Abnormal regulation of sympathetic nervous activity and heart rate after oral glucose in Type 1 (insulin-dependent) diabetic patients

Summary Oral glucose administration increased plasma noradrenaline concentration significantly in seven normal subjects (p<0.02), whereas in six young short-term Type 1 diabetic patients without complications plasma noradrenaline did not change. Basal plasma noradrenaline did not differ between the two groups. In the first 3 h after oral glucose administration, the mean heart rate in eight normal subjects was increased 3.5% above basal levels (p<0.05). In contrast, no such increase was found in eight Type 1 diabetic patients after glucose administration. In two normal subjects thoroughly examined before and after oral glucose administration, we observed a significant correlation between heart rate and systolic blood pressure (p<0.001) but this was not seen in two diabetic patients in whom neither heart rate nor systolic blood pressure increased. Our findings indicate that sympathetic nervous activity and cardiovascular function is abnormal in early diabetes during an oral glucose load.     

A Crossover Comparison of Continuous Insulin Infusion and Conventional Injection Treatment of Type I Diabetes

ABSTRACT. Helve E, Koivisto VA, Lehtonen A, Pelkonen R, Huttunen JK, NikkilÄ EA (Third Department of Medicine, University of Helsinki, and National Public Health Institute, Helsinki, Finland). A crossover comparison of continuous insulin infusion and conventional injection treatment of type I diabetes. We evaluated the feasibility and effectiveness of continuous subcutaneous insulin infusion therapy (CSII) as compared to conventional injection treatment (CIT) in an ordinary diabetic clinic in a one-year randomized crossover study of 65 type I diabetic patients. Home blood glucose levels were lower during CSII (8.6±0.2 mmol/1, mean ± SEM) than during CIT (9.1±0.3 mmol/1, p<0.05). During the first six months, HbA₁ fell on CSII therapy (from 10.6±0.4 to 9.7±0.3%, p<0.001), whereas no change occurred during CIT. After the crossover, HbA₁ decreased again on CSII (p<0.05), but rose in patients shifted from CSII to CIT (p<0.05). The fall in glycosylated haemoglobin during CSII correlated with the initial HbA₁ level (r=0.54, p<0.001). Ketoacidosis was more common during CSII (16 vs. 2 verified episodes). Hypoglycaemia occurred infrequently, without difference between CSII and CIT. Fifty-six per cent of the patients preferred CSII after the study. In conclusion, while CSII slightly improves the metabolic control, the improvement in the unselected study population is less than previously reported among highly selected patients.     

Plasma Neurotransmitters Throughout an Oral Glucose Tolerance Test in Non-Depressed Essential Hypertension Patients

The oral glucose tolerance test (OGTT) with plasma neurotransmitter assays and blood pressure measurements were performed on 68 hypertensive (A and B) and 68 paired normal controls (group C). Those patients who failed to show significant or persistent blood pressure reductions throughout OGTT constitute group A (37 subjects); and those who did show significant and persistent reductions constitute group B (31 subjects). The purpose of this study was to assess if there were any significant differences between those patients whose blood pressure levels normalized throughout OGTT and those who didn't and, further, compare them to their controls. In group A, noradrenaline (NA) was high at the O' (fasting) period, increasing further at 60' and 90'; however, circulating serotonin (p5HT) did not vary throughout OGTT. Group B, although showing high NA at O', did not show rises afterwards; whereas, significant and sustained p5HT rises registered throughout postprandial periods. In group C, both p5HT.     

Effect of Sulfonylurea on Glucose,Insulin and C-peptide Responses to a Meal Stimulus in a Patient with Type 2 Diabetes and Liver Disease

ABSTRACT The influence of two sulfonylureas on blood glucose and plasma immunoreactive insulin (IRI) and C-peptide responses to a standardized meal was investigated in a patient with type 2 diabetes and a liver disease with enhanced peripheral levels of liver enzymes. The very high fasting values of plasma IRI and C-peptide were further elevated by the meal. This response to the meal was markedly enhanced by both sulfonylureas, glipizide and glibenclamide. The blood glucose increment after the meal was diminished by sulfonyl-ureas. Sulfonylureas thus seem to have beneficial effects in this diabetic patient, who had a liver disease and markedly elevated basal levels of plasma IRI and C-peptide concentrations.     

