Risk Stratification in Women with Gestational Diabetes According to and Beyond Current WHO Criteria.

The pregnancy outcomes in women with gestational diabetes mellitus (GDM) and 'overt diabetes in pregnancy' were compared and the need for further subclassification was investigated with respect to postpartum outcome risk. Data from 944 women who had been uniformly diagnosed as having GDM in Munich, Germany, between 1998 and 2010, were re-classified into GDM and 'overt diabetes in pregnancy'. Pregnancy related outcomes in the offspring were derived from Bavarian birth registry data. Classification and regression trees were used to identify further GDM sub-phenotypes. In total, 88 women (9.3%) were re-classified as having 'overt diabetes in pregnancy'. Compared to women with GDM, women with 'overt diabetes in pregnancy' used insulin more frequently, and were at increased risk for large for gestational age infants [odds ratio 2.50 (95% confidence interval 1.02, 6.13)], preterm delivery [odds ratio 3.28 (1.02, 10.50)], and low APGAR-score at 5 min [odds ratio 12.70 (1.58, 102.2)]. In the 856 women with GDM, classification and regression tree analyses provided further risk stratification in that a combination of fasting glucose>5.3 mmol/l and 1-h glucose>11.1 mmol/l at GDM diagnosis predicted insulin requirement [OR 5.57 (3.75, 8.27) compared to the rest], and maternal body mass index (BMI)≥35 kg/m(2) predicted large for gestational age status. The new differentiation between GDM and 'overt diabetes in pregnancy' is a first step towards refining classification relevant to fetal and maternal postpartum risk. A combination of glucose levels and maternal BMI at diagnosis of GDM may provide further improvement.

Two Caucasian families with the hepatocyte nuclear factor-1alpha mutation Tyr218Cys.

We report on the first two Caucasian families with the MODY3 HNF-1alpha mutation Tyr218Cys. Clinical and laboratory examinations are shown in detail. Patients with HNF-1alpha related MODY may develop the full spectrum of diabetic complications. Therefore, early detection of family members with MODY3 is warranted.

[Diabetes mellitus and heart failure]. / Hohe Inzidenz, schlechte Prognose. Herzinsuffizienz bei Diabetikern.

Chronic heart failure (CHF) in patients with diabetes mellitus (DM) is a condition that is frequent and has a poor prognosis. Diabetes mellitus is an independent risk factor for CHF and vice versa. CHF is found in 10-15% of the patients with DM compared to 3% in individuals without DM. Apart from CHD and hypertension, hyperglycaemia and insulin resistance are directly linked to the development of diastolic dysfunction and to CHF. According to the stepwise diagnostic procedure recommended by the ESC in its guidelines from 2005, if heart failure is suspected, the disease should first be diagnosed by ECG, X-ray, or testing for natriuretic peptide and followed by echocardiography when test results are abnormal. Treatment of CHF in patients with diabetes mellitus is the same as that for nondiabetic patients and includes the use of ACEIs, ARBSs (as an alternative to or in combination with ACEIs), BBs, diuretics (in particular loop diuretics), aldosterone inhibitors and digitalis. Most importantly, meticulous glucose control is a must in patients with diabetes mellitus and CHF to improve prognosis. Contraindications for antidiabetic drugs such as glitazones for CHF-NYHA classes I-IV and metformin for NYHA classes III-IV need to be considered in patients with CHF and diabetes mellitus.

[Diabetes mellitus--differential diagnosis]. / Typ 1 bei Alteren, Typ 2 bei Kindern!

Differentiation of the various forms of diabetes is necessary for therapeutic reasons. Typical signs of type 2 diabetes are age over 40, obesity, and other markers for metabolic syndrome, a positive famitory, gradual development of the classical symptoms, and no evidence of ketosis. It is important to distinguish this from LADA (latent autoimmune diabetes of adulthood), a form of type 1 diabetes mellitus. To establish this differential diagnosis antibody testing is employed. Antibody tests in patients with newly manifest diabetes make good sense when the clinical diagnosis is not unequivocal, that is, to distinguish it from type 2 diabetes, MODY diabetes, hereditary and secondary forms. At present, immunodiagnosis is used too often in unambiguous cases of type 1 diabetes, but too rarely in supposed type 2 diabetes. As a rule, LADA patients are GADA-positive. If MODY diabetes is suspected, a genetic examination is indicated. In patients with GDM, antibody testing with GADA makes sense, in particular in slim patients receiving insulin treatment, since these patients have a high risk for developing a postpartum diabetes already in the first years.

