Hypoglycaemic episodes during intensified insulin treatment: increased frequency but no effect on cognitive function

Ninety-seven patients with insulin dependent diabetes mellitus (IDDM) were randomized to intensified conventional treatment (ICT, n = 44) or regular treatment (RT, n = 53). The mean HbA1c level (+/- SEM) was reduced from 9.5 +/- 0.2% to 7.4 +/- 0.1% in the ICT group (P less than 0.001), and from 9.4 +/- 0.2% to 9.0 +/- 0.2% (P less than 0.01) in the RT group. The difference between the groups was significant (P less than 0.001). During a period of 3 years, 57% of the ICT patients (95% confidence interval 44-73%) and 23% of the RT patients (95% CI, 11-34%) (P less than 0.001) had at least one episode of serious hypoglycaemia, with the need for third-party assistance or resulting in coma. Eighteen of the 32 ICT patients who initially had adrenergic symptoms during hypoglycaemia changed to predominantly neuroglycopenic symptoms. This was the case with only 8 of 38 RT patients (P less than 0.01). The change in symptoms was related to the increased frequency of serious hypoglycaemia, but neither symptoms nor frequency of hypoglycaemia bor any relationship to insulin dose, body mass index, duration of diabetes or autonomic nerve function. The results of several neuropsychological tests did not differ between the groups at baseline, and did not change during the study. There were no signs of deteriorating cognitive function in the patients with serious hypoglycaemic episodes.     

Glycaemic thresholds for hypoglycaemic symptoms, impairment of cognitive function, and release of counterregulatory hormones in subjects with functional hypoglycaemia

Nine patients with food-relieved hypoglycaemic symptoms, in whom insulinoma and other organic diseases presenting with hypoglycaemia had been ruled out, and nine matched controls, participated in the study. Subjects were studied during a 5-h controlled (Biostator) insulin-induced (1-2 mU kg-1 min-1) hypoglycaemic clamp. After 1 h of euglycaemia, we aimed to lower the glucose level in arterialized venous blood in a stepwise manner at 30-min intervals to 3.5, 3.0, and 2.0 mmol l-1, and to withhold these levels for a further 30 min. At euglycaemia and at the end of the latter steps, the visual reaction time and cognitive function (digit span, letter cancellation and trail making) were tested, together with recording symptoms and signs of hypoglycaemia. Counter-regulatory hormones were measured at 20-min intervals. In the patients, clinical signs and symptoms of hypoglycaemia developed at median blood glucose levels of 2.6-2.8 and 2.8-3.1 mmol l-1, respectively. By contrast, the blood glucose levels were 0.4-0.8 mmol l-1 lower in control subjects (P less than 0.05). Similarly, the median threshold for deterioration of visual reaction time was 2.8 mmol l-1 in patients and 2.1 mmol l-1 in controls (P less than 0.01). A similar trend was observed for the results of the neuropsychological tests. Visual reaction time deteriorated in all subjects, whereas the cognitive function of some of the subjects in each group remained unchanged during hypoglycaemia. The glycaemic thresholds for release of cortisol, glucagon and growth hormone were significantly higher in patients (P less than 0.05), whereas the thresholds for catecholamine release showed no significant difference from controls. Despite the comparable glucose infusion rates required to sustain each of the hypoglycaemic levels in the two groups, the control subjects achieved lower glucose levels, suggesting that there is resistance to insulin or glucose in functional hypoglycaemia. In conclusion, the present study suggests that the existence of a higher threshold for symptoms and signs, as well as for deterioration of brain function, may explain every-day hypoglycaemic symptoms, despite normal glucose levels, in subjects with functional hypoglycaemia. However, the hypothesis should be tested further using a blinded approach, including euglycaemic control studies.     

Altered recognition of hypoglycaemic symptoms in type I diabetes during intensified control with continuous subcutaneous insulin infusion

The effect of intensified metabolic control obtained with continuous subcutaneous insulin infusion (CSII) on the frequency and symptoms of hypoglycaemia was studied in type I diabetic patients. The reproducibility of the questionnaire used to evaluate the hypoglycaemic symptoms was verified in a control group receiving unchanged conventional insulin therapy for 2 months. Metabolic control was significantly improved during CSII (HbA1c 6.8 +/- 0.4% versus 8.7 +/- 0.7%, normal range up to 5.4%) in all patients while no change was seen in the control group. The results of frequent self glucose monitoring showed that the incidence of low glucose levels (below 3.5 mmol/l) increased about threefold in the CSII group. Awareness of hypoglycaemia was clearly changed during CSII with less pronounced adrenergic symptoms while no alterations were found in the group with unchanged metabolic control. These results emphasize the importance of regular self glucose monitoring during CSII and of informing the patients that their hypoglycaemic symptoms may change during intensified control.     

