Autoantibodies against zinc transporter 8 further stratify the autoantibody-defined risk for type 1 diabetes in a general population of schoolchildren and have distinctive isoform binding patterns in different forms of autoimmune diabetes: results from the Karlsburg Type 1 Diabetes Risk Study.

AIMS: To evaluate the diagnostic relevance of autoantibodies against zinc transporter 8 (ZnT8) in schoolchildren from the general population as well as in people with autoimmune diabetes. METHODS: A total of 137 schoolchildren positive for at least one of the three major diabetes-associated autoantibodies, without diabetes heredity or preselection on HLA typing, from the Karlsburg Type 1 Diabetes Risk Study, as well as 102 people at type 1 diabetes onset, 88 people with latent autoimmune diabetes in adults and 119 people with type 2 diabetes, were analysed for different ZnT8 autoantibody variants. RESULTS: Zinc transporter 8 autoantibody positivity was found in 18% of autoantibody-positive schoolchildren, with a noticeable association with other autoantibodies associated with type 1 diabetes and disease progression. Furthermore, ZnT8 autoantibody positivity was associated with diabetes progression in schoolchildren positive for autoantibodies against insulinoma-associated antigen-2 (IA-2) and, importantly, in seven IA-2 autoantibody-negative schoolchildren. Additionally, ZnT8 autoantibodies were found in 56% of people with type 1 diabetes, predominantly directed against all three ZnT8 variants and comparable to schoolchildren with multiple autoantibodies. In contrast, ZnT8 autoantibodies were detected in 10% of people with latent autoimmune diabetes in adults, none of them with reactivity to all three isoforms. CONCLUSION: Zinc transporter 8 autoantibodies are useful markers for prediction of type 1 diabetes in a general population, further stratifying the risk of progression in autoantibody-positive children. ZnT8 autoantibodies are also important markers in adult-onset diabetes, with a completely different reaction pattern in type 1 diabetes in comparison to latent autoimmune diabetes in adults, and may therefore help to differentiate between the two forms.

Autoantibody-defined risk for Type 1 diabetes mellitus in a general population of schoolchildren: results of the Karlsburg Type 1 Diabetes Risk Study after 18 years.

AIMS: To investigate the occurrence of diabetes-associated autoantibodies and cumulative Type 1 diabetes risk over 18 years in a general population of schoolchildren. METHODS: In the Karlsburg Type 1 Diabetes Risk Study, 11 986 schoolchildren from north-eastern Germany without a family history of diabetes were screened for glutamic acid decarboxylase antibodies, insulinoma-associated antigen-2 antibodies and insulin autoantibodies by radioligand binding assay. Those children found to be autoantibody-positive were invited to follow-up examinations and HLA-DQB1 genotyping, and were followed for progression to Type 1 diabetes. RESULTS: At first follow-up, 119 children had single and 36 children had multiple autoantibodies. Of the multiple autoantibody-positive children, 33 had at least one diabetes-associated HLA-DQB1 allele (*02 and/or *0302). A total of 26 children progressed to Type 1 diabetes, of whom 22 had multiple autoantibodies. The male-to-female ratio of those who progressed to Type 1 diabetes was 1.6. The positive predictive value of multiple autoantibodies was 61.1% compared with only 23.7% for diabetes-associated HLA-DQB1 genotypes among all those who were autoantibody-positive. The cumulative risk was 59.7% after 10 years and 75.1% after 18 years for children with multiple autoantibodies compared with 1.2 and 22.6%, respectively, for children with single autoantibodies (P<0.001). Among the three examined autoantibodies, insulinoma-associated antigen-2 antibodies conferred the highest risk. CONCLUSIONS: The diabetes risk in schoolchildren with multiple autoantibodies was similar to the risk reported in other studies for genetically preselected probands; thus, a combined autoantibody-based screening could effectively identify at-risk individuals from the general population for future intervention trials.

Daily insulin doses and injection frequencies of neutral protamine hagedorn (NPH) insulin, insulin detemir and insulin glargine in type 1 and type 2 diabetes: a multicenter analysis of 51 964 patients from the German/Austrian DPV-wiss database.