Prediction of type 1 diabetes postpartum in patients with gestational diabetes mellitus by combined islet cell autoantibody screening: a prospective multicenter study.

Women with gestational diabetes mellitus (GDM) have a considerable risk of developing diabetes later in life. To determine the predictive value of autoantibody markers in gestational diabetic pregnancy for the development of type 1 diabetes postpartum, we tested 437 patients with GDM (289 women treated with diet only [GDM-A] and 148 requiring insulin treatment during pregnancy [GDM-B]) for antibodies to islet cells (ICAs), GAD (GADAs), and tyrosine phosphatase ICA512/IA-2 (IA2As). We prospectively followed them with repeated oral glucose tolerance tests and antibody determinations for up to 7 years postpartum (mean, 1.6 years; range, 0-7.2 years). The cumulative risk of diabetes up to 5 years postpartum was 17% (95% CI 12-22%). The risk of type 1 diabetes was 3% (2-5%) by 9 months and 7% (4-9%) 2 years after delivery. At delivery, 8.5% of all patients were ICA+, 9.5% were GADA+, 6.2% were IA2A+, and 18.1% were positive for at least one antibody (12.6% for GDM-A vs. 30.4% for GDM-B, P < 0.0001). During follow-up, GADAs persisted in 75%, ICAs in 35%, and IA2As in 30% of the subjects positive for the respective marker at delivery. By 2 years postpartum, 29% (19-39%) of patients positive for at least one antibody developed type 1 diabetes, compared with 2% (1-4%) of antibody-negative patients (P < 0.0001). Thereby, the risk for type 1 diabetes 2 years postpartum increased with the number of antibodies present at delivery from 17% (6-28%) for one antibody, to 61% (30-91%) for two antibodies, and to 84% (55-100%) for 3 antibodies. Risk of progression to type 1 diabetes postpartum was also associated with the status of parity. Women with one or more pregnancies before the index pregnancy had a higher risk for type 1 diabetes 2 years after delivery (14.7% [4.9.-24.5%]) than women having their first (i.e., index) pregnancy (5% [2.9-7.1%]) (P < 0.006). A comparison of different prediction strategies showed that single antibody screening with GADA yielded the highest sensitivity of 63% (45-75%), compared with ICA (48% [31-65%]) and IA2A (34% [13-47%]). Combined screening with two autoantibodies increased sensitivity to 74% (58-90%) and 75% (60-92%) when using GADA plus ICA or GADA plus IA2A, respectively. Screening with all three markers improved sensitivity further to 82% (67-100%). Beta-cell autoantibodies determined at delivery in women with GDM are highly predictive for the development of type 1 diabetes postpartum. Autoantibody screening in pregnant women with GDM from populations at high risk for type 1 diabetes should therefore be considered to allow early diagnosis and appropriate therapy.

Exposure to exogenous insulin promotes IgG1 and the T-helper 2-associated IgG4 responses to insulin but not to other islet autoantigens.