Substitution of night-time continuous subcutaneous insulin infusion therapy for bedtime NPH insulin in a multiple injection regimen improves counterregulatory hormonal responses and warning symptoms of hypoglycaemia in IDDM

Summary In patients with insulin-dependent diabetes mellitus (IDDM) good glycaemic control confers an enhanced risk of hypoglycaemia. Nocturnal hypoglycaemia occurs frequently and contributes to the syndrome of hypoglycaemia unawareness. In order to avoid nocturnal hypoglycaemia we substituted night-time continuous subcutaneous insulin infusion (CSII) therapy in 14 patients with well-controlled IDDM using a multiple injection regimen for the more variable bedtime NPH insulin. During a stepwise hypoglycaemic clamp we studied the effect of this regimen on counterregulatory hormonal responses, warning symptoms and cognitive function. In addition, we investigated the incidence of daytime hypoglycaemia and the acceptability of night-time CSII treatment. CSII was associated with a lower frequency of hypoglycaemia (mean ± SEM): 16.1 ± 3.1 vs 23.6 ± 3.3) episodes during the last 6 weeks of treatment, p = 0.03 (CSII vs NPH)) with maintenance of good glycaemic control (HbA_1c 7.2 ± 0.2 vs 7.1 ± 0.2 %, p = 0.2). Hypoglycaemic thresholds for the growth hormone response and for autonomic symptoms were lower for CSII treatment than for NPH treatment. Of 14 patients 6 decided to continue with the nocturnal CSII treatment. In conclusion, nocturnal CSII improves warning symptoms and counterregulatory hormonal responses to hypoglycaemia and is an acceptable treatment strategy for patients suffering from hypoglycaemia unawareness, as demonstrated in this acute feasibility study. [Diabetologia (1998) 41: 322–329] Received: 21 July 1997 and in revised form: 7 October 1997     

Biphasic insulin aspart 30 plus metformin: an effective combination in type 2 diabetes

AIM: This study compared glycaemic control achieved with biphasic insulin aspart 30 (BIAsp 30) monotherapy, BIAsp 30 plus metformin and glibenclamide plus metformin in patients with type 2 diabetes not adequately controlled with metformin. METHODS: In this multinational, open-labelled, parallel group, 16-week trial, 341 patients (patients not adequately controlled with metformin for at least 1 month) with type 2 diabetes were studied. Patients were randomized to receive BIAsp 30, twice daily (n = 107 exposed to treatment), or BIAsp 30, twice daily, plus metformin (n = 108) or glibenclamide plus metformin (n = 114). The primary endpoint was HbA(1c) at end of trial; adverse events, hypoglycaemia episodes, blood lipids and weight were also monitored. RESULTS: In the total population (HbA(1c) 7.5-13.0% at screening), end-of-trial HbA(1c) levels were lower in patients receiving BIAsp 30 plus metformin compared with those receiving BIAsp 30 only [mean treatment difference (+/-s.e.m), 0.39 +/- 0.15%, p = 0.007]. In a subpopulation (HbA(1c) > or = 9.0% at baseline, n = 193), patients receiving BIAsp 30 plus metformin had significantly lower HbA(1c) levels at the end of the trial compared with those receiving glibenclamide plus metformin (treatment difference, 0.46 +/- 0.21%, p = 0.027). Mean body weight (+/-s.d) at the end of the trial was significantly lower in patients receiving glibenclamide plus metformin compared with those receiving BIAsp 30 only (84.3 +/- 13.3 kg vs. 88.9 +/- 16.9 kg, p < 0.001). No major hypoglycaemic episodes were recorded during the trial, and incidence rates for minor and symptoms-only hypoglycaemia were low and similar between treatment groups (0.03-0.04 events/patient/week). CONCLUSION: BIAsp 30 added to metformin could be an appropriate therapeutic option for achieving good glycaemic control, compared with the addition of a second oral agent, particularly where HbA(1c) > or = 9%.     

Impact of ubiquinone (coenzyme Q10) treatment on glycaemic control, insulin requirement and well-being in patients with Type 1 diabetes mellitus.