BACKGROUND: We performed a comparative analysis of the use of long-acting insulin (analogues) neutral protamine hagedorn (NPH), detemir (Det) and glargine (Gla), and quantified injection frequencies and daily insulin doses in patients with type 1 and 2 diabetes in daily practice. METHODS: A total number of 51 964 patients from 336 centres in Germany and Austria with type 1 and 2 diabetes with exclusive insulin therapy were retrospectively analysed. RESULTS: A total number of 42.1%/75.9% (type 1/type 2) of patients used NPH, 19.9%/6.7% Det and 38.0%/17.4% Gla, with similar glycaemic control and proportion of severe hypoglycaemia for NPH/Det/Gla in type 1 (Mean HbA(1c) 7.98%/7.98%/8.07%; mean proportion of severe hypoglycaemia 11.06%/11.93%/10.86%) and type 2 diabetes (Mean HbA(1c) 7.61%/7.78%/7.61%; mean proportion of severe hypoglycaemia 5.66%/4.48%/5.03%). In type 1 diabetes, the mean daily injection frequencies of NPH versus Det versus Gla were 1.9 vs 1.8 vs 1.1, and total daily insulin injections were 5.3 vs 5.6 vs 5.0. The adjusted mean daily basal insulin doses were 0.36, 0.39 and 0.31 IU/kg, mean daily total insulin dose was lowest for Gla (0.74 IU/kg), followed by NPH (0.76 IU/kg) and Det (0.81 IU/kg). In type 2 diabetes patients, mean daily injection frequencies were 1.6 for NPH, 1.4 for Det and 1.1 for Gla, total daily insulin injections were 4.0 vs 4.1 vs 3.6. The mean daily basal insulin dosages were 0.30 IU/kg (NPH), 0.33 IU/kg (Det) and 0.29 IU/kg (Gla), mean total insulin doses per day were 0.63 IU/kg (NPH), 0.77 IU/kg (Det) and 0.67 IU/kg (Gla). CONCLUSIONS: In a 'real-world' setting, the injection frequencies and doses of basal and total insulin per day are lowest with the use of insulin glargine compared with NPH-insulin or insulin detemir at similar glycaemic control and rates of severe hypoglycaemia.

[Comments on the 2013 ESC/EASD guidelines on diabetes, prediabetes and cardiovascular diseases]. / Kommentar zur ESC/EASD-Leitlinie zu Diabetes, Prädiabetes und kardiovaskulären Erkrankungen 2013.

Patients with type 2 diabetes mellitus have an increased cardiovascular risk compared with non-diabetics. The new guidelines provide physicians with orientation with respect to disorders in glucose metabolism and the risk of occurrence of cardiovascular diseases. An HBA1c level in the range of 6-8% is currently recommended, depending on cardiovascular comorbidities: in young diabetics 6% is recommended to avoid hypoglycemia and in older individuals with cardiovascular complications 8%. The target blood pressure given in the new guidelines is <140/85 mmHg. The guidelines still recommend bypass surgery instead of percutaneous coronary intervention (PCI) for diabetics; however, this recommendation is based on studies that do not reflect current practice and is disputable. Diagnostic measures and therapy of cardiac failure and arrhythmic disorders in the guidelines do not essentially differ between patients with and without diabetes, basically due to a lack of studies.

Multiple complications and frequent severe hypoglycaemia in 'elderly' and 'old' patients with Type 1 diabetes.

AIM: Elderly and old patients with Type 1 diabetes represent a growing population that requires thorough diabetes care. The increasing relevance of this subgroup, however, plays only a minor role in the literature. Here, we describe elderly patients with Type 1 diabetes on the basis of a large multi-centre database in order to point out special features of this population. METHOD: Data of 64609 patients with Type 1 diabetes treated by 350 qualified diabetes treatment centres were assessed and analysed by age group. RESULTS: Compared with the age group ≤ 60 years, patients aged >60 years (n=3610 61-80 years and n=377 >80 years old) were characterized by a longer diabetes duration (27.7 vs. 7.7 years), an almost double risk for severe hypoglycaemia (40.1 vs. 24.3/100 patient-years), a lower level of HbA(1c) [60 vs. 67 mmol/mol (7.6 vs. 8.3%)] and higher percentages of microalbuminuria (34.5 vs. 15.6%), diabetic retinopathy (45.2 vs. 8.3%), myocardial infarction (9.0 vs. 0.4%) or stroke (6.8 vs. 0.3%). Elderly patients used insulin pumps less frequently (12.2 vs. 23.8%), but more often used conventional premixed insulin treatment (10.8 vs. 3.8%). Differences between elderly and younger patient groups were significant, respectively. CONCLUSION: Diabetes care of elderly patients with Type 1 diabetes involves individualized treatment concepts. Increased hypoglycaemia risk and functional impairment attributable to diabetes-associated and/or age-related disorders must be taken into account.

