The insertion/deletion polymorphism in the angiotensin-converting enzyme gene and hypoglycemia awareness in patients with type 1 diabetes.

Impaired hypoglycemia awareness affects approximately 25% of all patients with type 1 diabetes (T1DM). Duration of diabetes and tight glycemic control represent main risk factors of impaired hypoglycemia awareness. However, even among patients with good glycemic control and longstanding T1DM, awareness of hypoglycemia may be intact. Genetic factors might explain some of this remaining variability. Recently, the insertion/deletion ( I/ D) polymorphism in angiotensin converting enzyme gene ( ACE) was shown to be associated with significantly higher risk of hypoglycemic events in subjects with T1DM. Here, we studied the effects of genetic polymorphisms in the ACE on impaired hypoglycemia awareness in 231 Caucasian T1DM patients. Hypoglycemia awareness status was determined using standardized questionnaires (Clarke et al. and Edinburgh Hypoglycemia Scale). ACE I/ D genotype was determined by PCR amplification of the respective fragments from intron 16 of the ACE and size fractionation (I allele frequency=0.49; P=0.74 for Hardy-Weinberg equilibrium). In the logistic regression analysis, significant risk factors of impaired hypoglycemia awareness were duration of diabetes, C-peptide and HbA (1c) (all P<0.01). However, no significant effect of the I/ D polymorphism on impaired hypoglycemia awareness was observed with and without adjustment for age, diabetes duration, C-peptide and HbA (1c). Even though the study provides a relatively large dataset, it is possible that small differences may have been missed.

Clinical characterisation of severe hypoglycaemia--a prospective population-based study.

AIM: To determine the clinical characteristics of severe hypoglycaemia (SH) in a nonselected German population. SH was defined as an event requiring intravenous glucose or glucagon injection. METHODS: The prospective population-based study screened sensitively for SH in a region with 200,000 inhabitants between 1997 and 2000. All 30,768 patients who presented to the regional central hospital emergency department, and 6,631 (85 %) of 7,804 patients attended by the emergency medical service in the region were given an initial blood glucose test to detect atypical hypoglycaemia. RESULTS: Altogether, 264 cases of SH were registered, which occurred either spontaneously (n = 14; 5 %), in subjects with type 1 (n = 92; 35 %) or type 2 diabetes (n = 148; 56 %), or in subjects with a non-classified form of diabetes (n = 10; 4 %). On the basis of the estimated local number of diabetic patients the annual rate of SH was 1.5 episodes per 100 patients in insulin-treated type 2 diabetics compared with a rate of 0.4 episodes per 100 patients for the overall group of type 2 diabetic patients. Nocturnal hypoglycaemia accounted for 44 % of episodes in patients with type 1 diabetes on intensified therapy but for only 25 % in patients with type 2 diabetes. 26 % of the hypoglycaemic individuals with type 1 diabetes had an impaired awareness of hypoglycaemia and thus recurrent hypoglycaemic episodes. Irrespective of the treatment, the most frequent contributing factors for SH in type 2 diabetic patients were advanced age (76 +/- 12 years), multimorbidity (3.6 +/- 2.6 concomitant diseases)--in particular renal impairment (54 % [80/148])--and polypharmacy (4 +/- 2.7 concomitant drugs). 34 % (50/148) of the subjects with type 2 diabetes lived in nursing homes or were cared for by a home nursing service. With standardised treatment zero mortality of SH in diabetic patients was achieved, only one non-diabetic died due to hepatic failure. CONCLUSION: In elderly, multimorbid patients approaching the insulin-deficient end of the spectrum of type 2 diabetes the risk of developing SH increases considerably, nearing that in patients with type 1 diabetes. In order to avoid SH in geriatric patients, the treatment targets should be defined critically, taking into account individual quality of life and life expectancy. Hypoglycaemia unawareness is a major risk factor for SH in type 1 diabetes.

Lipodystrophy and metabolic disorders as complication of antiretroviral therapy of HIV infection.

Peripheral lipodystrophy, central adiposity, hyperlipidaemia, insulin resistance, and diabetes mellitus, in varying constellations, are frequent complications of highly active antiretroviral therapy in HIV1-infected patients. The pathogenetic significance of protease inhibitors toxicity has been demonstrated by the partial reversal of metabolic disorders after switching to other antiretroviral regimens. The therapeutic and prognostic implications of these metabolic disorders are not yet clear. The dramatic improvements in the prognosis and quality of life of people with HIV since the introduction of highly active antiretroviral therapy call for evidence based concepts for the management of treatment-related metabolic disturbances.