AIM: To investigate the effect of ubiquinone (coenzyme Q10) on glycaemic control and insulin requirement in patients with Type 1 diabetes mellitus (DM). METHODS: We investigated 34 patients with Type 1 DM in a randomized, double-blind, placebo-controlled study. Patients received either 100 mg Q10 or placebo daily for 3 months. The insulin doses were adjusted according to patients' home measurements of blood glucose concentrations and reported experience of hypoglycaemia. RESULTS: At randomization no differences existed between the Q10 and the placebo groups in age, body mass index (BMI), HbA1c, daily insulin dose or mean daily blood glucose concentration. Serum Q10 concentration increased in the Q10 group (mean +/- SD: 0.9+/-0.2 vs. 2.0+/-1.0 microg/ml, P<0.005), with no change in the placebo group (0.9+/-0.3 vs. 0.9+/-0.3 microg/ml, not significant (NS)). Following intervention no differences existed between the Q10 and the placebo groups regarding HbA1c (7.86+/-0.88 vs. 7.84+/-0.84%), mean daily blood glucose concentrations (8.06+/-1.86 vs. 8.53+/-1.88 mM), mean insulin dose (52.1+/-13.2 vs. 52.6+/-21.4 U), hypoglycaemic episodes (2.0+/-1.8 vs. 2.5+/-2.1 episodes/week), or cholesterol concentrations (4.81+/-0.91 vs. 4.78+/-1.07 mM). Furthermore, no differences existed in the well-being of the patients reported from a visual analogue scale (physical: 0.67+/-0.21 vs. 0.71+/-0.18, psychological: 0.70+/-0.25 vs. 0.73+/-0.24). CONCLUSION: Q10 treatment does not improve glycaemic control, nor does it reduce insulin requirement, and it can therefore be taken by patients with Type 1 DM without any obvious risk of hypoglycaemia. No major beneficial or unfavourable effects on the investigated parameters could be demonstrated and no major changes in the sense of well-being occurred in the patients.     

Long-term benefits of continuous subcutaneous insulin infusion in children with Type 1 diabetes: a 4-year follow-up.

AIM: To determine the safety and effectiveness of continuous subcutaneous insulin infusion (CSII) in attaining long-term glycaemic control in paediatric patients with Type 1 diabetes and to compare the results with those previously recorded in the same patients taking multiple daily injections (MDI) (four injections a day). METHODS: Forty-two patients (mean age 12.2 +/- 3.4 years; range 4.5-17 years; 24 males; mean duration of Type 1 diabetes 5.1 +/- 3.0 years) were studied. The following parameters were assessed in the year before starting CSII treatment (during MDI treatment) and during the 4 years of insulin pump treatment: annual mean HbA1c, insulin requirements (U/kg per day), annual mean of body mass index (BMI) z scores, and adverse events (severe hypoglycaemia and diabetic ketoacidosis/patient per year). Two patients discontinued pump therapy (after 1-year and 2-year follow-up, respectively) because of non-compliance with CSII therapy. RESULTS: Compared with the annual mean HbA1c observed prior to CSII therapy (8.9 +/- 1.0%), the mean HbA1c levels were lower during the first (8.2 +/- 0.9%; P = 0.00), second (8.6 +/- 1.0%; P = 0.05), third (8.4 +/- 0.9%; P = 0.01) and fourth (8.2 +/- 1%; P = 0.00) year of CSII therapy. The insulin requirements (U/kg per day) decreased during CSII treatment compared with MDI treatment. Compared with the annual mean of BMI z scores prior to CSII therapy, BMI z scores were significantly lower during the third and fourth years of CSII therapy. Through the first, second, third and fourth years of follow-up the number of episodes of severe hypoglycaemia (20.0, 20.0, 20.0 and 0 episodes/1000 patient-years, respectively) and diabetic ketoacidosis (0.05, 0.00, 0.03 and 0.00 episodes/patient per year, respectively), events were similar to that in the year preceding CSII therapy (20.0 and 0.03, respectively). CONCLUSION: In this population of selected patients in our clinic, CSII appears to be a safe and effective therapeutic alternative to MDI treatment. This therapy may ensure a stable improvement in long-term glycaemic control in paediatric patients, with no increase in diabetic ketoacidosis and severe hypoglycaemic events and, on the other hand, with a trend of reduction in BMI z scores.     

Hypoglycaemia with insulin aspart: a double-blind, randomised, crossover trial in subjects with Type 1 diabetes.