[Characteristics of therapy of acute myocardial infarction in diabetes]. / Besonderheiten der Infarkttherapie bei Diabetes.

Therapy of acute myocardial infarction (STEMI and NSTEMI) in diabetics does not principally differ from that of non-diabetic patients. Due to the higher mortality in diabetics reperfusion measures, such as direct percutaneous coronary intervention (PCI), should be rapidly performed. An intensive drug treatment with thrombocyte aggregation inhibitors, angiotensin-converting enzyme (ACE) inhibitors and beta-receptor blocking agents must be carried out according to the current guidelines. An important factor is the high risk of renal failure due to the contrast dye administered during PCI in the presence of pre-existing diabetic kidney damage which should be limited to 100 ml if possible. Direct PCI should be limited to the infarcted vessel. After stabilization a comprehensive strategy to cure coronary artery disease, whether with PCI or coronary artery bypass graft (CABG) should be finalized. If severe coronary 3-vessel disease is present, CABG should be favored in diabetic patients. After surviving an acute myocardial infarction differentiated metabolic monitoring is mandatory.

Diabetic retinopathy in type 1 diabetes-a contemporary analysis of 8,784 patients.

AIMS/HYPOTHESIS: The aim of this study was to analyse the risk profile for diabetic retinopathy under real-life conditions in a large cohort of patients with type 1 diabetes. METHODS: Patients (n = 18,891) with childhood, adolescent or adult onset of type 1 diabetes from the prospective German Diabetes Documentation System survey were analysed. A total of 8,784 patients fulfilled the inclusion criterion, which was availability of retinopathy status. Retinopathy grading (any retinopathy, advanced retinopathy), treatment regimens and risk factors were prospectively recorded and tested as covariates by Kaplan-Meier analysis and logistic regression. RESULTS: Any retinopathy was present in 27.4% and advanced retinopathy (severe non-proliferative or proliferative diabetic retinopathy) in 8.0% of the cohort. After 40 years of diabetes, the cumulative proportion of patients with any retinopathy and advanced retinopathy was 84.1% and 50.2%, respectively. In multiple regression analysis, risk factors for any retinopathy were diabetes duration (OR 1.167 per year), HbA(1c) >7.0% (53 mmol/mol) (OR 2.225), smoking (OR 1.295) and male sex (OR 1.187) (p < 0.0001 for all). Young age at onset (5 vs 15 years at disease onset) was protective (0.410, p < 0.0001). No glycaemic threshold was detected for retinopathy protection. Risk factors for advanced retinopathy were duration (1.124 per year, p < 0.0001), male sex (1.323, p = 0.0020), HbA(1c) >7.0% (53 mmol/mol) (1.499, p < 0.0001), triacylglycerol >1.7 mmol/l (1.398, p = 0.0013) and blood pressure >140/90 mmHg (1.911, p < 0.0001). CONCLUSIONS/INTERPRETATION: The prevalence of retinopathy remains significant in type 1 diabetes. Any improvement of metabolic control and non-smoking is protective, while hypertension affects progression to severe levels under real-life conditions. These data reinforce the validity of multifactorial concepts for morbidity protection in type 1 diabetes.

[Cardial target-organ damage in diabetes]. / Kardiale Endorganschäden bei Diabetes.

Coronary heart disease and type 2 diabetes mellitus can be considered as a syntropy. Accordingly, cardiologists and diabetologists should organize an interdisciplinary car of the patient with both cardiac disease and diabetes mellitus. Arterial hypertension is frequently present in the diabetic condition and increases further morbidity and mortality rates due to the involvement of the coronary microcirculation. Coronary artery disease is characterized by a rapid progression and a diffuse distribution particularly in the periphery. Consequently in severe diabetic coronary artery disease coronary bypass surgery should be preferred rather than percutaneous coronary stenting, which should be favored in less severe cases. In the antihyperglycemic treatment a reduction in cardiovascular endpoints has only be documented after metformin. Therapy with thiazolidinediones has been terminated due to an increase in coronary morbidity and mortality under rosiglitazone. In as much glucagon-like peptide-I analogues and dipeptidylpeptidase 4 inhibitors will reduce cardiovascular endpoints has to be waited for. Thus an endpoint orientated antihyperglycemic treatment is limited to insulin, metformin and sulfonylureas.