Insulin immunization in animal models induces T-helper (Th) 2-like antibody subclass responses to insulin and other beta-cell antigens. The aim of this study was to determine whether exposure to insulin in humans resulted in a similar subclass bias of the humoral immune response. Levels of IgG subclass antibodies to insulin (IAs), GAD, and IA-2 were measured before and after treatment with insulin in the following groups of patients: 29 patients with newly diagnosed type 1 diabetes treated with intravenous and/or subcutaneous insulin; 10 newly diagnosed patients randomized to cyclosporin A (CsA) or placebo plus subcutaneous insulin for 12 months; and 14 islet cell antibody-positive relatives receiving either intravenous and subcutaneous insulin prophylaxis or no treatment. At the onset of diabetes, the major subclass distributions of insulin autoantibodies (IAAs) were IgG1 and, to a lesser extent, IgG4. After insulin treatment in the 29 new-onset patients, IAs were initially of the IgG1 subclass. IgG4-IAs appeared later, but at 12 months, they were at higher levels than IgG1-IAs in 11 patients. Responses were higher in children compared with adults and were higher in subjects with IAAs (P < 0.001). Insulin prophylaxis in relatives showed a similar profile, with a decline in levels of IgG1-IAs after cessation of daily subcutaneous insulin. Patients treated with CsA took longer to develop IAs and showed suppressed levels of IgG4-IAs; however, their levels of high-titer IgG1-IAs persistently rebounded after completion of CsA therapy. Despite the presence of IgG4-IAs in most insulin-treated patients and relatives, a shift to IgG4-anti-GAD or IgG4-IA-2 was not found for up to 3 years after the initiation of insulin therapy. While our findings need to be correlated with T-cell cytokine responses, we suggest that the strong IgG4-IA response in insulin-treated patients is consistent with an enhancement of Th2 immunity, but there is no evidence of subsequent spreading of potentially Th2-associated IgG4 responses to other autoantigens.

Perinatal autoimmunity in offspring of diabetic parents. The German Multicenter BABY-DIAB study: detection of humoral immune responses to islet antigens in early childhood.

IDDM results from immune-mediated destruction of insulin-producing pancreatic beta-cells in individuals genetically susceptible for the disease. There is evidence that the 65-kDa isoform of GAD plays a critical role in the induction of autoimmune diabetes in NOD mice. In humans, it is still unclear when and to what beta-cell antigens autoreactive lymphocytes become activated during early disease. We conducted a prospective study from birth, BABY-DIAB, among children of mothers with IDDM or gestational diabetes or fathers with IDDM, and we investigated the temporal sequence of antibody responses to islet cells (ICA), insulin (IAA), GAD (GADA), and the protein tyrosine phosphatase IA-2/ICA512 (IA-2A). Of 1,019 children included at birth, we have currently followed 513 to the age of 9 months, 214 to the age of 2 years, and 37 to the age of 5 years. At birth, all antibody specificities were frequent in newborns of diabetic mothers but not fathers and are suggested to be transplacentally acquired because they are strongly correlated with antibody levels in their diabetic mothers. In early childhood, antibody levels were <99th percentile of control subjects in the majority of children. However, 37 children exhibited elevated antibody levels; these were most frequently detected at the age of 2 years. The antibody prevalence at age 2 years was 2.3% for ICA, 7% for IAA, 4.2% for GADA, and 2.8% for IA-2A (8.9% positive for at least one antibody). Children of diabetic fathers were positive for at least one antibody more frequently than were children of diabetic mothers (9 months of age: 8.5 vs. 3.6%; 2 years of age: 16.7 vs. 7.9%). There was no specific sequence in the appearance of positive autoantibodies, but 13 (35%) antibody-positive cases already had more than one ICA before the age of 2 years and 7 (19%) showed reactivity to three islet cell antigens before age 5 years. The presence of multiple antibodies confers high risk for the future development of diabetes; three of six children who exhibited positive antibody responses to all four antibodies tested and another child with two positive antibodies developed clinical diabetes at the ages of 13, 21, and 27 months and 5 years. We conclude that loss of tolerance to beta-cell autoantigens and appearance of autoimmune phenomena occur very early in life in individuals with genetic susceptibility for IDDM. Screening programs to identify candidates for disease-prevention therapies can therefore be focused on this young age-group, in whom the disease process may be less advanced and who may therefore be best suited to such therapies.

No major association of breast-feeding, vaccinations, and childhood viral diseases with early islet autoimmunity in the German BABYDIAB Study.