AIMS: To compare the effects of the rapid-acting insulin analogue insulin aspart and soluble human insulin on hypoglycaemia and glycaemic control in patients with Type 1 diabetes when injected immediately before meals as part of intensive insulin therapy. METHODS: In this multinational, double-blind, randomised, crossover trial, 155 patients with Type 1 diabetes (HbA(1c) < 8.0%) were symmetrically randomised to two 16-week treatment periods on either type of insulin, both injected 0-5 min before meals. NPH insulin was given as basal insulin once or twice daily as needed, and insulin dosages were regularly adjusted using pre-defined algorithms to maintain tight glycaemic control. Treatment periods were separated by a 4-week washout. RESULTS: The rate of major nocturnal (24.00-06.00 h) hypoglycaemic episodes was 72% lower with insulin aspart than with human insulin (0.067 vs. 0.225 events/month; P = 0.001). Total rate of major hypoglycaemia did not differ significantly between treatments (insulin aspart/human insulin relative risk 0.72; 95% CI 0.47-1.09, P = 0.12). The rate of minor events was significantly reduced by 7% with insulin aspart (P = 0.048). Reductions in rate of hypoglycaemia were achieved with maintained overall glycaemic control: Mean HbA(1c) remained constant, slightly below 7.7% on both treatments. CONCLUSIONS: The use of insulin aspart in an intensive insulin regimen in patients with tightly controlled Type 1 diabetes led to clinically significant reductions in major nocturnal hypoglycaemia with no deterioration in glycaemic control. Major nocturnal hypoglycaemia appears to be a strong clinical indication for the use of rapid-acting insulin analogues during intensive insulin therapy.     

A randomized controlled trial examining combinations of repaglinide, metformin and NPH insulin.

AIMS: To compare combination use of repaglinide, metformin and bedtime Neutral Protamine Hagedorn (NPH) insulin with conventional approaches of insulin initiation in patients with Type 2 diabetes (T2DM). METHODS: Eighty-two patients with T2DM with suboptimal glycaemic control on oral glucose-lowering agents were randomized to one of three treatment regimens for 4 months. Group 1 received metformin and twice daily biphasic 30/70 human insulin mixture (n = 27), group 2 metformin and bedtime NPH insulin (n = 26) and group 3 metformin, bedtime NPH insulin and mealtime repaglinide (n = 25). RESULTS: Seventy-five patients completed the study. Baseline and end-point mean HbA1c levels fell from 9.0 +/- 1.1 to 7.9 +/- 1.1% in group 1, 10.0 +/- 2.2 to 9.2 +/- 1.4% group 2 and 10.0 +/- 1.7 to 8.1 +/- 1.5% in group 3, respectively. All groups showed improvements in HbA1c. There was no significant difference between groups in the proportions of patients experiencing hypoglycaemia (29.6, 25.0 and 16.7%, respectively; P = 0.55) or in mean weight gain (2.9, 0.7 and 2.2 kg, respectively; P = 0.06). By 4 months, insulin doses were 0.63 +/- 0.32 IU/kg in group 1, 0.58 +/- 0.21 IU/kg in group 2 and 0.37 +/- 0.22 IU/kg in group 3 (group 3 vs. groups 1 and 2: P < 0.002). CONCLUSIONS: The approach using repaglinide, metformin and NPH insulin improved glycaemic control with a similar safety profile to conventional insulin initiation in T2DM and produced final glycaemic control similar to metformin and a twice daily biphasic insulin mixture.     

Sensitivity to sulphonylureas in patients with hepatocyte nuclear factor-1alpha gene mutations: evidence for pharmacogenetics in diabetes.

