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To evaluate risk factors for severe hypoglycaemia (SH) in patients with type 1 diabetes (T1DM).Retrospective observational and comparative study. All SH occurring between 2007 and 2014 in a German population (Lippe-Detmold) were captured. Characteristics of patients with T1DM and SH were compared with a control group being equivalent concerning age, diabetes duration, HbA1c, comorbidity, and β-blocker treatment. SH was defined as a symptomatic event requiring treatment with intravenous glucose or glucagon administration and being confirmed by a blood glucose measurement of

Aims To determine the influence of daytime, weekdays and seasons on the frequency of severe hypoglycemia (SH) in a German population. Methods Prospective population-based observational study capturing all episodes of SH between 2007 and 2014 in the Lippe-Detmold area. SH was defined as a symptomatic event requiring treatment with intravenous glucose or administration of glucagon and being confirmed by a blood glucose measurement of Results A total of 1080 episodes of SH in 747 patients were registered. 37.5% of cases (405/1080) were related to T1DM, 51.9% (561/1080) to T2DM, 3.2% (35/1080) to pancreatic diabetes and 7.3% (79/1080) to non-diabetic individuals. In cases with T1DM we observed a significantly higher event rate of SH at weekends versus the rest of the week: 2.87 events/weekend-hour versus 2.15 events/weekday-hour ( p =0.004), especially on Saturdays. We found significantly increased incidences of SH in spring (31.2%) and summer (26.7%) versus autumn (20.3%) and winter (21.8%). There were no corresponding significant seasonal variations of HbA1c and insulin doses. The seasonal distribution of SH in subjects with T2DM was balanced with no peak incidence at weekends. Conclusions For the risk of SH, time factors appear to contribute more substantially in individuals with T1DM than in patients with T2DM. The enhanced frequency of SH in patients with T1DM at weekends and in warm seasons was probably caused by short-term changes in behavior. Intensification of diabetes care and education with better adjustment of insulin doses in these susceptible periods could be an appropriate approach to prevent SH.

Diabet. Med. 29, 1268–1271 (2012) Abstract Objective To assess the number and sex ratio of children in individuals with Type 1 diabetes mellitus and the influence of parental diabetes on age at onset of Type 1 diabetes in our cohort. Methods In a cross-sectional study in a German region comprising 350 000 inhabitants, 697 subjects with Type 1 diabetes (364 women, 333 men) underwent a standardized assessment regarding the number and sex of their children and the family history of diabetes. Results Compared with 1.36 children per woman in the German background population, the total fertility rate in the calendar year of 2010 in our female cohort with Type 1 diabetes (age 18–49 years) was 0.88. Men with Type 1 diabetes had a fertility rate of 0.65. More men (51.1%) than women (35.7%; P

Severe hypoglycaemia (SH) induced by sulfonylureas is a life-threatening condition. We hypothesized that recently identified polymorphisms associated with insulin secretion in GCKR, GIPR, ADCY5 and VPS13C genes affect the response to sulfonylureas in patients with type 2 diabetes (T2D) and so, result in reduced risk for SH.We assessed the prevalence of GCKR, GIPR, ADCY5 and VPS13C polymorphisms in a case-control study including 111 patients with SH and 100 patients with T2D but without a history of SH. All patients were treated with the sulfonylurea drugs glimepiride, glibenclamide or gliquidon. SH was defined as a symptomatic event with blood glucose of50 mg/dl requiring treatment with intravenous glucose.In logistic regression analyses, a low HbA(1c) and a higher sulfonylurea dose appeared to be the only predictors of SH (P=0.001 and P=0.04, respectively). There was no significant difference in the genotype distribution between the control group and the cases with SH for any of the investigated polymorphisms (OR and 95% confidence intervals - 0.90 (0.59-1.38) for GCKR; 1.11 (0.67-1.85) for GIPR; 0.75 (0.48-1.17) for ADCY5; 1.43 (0.95-2.15) for VPS13C; all P-values0.05). Also, there was no significant effect of the examined genetic variants on HbA1c levels (all P-values0.05 adjusted for age, sex, BMI, diabetes duration, sulfonylurea dose).We found no detectable effect (with an OR2.1) of the variants in GCKR, GIPR, ADCY5 and VPS13C on the response to sulfonylurea treatment, indicating that these variants are not significantly contributing to the risk of SH in patients with T2D.

