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Fear of hypoglycaemia in adults with Type 1 diabetes

Diabet. Med. 27, 1151–1158 (2010)

Day-to-day variation of insulin sensitivity in patients with type 1 diabetes: role of gender and menstrual cycle.

The aim of the present study was to compare the day‐to‐day variations of the insulin sensitivity in male and female Type 1 diabetic patients and to assess the insulin sensitivity in the follicular and luteal phases of the menstrual cycle. Ten male and 20 female Type 1 diabetic patients participated in the study. The insulin sensitivity was assessed by the insulin (0.4 mU kg−1min−1)‐glucose/(4.5 mg kg−1min−1)‐infusion test (IGIT). In 5 of the female patients, a simultaneous i.v. influsion of somatostatin (100 μgh−1) was given (SIGIT). Each patient was studied twice, with 2 weeks separating the two tests. The day‐to‐day variations of the insulin sensitivity were almost identical in the male and female patients, the coefficients of variation being 13% in both groups. In 15 of the female patients, ovulation occurred. In these women, the mean blood‐glucose levels between 120 and 240 min after the onset of the IGIT/SIGIT were 9.8 ± 1.1 mmol l−1 in the follicular phase and 10.3 ± 1.0 mmol l−1 in the luteal phase, n.s. (95% confidence interval for the difference (luteal‐follicular) −0.8–1.9 mmol l−1). Although the present study cannot exclude minor changes of insulin sensitivity during the menstrual cycle, our results suggest that the changes of the metabolic control during the menstrual cycle, experienced by many women with Type 1 diabetes, are largely attributable to mechanisms other than variations of insulin sensitivity.

A repeated cross-sectional survey of severe hypoglycaemia in 178 Type 1 diabetes mellitus patients performed in 1984 and 1998.

Aims To study the prevalence of severe hypoglycaemia (SH) in relation to risk factors in Type 1 diabetic (T1 DM) patients over a period of 14 years.

The role of sulphonylurea in combination therapy assessed in a trial of sulphonylurea withdrawal

Aims To evaluate the effect of adding insulin to sulphonylurea (SU) and the effect of SU withdrawal on glycaemic control in Type 2 diabetic patients who failed on treatment with SU alone.

Glycaemic responsiveness to long-term insulin plus sulphonylurea therapy as assessed by sulphonylurea withdrawal.

Aims  To assess the effect of sulphonylurea (SU) in patients with Type 2 diabetes undergoing long‐term combination therapy with insulin, by withdrawal of SU, and to identify clinically useful markers of long‐term response.

Decreasing postprandial C-peptide levels over time are not associated with long-term use of sulphonylurea: An observational study

AIM The present study aimed to describe changes over 10 years in HbA(1c) and beta-cell function, as assessed by postprandial C-peptide (PP-CPT) and C-peptide/glucose (PP-CPT/glucose) ratio, and to investigate whether treatment with sulphonylurea (SU) exerts a deleterious effect on beta-cell function. METHODS During 1997-1998, HbA(1c), PP-CPT and PP glucose were measured in 462 patients. Ten years later, 171 of the 341 patients who were still alive were followed-up. RESULTS HbA(1c) decreased from 7.41 to 6.96% (P=0.002) as treatments were intensified. There was a decrease in both PP-CPT (P<0.001) and PP-CPT/glucose ratio (P=0.063). A multivariable-regression model was used to evaluate the effects on beta-cell function changes, using the following variables as effect modifiers: gender; age; BMI; diabetes duration; baseline PP-CPT/glucose ratio; HbA(1c); GAD-antibody class; and SU treatment (continuously, periodically, never). Baseline PP-CPT/glucose ratio was the most important variable (R(2)=45%; P<0.001) for explaining variations in beta-cell function. An increase in HbA(1c) was associated with a decrease in beta-cell function, and beta-cell function remained unchanged if glycaemic control was improved. Long-term treatment with SU had no effect on long-term changes in beta-cell function (R(2)=0.1%; P=0.894). CONCLUSION Both HbA(1c) and beta-cell function decreased over 10 years with SU treatment, but such treatment was not associated with a pronounced decline in beta-cell function. These results, however, need to be interpreted with caution, as this was an observational study. Nevertheless, the present study findings do not support the notion that SU, as used in clinical practice, is harmful to beta-cell function.

Effects of C-peptide on insulin-induced hypoglycaemia and its counterregulatory responses in IDDM patients

Recent studies indicate that C‐peptide, when given to patients with insulin‐dependent (Type 1) diabetes mellitus (IDDM), exerts significant effects on microvascular and neuronal functions. Adjuvant therapy with C‐peptide has been advocated in the treatment of IDDM patients. Since endogenous insulin secretion is believed to be of importance for the alpha‐cell function, we addressed the issue whether C‐peptide given acutely interferes with the responses to hypoglycaemia. Seven IDDM patients were randomly exposed to hypoglycaemia with and without exogenous C‐peptide. Insulin and and C‐peptide were given intravenously in equimolar amounts for 3 hours. The decrease of blood glucose was faster and more pronounced during C‐peptide infusion, yielding a significantly lower AUC 0–180 min of blood glucose (38.5 ± 1.6 vs 44.4 ± 2.2 mmol l−1 h−1 ; p  = 0.032). No difference between the two experiments was found concerning glucagon when the AUC, Δ‐values or levels at separate points of time were calculated. In conclusion, the main finding of this study was that exogenous C‐peptide, given acutely, gave rise to a more rapid onset of hypoglycaemia yielding no detectable differences with respect to the response of glucagon and other counterregulatory hormones.

