Tumour-induced hypoglycaemia in a patient with insulin-dependent diabetes mellitus

We report on a case of malignant insulinoma occurring in a patient with genuine insulin-dependent diabetes mellitus (IDDM). A review of cases concerning patients with diabetes mellitus and insulinomas is presented, and reveals only patients with non-insulin-dependent diabetes mellitus (NIDDM). Our case appears to be the first in showing the combination of IDDM and a functioning malignant insulinoma.     

Spontaneous hypoglycaemia after pancreas transplantation in Type 1 diabetes mellitus

Hypoglycaemia is an important complication of insulin treatment in Type 1 diabetes mellitus (DM). Pancreas transplantation couples glucose sensing and insulin secretion, attaining a distinctive advantage over insulin treatment. We tested whether successful transplantation can avoid hypoglycaemia in Type 1 DM. Combined kidney and pancreas transplanted Type 1 DM who complied with good function criteria (KP-Tx, n = 55), and isolated kidney or liver transplanted non-diabetic subjects on the same immunosuppressive regimen (CON-Tx, n = 14), underwent 1-day metabolic profiles in the first 3 years after transplantation, sampling plasma glucose (PG) and pancreatic hormones every 2 hours. KP-Tx had lower PG than CON-Tx in the night and in the morning and higher insulin concentrations throughout the day. KP-Tx had lower PG nadirs than CON-Tx (4.40 ± 0.05 vs 4.96 ± 0.16 mmol l⁻¹, ANOVA p = 0.001). Nine per cent of KP-Tx had hypoglycaemic values (PG ≤3.0 mmol l⁻¹) in the profiles, both postprandial and postabsorptive, whereas none of CON-Tx did (p < 0.02). In conclusion, after pancreas transplantation, mild hypoglycaemia is frequent, although its clinical impact is limited. Compared to insulin treatment in Type 1 DM, pancreas transplantation improves but cannot eliminate hypoglycaemia. Copyright © 1998 John Wiley & Sons, Ltd.     

Intranasal glucagon treatment relieves hypoglycaemia in children with Type 1 (insulin-dependent) diabetes mellitus

Summary The aim of the present study was to compare intranasal glucagon with subcutaneous glucagon as a treatment of insulin-induced hypoglycaemia in 11 children, 7–12 years old, with Type 1 (insulin-dependent) diabetes mellitus. Hypoglycaemia (1.6±0.1 vs 1.8±0.2 mmol/l) was induced twice in each child by continuous insulin and variable glucose infusions. One milligram of intranasal glucagon or 0.5 mg of subcutaneous glucagon was given in a randomized order. At 15 min after the administrations of either intranasal or subcutaneous glucagon, the blood glucose concentration increased by 1.5±0.2 mmol/l or 1.7±0.2 mmol/l above the glucose nadir, respectively. After nasal administration, the maximal rise in blood glucose was seen after 25 min. Subcutaneous injections induced higher and more sustained plasma glucagon concentrations but the children suffered more often from nausea than when they were treated intranasally. In conclusion, treatment with intranasal glucagon seems to be efficient and results in a rapid correction of insulin-induced hypoglycaemia with few side-effects.     

Permanent neuropsychological impairment after recurrent episodes of severe hypoglycaemia in man

Summary Seventeen Type 1 (insulin-dependent) diabetic patients with a history of recurrent and severe hypoglycaemia and Type 1 diabetic patients with no severe hypoglycaemia were compared as regarded performances in tests of neuropsychological functioning. To test the hypothesis that recurrent severe hypoglycaemia gives rise to permanent cognitive impairment, the study group was selected among those patients who had met with repeated attacks over the last three years or more as identified by a questionnaire among almost 600 insulin-treated diabetic patients. The comparison group without known severe reactions were comparable to the study group with respect to type of diabetes, sex, age, age at onset, duration of diabetes, socio-economic parameters, and prevalence of neuropathy and retinopathy. The results indicate that Type 1 diabetic patients with recurrent severe hypoglycaemia scored lower than those without severe hypoglycaemia in tests of motor ability, short-term and associative memory and visuospatial tasks assessing ability in general problem-solving. Type 1 diabetic patients with severe hypoglycaemia also displayed a higher frequency of perspective reversals suggesting frontal-lobe involvement. These data can be interpreted in two ways. One interpretation implies that the cognitive impairment of Type 1 diabetic patients with severe hypoglycaemia reflects a selection factor, the other that recurrent episodes of severe hypoglycaemia result in permanent cognitive impairment.     