OBJECTIVE: Environmental factors have been suggested to play an important role in the pathogenesis of type 1 diabetes. The aim of this study was to assess the influence of breast-feeding, vaccinations, and childhood viral diseases on the initiation of islet autoimmunity in early childhood. RESEARCH DESIGN AND METHODS: Data were prospectively collected from questionnaires obtained at birth, at 9 months of age, and at 2 years of age in 823 offspring from parents with type 1 diabetes. By 2 years of age, 31 offspring had islet antibodies, and 10 developed overt diabetes by the time of follow-up. RESULTS: In offspring from mothers with type 1 diabetes, duration of exclusive and total breast-feeding did not differ between islet antibody-positive and -negative children, regardless of HLA genotype, and breast-feeding of 3 months or longer was not associated with protection from antibody development or diabetes onset. In offspring from diabetic fathers, non-statistically significant reductions in exclusive and total breast-feeding times were observed in the antibody-positive cohort. Neither type nor quantity of vaccinations (including Bacille Calmette-Guerin vaccine; haemophilus influenzae vaccine; diphtheria, tetanus, and pertussis vaccine; tick-born encephalitis vaccine; or measles, mumps, and rubella vaccine) were associated with the development of islet antibodies and diabetes. Measles, mumps, and rubella were not reported in children with islet antibodies or diabetes. CONCLUSIONS: This study showed no evidence that proposed environmental factors affect islet antibody development in the first 2 years of life in offspring from parents with type 1 diabetes.

Clinical efficacy of new thiazolidinediones and glinides in the treatment of type 2 diabetes mellitus.

A central finding of the UKPDS was that in type 2 diabetic patients, tight glycemic control with HbA1c targets as close to the normal range as possible must be achieved to further reduce diabetes related-complications, -mortality, and -cardiovascular disease, highlighting the need for new, optimized treatment strategies. With a focus on clinical efficacy, this paper discusses the results from the 20 major therapeutical trials published in the years 1997-1999, that evaluated the new insulinsensitizing thiazolidinediones Rosiglitazone and Pioglitazone and the new insulin-releasing potassium channel blockers Repaglinide and Nateglinide. While for Nateglinide, promising, but only preliminary data is available at current, Rosiglitazone, Pioglitazone, and Repaglinide have been shown appropriate for both mono- and combination therapy with current standard drug treatment of type 2 diabetes. Similar to the known, older antidiabetic drugs, the new agents discussed have comparable blood glucose lowering potentials with a dose-related capacity of 0.5 to 1.5% HbA1c reduction. These beneficial effects were both seen in drug-naive patients previously treated with diet only and in combination therapies where patients had previous antidiabetic standard drug treatment suggesting effectiveness of glitazones and glinides also in more advanced stages of the disease. Problems with adverse effects appeared minor although long-range implications of weight gain, edema, lowering of hemoglobin, increase of total cholesterol for the glitazones, and hypoglycemia for glinides warrant further consideration. What becomes clear from the variety of most recent mono- and combination treatment studies with as much as five different classes of antidiabetic drugs is that individually tailored therapies that recognize quality of life parameters and target the predominant features of metabolic pathology (such as early postprandial versus fasting hyperglycemia, degree of insulin resistance, progressive loss of 1-cell function) may become a feasible goal in the future.

Antibodies to bovine serum albumin (BSA) in type 1 diabetes and other autoimmune disorders.

Clinical and experimental studies have delineated a link between dietary cow milk protein and the development of insulin-dependent diabetes mellitus (IDDM), and bovine serum albumin (BSA) was proposed as one candidate mediator of this effect. The demonstration of anti-BSA antibodies in new onset type 1-diabetic children from Finland initiated a controversial debate on the utility of BSA antibodies as a disease marker and on the role of BSA in IDDM. Here we analyzed BSA antibodies in newly diagnosed type 1-diabetic patients and their first degree relatives, patients with other autoimmune diseases, and children with Down's syndrome from Germany. Blinded serum samples (n = 308) were screened for IgG anti-BSA antibodies by particle concentration fluoroimmunoassay (PCFIA). The prevalence of elevated BSA antibodies in newly diagnosed type 1-diabetic patients was low (11%), although mean BSA antibody levels were significantly increased in diabetic patients as compared to controls (1.94 +/- 1.51 vs. 0.97 +/- 0.93 kFU, p < 0.0007). Mean BSA antibody levels were also increased in ICA+ and/or IAA+ first degree relatives (1.32 +/- 0.43, p < 0.002) and in children with Down's syndrome (3.01 +/- 1.93, p < 0.0007), but not in the other autoimmune disorders tested. The low prevalence of elevated anti-BSA levels in IDDM patients limits the clinical usefulness of this immune marker. We conclude that current anti-BSA assays do not substantially contribute to the prediction and diagnosis of IDDM.