Association between depression and subclinical carotid atherosclerosis in patients with Type 1 diabetes.

AIMS: Recent studies have suggested an association between depression and subclinical atherosclerosis as measured by presence of carotid atherosclerotic plaque and increased intima-media thickening in non-clinical populations. Given the high prevalence of depression in patients with Type 1 diabetes and the diabetes-related risk factors for atherosclerosis, we hypothesized that this relation might also be of special relevance in Type 1 diabetic patients. METHODS: Intima-media thickness (IMT) and the presence of plaques in the carotid arteries were quantitatively assessed by high-resolution ultrasound in 175 adults (89 men, 86 women) with an established diagnosis of Type 1 diabetes. Having been treated for depression or current Beck Depression Inventory scores > 10 were considered to indicate depression. RESULTS: In men, the risk of plaque was higher in depressed subjects relative to non-depressed participants after adjustment for age, smoking status, systolic blood pressure, dyslipidaemia and body mass index [odds ratio (OR) 5.19; 95% confidence interval (CI) 1.29, 20.81]. Depressed women did not have an increased risk of plaque compared with non-depressed women (OR 0.97; 95% 95% CI 0.22, 4.34). We did not observe an association between depression and IMT, in men or in women. CONCLUSIONS: In line with previous research, our findings suggest a link between depression and subclinical atherosclerosis in Type 1 diabetic men, but not in women.

Is the frequency of self-monitoring of blood glucose related to long-term metabolic control? Multicenter analysis including 24,500 patients from 191 centers in Germany and Austria.

Blood glucose measurements are generally accepted components of a modern diabetes self-management. The value of self-monitoring of blood glucose (SMBG) is, however, discussed controversially and only a few studies addressed the efficacy of SMBG under real-life conditions so far. In order to investigate whether the frequency of SMBG is related to long-term metabolic control, data from the DPV-Wiss-database, a standardized,prospective, computer-based documentation of diabetes care and outcome, were analyzed for patients with type 1(n = 19,491) and type 2 (n = 5,009) diabetes from 191 centers in Germany and Austria. Local HbA1c reference ranges were mathematically adjusted to the DCCT reference. For each patient, data from the most recent year of diabetes care were used. On average,patients with type 1 diabetes performed 4.4 blood glucose measurements/day. Corrected for age, gender, diabetes duration,on intensified (>or=4 daily injections or CSII) therapy (HbA1c reduction of 0.32% for one additional SMBG/day) compared to patients on conventional (1-3 daily injections) therapy(HbA1c-reduction of 0.16% for one additional SMBG/day). In 2,021 patients with insulin-treated type 2 diabetes (2.7 measurements/day), more frequent SMBG was associated with better metabolic control (HbA1c-reduction of 0.16% for one additionalSMBG/day, p < 0.0001), while in 2,988 patients on OAD or diet alone (2.0 measurements/day), more frequent blood glucose measurements were associated with higher HbA1c-levels(HbA1c-increase of 0.14% for one additional SMBG/day,p < 0.0001). These data indicate that more frequent SMBG are associated with better metabolic control in both, patients with type 1 and insulin-treated type 2 diabetes. Since no benefit ofSMBG on metabolic control was found in patients with type 2 diabetes on OAD or diet alone, SMBG should primarily be recommended for those patients with suboptimal metabolic control whereas the benefit of SHBG in non-insulin-treated patients with adequate HbA1c-levels remains uncertain.insulin therapy and center difference, the SMBG frequency was associated with better metabolic control (HbA1c-reduction of0.26% for one additional SMBG/day, p < 0.0001). HbA1c-reduction with higher frequency of SMBG was more pronounced in patients Blood glucose measurements are generally accepted components of a modern diabetes self-management. The value of self-monitoring of blood glucose (SMBG) is, however, discussed controversially and only a few studies addressed the efficacy of SMBG under real-life conditions so far. In order to investigate whether the frequency of SMBG is related to long-term metabolic control, data from the DPV-Wiss-database, a standardized,prospective, computer-based documentation of diabetes care and outcome, were analyzed for patients with type 1(n = 19,491) and type 2 (n = 5,009) diabetes from 191 centers in Germany and Austria. Local HbA1c reference ranges were mathematically adjusted to the DCCT reference. For each patient, data from the most recent year of diabetes care were used. On average,patients with type 1 diabetes performed 4.4 blood glucose measurements/day. Corrected for age, gender, diabetes duration,insulin therapy and center difference, the SMBG frequency wasassociated with better metabolic control (HbA1c-reduction of 0.26% for one additional SMBG/day, p < 0.0001). HbA1c-reduction with higher frequency of SMBG was more pronounced in patients on intensified (>or= 4 daily injections or CSII) therapy (HbA1c reduction of 0.32% for one additional SMBG/day) compared to patients on conventional (1-3 daily injections) therapy(HbA1c-reduction of 0.16% for one additional SMBG/day). In 2,021 patients with insulin-treated type 2 diabetes (2.7 measurements/day), more frequent SMBG was associated with better metabolic control (HbA1c-reduction of 0.16% for one additionalSMBG/day, p < 0.0001), while in 2,988 patients on OAD or diet alone (2.0 measurements/day), more frequent blood glucose measurements were associated with higher HbA1c-levels(HbA1c-increase of 0.14% for one additional SMBG/day, p < 0.0001). These data indicate that more frequent SMBG are associated with better metabolic control in both, patients with type 1 and insulin-treated type 2 diabetes. Since no benefit of SMBG on metabolic control was found in patients with type 2 diabetes on OAD or diet alone, SMBG should primarily be recommended for those patients with suboptimal metabolic control whereas the benefit of SHBG in non-insulin-treated patients with adequate HbA1c-levels remains uncertain.