Effect of Dietary Fibre on Blood Glucose,Plasma Immunoreactive Insulin,C-peptide and GIP Responses in non Insulin Dependent (Type 2) Diabetics and Controls

ABSTRACT A high fibre and a low fibre breakfast meal were given to eight non insulin dependent diabetics (NIDD), and eight controls. Blood glucose response was monitored continuously for three hours and characterized using a straight line model. After the high fibre meal the rates of increase and decrease in blood glucose concentration were slower both in diabetics and controls than after the low fibre meal. The delay time, however, i.e. the time from meal intake to the start of glucose increase, hypothetically corresponding to gastric emptying time, was the same after both test meals. The postprandial glucose increment calculated as the area under the 0–120 min curve was lower after the high fibre meal in the NIDD, but not in the controls. The two-hour C-peptide and gastric inhibitory polypeptide values were lower for the diabetics after the high fibre breakfast. The results indicate a prolonged carbohydrate digestion and/or absorption after high fibre breakfast.     

Overnight versus 24 Hours of Continuous Subcutaneous Insulin Infusion as Supplement to Oral Antidiabetic Drugs in Type 2 Diabetes

Background

Basal continuous subcutaneous insulin infusion (CSII) therapy at a fixed rate may effectively improve glycemic control in patients with type 2 diabetes when oral antidiabetic treatment fails. Regimens of simple constant subcutaneous delivery of insulin may provide theoretical advantages in type 2 diabetes.

Methods

Ten subjects with type 2 diabetes who obtained insufficient glycemic control on oral antidiabetic drugs were included. Following an initial control day, two periods of 3 days with CSII of a rapid-acting insulin analogue, 1.5 IU/h (dose obtained from a preceding study), for 8 hours overnight and for 24 hours, respectively, were carried out in random order. Profiles of serum insulin aspart, serum endogenous insulin, and plasma glucose were recorded.

Results

Compared to the control day, an 8-hour overnight insulin infusion during a 3-day period improved fasting plasma glucose (FPG) (mean differences ± SEM; Δ59.0 ± 10.1 mg/dl; p < 0.01) and 2-hour postprandial plasma glucose (PPPG) (Δ57.8 ± 10.6 mg/dl; p < 0.01) after breakfast. Compared to an 8-hour overnight infusion, a 24-hour infusion further improved all three PPPG values after breakfast, lunch, and dinner (Δ28.8 ± 8.1 mg/dl, Δ30.6 ± 8.1 mg/dl, and Δ35.1 ± 7.9 mg/dl; p < 0.01). During insulin infusion, only one hypoglycemic episode with PG <55.8 mg/dl and mild symptoms was recorded.

Conclusion

Continuous subcutaneous insulin infusion with a rapid-acting insulin analogue at a fixed rate of 1.5 IU/h, either overnight or for 24 hours, improved glycemic control without safety concerns in patients with type 2 diabetes who had secondary failure to oral antidiabetic drugs. The effect on FPG was similar for both treatments, whereas the effect on PPPG was superior when insulin was infused during the entire 24 hours.     

A Single-blind,Placebo-controlled,Dose-ranging Trial of Oral Hepatic-directed Vesicle Insulin Add-on to Oral Antidiabetic Treatment in Patients With Type 2 Diabetes Mellitus

The dose response of postprandial plasma glucose (PPG) to add-on, premeal oral hepatic-directed vesicle-insulin (HDV-I), an investigational lipid bio-nanoparticle hepatocyte-targeted insulin delivery system, was evaluated in a 3-test-meal/day model in type 2 diabetes patients. The single-blind, placebo-controlled, dose-escalating trial enrolled 6 patients with HbA_1c 8.6 ± 2.0% (70.0 ± 21.9 mmol/mol) and on stable metformin therapy. Patients received oral HDV-I capsules daily 30 minutes before breakfast, lunch, and dinner as follows: placebo capsules, 0.05, 0.1, 0.2, and 0.4 U/kg on days 1, 2, 3, 4, and 5, respectively. Outcome measures were PPG and incremental PPG area under the concentration-time curve (AUC). All 4 doses of oral HDV-I statistically significantly lowered mean PPG (P ≤ .0110 each) and incremental PPG (P ≤ .0352 each) AUC compared to placebo. A linear dose response was not observed. The 0.05 U/kg dose was the minimum effective dose in the dosage range studied. Three adverse events unrelated to treatment were observed. Add-on oral HDV-I 0.05-0.4 U/kg significantly lowered PPG excursions and the dose response curve was flat. These results are consistent with the lack of a linear dose response between portal and systemic plasma insulin concentrations in previous animal and human studies. Oral HDV-I was safe and well tolerated.     