Nocturnal electroencephalogram registrations in Type 1 (insulin-dependent) diabetic patients with hypoglycaemia

Summary Eight Type 1 (insulin-dependent) diabetic patients with no diabetic complications were studied overnight for two consecutive and one subsequent night with continuous monitoring of electroencephalogram and serial hormone measurements. The aims were: 1) to evaluate the influence of spontaneous and insulin-induced hypoglycaemia on nocturnal electroencephalogram sleep-patterns and, 2) to evaluate counter-regulatory hormone responses. Spontaneous hypoglycaemia occurred on six nights (38%) with blood glucose concentrations <3.0 mmol/l and on four nights <2.0 mmol/l. All the patients experienced insulin-induced hypoglycaemia with a blood glucose nadir of 1.6 (range 1.4–1.9) mmol/l. The electroencephalogram was analysed by a new method developed for this purpose in contrast to the traditional definition of delta-, theta-, alpha- and beta-activity. The blood glucose concentration could be correlated to the rank of individual electroencephalogram-patterns during the whole night, and specific hypoglycaemic amplitude-frequency patterns could be assigned. Three of the eight patients showed electroencephalogram changes at blood glucose levels below 2.0 (1.6–2.0) mmol/l. The electroencephalogram classes representing hypoglycaemic activity had peak frequencies at 4 and 6 Hz, respectively, clearly different from the patients' delta- and theta-activity. The changes were not identical in each patient, however, they were reproducible in each patient. The changes were found equally in all regions of the brain. The three patients with electroencephalogram changes during nocturnal hypoglycaemia could only be separated from the other five patients by their impaired glucagon responses. Against this background the possibility of protection by glucagon, against neurophysiologic changes in the brain during hypoglycaemia may be considered.     

Nocturnal hypoglycaemia in type 1 diabetes--consequences and assessment

Hypoglycaemia is inevitable when striving for low HbA1c values. Nocturnal hypoglycaemia often occurs without symptoms, but results in diminished next day well-being and hypoglycaemia unawareness. Frequency of nocturnal hypoglycaemia was first assessed in research ward settings, but suffered from insufficient glucose sampling frequency. This may have resulted in overestimation of the duration of hypoglycaemic episodes. The advent of the first continuous glucose sensor, the needle-type MedtronicMiniMed Continuous Glucose Measurement System, revolutionized the assessment of glucose values. However, on scrutiny, the first version of this sensor showed a drift into the hypoglycaemic area and delayed recovery from hypoglycaemia. Using the microdialysis-based GlucoDay system, our group reported a lower frequency of nocturnal hypoglycaemia in type 1 diabetes patients using an insulin pump, than that expected from the existing literature. Today, more than 80 years after the introduction of insulin for the treatment of type 1 diabetes, the associated frequency of nocturnal hypoglycaemia still awaits its definitive assessment.     

Acute insulin response to intravenous glucose,glucagon and arginine in some subjects at risk for Type 1 (insulin-dependent) diabetes mellitus

Summary The relationships between first-phase insulin secretion to i.v. glucagon and i.v. arginine were studied in 19 healthy adult volunteers (Group I) and in 21 subjects at risk for Type 1 (insulin-dependent) diabetes mellitus with either a normal (n=11; Group II a) or a low insulin response to i.v. glucose (n=10; Group II b). Groups I and II a displayed similar insulin responses to the three secretagogues. In contrast, Group II b demonstrated lower insulin responses to both glucagon and arginine than control subjects (p}<0.007 and (p}<0.04 respectively) orthan normo-responders to glucose (#x007D;<0.007 and p<0.04 respectively). In Group II b however, arginine-stimulated insulin release was increased compared to the response to glucose (p}<0.006), while glucagon and glucose led to non-statistically different responses. Five low-responders developed Type 1 diabetes. As a group, they displayed lower responses to glucagon and to arginine than subjects who up to now have not developed the disease (p<0.05 and p<0.0003 respectively). In the subjects who progressed to diabetes, the responses to glucose and glucagon were similarly blunted. In the low-responders who have not developed the disease, no statistical difference could be detected between mean responses to glucagon and glucose, but four out of these five subjects had a glucagon-stimulated response within the control range and higher than their corresponding response to glucose. Arginine led to a higher stimulation than glucose, in subgroups that either progressed to diabetes (p<0.006) or did not (p<0.002). Finally, low-responders who did not develop diabetes displayed similar responses to both glucagon and arginine than normo-responders to glucose. A progressive decrease of arginine-stimulated insulin response may be a later event during pre-Type 1 diabetes than a blunted response to glucose, while a loss of glucagon-stimulated insulin release may be intermediate. Diminished response to all secretagogues may offer better prediction than a low response to glucose alone.     