Experience of long-term intraperitoneal insulin treatment using a new percutaneous access device

A pilot study was conducted to determine the efficacy of a new percutaneous device, designed to help to deliver insulin from an external, multiprogrammable pump to the abdominal cavity in patients with Type 1 (insulin‐dependent) diabetes. Six patients received intraperitoneal insulin therapy for 15–24 months, a total experience of 9.4 patient‐years. Glycosylated haemoglobin stabilized at 7.6 ± 0.7 % with no change in insulin dose. Four patients had to submit to reimplantation after 30 to 60 weeks. One patient met with inconvenient location of the device and three had blockage of the system. In four patients treatment had to be interrupted due to blockage of the intraperitoneal catheter by omental‐tissue encapsulation. In two of those patients this blockage was combined with deeper infections. In another patient treatment had to be interrupted due to chronic, local, subcutaneous infection.

Adding glimepiride to insulin + metformin in type 2 diabetes of more than 10 years’ duration—A randomised, double-blind, placebo-controlled, cross-over study

AIMS To investigate the effect on glycaemic control of adding glimepiride to on-going treatment with metformin and insulin in patients with known diabetes more than 10 years. METHODS Glimepiride 4 mg or placebo was added in randomised order for three months with a washout period of 6 weeks. All insulin regimens were allowed. Insulin doses were reduced if considered necessary. Continuous glucose monitoring was performed at the end of each period. RESULTS Forty-three patients, median age 66 years (46-74), diabetes duration 16 (10-30), BMI 30 kg/m(2) (25-37) and mean HbA1c 7.1% NGSP, (64 mmol/mol IFCC) were randomised. With placebo there was no change in HbA1c while a decrease of 0.6%, (7 mmol/mol IFCC) (P < 0.001), was observed with glimepiride even though insulin doses had to be reduced in 23 patients (median change 29%, range 2-100%). Minor hypoglycaemia was reported but no severe hypoglycaemic event was observed. The ratio between C-peptide/glucose increased significantly (P < 0.001) with glimepiride, both fasting and postprandially and, in a stepwise multiple regression analysis of possible predictive factors for response, a more pronounced decrease in HbA1c was associated with the magnitude of the increment in C-peptide/glucose. Older age was associated with a smaller response. Twenty-nine patients (67%) were defined as responders if this was defined as an HbA1c decrease ≥0.5% (5 mmol/mol IFCC) or an insulin dose reduction ≥20%. CONCLUSIONS Even after long duration of diabetes, addition of glimepiride to insulin and metformin can be effective in lowering HbA1c and/or reducing the need for exogenous insulin.

An Analysis of the Glucagon Response to Hypoglycaemia in Patients with Type 1 Diabetes and in Healthy Subjects

The study aimed to analyse the glucagon response during hypoglycaemia in relation to gender, level of hypoglycaemia, and hyperinsulinaemia as well as its relation to other counterregulatory hormones in patients with Type 1 diabetes and in nondiabetic subjects. Mild hypoglycaemia was induced by an i.v. insulin infusion (244 pmol kg−1h−1) for 180 min in 43 Type 1 diabetic patients and 22 nondiabetic subjects. Venous blood glucose, plasma free insulin, glucagon, adrenaline, noradrenaline, growth hormone, and cortisol were measured every 15–30 min. The hormonal responses during hypoglycaemia were evaluated from the incremental areas under their respective curves. There was a linear correlation between the glucagon response and the decremental area of blood glucose (p < 0.005), but the slope of the regression line in the diabetic group was less steep than in the controls (p < 0.5), and, in spite of the deeper hypoglycaemia in the diabetic groups, their glucagon response was diminished (p < 0.05). Plasma, adrenaline, growth hormone and cortisol all increased during hypoglycaemia. The glucagon response correlated with the responses of growth hormone and cortisol in both groups, while it was positively correlated with the adrenaline response (p < 0.001) and inversely with the plasma insulin (p < 0.001) only in the diabetic patients. Although the insulin infusion rate was identical, the female diabetic patients had a lower metabolic clearance rate of insulin as compared with the males (p < 0.05). There was no statistical difference in the counterregulatory hormone responses between males and females in neither of the groups. In conclusion, this study suggests that the glucagon response to hypoglycaemia in Type 1 diabetic patients, may be suppressed by circulating insulin within its therapeutic range, and stimulated by the simultaneously secreted adrenaline. Furthermore, female Type 1 diabetic patients have a lower metabolic clearance rate of insulin than males, yielding a more pronounced hypoglycaemia in response to the same dose of insulin, although this study does not provide evidence of a gender difference in the responsiveness of counterregulatory hormones to hypoglycaemia.