A Pilot Study of Flat and Circadian Insulin Infusion Rates in Continuous Subcutaneous Insulin Infusion (CSII) in Adults with Type 1 Diabetes (FIRST1D)

Background:Initiation of continuous subcutaneous insulin therapy (CSII) in type 1 diabetes requires conversion of a basal insulin dose into a continuous infusion regimen. There are limited data to guide the optimal insulin profile to rapidly achieve target glucose and minimize healthcare professional input. The aim of this pilot study was to compare circadian and flat insulin infusion rates in CSII naïve adults with type 1 diabetes.Methods:Adults with type 1 diabetes commencing CSII were recruited. Participants were randomized to circadian or flat basal profile calculated from the total daily dose. Basal rate testing was undertaken on days 7, 14 and 28 and basal rates were adjusted. The primary outcome was the between-group difference in absolute change in insulin basal rate over 24 hours following three rounds of basal testing. Secondary outcomes included the number of basal rate changes and the time blocks.Results:Seventeen participants (mean age 33.3 (SD 8.6) years) were recruited. There was no significant difference in absolute change in insulin basal rates between groups (P = .85). The circadian group experienced significant variation in the number of changes made with the most changes in the morning and evening (P = .005). The circadian group received a greater reduction in total insulin (−14.1 (interquartile range (IQR) −22.5-12.95) units) than the flat group (−7.48 (IQR −11.90-1.23) units) (P = .021).Conclusion:The initial insulin profile does not impact on the magnitude of basal rate changes during optimization. The circadian profile requires changes at specific time points. Further development of the circadian profile may be the optimal strategy.     

Continuous Glucose Monitoring during Exercise in Patients with Type 1 Diabetes on Continuous Subcutaneous Insulin Infusion

Aim

Exercise is associated with an increased risk of hypoglycemic or hyperglycemic events. The aim of this study was to assess glucose changes during and after physical exercise in patients with type 1 diabetes managed by continuous subcutaneous insulin infusion before and after a 14-day moderate or intense exercise program.

Methods

Sixteen male patients [hemoglobin A1c 7.3 ± 0.8% (mean ± standard deviation), age 39 ± 11 years, body mass index 26.0 ± 2.7 kg/m²] were enrolled in this single-center, randomized, open-label study. They underwent exercise challenges before and after a 14-day moderate (group A, n = 8) and intense (group B) exercise program. Changes in glucose levels were monitored continuously by means of a microdialysis technique.

Results

Patients in group A trained less intensively than the patients in group B. The treadmill exercise led to a comparable level of challenge in both patient groups. Neither heart rate nor energy consumption differed within the groups or between the groups. Patients in both groups had a comparable basal insulin infusion rate. Prandial insulin doses were higher pretraining than posttraining in both groups. Identical amounts of additional carbohydrates were consumed by the patients in both groups during the 21 h after the exercise challenge. Glucose profiles recorded showed a wide variability. No differences in the glucose profiles with respect to the training intensity could be observed within and between the groups. Patients in group A tended to spend a shorter period of time in hypoglycemia after the exercise challenge posttraining compared to pretraining, but not the patients in group B. The number of hypoglycemic episodes was not different between the groups.

Conclusions

The patients with type 1 diabetes exhibit the expected wide variability in glucose profiles before, during, and after physical exercise. Use of continuous glucose monitoring allows handling of this situation without running into the risk of acute metabolic deteriorations.     

Basal Insulin Requirements on Continuous Subcutaneous Insulin Infusion During the First 12 Months After Diagnosis of Type 1 Diabetes Mellitus

Introduction

While the endogenous first-phase insulin response has disappeared by the time of diagnosis of type 1 diabetes mellitus (T1DM), anecdotal evidence suggests that these patients can continue to have a second-phase insulin response during the first 12 months after diagnosis. We hypothesized that patients who are started on continuous subcutaneous insulin infusion (CSII) at the time of diagnosis of T1DM would have a lower basal insulin requirement than the 40-60% usually expected.

Methods

We analyzed 38 patients with T1DM, age 9.9 ± 6.4 years, 71% male, who were started on CSII within the first month of diagnosis.

Results

Average basal insulin requirements were 47–49% of total daily dose during the first 12 months after diagnosis and decreased from 0.30 U/kg/day at diagnosis to 0.20 U/kg/day by 12 months. Baseline percentage of basal insulin was significantly correlated with hemoglobin A1c at baseline and at six months. The percentage of basal insulin requirement at 12 months after diagnosis was significantly correlated with baseline body mass index (BMI) and current BMI. No other correlations between percentage of basal insulin requirements and any other factors were seen.

