more sophisticated, although still slightly different technologies, i.e. GC-MS/MS with pre-column derivatization and immunoaffinity chromatography followed by HPLC-MS/MS. Both the extremely different concentrations of prostaglandins in adult and paediatric patients with type 1 diabetes on the one hand, and the apparently missing link between glycaemic variability and oxidative stress in patients with type 1 and type 2 diabetes on the other hand indicate that i) oxidative stress is higher in paediatric patients with type 1 diabetes and probably reflects more complex metabolic aberrations rather than glycaemic variability, and/or ii) that the pathological mechanisms behind either diabetes form differ.
The present study has several limitations and the results might be biased due to the fact that i) patients on CSII treatment tended to have longer duration of diabetes than those using MDI therapy, ii) some patients were previously transferred from MDI to CSII therapy because of unstable diabetes and recurrent hypoglycaemia and iii) metabolic differences between both groups of patients are likely to be underestimated by the parallel design. However, due to ethical reasons, a (randomized) cross-over study design was not feasible in this paediatric patient cohort. Indeed, children and their parents usually fight for the permission, to use an insulin pump instead of MDI therapy and one can hardly imagine that these parents and patients accept the withdrawal of the pump and go back to MDI therapy. Patients had to adapt to this "new" therapy for several months before reapplication of CGM will yield reliable data on glycaemic variability.
In conclusion, this observational cohort study carried out under "real-life" conditions revealed lower glycaemic variability and glycaemic risk profile in paediatric patients with type 1 diabetes on CSII compared with MDI therapy. However, whether on the long-run CSII is superior to MDI to delay the occurrence of diabetes associated complications remains to be elucidated in carefully designed prospective trials.
Discussion
High glycaemic variability is a common feature in patients with diabetes and has been accused to be the main responsible factor for co-morbidities, e. g. diabetic nephropathy and retinopathy. In general, self-monitoring of glucose two-to-four times per day with concomitant adjustment of insulin dosages and carbohydrate intake is used to ensure glucose homeostasis, whereas HbA1c is used as an established marker of long-term metabolic control. It is still a matter of discussion whether or not the additional costs related to CSII are justified from a medical point of view, i.e. whether CSII is superior to MDI in terms of metabolic control and prevention of glycaemic excursions. Instead of individual glucose measurements several hours apart, CGM appears to be ideally suited to detect "automatically" otherwise unheralded extremes and fluctuations of glucose concentrations during a reasonable period of times, i.e. to record glucose concentrations every one or five minutes for at least 72 h. Despite being a very appealing approach and necessary step towards the development of closed loop systems, one ends with huge amounts of data. The latter requires additional tools and algorithms to separate out and highlight information relevant to answer the question at hand. Several indices and statistical tools have been suggested for this purpose. Among these, the mean and standard deviation of the glucose concentration during the entire observation period are fairly direct characteristics, whereas MODD and CONGAn as marker of inter- and intraday glycaemic variation are more sophisticated ones. Both MODD and CONGAn were quite similar in children on MDI and CSII therapy respectively. This may at least in part simply be due to the fact that our patients used CGM under conditions of everyday life rather than during an artificial hospital setting with highly standardized meals and activities. Furthermore, it highlights the inherent danger of data reduction, as those parameters directly calculated from the entire set of data indicate significant differences between groups (see below).
While our data for MODD are well in line with those reported earlier for smaller groups of adult (n = 28) and paediatric (n = 10) patients with type 1 diabetes, the CONGA values in our study were about one-third of those described earlier. The latter may be due to the fact that activities and meals during everyday life in children are quite homogeneous compared with adults. Furthermore, none of the aforementioned studies was conducted to decipher differences related to the mode of therapy, but rather to compare patients and healthy controls. There is one recent report indicating that CONGA-4 values are lower only in adults with type 1 diabetes on CSII therapy with already good metabolic control (HbA1c ≤ 58 mmol/mol (≤ 7·5%)). In those with poor metabolic control (HbA1c > 77 mmol/mol (> 9·2%)), the results for patients on CSII therapy were even worse compared with those on MDI therapy. In our patients, averaged and actual HbA1c values indicate neither good nor poor metabolic control and even did not differ between groups. In this regard, our findings are well in line with the data reported by Lepore et al.