Hormonal counterregulation during severe hypoglycaemia under everyday conditions in patients with type 1 and insulin-treated type 2 diabetes mellitus.

AIM: To determine the counterregulatory hormonal responses to severe hypoglycaemia (SH) in type 1 versus insulin-treated type 2 diabetic patients under everyday conditions. METHODS: Counterregulatory hormones were determined in 28 consecutive type 1 and thirteen insulin-treated type 2 diabetic patients (age 54 +/- 18 vs. 75 +/- 13 yrs; diabetes duration 27 +/- 16 vs. 21 +/- 6 yrs) with SH requiring emergency treatment. Blood samples were taken prior to and after effective treatment of SH. SH was defined as an event with neuroglycopenic presentation requiring external intervention by administration of intravenous glucose or oral carbohydrates. 68 % (19/28) of type 1 diabetic patients but none of those with type 2 diabetes had reduced awareness of hypoglycaemia. RESULTS: Plasma glucose levels were 30 +/- 14 prior to and 179 +/- 82 mg/dl after treatment of SH; the time between the two measurements was 54 +/- 26 minutes. With the exception of higher levels of human growth hormone in type 1 patients - which were attributed to younger age - the other counterregulatory responses to SH showed no significant differences in type 1 vs. type 2 diabetic patients. In both groups glucagon responses were virtually absent while moderate catecholamine responses could be demonstrated. Treatment with beta-blockers did not affect hormonal counterregulation in type 1 diabetic patients. CONCLUSIONS: In patients approaching the insulin-deficient end of the spectrum of type 2 diabetes the hormonal responses to SH are comparable to those in patients with longstanding type 1 diabetes. Thus, in advanced type 2 diabetes the risk of developing SH may be similar to that in individuals with type 1 diabetes.

Blood glucose self-monitoring from abdominal skin: a precise and virtually pain-free method.

For many diabetic patients, years of blood glucose self-monitoring (SM) with readings taken several times daily is an inevitable aspect of insulin therapy. We investigated whether SM from abdominal skin might be an alternative to the established fingertip method. A total of 63 diabetic patients and 16 nondiabetic volunteers determined their blood glucose in parallel in capillary blood from the tip of the finger and from abdominal skin 5 times daily on 5 successive days. The blood samples were collected from the two test regions using lancing devices, and the SM determinations were all done with a meter. Consecutive specific enzymatic glucose determinations in blood from the fingertip served as the reference method. The results of the SM from abdominal skin, a method perceived as virtually painless, were in close correlation with the control laboratory determinations and with SM from the finger (Pearson's r, 0.94 and 0.95). The comparison of SM method for abdomen vs. finger laboratory control gave a linear regression equation of y=8.35+0.94x (r=0.94). Error grid analysis revealed: range A, 93.6%; range B, 5.4%; range C, 0.05%; range D, 1.0%; and range E, 0%. Bland and Altman analysis yielded the mean of the differences, 0.2 mg/dl; 2 SD, 32 mg/dl; minimum, -162 mg/dl; maximum, 148 mg/dl. Laboratory glucose determinations in capillary blood from the fingertip and from abdominal skin led in 99.7% of the cases to concordant therapeutic decisions in the diabetics; the sample material was therefore equivalent. The practical aspects (afterbleeding, number of punctures, test strip consumption) of SM from the two regions showed no essential differences. However, only 22% of the diabetic patients investigated continued to perform SM from abdominal skin on a longer basis. In a further 5 adipose diabetic patients (BMI, 32 kg/M2), SM from abdominal skin was not practicable, as there was insufficient blood to collect. SM from abdomal skin is a simple, virtually pain-free and precise method. It provides certain diabetic patients with an alternative to the established method of SM from the fingertip.

Association between CYP2C9 slow metabolizer genotypes and severe hypoglycaemia on medication with sulphonylurea hypoglycaemic agents.