Conclusion

Our data suggest that, even though some endogenous insulin production remains during the first year after diagnosis of T1DM, the distribution of basal versus total daily insulin requirements remains the same as in the general population of people with diabetes. There may be benefits to starting patients on a higher basal rate at time of diagnosis for overall glycemic control during the first six months. Further research is needed to optimize starting insulin doses to maximize their potential in preserving beta-cell function.     

The Benefits of Continuous Glucose Monitoring and a Glucose Monitoring Schedule in Individuals with Type 1 Diabetes during Recreational Diving

Background

Our objective is to evaluate the Medtronic CGMS^® continuous glucose monitoring system and plasma glucose (PG) measurement performed in a monitoring schedule as tools to identify individuals with type 1 diabetes at risk when diving.

Methods

We studied 24 adults, 12 type 1 diabetes subjects and 12 controls, during 5 recreational scuba dives performed on 3 consecutive days. The CGMS was used by all participants on all the days and all the dives. Comparisons were made between PG performed in a monitoring schedule during the days of diving, self-monitored blood glucose (SMBG) performed 2 weeks prior to diving, and the CGMS during the study.

Results

One hundred seventeen dives were performed. Hypoglycemia (<70 mg/dl) was found in six individuals and on nine occasions. However, no symptoms of hypoglycemia were present during or immediately postdiving. In one case, repetitive hypoglycemia prediving gave rise to a decision not to dive. None of the dives were aborted. The number of hypoglycemic episodes, 10 min prediving or immediately postdiving, were related to the duration of diabetes, r = 0.83 and p =0.01, and the percentage of SMBG values below target (<72 mg/dl), r = 0.65 and p =0.02. Moreover, the number of hypoglycemic episodes was also related to the total duration below low limit (<70 mg/dl), measured by the CGMS, r =0.74 and p =0.006.

Conclusion

Safe dives are possible to achieve by well-informed, well-controlled individuals with type 1 diabetes. Using downloaded SMBG, CGMS, and repetitive PG in a monitoring schedule, it is possible to identify those subjects who are suitable for diving.     

Use of Continuous Glucose Monitoring to Estimate Insulin Requirements in Patients with Type 1 Diabetes Mellitus During a Short Course of Prednisone

Background

Insulin requirements to maintain normoglycemia during glucocorticoid therapy and stress are often difficult to estimate. To simulate insulin resistance during stress, adults with type 1 diabetes mellitus (T1DM) were given a three-day course of prednisone.

Methods

Ten patients (7 women, 3 men) using continuous subcutaneous insulin infusion pumps wore the Medtronic Minimed CGMS^® (Northridge, CA) device. Mean (standard deviation) age was 43.1 (14.9) years, body mass index 23.9 (4.7) kg/m², hemoglobin A1c 6.8% (1.2%), and duration of diabetes 18.7 (10.8) years. Each patient wore the CGMS for one baseline day (day 1), followed by three days of self-administered prednisone (60 mg/dl; days 2–4), and one post-prednisone day (day 5).

Results

Analysis using Wilcoxon signed rank test (values are median [25th percentile, 75th percentile]) indicated a significant difference between day 1 and the mean of days on prednisone (days 2–4) for average glucose level (110.0 [81.0, 158.0] mg/dl vs 149.2 [137.7, 168.0] mg/dl; p = .022), area under the glucose curve and above the upper limit of 180 mg/dl per day (0.5 [0, 8.0] mg/dl·d vs 14.0 [7.7, 24.7] mg/dl·d; p = .002), and total daily insulin dose (TDI) , (0.5 [0.4, 0.6] U/kg·d vs 0.9 [0.8, 1.0] U/kg·d; p = .002). In addition, the TDI was significantly different for day 1 vs day 5 (0.5 [0.4, 0.6] U/kg·d vs 0.6 [0.5, 0.8] U/kg·d; p = .002). Basal rates and insulin boluses were increased by an average of 69% (range: 30–100%) six hours after the first prednisone dose and returned to baseline amounts on the evening of day 4.

Conclusions

For adults with T1DM, insulin requirements during prednisone induced insulin resistance may need to be increased by 70% or more to normalize blood glucose levels.     

Nonlinear Metabolic Effect of Insulin across the Blood Glucose Range in Patients with Type 1 Diabetes Mellitus

Background

For insulin therapy to successfully maintain blood glucose (BG) levels of patients with type 1 diabetes mellitus (T1DM) in normoglycemia, it is necessary to understand if the metabolic effect of insulin across the BG range is linear or not.