Prevalence and comorbidities of double diabetes.

BACKGROUND: A growing number of people with type 1 diabetes (T1DM) are identified with features of metabolic syndrome (MS) known as "double diabetes", but epidemiologic data on the prevalence of MS in T1DM and its comorbidities are still lacking. Aim of this cross sectional study is to better estimate the prevalence of MS in T1DM, and to assess its association with comorbidities. METHODS: Data of 31,119 persons with autoimmune diabetes mellitus were analysed for signs of MS and presence of late complications. Double diabetes was defined as T1DM coexisting with MS (obesity, hypertension, dyslipidemia). Multiple linear or logistic regression analyses were performed to identify associations between double diabetes and late complications. RESULTS: 25.5% (n=7926) of persons with T1DM presented additionally the MS. Persons with double diabetes showed significantly more macrovascular comorbidities (coronary heart disease 8.0% versus 3.0% w/o MS, stroke 3.6% versus 1.6%, diabetic foot syndrome 5.5% versus 2.1%). Also microvascular diseases were increased in people with double diabetes (retinopathy 32.4% versus 21.7%, nephropathy 28.3% versus 17.8%). Both macrovascular and microvascular comorbidities were increased independent of glucose control, even if patients with good metabolic control (HbA1c <7.0%, 53mmol/mol) showed significantly less macrovascular (coronary heart disease 2.3% versus 1.8%, p<0.0001) and microvascular problems (retinopathy 8.7% versus 6.6%, p<0.0001). CONCLUSIONS: Double diabetes seems to be an independent and important risk factor for persons with T1DM in developing macrovascular and microvascular comorbidities. Therefore, patients should be identified and development of MS should be avoided. Longterm studies are needed to observe the effect of insulin resistance on patients with autoimmune diabetes.

Differential effects of human and pork insulin-induced hypoglycemia on neuronal functions in humans.