Effect of insulin degludec versus insulin glargine U100 on nocturnal glycaemia assessed by plasma glucose profiles in people with type 1 diabetes prone to nocturnal severe hypoglycaemia

Aim

To compare nocturnal glucose profiles according to hourly plasma glucose measurements during treatment with insulin degludec and insulin glargine U100 in a cohort of people with type 1 diabetes prone to nocturnal severe hypoglycaemia.

Materials and methods

The HypoDeg trial is a 2-year investigator-initiated, randomized, controlled crossover trial in 149 participants randomized to treatment with insulin degludec and insulin glargine U100 for 12 months each. The 51 participants in this predefined substudy stayed at least one night in hospital during each treatment arm for plasma glucose samples to be taken. Endpoints were glucose profiles, including mean plasma glucose, glycaemic variability and risk of hypoglycaemia.

Results

There were no differences between treatments regarding mean plasma glucose. We saw a flatter glucose profile during insulin degludec compared with insulin glargine U100 treatment, which had a nadir at 4:00 AM, with a subsequent rise. During treatment with insulin degludec, the participants had lower glycaemic variability, with an estimated treatment difference of −4.3% (95% confidence interval [CI] −8.1 to −0.5; P < 0.05). Participants treated with insulin degludec were less likely to experience nocturnal hypoglycaemia below 3.0 mmol/L (hazard ratio 0.36 [95% CI 0.17-0.73; P < 0.05]).

Conclusion

Based on nocturnal plasma glucose measurements, treatment with insulin degludec compared with insulin glargine U100 administered in the evening results in lower glycaemic variability and lower risk of nocturnal hypoglycaemia without differences in mean plasma glucose.     

Exercise capacity in subjects with type 1 diabetes mellitus in eu- and hyperglycaemia

BACKGROUND: Circumstantial evidence suggests that an increase in plasma glucose availability improves exercise capacity in subjects with type 1 diabetes mellitus. The aim of this study was to assess exercise capacity in eu- and hyperglycaemic conditions in subjects with type 1 diabetes. METHODS: Eight moderately exercise-trained male subjects with type 1 diabetes on continuous subcutaneous insulin infusion were studied. Using identical insulin infusion rates, the patients were randomly allocated to perform two stepwise ergometer tests in eu- and hyperglycaemic clamp conditions. The primary endpoint was the peak power output; the secondary endpoints comprised the rate of perceived exertion, lactate levels, heart rate, and respiratory exchange ratio. RESULTS: Eu- and hyperglycaemic clamp conditions were observed at a plasma glucose concentration of 5.3 +/- 0.6 mmol/L and 12.4 +/- 2.1 mmol/L, respectively (mean +/- SD), and remained stable throughout the physical exercise. Insulin levels were similar in both conditions. Hyperglycaemia did not result in a significant increase in the peak power output compared to euglycaemia (mean paired difference of 4.96 W, 95% CI - 11.3 to 21.2, p = 0.49). Hyperglycaemia did not have a significant impact on the secondary endpoints compared to euglycaemia. Sensitivity analyses confirmed these results. CONCLUSIONS: In subjects with type 1 diabetes, exercise capacity is not influenced by hyperglycaemia. Comparable levels of lactate and similar respiratory exchange ratio suggest that an increase in extracellular glucose availability did not translate into increased intracellular glucose oxidation.     

Altered islet Beta-cell function before the onset of Type 1 (insulin-dependent) diabetes mellitus

Summary To define the glucose to insulin dose-response relationship before the onset of diabetes, we studied 22 nondiabetic co-twins of patients with Type 1 (insulin-dependent) diabetes mellitus and nine control subjects. All had intravenous glucose tests at 0.02, 0.1 and 0.5 g/kg and were followedup prospectively for at least 6 years. Seven twins developed diabetes a mean of 7 months later; the remaining 15 are now unlikely to develop diabetes. The seven pre-diabetic twins had higher fasting insulin levels than control subjects (4.2±2.0 vs 1.8±1.8 nmol/l; p<0.05); but lower glucose clearance (1.0±0.5 vs 1.9±0.7 %/min; p<0.05), first phase insulin response at 0.5 g/kg (21.1±23.2 vs 143±50 nmol/l; p<0.0001), and total insulin responses at 0.1 g/kg (p<0.05) and 0.5 g/kg (p<0.00005). Using a curve-fitting programme, the normal glucose to insulin relationship was lost in prediabetic twins who had lower coefficient of determination (R²) than control subjects (p<0.01). In contrast, 15 low-risk twins and their nine control subjects had similar fasting glucose and insulin levels, glucose clearance, R² and insulin secretory responses to different glucose loads. The positive predictive values of subnormal R² and subnormal first phase insulin response were 67 % and 58 % respectively. These observations demonstrate an altered glucose to insulin dose-response relationship and loss of maximum insulin secretory response to glucose before the onset of Type 1 diabetes.