INTRODUCTION: Maturity-onset diabetes of the young (MODY) is characterized by autosomal dominantly inherited, early-onset, non-insulin-dependent diabetes. Mutations in the hepatocyte nuclear factor (HNF)-1alpha gene are the commonest cause of MODY. Individual patients with HNF-1alpha mutations have been reported as being unusually sensitive to the hypoglycaemic effects of sulphonylurea therapy. We report three patients, attending a single clinic, with HNF-1alpha mutations that show marked hypersensitivity to sulphonylureas. CASE REPORTS: In cases 1 and 2 there were marked changes in HbA1c on cessation (4.4% and 5.8%, respectively) and reintroduction (5.0% and 2.6%) of sulphonylureas. Case 3 had severe hypoglycaemic symptoms on the introduction of sulphonylureas despite poor glycaemic control and was shown with a test dose of 2.5 mg glibenclamide to have symptomatic hypoglycaemia (blood glucose 2 mmol/l) after 4 h despite eating. CONCLUSIONS: HNF-1alpha MODY diabetic subjects are more sensitive to sulphonylureas than Type 2 diabetic subjects and this is seen in different families, with different mutations and may continue up to 13 years from diagnosis. This is an example of pharmacogenetics, with the underlying aetiological genetic defect altering the pharmacological response to treatment. The present cases suggest that in HNF-1alpha MODY patients: (i) sulphonylureas can dramatically improve glycaemic control and should be considered as initial treatment for patients with poor glycaemic control on an appropriate diet; (ii) hypoglycaemia may complicate the introduction of sulphonylureas and therefore very low doses of short acting sulphonylureas should be used initially; and (iii) cessation of sulphonylureas should be undertaken cautiously as there may be marked deterioration in glycaemic control.     

Glargine is superior to neutral protamine Hagedorn for improving glycated haemoglobin and fasting blood glucose levels during intensive insulin therapy

AIM: To compare glycaemic control and symptomatic hypoglycaemia rates with glargine versus neutral protamine Hagedorn (NPH) in poorly controlled type 1 diabetes patients. METHODS: Patients (n = 125) received preprandial insulin lispro and either glargine (n = 62) or NPH (n = 63) at bedtime for 30 weeks in a multicentre, randomized, single-blind (a blinded investigator made titration decisions) study. Basal insulin dosage was titrated to achieve fasting blood glucose (FBG) values < 5.5 mmol/L. RESULTS: Baseline characteristics were similar for the two groups (mean diabetes duration 17.5 +/- 10.1 years) except mean glycated haemoglobin (HbA(1c)), which was lower in the glargine versus NPH group (9.2 +/- 1.1% vs 9.7 +/- 1.3%; P < 0.02). At end-point, mean HbA(1c) was 8.3 versus 9.1% for the glargine versus NPH groups. Adjusted least-squares mean (LSM) change from baseline was -1.04 versus -0.51%, a significant treatment benefit of 0.53% for HbA(1c) in favour of glargine (P < 0.01). Mean baseline FBG were similar for the glargine and NPH groups (11.2 vs 11.4 mmol/L). The means for end-point FBG were 7.9 versus 9.0 mmol/L. Adjusted LSM change from baseline was -3.46 versus -2.34 mmol/L, with a significant difference of 1.12 mmol/L in favour of glargine (P < 0.05). There were similar total numbers of daytime mild, moderate or severe hypoglycaemia episodes in the two treatment arms. However, significantly fewer moderate or severe nocturnal hypoglycaemic episodes were observed in the glargine group (P = 0.04 and P = 0.02). CONCLUSION: Glargine is superior to NPH for improving HbA(1c) and FBG levels during intensive insulin therapy in patients with type 1 diabetes, and is associated with less severe nocturnal hypoglycaemia.     

Long-term improvement of metabolic control without increased risk of hypoglycaemia by intensive insulin regimens in type 1 diabetes patients treated in a regular clinical setting.

AIM: To evaluate if intensive insulin regimen with multiple daily injections (MDI) is successful for treating type 1 diabetes patients over a long period of time in a regular clinical setting. METHOD: This is a prospective, observational seven-year study. Fifty-nine (35 male) type 1 diabetic patients with bad metabolic control (HbA1c> or =9%), aged 31.9 years, range 18-47 were included in the present study. All of them had had at least 5 years of diabetes duration after diagnosis and showed negative responses of serum C-peptide to a standard breakfast. The main control variables are: Metabolic control measured by serum HbA1c values (values < 6.2 % was the treatment objective) and the frequency of hypoglycaemic episodes (episodes/patient-month). RESULTS: Significant decreases in mean+/-SD HbA1c values in this group of patients were observed from the first year of follow-up, with the mean values being: 7.5+/-1.5%, 7.2+/-1.8%, 7.6+/-1.6%, 7.1+/-1.7%, 7+/-1.4, 6.6+/-1.6% and 6.8+/-1.4% for the first, second, third, fourth, fifth, sixth and seventh years of follow-up respectively. Sixteen %, 27.5%, 15.7%, 33.3%, 28.6%, 42% and 33% of the patients reached the treatment objective (HbA1c values<6.2%) for each year of follow-up. Throughout the study period the rate of severe hypoglycaemia (episodes/patient-year) was 0.32+/-0.2 which was not significantly different compared with the value of 0.28+/-0.1 observed the year before the study began. Similarly frequencies of mild/moderate hypoglycaemia episodes (episodes/patient-month) varies between 16.5+/-4 and 21.7+/-5, which are not significantly different from the value of 17.7+/-6 observed the year before the study began. CONCLUSION: Long-term improvement in metabolic control was observed in this group of type 1 diabetes patients with previous bad control, during treatment in a regular clinical setting. A considerable percentage of type 1 diabetic patients with MDI reached the treatment objective in every year of follow-up. Furthermore improvement in metabolic control is not associated with significantly increased frequency of hypoglycaemia episodes.     