Insulin has been found to cross the blood-brain barrier, and insulin receptors have been detected in different structures of the brain. However, the biological significance of insulin acting in the brain remains unclear. Reports of differential awareness of hypoglycemic symptoms during human insulin (HI)- and pork insulin (PI)-induced hypoglycemia hint at a modulatory influence of insulin on sensory processing. In a double-blind study, we recorded auditory-evoked potentials (AEPs), indexing neuronal transmission along sensory pathways, in 30 healthy male subjects during a baseline condition and HI- and PI-induced mild hypoglycemia of 2.65 mM. Fifteen subjects were tested after 20 min and another 15 after 50 min of constant hypoglycemia. During hypoglycemia, subjects had to indicate the severity of hypoglycemic symptoms and their current mood. Hypoglycemia increased latencies of the P3 component and reduced amplitudes of the N1, P2, and P3 components. Despite identical blood glucose and serum insulin levels in both sessions, effects of PI-induced hypoglycemia on AEP components were significantly stronger than those of HI-induced hypoglycemia (P less than 0.05). Differences between the effects of the insulins were consistently apparent after 20 min of hypoglycemia, indicating a short-term action of these hormones on central nervous system functions. Also, after 20 min, but not after 50 min, of steady-state hypoglycemia, subjects felt more excited during PI than HI infusion (P less than 0.05). The results indicate different influences of HI and PI on sensory function during hypoglycemia. These differences, occurring during early hypoglycemia, could contribute to the differential awareness of hypoglycemic warning symptoms during HI- and PI-induced hypoglycemia in diabetic patients.

Evidence for effects of insulin on sensory processing in humans.

Systemic insulin passes the blood-brain barrier and insulin receptors have been detected in various brain regions. Yet, the biological significance of insulin acting on the brain remains rather unclear. Reports of different awareness of hypoglycemic symptoms during hypoglycemia induced by human insulin (HI) and porcine insulin (PI) suggest a modulatory influence of insulin on sensory processing. In a double-blind, within-subject, crossover comparison, we recorded visual-evoked potentials (VEP) in 30 healthy men during euglycemia and after 20 or 50 min of constant hypoglycemia of 2.66 mM (47.9 mg/dl) induced by HI and PI. Blood glucose and serum insulin levels were identical in both sessions. Hypoglycemia reduced amplitudes of the VEP components P1 and N2 and increased latencies of N1, P1, and N2. However, hypoglycemia-induced changes in VEP amplitudes and latencies were significantly stronger during PI and HI infusion: P1-N2 difference amplitude decreased from (mean +/- SE) 11.9 +/- 0.9 to 10.7 +/- 0.8 muV during HI and from 12.4 +/- 0.9 to 8.7 +/- 0.7 muV during PI infusion (P < 0.002). P1 latency increased from 112.0 +/- 3.2 to 118.8 +/- 3.2 ms during HI and from 114.0 +/- 3.3 to 126.3 +/- 4.6 ms during PI infusion (P < 0.05). Differences between the effects of the insulins were consistently apparent after 20 min of hypoglycemia, which indicates a short-term action of the hormone. The results add to those of a foregoing study demonstrating differential effects of HI- and PI-induced hypoglycemia on auditory evoked potentials.(ABSTRACT TRUNCATED AT 250 WORDS)

Mutations in the hepatocyte nuclear factor-1alpha gene in MODY and early-onset NIDDM: evidence for a mutational hotspot in exon 4.

We have recently shown that mutations in the gene encoding the transcription factor hepatocyte nuclear factor (HNF)-1alpha are the cause of one form of maturity-onset diabetes of the young (MODY3). Here, we report the exon-intron organization and partial sequence of the human HNF-1alpha gene. In addition, we have screened the ten exons and flanking introns of this gene for mutations in a group of 25 unrelated white subjects from Germany who presented with NIDDM before 35 years of age and had a first-degree relative with NIDDM. Mutations were identified in nine of these individuals, suggesting that mutations in the HNF-1alpha gene are a common cause of diabetes in German subjects with early-onset NIDDM and a family history of diabetes. Thus, screening for mutations in this gene may be indicated in subjects with early-onset NIDDM. Interestingly, three of the nine mutations occurred at the same site in exon 4 with insertion of a C in a polyC tract, centered around codon 290 (designated Pro291fsinsC), thereby resulting in a frameshift during translation and premature termination. Analyses of linked DNA polymorphisms in the HNF-1alpha gene indicated that the Pro291fsinsC mutation was present on a different haplotype in each subject, implying that the polyC tract represents a mutational hot spot. We have also identified the mutation in the HNF-1alpha gene in the Jutland pedigree, one of the original MODY pedigrees reported in the literature, as being a T-->G substitution in codon 241, resulting in the replacement of a conserved Cys by Gly (C241G). The information on the sequence of the HNF-1alpha gene and its promoter region will facilitate the search for mutations in other subjects and studies of the role of the gene in determining normal beta-cell functions.