Lupus-like panniculitis in a patient with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder, characterised by a loss of self-tolerance to endocrine tissues, chronic candidiasis and ectodermal disorders. APECED is associated with mutations of a single gene, designated autoimmune regulator (AIRE). We describe a 31-year-old APECED patient with non-traumatic, cutaneous ulcers on both forearms with features of a lupus-like panniculitis. On admission to the ICU in September 2001, the patient suffered from a ketoacidotic, hyperglycemic coma and adrenal crisis due to an Enterobacter-cloacae sepsis, originating from multiple, necrotising deep cutaneous ulcers. These ulcers spontaneously developed on both forearms, some of which were just emerging, full blown or healing with scars. Histological examination showed signs of a scarring panniculitis and vasculitis. Immunohistochemistry and direct immunofluorescence with characterisation of immunoglobulin and complement-factor binding pattern revealed features of a lupus-like panniculitis. Sequence analysis of all 14 exons of the AIRE gene revealed a R257 X mutation in exon 6 resulting in a nonsense mutation at codon 257 confirming the diagnosis of APECED. Oral treatment with 60 mg/day corticosteroids for two weeks led to complete resolution of all ulcers. In conclusion, mutations in the AIRE gene may provide the genetic background against which additional factors can initiate an autoimmune process. Here, autoimmune panniculitis appears to be an associated feature of the APECED syndrome. Our findings support the use of immunosuppressive therapy for autoimmune disease components of the APECED syndrome.

[Inflammation and diabetes]. / Chronische Entzündung schon bei leicht gestörter Glukosetoleranz. Schützt antiinflammatorische Therapie vor Hypertonie und Diabetes?

The focus of current diabetes research is the clarification of the pathogenetic relationships between subclinical inflammation, diabetes and arteriosclerosis. Even minimal disturbances in glucose tolerance are associated with a chronic, generalized inflammatory reaction that links components of the metabolic syndrome and contributes to the development of diabetic complications as well as to the development and progression of arteriosclerosis. The most important mediators and markers of this inflammation cascade are NF-kappaB, TNF-alpha, IL-6, CRP and PAI-1. For the treatment of subclinical inflammation, substances with anti-inflammatory properties such as statins or ACE inhibitors are of increasing importance.

[62 year-old patient with rapid progressive edema, low potassium and hypertension]. / Hypertonie, Hypokaliämie und rasch progrediente Odeme bei einem 62-jährigem Diabetiker.

A 62 year-old patient was admitted to hospital with rapid progressive edema, low potassium and hypertension. This symptoms are caused by Cushing's syndrome through ectopic paraneoplastic ACTH-production. Primary neoplasm is a small cell cancer. A Sertoli-cell-tumor of the testis was diagnosed as an additional carcinoma. Palliative chemotherapy and adrenostatic agents did not improve the clinical findings and the patient died eight weeks after admission.

Transfer of diabetes from prediabetic NOD mice to NOD-SCID/SCID mice: association with pancreatic insulin content.