Metabolic control and complications over 3 years in patients with insulin dependent diabetes (IDDM): the Stockholm Diabetes Intervention Study (SDIS)

In a planned 5-year study, 97 patients with insulin dependent diabetes mellitus (IDDM), non-proliferative retinopathy and unsatisfactory blood glucose control were monitored for 3 years. The patients were randomized to an intensified conventional treatment (ICT, n = 44) or a regular treatment (RT, n = 53) group. HbA1c (normal range 3.9-5.7%) was reduced from 9.5 +/- 0.2 (mean value +/- SEM) to 7.4 +/- 0.1% in the ICT group (P = 0.0001), and from 9.5 +/- 0.2 to 9.0 +/- 0.2% in the RT group (P = 0.004). Nerve conduction velocities in the sural and peroneal nerves (P = 0.01-0.0001) were impaired in the RT group, but not in the ICT group. Retinopathy increased in both groups. The condition of 22 ICT patients (50%, 95% confidence interval 34-66%) and 37 RT patients (73%, 61-84%) deteriorated with regard to at least one microvascular complication (retinopathy, nephropathy, neuropathy) (P = 0.024). Lower HbA1c levels during the study significantly reduced the risk of deterioration (P = 0.01). In total, 57% of the ICT patients had at least one episode of serious hypoglycaemia, compared with 23% in the RT group (P = 0.001). The patients in the ICT group also gained weight (P = 0.0001). Improved blood glucose control slowed down the progression of microangiopathy during a 3-year period in patients with non-proliferative retinopathy, but at the price of an increased frequency of serious hypoglycaemic episodes, and some gain in body weight.     

The contribution of metformin to glycaemic control in patients with Type 2 diabetes mellitus receiving combination therapy with insulin

Combination therapy of oral hypoglycaemic agents and insulin is a therapeutic option for those who have deterioration in glycaemic control. We examined the contribution of metformin by withdrawing it from Type 2 diabetic patients who had been stabilised on combination therapy. Fifty-one subjects with Type 2 diabetes and secondary oral hypoglycaemic agent failure were studied in a randomised, open and parallel study. In the first phase of 36 weeks, subjects were stabilised on combined therapy of sulphonylureas and nocturnal insulin, with or without metformin. During the second phase, metformin was withdrawn. The primary variables for efficacy were HbA(1c), fasting plasma glucose and 3-point capillary blood glucose profiles. After stabilisation with combination therapy, those subjects on metformin used less insulin to maintain glycaemic control (13.7+/-6.8 vs. 23.0+/-9.4 U/day, P=0.001) and had lower HbA(1c) values (8.13+/-0.89 vs. 9.05+/-1.30%, P=0.003) compared with those not given metformin. Withdrawal of metformin therapy caused deterioration in HbA(1c) (P=0.001). This study confirms that metformin plays an important role in the success of the combination therapy. The rational use of metformin and sulphonylurea together with insulin will help to improve metabolic control in Type 2 diabetes patients who have secondary drug failure.     

Postprandial hyperglycaemia following a morning hypoglycaemia in type 1 diabetes mellitus

The occurrence of hyperglycaemia following a morning hypoglycaemic episode was studied in nine patients with Type 1 diabetes. Each patient was studied twice, once following induced hypoglycaemia and once in a control study when hypoglycaemia was prevented by glucose infusion. After the initial hypoglycaemic/control period the patients were maintained on their regular insulin regimens and were given standard meals. Hypoglycaemia induced postprandial hyperglycaemia (3.1 +/- 0.8 mmol l-1 above control) which lasted for about 8 h. Maximal growth hormone levels were seen 40 min after glucose nadir (control 7.8 +/- 3.2, hypoglycaemia 74.0 +/- 12.3 mU l-1) and the magnitude of the hyperglycaemia was related to the growth hormone levels following the hypoglycaemia (r = 0.80, p less than 0.01).     