Excess triiodothyronine as a risk factor of coronary events.

BACKGROUND: Abnormalities in cardiac function, eg, arrhythmias and congestive heart failure, often accompany thyrotoxicosis. A relationship between thyroid hormone excess and the cardiac complications of angina pectoris and myocardial infarction (MI) remains largely speculative. METHODS: The results of thyroid function studies on blood samples drawn from a total of 1049 patients (aged 40 years or older) immediately on emergency medical admission were related to frequencies of angina pectoris and myocardial infarction as determined according to current diagnostic algorithms. After 3 years, those patients who had initially presented with angina pectoris or acute MI were observed for subsequent coronary events; of these (n=185), 98% of the subjects (n=181) could be reevaluated. RESULTS: On hospital admission, the relative rate of angina pectoris and MI was markedly high (odds ratio, 2.6; 95% confidence interval, 1.3-5.2; P=.007) in patients with elevated serum free and total triiodothyronine (T(3)) levels. An initially elevated free T(3) level was a risk factor for subsequent coronary events during the 3-year follow-up (adjusted odds ratio, 4.8; 95% confidence interval, 1.3-17.4; P=.02). CONCLUSIONS: An elevation of serum free T(3) levels at hospital admission is associated with a 2.6-fold greater likelihood of the presence of a coronary event. Moreover, an initially elevated T(3) level is associated with a 3-fold higher risk of developing a subsequent coronary event during the next 3 years. Excess T(3) seemed to be a factor associated with the development and progression of acute myocardial ischemia.

Comparison of the biologic activity of biosynthetic human insulin and natural pork insulin in juvenile-onset diabetic subjects assessed by the glucose controlled insulin infusion system.

To assess the biologic activity of biosynthetic human insulin (BHI) synthesized by Escherichia coli, six insulin-dependent juvenile-onset diabetic subjects were studied with BHI and natural pork insulin, by means of the glucose controlled insulin infusion system (GCIIS). First, after an overnight normalization of blood glucose levels, the 24-h insulin requirement was determined while the patients were consuming a diet of 30 kcal/kg. Then, the amount of glucose necessary to maintain normal blood glucose levels during a 5-h intravenous infusion of BHI and pork insulin, respectively, was assessed. Both studies demonstrate that in the insulin-dependent diabetic subject, BHI is at least as effective as natural pork insulin and may, therefore, be useful for the treatment of insulin-dependent diabetes mellitus.

Symptom awareness is affected by the subjects' expectations during insulin-induced hypoglycemia.

OBJECTIVE: To assess how expectations and symptom beliefs based on a previous episode of insulin-induced hypoglycemia influence symptom awareness after a second insulin injection in healthy subjects. RESEARCH DESIGN AND METHODS: After a first episode of insulin-induced hypoglycemia in session 1, half of 40 healthy male subjects were told at the beginning of session 2 that they would receive human insulin (0.05 IU/kg), the other half saline. According to a 2 x 2 balanced placebo design, only half of each group received the announced substance, whereas the other half received the substance contrary to their expectations. Data collection at 10-15 min intervals included a symptom checklist, blood pressure, heart rate, plasma glucose, and counterregulatory hormone levels. RESULTS: The expectation of a repeated hypoglycemia clearly influenced the subjects' psychophysiological responses. Without knowledge about the actual treatment, there was only an average maximum confidence of 65% of having received insulin. Expecting the insulin injection led to an increased sum score of neuroglycopenic symptoms but not of autonomic symptoms. Subjects expecting the insulin injection reported more weakness, blurred vision, and inner restlessness than those subjects expecting the saline injection. Those subjects correctly informed about receiving insulin experienced the most drowsiness, dizziness, and headaches. The expectations of the insulin injection increased the norepinephrine levels and the heart rate. The told insulin/given insulin group showed the highest glucagon levels. CONCLUSIONS: The results support the hypothesis that the subjects' expectations influence their perceived symptoms.

Incidence of hypoglycemic episodes in diabetic patients under continuous subcutaneous insulin infusion and intensified conventional insulin treatment: assessment by means of semiambulatory 24-hour continuous blood glucose monitoring.