Splenocytes from prediabetic female NOD mice can transfer diabetes to NOD-SCID mice. Whereas the kinetics of disease transfer was shown to be a function of the age of donor splenocytes, information is scarce as to how the stage of autoimmune disease, as evaluated by pancreatic insulin content, is related to the diabetogenic potency of splenic T-cells. We therefore determined individual diabetes transfer times after an i. v. injection of splenocytes from prediabetic NOD mice of different ages into female NOD-SCID mice in relation to the diabetes incidence in NOD donor mice and their pancreatic insulin contents. Three groups (n = 8) of NOD mice aged 5, 11, and 17 weeks (wk) underwent splenectomy and hemipancreatectomy. After that, 10x10 (6) splenocytes either pooled from all donor NOD mice of the different age groups or individually from single donor mice were transferred to groups of four 6-week-old NOD-SCID mice, respectively, in two sets of experiments. Insulin was extracted from the resected hemipancreas, and the insulin content was determined by a RIA. Diabetes in the NOD-SCID cohort occurred after a mean time of 126 days after transfer of pooled splenocytes from 5-week-old NODs, after 68 days (transfer from 11-week-old NODs), and after a mean time of 43 days (transfer from 17-week-old NODs, 5 vs. 11 wk: p < 0.02, 11 vs. 17 wk: p < 0.001). Individual time to diabetes positively correlated with diabetes transfer times in NOD-SCID recipients (p < 0.0001) in the 17-week-old NOD mice, confirming previous diabetes transfer studies in hemi-pancreatectomized NOD mice. Furthermore, individual insulin concentrations in 17-week-old NOD mice also positively correlated to diabetes transfer times in recipient mice (p < 0.0001). No such correlations for these parameters were seen for the 5 and 11-week-old NOD mice (time to diabetes: 11 wk, p = 0.14, 5 wk, p = 0.75; insulin content: 11 wk, p = 0.81, 5 wk, p = 0.14). These data suggest that destructive T-cell activity increases during the course of islet autoimmunity. The immune response seems to be programmed for beta-cell destruction just before diabetes onset. This is the only time that pancreatic insulin content predicts the impending onset of diabetes.

Relationship between the incidence of type 1 diabetes and maternal enterovirus antibodies: time trends and geographical variation.

AIMS/HYPOTHESIS: We have previously observed an inverse correlation between the incidence of type 1 diabetes and enterovirus infections in the background population. The aim of this study was to analyse whether maternal enterovirus antibody status, which reflects both the frequency of enterovirus infections and the protection conferred by the mother on the offspring, also correlates with the incidence of type 1 diabetes. METHODS: Maternal enterovirus antibodies were analysed from serum samples taken from pregnant women between 1983 and 2001 in Finland and Sweden using enzyme immunoassay and neutralisation assays. Comparable samples were also taken between 1999 and 2001 in countries with a lower incidence of diabetes (Estonia, Germany, Hungary, Israel, Lithuania, Russia). RESULTS: A clear decrease was observed in maternal enterovirus antibody levels over the past 20 years (p<0.0001). The frequency of enterovirus antibodies was higher in countries with a low or intermediate incidence of type 1 diabetes compared with high-incidence countries (p<0.0001). CONCLUSIONS/INTERPRETATION: These findings are in line with our previous observations supporting the hypothesis that a low frequency of enterovirus infection in the background population increases the susceptibility of young children to the diabetogenic effect of enteroviruses.

The role of oral antidiabetic agents: why and when to use an early-phase insulin secretion agent in Type II diabetes mellitus.

Evidence obtained in the 1990's strongly supports the notion that glycaemic control is important not only in Type I (insulin-dependent), but also in Type II (non-insulin-dependent) diabetes mellitus. Although measurement of HbA(1c) is the standard for assessing the effect of glucose control in the occurrence and prevention of diabetic sequelae, more recent evidence indicates that other glucose parameters are also important. Postchallenge and postprandial hyperglycaemic peaks seem to be prospective determinants of vascular damage in early Type II diabetes. Currently, there is no overall accepted standard approach for the pharmacological management of Type II diabetes. The United Kingdom Prospective Diabetes Study has shown that reaching a near-normal glycaemic target is critically important and the pharmacotherapy of this progressive disease is difficult. Loss of endogenous insulin secretion has been substantiated to cause the progression of Type II diabetes in the United Kingdom Prospective Diabetes Study. Early insulinization, however, was not advantageous over other forms of therapy. The advent of polypharmacy in recent years has greatly strengthened the treatment of this disease. This synergy has been extended of late with the development of early-phase insulin secretion agents. Two such agents, nateglinide and repaglinide, can be used to reduce mealtime glucose excursions and HbA(1c) as monotherapy, and in combination with metformin; their antidiabetic potential is similar to the combination treatment with glibenclamide and metformin. Additional substantiation of their long-term effect on improving life expectancy and reducing diabetic complications in Type II diabetic patients is now required.