AIMS: The genetically polymorphic cytochrome P450 (CYP) enzyme CYP2C9 metabolizes most sulphonylurea oral hypoglycaemic agents. The aim of this study was to test the hypothesis that individuals with genotypes predicting low CYP2C9 activity may be at a higher risk of severe drug-associated hypoglycaemia. METHODS: In a case-control study, 20 diabetic patients admitted to the emergency department with severe hypoglycaemia during sulphonylurea drug treatment were compared with a control group of 337 patients with type 2 diabetes but without a history of severe hypoglycaemia. A large sample of 1988 healthy Caucasian subjects served as a second control group. RESULTS: The CYP2C9 genotypes *3/*3 and *2/*3 that are predictive of low enzyme activity were more common in the hypoglycaemic group than in the comparison groups (10%vs <2%, respectively: odds ratio 5.2; 95% confidence interval 1.01, 27). Furthermore, the diabetic patient group with severe hypoglycaemia exhibited lower body mass indexes, higher rates of renal failure, were older compared with the diabetic group without severe hypoglycaemia, and were being treated with higher doses of glibenclamide. CONCLUSIONS: These findings suggest that among other factors, individuals with genetically determined low CYP2C9 activity are at an increased risk of sulphonylurea-associated severe hypoglycaemia. Thus, genotyping might be a tool for the better prediction of adverse effects caused by oral hypoglycaemic agents.

Characteristics and time course of severe glimepiride- versus glibenclamide-induced hypoglycaemia.

OBJECTIVE: To compare the clinical characteristics and time course of severe hypoglycaemia (SH) on glimepiride and the reference drug glibenclamide. METHODS: SH was defined as a symptomatic event requiring administration of i.v. glucose or of glucagon. Four hundred doctors working in acute care hospitals were randomly selected from the membership directory of the German Diabetes Association and sent a standardised questionnaire about sulphonylurea-induced SH that occurred between June 2001 and August 2002. Detailed data on history, medication, laboratory parameters, treatment and time course of the SH were analysed. RESULTS: Altogether, 93 episodes of SH were registered, 37 on glimepiride and 56 on glibenclamide. The characteristics of the glimepiride- versus glibenclamide-induced SH were as follows: initial blood glucose 1.9+/-0.66 mmol/l versus 1.8+/-0.89 mmol/l, P=0.17; age 77+/-11.2 years versus 78+/-9.6 years, P=0.35; HbA1c 5.4+/-0.7% versus 5.2+/-0.9%, P=0.18; creatinine clearance 38+/-23 ml/min versus 54+/-32 ml/min, P=0.005; co-medication 6.2.+/-3 versus 3.6+/-3 preparations, P< 0.0001. Even very low doses of glimepiride (0.5 mg) and glibenclamide (0.88 mg) were associated with SH. Prolonged hypoglycaemia requiring more than 12 h i.v. glucose administration occurred in 8 of 37 of the glimepiride-treated subjects and 5 of 56 of those on glibenclamide. Prolonged hypoglycaemia necessitated infusion of 308+/-256 g (104-862 g) i.v. glucose over 43+/-16 h (24-64 h) in glimepiride-treated patients compared with 168+/-98 g (66-300 g) over 33+/-28 h (14-80 h) in glibenclamide-treated patients. Impaired renal function was present in 11 of 13 of all patients with prolonged hypoglycaemia and impaired liver function in 1 of 13. CONCLUSION: In glimepiride- and glibenclamide-treated individuals with SH, no essential differences in the clinical characteristics or time course were shown; prolonged courses also occurred on glimepiride. Even in patients with only mild renal failure both preparations should be used with caution.

Structural and process quality in the management of diabetic emergencies in Germany.

OBJECTIVE: Although acute complications of diabetes account for approximately 3% of all emergency calls, clinically relevant indicators of structural and process quality in the management of diabetic emergencies have not yet been studied. The purpose of this investigation was, therefore, to collect representative data on these indicators for the whole of Germany. METHODS: Standardized questionnaires comprising 20 items were sent to all 312 emergency medical services in Germany. Apart from demographic data, information was obtained about the diagnostic materials and drugs carried by the ambulances, methods of blood glucose measurement, the level of qualification of the emergency teams, the frequency of diabetic emergencies, and the need for further training. RESULTS: The return rate of the questionnaires was 55%, corresponding to 172 emergency medical service districts serving a total population of 45.3 million. The data revealed deficits with regard to structural and process quality. Thus, only 6% of ambulances carried glucagon and only 11% ketone test strips. In 57% capillary blood was used for glucose determination, in 17% visually read test strips were still used. While in some districts hospital admission after hypoglycaemic episodes was mandatory even for patients well educated about their diabetes, in other districts multimorbid patients on oral antidiabetics were sometimes only treated at the emergency scene. Emergency medical technicians increasingly carried out both the diagnosis and treatment of diabetic emergencies. CONCLUSIONS: The structural and process quality of the management of diabetic emergencies in Germany is in need of improvement. The most important factor is continuing education of the entire emergency team.