The incidence and magnitude of hypoglycemia (i.e., blood glucose values less than 50 mg/dl) were assessed by continuous blood glucose monitoring over 24 h in 10 insulin-dependent diabetic (IDD) patients treated with continuous subcutaneous insulin infusion (CSII) and 9 IDD patients under intensified conventional treatment (ICT). A newly developed, battery-powered blood glucose monitor was employed. Patients were thus enabled to move freely in the hospital premises. Despite similar quality of previous blood glucose control (HbA1: 8.0 +/- 0.05% CSII versus 8.0 +/- 0.3% ICT, mean +/- SEM), the obtained profiles showed better regulation under CSII treatment (mean blood glucose [MBG], 99.6 +/- 10.0 versus 133.1 +/- 7.4 mg/dl; M-value, 12.3 +/- 3.5 versus 26.2 +/- 4.1; mean amplitude of glycemic excursion [MAGE], 71.9 +/- 8.7 versus 132.9 +/- 14.2 mg/dl; CSII versus ICT, mean +/- SEM). The incidence of blood glucose values less than 50 mg/dl was 9/10 patients (CSII) and 5/9 patients (ICT). In both groups, hypoglycemia was most frequent at noon and was related to elevated pre- and postprandial free insulin levels. Patients became aware of hypoglycemia only in 6/23 episodes (CSII) and 6/8 episodes (ICT). Our data indicate that CSII as well as ICT may result in postprandial hyperinsulinemia leading to frequent hypoglycemic episodes of variable length, reassessing the traditional experience of close correlation between aggressive insulin therapy and enhanced hypoglycemic risk.

[Pitfalls in the diagnosis and treatment optimization of type 2 diabetes]. / Auch für die Therapie von Bedeutung. Fallstricke in der Diabetesdiagnostik.

The diagnosis of diabetes mellitus would appear a simple matter. However, potential pitfalls in clinical practice need to be avoided, and this requires knowledge and attention. An initially pathological oral glucose tolerance test should be repeated before establishing a final diagnosis, since such necessary preconditions as a 10 to 16 hours fast, or alcohol abstinence, are difficult to monitor in the clinical setting. Accurate glucose testing requires appropriate sample preparation and handling. Further pitfalls may be encountered during treatment: HbA1c assessment is associated with certain limitations and does not permit the estimation of glucose variations. To establish a differential diagnoses between type 1 (LADA) and type 2 diabetes in older patients GAD must be measured. New biochemical markers such as adiponectin and intact proinsulin may facilitate treatment decisions and monitoring in patients with type 2 diabetes.

Preserved counterregulatory hormone release and symptoms after short term hypoglycemic episodes in normal men.

To test the hypothesis that subsequent neuroendocrine and symptomatic responses are sustained after short term hypoglycemic episodes of less than 1-h duration, we studied hypoglycemia on 4 consecutive days and after an 8-day pause in 10 nondiabetic men. Highly reproducible decreases in plasma glucose (< 2.8 mmol/L) occurred on study days 1, 2, 3, 4, and 12 after iv insulin boluses (0.04 U/kg). Levels of the counterregulatory hormones rose during the hypoglycemic episodes in all instances, but maximal concentrations on study day 4 were not attenuated: glucagon (peaks on day 1 vs. day 4), 150 +/- 10 vs. 180 +/- 20 ng/L; cortisol, 400 +/- 30 vs. 420 +/- 40 nmol/L; ACTH, 12 +/- 2 vs. 13 +/- 2 pmol/L; GH, 11.1 +/- 1.8 vs. 12.5 +/- 2.2 micrograms/L; norepinephrine, 1.68 +/- 0.17 vs. 1.65 +/- 0.13 nmol/L; and epinephrine, 1370 +/- 440 vs. 1520 +/- 480 pmol. On each study day, symptoms of hypoglycemia were produced after induction of hypoglycemia, and there was no decrease in the degree of symptomatology on subsequent days. The multivariate analysis of variance showed no day to day differences in plasma glucose, counterregulatory hormones, or hypoglycemic symptoms. We conclude, firstly, that after short term hypoglycemic episodes, the neuroendocrine and symptomatic responses remain completely intact in normal individuals and, secondly, that short term periods of hypoglycemia are fundamentally different from prolonged periods, as described previously.