Effect of acarbose on additional insulin therapy in type 2 diabetic patients with late failure of sulphonylurea therapy.

AIM: The present study investigated the effect of acarbose on insulin requirements and glycaemic control in patients with type 2 diabetes receiving exogenous insulin due to secondary failure of maximum dose sulphonylurea therapy. METHODS: A single-centre, double-blind, randomized, placebo-controlled study was performed in 48 type 2 diabetic patients with late-term failure following at least 3 years of sulphonylurea therapy requiring additional insulin therapy to determine the impact of acarbose on glycaemic control and insulin requirements. The primary end points were glycaemic response rate (responders being predefined as patients who achieve a decrease in HbA1c to less than 8% or a reduction by at least 15% as compared to the baseline values) and the daily insulin dose at 6 months. Secondary parameters assessed included postprandial changes in blood glucose, serum insulin and C-peptide during the treatment period. RESULTS: There were significantly more responders in the acarbose-treated group compared with the placebo group (20/24 patients vs. 10/19 patients; p < 0.05). The mean daily insulin dose after 24 weeks of treatment was 16.4 +/- 10.1 IU in the acarbose group and 22.4 +/- 12.2 IU in the placebo group (mean +/- s.d.; p < 0.07). Postprandial increases in blood glucose, insulin and C-peptide were consistently lower in the acarbose-treated group than in the placebo group. For example, the mean increase in 2-h postprandial serum insulin remained almost unchanged in the acarbose group at the end of 24 weeks of treatment compared to an increase to 43 +/- 29 microU/ml (mean +/- s.d.) at the end of the study period for the placebo group. CONCLUSIONS: The findings of this study suggest that the addition of acarbose to sulphonylurea/insulin combination therapy can improve glycaemic control in type 2 diabetic patients. Acarbose may also reduce insulin resistance and hyperinsulinaemia.

No evidence for an association of coxsackie virus infections during pregnancy and early childhood with development of islet autoantibodies in offspring of mothers or fathers with type 1 diabetes.

Recent case-control studies reported an increased frequency of antibodies against Coxsackie virus (CV) antigens in patients with newly diagnosed type 1 diabetes and during pregnancy in mothers of diabetic offspring, suggesting a role for CV infections in the pathogenesis of type 1 diabetes (T1D). However, it is not known whether CV infections are causally related to the development of islet autoantibodies or merely represent secondary events in subjects already affected with established islet autoimmunity. Therefore we have prospectively evaluated CV infections from birth, prior to and in parallel with the appearance of islet autoantibodies in offspring of parents with T1D. Using indirect ELISAs, IgG-antibodies (abs) against a panel of CV, and IgG- and IgM-abs to CVB3, CVB4, and CVB5 were measured at 9 months, 2, 5, and 8 years in 28 offspring of mothers or fathers with T1D or of mothers with gestational diabetes who developed persistent islet antibodies (IAA, GADA, IA-2A), and compared to 51 islet autoantibody-negative offspring matched for place and date of birth. CV infections were also determined at delivery in 16 mothers whose offspring developed islet autoantibodies later in life and compared to 110 mothers (matched for HLA-DR, place and date of birth) whose offspring remained islet autoantibody-negative during early childhood. CV-antibodies were detected in only 2/28 (7.1%) offspring who developed islet autoantibodies during follow up and in 7/51 (13.7%) offspring without islet autoantibodies (median follow up time 3.0 years, range 2.0-8.7). CV-IgG abs were detected in one mother (6.3%), whose offspring developed islet autoantibodies during early childhood, compared to 15 mothers (13.6%) with islet autoantibody-negative offspring (P=0.5). Also, partum levels of CV-IgG and CVB3-, -4-, and -5-IgM abs were similar in both groups (median 35 U, 0.08 index (I), 0.08, 0.05 vs. 35 U, 0.06 I, 0.11, and 0.06, resp., P> 0.35 in each case). These data make it unlikely that CV infections during pregnancy or in early childhood play a major role in the induction of islet autoimmunity in offspring of mothers or fathers with T1D or of mothers with gestational diabetes.