In contrast to MODD and CONGAn, the mean amplitude of glycaemic excursions (MAGE) as an individually standardized index of glucose fluctuations differed significantly between patients on MDI and CSII therapy respectively. The "glucose pentagon" has been suggested as a model to integrate different parameters related to acute glycaemic variability (CGM data) and long-term metabolic control (HbA1c). Although all values entered into this model only tended to be higher in patients on MDI therapy, the GRP was significantly worse in patients on MDI therapy compared with both healthy controls and patients using CSII therapy. This result is remarkable, in that i) the duration of disease tended to be longer in patients on CSII therapy and that ii) apparently all patients in our study group were started on MDI and a subgroup was switched to CSII later. Keeping this in mind, the glucose pentagons and the derived GRP indicate that on average two years of CSII are sufficient to significantly reduce, but not normalize, the GRP. In other words, switching from MDI to CSII therapy several years after onset of disease has only limited potential to normalize the GRP and this might be especially valid for those patients showing initially poor glycaemic control with MDI therapy.
Another parameter to be considered when speculating on glycaemic risk and complications of diabetes is oxidative stress. A strong linear relationship between urinary 8-iso PGF2 has been described in a recent study with adults suffering from type 2 diabetes and being treated with oral anti-diabetic agents rather than insulin. By contrast, we and others were unable to show any association between glycaemic variability and urinary excretion of PGF2 or FISO in paediatric and adult patients with type 1 diabetes. But perhaps even more impressive is the notion that our patients had approximately 100-fold higher urinary creatinine normalized PGF2 and FISO excretion than adults with either form of diabetes. First of all, methodological problems related to the quantitative determination of individual isoforms of the PGF2 family of prostaglandins have to be considered. While a combination of solid-phase extraction and enzyme-immunoassay was used by Monnier et al., we and Wentholt et al. applied more sophisticated, although still slightly different technologies, i.e. GC-MS/MS with pre-column derivatization and immunoaffinity chromatography followed by HPLC-MS/MS. Both the extremely different concentrations of prostaglandins in adult and paediatric patients with type 1 diabetes on the one hand, and the apparently missing link between glycaemic variability and oxidative stress in patients with type 1 and type 2 diabetes on the other hand indicate that i) oxidative stress is higher in paediatric patients with type 1 diabetes and probably reflects more complex metabolic aberrations rather than glycaemic variability, and/or ii) that the pathological mechanisms behind either diabetes form differ.
The present study has several limitations and the results might be biased due to the fact that i) patients on CSII treatment tended to have longer duration of diabetes than those using MDI therapy, ii) some patients were previously transferred from MDI to CSII therapy because of unstable diabetes and recurrent hypoglycaemia and iii) metabolic differences between both groups of patients are likely to be underestimated by the parallel design. However, due to ethical reasons, a (randomized) cross-over study design was not feasible in this paediatric patient cohort. Indeed, children and their parents usually fight for the permission, to use an insulin pump instead of MDI therapy and one can hardly imagine that these parents and patients accept the withdrawal of the pump and go back to MDI therapy. Patients had to adapt to this "new" therapy for several months before reapplication of CGM will yield reliable data on glycaemic variability.
In conclusion, this observational cohort study carried out under "real-life" conditions revealed lower glycaemic variability and glycaemic risk profile in paediatric patients with type 1 diabetes on CSII compared with MDI therapy. However, whether on the long-run CSII is superior to MDI to delay the occurrence of diabetes associated complications remains to be elucidated in carefully designed prospective trials.
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