Lower incidence of severe hypoglycaemia in patients with type 2 diabetes treated with glimepiride versus glibenclamide.

BACKGROUND: Severe hypoglycaemia is a potentially life-threatening condition. The aim of the present study was to compare the frequency of severe hypoglycaemia in patients with type 2 diabetes treated with glimepiride versus glibenclamide. METHODS: This prospective, population-based, 4-year study examined the incidence of severe hypoglycaemia in a region of Germany with 200 000 inhabitants. The blood glucose of all 30 768 patients who attended the emergency department of the region's central hospital was determined to detect severe hypoglycaemia, which was defined by the requirement for intravenous glucose or glucagon injection and blood glucose value of <2.8 mmol/l. Additionally, 6631/7804 patients (85%) attended to by the emergency medical services received a blood glucose test at the emergency site. The regional prescribing frequency of both sulphonylureas was determined by an independent external institute. RESULTS: Despite glimepiride being prescribed more frequently than glibenclamide (6976 vs 6789 person-years), glimepiride induced fewer episodes of hypoglycaemia (6 vs 38 episodes); one episode occurred with a combination of the two preparations. The incidence of severe hypoglycaemia was 0.86/1000 person-years for glimepiride and 5.6/1000 person-years for glibenclamide. The characteristics of the 45 patients who presented with sulphonylurea-associated hypoglycaemia were as follows: mean age 79 years (95% CI 75.2; 82.6); glycosylated haemoglobin 5.4% (95% CI 5.1; 5.7); impaired renal function in 62%. CONCLUSIONS: In people with type 2 diabetes, glimepiride was associated with fewer episodes of severe hypoglycaemia than glibenclamide in routine clinical use. However, severe hypoglycaemia did occur with glimepiride and may be minimised if treatment targets are determined on an individual basis.

Prehospital management of diabetic emergencies--a population-based intervention study.

BACKGROUND: Diabetes-related emergencies are frequent and potentially life-threatening. A study was performed to obtain reliable data about the prevalence of diabetic emergencies and to improve the quality of prehospital care of patients with diabetes-related emergencies. METHODS: A prospective population-based study in a German emergency medical service district in the period from 1997 to 2000 was conducted. After initial diabetes training for the entire emergency team, a standardized protocol was introduced for prehospital emergency therapy of severe hypoglycaemia (SH) and severe hyperglycaemic disorders. A rapid blood glucose test was performed on all emergency patients with the exception of resuscitations and deaths. Indicators of treatment quality before and after these interventions were compared. RESULTS: A rapid blood glucose test was performed in 6631 (85%) of the 7804 emergencies that occurred during the period investigated. The prevalence of acute diabetic complications was 3.1%, and 213 cases of SH and 29 severe hyperglycaemic disorders were recorded. Education of the emergency team led to a significant improvement in the quality of treatment. Larger volumes of iv 40% glucose solution (50 +/- 20 ml (1997-2000) vs. 25 +/- 17 ml (1993-96); P < 0.0001) were administered to patients with SH. Insulin-treated patients who were well educated about their diabetes were more often treated only at the emergency scene, after SH (25% vs. 8%; P = 0.007), and without complications. In 50 patients who experienced sulfonylurea-induced SH, the mandatory additional glucose infusions and hospitalization for further observation reduced mortality from 4.9% to 0% (P = 0.2). CONCLUSION: Training of the emergency team is an effective and efficient intervention to improve quality of treatment and prognosis outcome for patients with diabetic emergencies. Treatment of SH at the emergency scene only was demonstrated to be safe in type 1 diabetic patients who had previously received structured patient education.

Clinical implications of hepatogenous diabetes in liver cirrhosis.

BACKGROUND: Hepatogenous diabetes is a common complication of liver cirrhosis. The aim of the present study was to examine the clinical and therapeutic implications and the prognostic significance of hepatogenous diabetes in patients with liver cirrhosis. METHODS: The prospective cohort study was conducted in 52 patients with histologically confirmed liver cirrhosis (44% Child A, 37% Child B, 19% Child C). The examination included a history, determination of basal C-peptide and glycosylated hemoglobin (HbA(1c)) and, in some cases, a 3 h oral glucose tolerance test with 100 g glucose. Patients were also examined for signs of diabetic retinopathy and information on the further course of illness was obtained. RESULTS: Seventy-one percent of patients with liver cirrhosis had manifest diabetes, 25% had impaired glucose tolerance and only 4% had normal glucose tolerance. In most cases, the hepatogenous diabetes was clinically asymptomatic. Sixteen percent of patients with hepatogenous diabetes had a family history of diabetes; only 8% had retinopathic complications. Within 5.6 +/- 4.5 years after diagnosis of liver cirrhosis, 52% of the diabetics had died, mainly of complications of the cirrhosis. There were no diabetes-associated or cardiovascular deaths. CONCLUSIONS: Hepatogenous diabetes differs from type 2 diabetes in that there is less often a positive family history and that the cardiovascular and retinopathic risk is low. The prognosis of cirrhotic patients with diabetes is more likely to be negatively affected by the underlying hepatic disease and its complications than by the diabetes. Antihyperglycemic treatment of hepatogenous diabetes should always be carefully weighed up in each individual case.