Short-term effects of cognitive behavioural group training (CBGT) in adult Type 1 diabetes patients in prolonged poor glycaemic control. A randomized controlled trial.

AIMS: To assess the effects of cognitive behavioural group training (CBGT) on glycaemic control, diabetes self-efficacy and well-being in Type 1 diabetes patients in persistent poor glycaemic control. METHODS: In a randomized controlled trial, a total of 107 patients with Type 1 diabetes in poor glycaemic control (HbA(1c) > or = 8%) were assigned to a 6-week CBGT or blood glucose awareness training (BGAT) as control condition. The intervention was preceded by a 3-month run-in period. Glycaemic control (HbA(1c)), diabetes-specific self-efficacy (CIDS), diabetes-related distress (PAID) and depressive symptoms (CES-D), were assessed at baseline (T1), directly before (T2) and 3 months after (T3) the intervention. RESULTS: No significant changes in HbA(1c) were found after CBGT, whilst diabetes self-efficacy increased (mean CIDS score 71.6 +/- 14.0 to 74.3 +/- 12.2) and diabetes-related distress (mean PAID score 47.0 +/- 21.6 to 42.6 +/- 20.8) and depressive symptoms decreased (mean CES-D score 16.9 +/- 12.8 to 13.5 +/- 12.6). Changes in psychological outcomes were similar for both treatment groups. Diabetes self-care behaviours improved equally. Drop-out rate, which was higher among CBGT participants, was relatively low overall (total n = 15, 17.05%), and both interventions were well-appreciated by the participants. CONCLUSIONS: CBGT was successful in improving self-efficacy, diabetes-related distress and mood at 3 months' follow-up, but not in improving glycaemic control.     

Continuous intraperitoneal insulin infusion partly restores the glucagon response to hypoglycaemia in type 1 diabetic patients

The glycaemic and hormonal responses to a hypoglycaemic event induced by an i.v. bolus of insulin was studied in seven type 1 diabetic patients treated first with continuous subcutaneous insulin infusion (CSII) and subsequently with continuous intraperitoneal insulin infusion (CIPII). Arterialised blood glucose and venous hormonal responses were analyzed. HbA1c was improved by CIPII. Although a regimen of a higher basal insulin infusion rate was applied during CIPII the basal peripheral venous insulin levels were lower. The i.v. bolus of insulin resulted in hypoglycaemia in both tests but was more pronounced during the CSII test expressed as a smaller area under the curve (AUC) for the first hour (13.0 +/- 2.3 vs. 13.7 +/- 1.2 mmol l(-1) h(-1), p=0.016, CSII vs. CIPII). The hypoglycaemia resulted in a significant and similar increase in the plasma levels of adrenaline, cortisol and growth hormone in both experiments. A significant increase in the glucagon level was only observed during CIPII. The incremental glucagon response was also significantly more pronounced in the CIPII test expressed as maximal responses (7.5 +/- 3.0 vs. 17.0 +/- 3.1 pg ml(-1), p =0.048, CSII vs. CIPII) as well as incremental AUC (5.1 +/- 12.0 vs. 44.4 +/- 13.2 pg ml(-1) h(-1), p =0.027, CSII vs. CIPII). It seems that CIPII in type 1 diabetic patients could improve the glucagon release to hypoglycaemia. This observation may contribute in explaining why CIPII is associated with a lower incidence of hypoglycaemia in spite of an improvement in metabolic control.     

Results of a randomised controlled cross-over trial on the effect of continuous subcutaneous glucose monitoring (CGMS) on glycaemic control in children and adolescents with type 1 diabetes.