Methods

We assess the ability of insulin to lower BG in patients with T1DM in hypoglycemia and hyperglycemia. The net metabolic effect of insulin, defined as the total effect resulting from both reduced endogenous glucose production and increased glucose uptake, was used to define the insulin effectiveness (IE), a measure that indicates the amplitude of glucose lowering that a unit of active insulin can achieve at a given BG level. The IE was assessed in hypoglycemia and hyperglycemia through two separate studies. In the first study, patients were subjected to a hyperinsulinemic euglycemic and hypoglycemic glucose clamp. In the second study, another group of patients were clamped at a hyperglycemic level.

Results

The IE increased by 75% when BG dropped from 90 to 50 mg/dl at a steady rate of 1 mg/dl/min and decreased by 10% when BG was increased from 100 to 200 mg/dl.

Conclusions

The net metabolic effect of insulin is nonlinear across the BG range and is amplified in hypoglycemia and dampened in hyperglycemia. Most importantly, the BG lowering per unit of insulin is accelerated when falling into hypoglycemia. The understanding of the accelerated risk for hypoglycemia with falling glucose levels will help the design of more robust hypoglycemia prevention and detection systems.     

Nocturnal Blood Glucose Profiles in Patients with Type 1 Diabetes Mellitus on Multiple (≥4) Daily Insulin Injection Regimens

The aim of the study was to examine nocturnal blood glucose profiles in Type 1 diabetic patients on multiple (⩾4) daily insulin injections. Nocturnal blood glucose profiles were evaluated in 31 patients collecting blood samples half-hourly from 23.00 till 07.30 h, while they were asleep. Nocturnal episodes of hypoglycaemia (blood glucose <3.0 mmol l⁻¹) occurred in 29 % of these nights; 67 % of episodes were asymptomatic. In the early night (23.00–01.00 h), five episodes occurred with a median duration of 1 h. In the early morning (04.00–07.30 h) seven episodes occurred with a median duration of 3 h. No hypoglycaemia was noted from 01.00 to 04.00 h. Bedtime glucose levels appeared to predict ‘early night’ hypoglycaemia but not ‘early morning’ hypoglycaemia. Fasting glucose levels <5.5 mmol l⁻¹ were indicative of preceding ‘early morning’ hypoglycaemia. There was a large intra-individual variation in nocturnal blood glucose profiles. It is concluded that daily monitoring of bedtime and fasting blood glucose levels may be both more reliable and convenient for the prevention of nocturnal hypoglycaemia than periodic testing of blood glucose at 03.00h as is often advised. Setting a target of >5.5 mmol l⁻¹ for fasting blood glucose may decrease the frequency of nocturnal hypoglycaemia.     

Use of Personal Continuous Glucose Monitoring Device Is Associated With Reduced Risk of Hypoglycemia in a 16-Week Clinical Trial of People With Type 1 Diabetes Using Continuous Subcutaneous Insulin Infusion

Aims:Continuous glucose monitoring (CGM) has the potential to promote diabetes self-management at home with a better glycemic control as outcome. Investigation of the effect of CGM has typically been carried out based on randomized controlled trials with prespecified CGM devices on CGM-naïve participants. The aim of this study was to investigate the effect on glycemic control in people using their personal CGM before and during the trial.Materials and Methods:Data from the Onset 5 trial of 472 people with type 1 diabetes using either their personal CGM (n = 117) or no CGM (n = 355) and continuous subcutaneous insulin infusion in a 16-week treatment period were extracted. Change from baseline in glycated hemoglobin A1c (HbA_1c), number of hypoglycemic episodes, and CGM metrics at the end of treatment were analyzed with analysis of variance repeated-measures models.Results:Use of personal CGM compared with no CGM was associated with a reduction in risk of documented symptomatic hypoglycemia (event rate ratio: 0.82; 95% CI: 0.69-0.97) and asymptomatic hypoglycemia (event rate ratio: 0.72; 95% CI: 0.53-0.97), reduced time spent in hypoglycemia (P = .0070), and less glycemic variability (P = .0043) without a statistically significant increase in HbA_1c (P = .2028).Conclusions:Results indicate that use of personal CGM compared with no CGM in a population of type 1 diabetes is associated with a safer glycemic control without a statistically significantly deteriorated effect on HbA_1c, which adds to the evidence about the real-world use of CGM, where device type is not prespecified, and users are not CGM naïve.