Practicality and accuracy of prehospital rapid venous blood glucose determination.

Blood glucose testing plays an important role in emergency medicine. Although the use of visual reagent test strips is widely established in this setting, the accuracy of reflectometric blood glucose determinations under emergency conditions has rarely been investigated. In a prospective study, 522 of a total of 3,217 patients undergoing emergency blood glucose testing had parallel blood glucose measurements performed using a specific enzymatic method. These 522 patients (aged 61.4 years, 54% men, 90 cases of severe hypoglycemia) had an intravenous access placed at the scene of the emergency. Venous whole blood from the introducer needle of the access was applied to the test strip and the glucose measured with a GlucoTouch reflectometer (LifeScan, Inc.). A blood sample from the intravenous access was then immediately collected in a monovette for subsequent glucose determination in a chemical laboratory (hexokinase method) within 20 to 40 minutes. The emergency glucose measurements (mean: 7.3 mmol/L [95% confidence interval [CI] 6.9 to 7.7]; range: 0.55 to 27.7) correlated well with the reference laboratory results (Pearson's r = .98; linear regression analysis: slope 1.0, axial intercept 1.74). Error grid analysis also showed good agreement between corresponding measurements: zone A 96.7%, B 2.5%, C 0% and D 0.8%. The mean difference using the Bland-Altman method was 0.14 mmoVL; 2 SD 1.8 mmol/L; minimum -7.0 mmol/L; maximum 4.4 mmol/L. The accuracy of the rapid venous blood glucose determination by constantly changing emergency teams was high. Especially in 90 hypoglycemic patients, there were no deviations from the reference method that could have led to clinically relevant wrong decisions. The method of collecting whole blood directly from the venous access is simple and robust, and is independent of the hemodynamic status of the patient.

Hormonal counterregulation and consecutive glimepiride serum concentrations during severe hypoglycaemia associated with glimepiride therapy.

OBJECTIVE: To examine the release of counterregulatory hormones and consecutive glimepiride serum concentrations during severe hypoglycaemia (SH) associated with glimepiride therapy. METHODS: In nine type-2 diabetic patients [age 81+/-9 (65-93) years; diabetes duration 9+/-4 (3-15) years; initial blood glucose 33+/-16 (10-54) mg/dl (1.8+/-0.9 mmol/l); HbA1c 7.2+/-1.1 (5.6-8.7)%; creatinine clearance 49+/-33 (15-107) ml/min] who experienced SH associated with glimepiride therapy with neuroglucopenic presentation, insulin, C-peptide, glucagon, epinephrine, norepinephrine, cortisol, adenocorticotrophic hormone (ACTH), human growth hormone (HGH) and pancreatic polypeptide (PP) were determined in blood samples taken at 4-h intervals prior to and during treatment with glucose i.v. Serum from the same samples was screened for sulphonylurea-type oral antidiabetics. Glimepiride concentrations were determined by a validated atmospheric pressure chemical ionization liquid chromatographic-mass spectrometry (APCI-LC-MS) assay. RESULTS: Once treatment had begun, normoglycaemia was maintained; most glimepiride levels were below the limit of detection (LOD <0.01 mg/l) and further sulphonylureas could be excluded. The secretion of glucagon and epinephrine as counterregulatory hormonal responses was unaffected. In addition, protracted marked increases of cortisol and norepinephrine levels were demonstrated. Protracted stimulation of insulin and C-peptide occurred in a period of up to 24 h after SH. No significant protracted responses were observed for ACTH, HGH or PP. CONCLUSION: In SH associated with glimepiride therapy, no correlation between glimepiride serum concentrations and the protracted stimulation of insulin and C-peptide was observed. The secretion of glucagon and epinephrine as counterregulatory hormonal responses was unaffected. Protracted increased release of cortisol might be a medium-term indicator of glimepiride-associated SH.