OBJECTIVE To compare the incidences of severe hypoglycemia and corresponding clinical circumstances in a German population between 2007–2010 and 1997–2000. RESEARCH DESIGN AND METHODS A screening for severe hypoglycemia was performed in the Lippe-Detmold area in Germany to sensitively detect severe hypoglycemia. This was defined as a symptomatic event requiring treatment with intravenous glucose and being confirmed by a blood glucose measurement of RESULTS Severe hypoglycemia increased considerably from 264 events in 1997–2000 to 495 events in 2007–2010, which translated into an increase in frequency of severe hypoglycemia among all emergency admissions from 0.68 to 0.83% (P = 0.015). This was mostly related to intensification of antihyperglycemic therapy, particularly in the increasingly morbid group of hypoglycemic patients with type 2 diabetes indicated by lower HbA1c, more comedication (3.3 vs. 7.7 drugs), and more concomitant diseases (3.6 vs. 4.4) (all P values CONCLUSIONS Within a 10-year period, there was an intensification of antihyperglycemic therapy in increasingly comorbid subjects, leading to a considerably higher incidence of severe hypoglycemia.

The established risk factors for severe sulfonylurea-induced hypoglycemia (SH) include low hemoglobin (Hb)A(1c), advanced age, long duration of diabetes, multimorbidity, and polypharmacy. As the genetically polymorphic cytochrome P450 (CYP), enzyme CYP2C9 is mainly responsible for the hepatic metabolism of sulfonylureas (SUs), we hypothesized that the slow-metabolizer genotypes *2/*2, *2/*3, and *3/*3 might be overrepresented in type 2 diabetic patients with SH.In a prospective population-based case-control study, CYP2C9 allelic variants of 102 diabetic patients with SH were compared with a matched group of 101 SU-treated patients without a history of SH. The 203 Caucasian patients had been treated with the SUs glimepiride, glibenclamide, or gliquidone. SH was defined as a symptomatic event requiring treatment with intravenously administered glucose and was confirmed by a blood glucose measurement of50 mg/dl (2.8 mmol/l). As two control groups, we selected 337 Caucasian diabetic patients receiving antidiabetic drugs per os and 1,988 healthy Caucasian volunteers who had been genotyped earlier.In the univariate analysis, only a low HbA(1c) value (p = 0.0004) was shown as a risk factor for SH. There was no overrepresentation of the CYP2C9 *2/*2, *2/*3, and *3/*3 variants in the SH group (2%) compared with the control group (5%). However, in the control group, patients with CYP2C9 genotypes, predicting slower metabolism of SU drugs, were treated with significantly lower doses (p = 0.027) than were extensive metabolizers, whereas in the patient group with severe hypoglycemia, the dose was the same for all genotype groups.In the present cohort of 102 patients with SH, a low HbA(1c) value was related to the risk for SH. There was no overrepresentation observed of the CYP2C9 slow-metabolizer genotypes in the hypoglycemic patients group, but the drug exposure in the slow-metabolizer genotypes was estimated to be higher in hypoglycemic patients, which might partly have contributed to their risk for SH.

To assess the number and sex ratio of children in individuals with Type 1 diabetes mellitus and the influence of parental diabetes on age at onset of Type 1 diabetes in our cohort.In a cross-sectional study in a German region comprising 350,000 inhabitants, 697 subjects with Type 1 diabetes (364 women, 333 men) underwent a standardized assessment regarding the number and sex of their children and the family history of diabetes.Compared with 1.36 children per woman in the German background population, the total fertility rate in the calendar year of 2010 in our female cohort with Type 1 diabetes (age 18-49 years) was 0.88. Men with Type 1 diabetes had a fertility rate of 0.65. More men (51.1%) than women (35.7%; P0.0001) were childless. Twenty per cent of all women aged 41-45 years in the background population were childless compared with 36.2% of all women and 52% of all men in this specific age group from our cohort. The sex ratio of female vs. male offspring of individuals with Type 1 diabetes did not differ significantly from the expected 1:1 ratio. Maternal Type 1 or Type 2 diabetes increased the age at onset of Type 1 diabetes from 22.9 ± 13.7 (no maternal diabetes) to 28.6 ± 16.8 and 30.1 ± 15.1 years (p0.0001), respectively.Compared with the German reference population, individuals with Type 1 diabetes had significantly fewer children and were more often childless. The sex ratio female vs. male offspring of women and men with Type 1 diabetes was unaffected. Maternal history of Type 1 and Type 2 diabetes was associated with a significant later onset of Type 1 diabetes.

A letter in response to: Sato R, Watanabe H, Genma R et al. ABCC8 polymorphism (Ser1369Ala): influence on severe hypoglycemia due to sulfonylureas. Pharmacogenomics 11(12), 1743–1750 (2010).