OBJECTIVE: To study the feasibility and the influence on glycaemic control of continuous glucose monitoring (CGMS) in young patients with type 1 diabetes. DESIGN AND METHODS: A double-blinded, cross-over study was performed in 30 children (median age 11.1 years [range: 2.3 - 16.3], diabetes duration 2.1 years [0.2 - 7.1]). Patients were randomised into an open (A) or blind study arm (B). Both groups performed standardised self-monitoring blood glucose (SMBG) and received CGMS at the beginning of the study, at 3 and 6 months, each. In the blinded arm, patients and investigator were concealed from CGMS data. After 3 months, open and blinded study arms crossed over. Average glucose values and area under the glucose curve (AUC) per 24 h, above 180 and below 60 mg/dl were calculated from CGMS. Haemoglobin A1c (HbA1c) was measured at each study point. RESULTS: Despite comparable clinical characteristics between the 15 patients of each arm, mean HbA1c was slightly lower in arm A than in B at baseline (7.8 +/- 1.2 % vs. 8.4 +/- 1.1 %, p = 0.148), at 3 months (7.8 +/- 1.1 % vs. 8.3 +/- 1.1 %, p = 0.233), and significantly lower at 6 months (7.6 +/- 1.1 % vs. 8.5 +/- 0.9 %, p = 0.026). However, no significant change of HbA1c occurred within each arm (A, p = 0.183 and B, p = 0.823), irrespectively whether CGMS data were blinded or not. Likewise, mean glucose and hyper- or hypoglycaemia values did not change significantly. CONCLUSIONS: In this setting, CGMS did not decisively influence glycaemic control of a total study cohort. More frequent use of CGMS at shorter intervals in single patients with hyper- or hypoglycaemic problems may be of greater value than SMBG.     

The relationship between symptomatic and biochemical hypoglycaemia in insulin-dependent diabetic patients

The relationship between symptomatic (subjective feelings) and biochemical (blood glucose concentration less than 3 mmol l-1) hypoglycaemia was studied in 66 randomly selected insulin-dependent diabetic out-patients under normal conditions of daily life with conventional insulin injection regimens. The patients (a) collected 7-point diurnal blood glucose profiles at home on three consecutive days and then once weekly for 3 weeks, (b) indicated whether they felt hypoglycaemic at sampling times, and (c) collected extra samples if they felt hypoglycaemic at any time during the study period. The weekly frequencies of symptomatic and biochemical hypoglycaemia were 0.99 and 1.75 per patient, respectively. Biochemical hypoglycaemia was present in 29% of the symptomatic episodes, and symptomatic hypoglycaemia accompanied 16% of the biochemical episodes. Symptomatic hypoglycaemia was experienced at a median blood glucose concentration of 3.4 mmol l-1 (range 1.4-14.9 mmol l-1). Fifty per cent of both symptomatic and biochemical episodes occurred before lunch, while the remainder were evenly distributed throughout the day. The occurrence of biochemical hypoglycaemia, but not of symptomatic hypoglycaemia, was inversely correlated with HbA1c and median blood glucose concentration. Thus symptomatic hypoglycaemia is an unreliable indicator of biochemical hypoglycaemia and of the degree of glycaemic control. Blood glucose measurements are a prerequisite for the diagnosis of hypoglycaemia.     

Efficacy of continuous subcutaneous insulin infusion in Type 1 diabetes: a 2-year perspective using the established criteria for funding from a National Health Service.

AIM: To determine the 2-year efficacy of continuous subcutaneous insulin infusion (CSII) following the current established criteria for funding of a National Health Service. METHODS: Longitudinal, prospective, observational unicentre study. Included in the study were 153 Type 1 diabetes (T1D) subjects, previously treated with multiple daily injections (MDI) of insulin, in whom CSII was started in accordance with the criteria for reimbursement of the Catalan National Health Service. At baseline, we recorded data on age, gender, duration of the disease, body mass index (BMI), insulin dose and indications for CSII. Glycated haemoglobin (HbA(1c)) and the frequency of hypoglycaemic events were used to assess glycaemic control. Quality of life was assessed using three different self-report questionnaires. After 24 months, these same items were remeasured in all subjects. Serious adverse events and injection-site complications were also recorded. RESULTS: In 96% of subjects, CSII indication included less than optimal glycaemic control using MDI. HbA(1c) fell from 7.9 +/- 1.3 to 7.3 +/- 1.1% (P < or = 0.001) after 24 months of CSII. Insulin requirements were significantly lower at the end of follow-up (0.55 +/- 0.21 U/kg body weight) in comparison with before use of CSII (0.70 +/- 0.20, P < or = 0.001). BMI increased from 24.0 +/- 3.1 to 24.4 +/- 3.2 kg/m(2) after 24 months (P < or = 0.025). The rate of episodes of diabetic ketoacidosis per year remained unchanged. Mild and severe hypoglycaemic episodes were significantly reduced. The scores in all subsets of the Diabetes Quality-of-Life (DQoL) questionnaire significantly improved after 24 months of CSII. CONCLUSIONS: CSII, commenced according to the criteria for a nationally funded clinical programme, improves glycaemic control and quality-of-life outcomes with fewer hypoglycaemic episodes in T1D subjects previously conventionally treated with MDI.