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OBJECTIVE Assess the prevalence of nonalcoholic fatty liver disease (NAFLD) and of liver fibrosis associated with nonalcoholic steatohepatitis in unselected patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS A total of 561 patients with T2DM (age: 60 ± 11 years; BMI: 33.4 ± 6.2 kg/m2; and HbA1c: 7.5 ± 1.8%) attending primary care or endocrinology outpatient clinics and unaware of having NAFLD were recruited. At the visit, volunteers were invited to be screened by elastography for steatosis and fibrosis by controlled attenuation parameter (≥274 dB/m) and liver stiffness measurement (LSM; ≥7.0 kPa), respectively. Secondary causes of liver disease were ruled out. Diagnostic panels for prediction of advanced fibrosis, such as AST-to-platelet ratio index (APRI) and Fibrosis-4 (FIB-4) index, were also measured. A liver biopsy was performed if results were suggestive of fibrosis. RESULTS The prevalence of steatosis was 70% and of fibrosis 21% (LSM ≥7.0 kPa). Moderate fibrosis (F2: LSM ≥8.2 kPa) was present in 6% and severe fibrosis or cirrhosis (F3–4: LSM ≥9.7 kPa) in 9%, similar to that estimated by FIB-4 and APRI panels. Noninvasive testing was consistent with liver biopsy results. Elevated AST or ALT ≥40 units/L was present in a minority of patients with steatosis (8% and 13%, respectively) or with liver fibrosis (18% and 28%, respectively). This suggests that AST/ALT alone are insufficient as initial screening. However, performance may be enhanced by imaging (e.g., transient elastography) and plasma diagnostic panels (e.g., FIB-4 and APRI). CONCLUSIONS Moderate-to-advanced fibrosis (F2 or higher), an established risk factor for cirrhosis and overall mortality, affects at least one out of six (15%) patients with T2DM. These results support the American Diabetes Association guidelines to screen for clinically significant fibrosis in patients with T2DM with steatosis or elevated ALT.

OBJECTIVE Type 1 diabetes is associated with compositional differences in gut microbiota. To date, no microbiome studies have been performed in maturity-onset diabetes of the young 2 (MODY2), a monogenic cause of diabetes. Gut microbiota of type 1 diabetes, MODY2, and healthy control subjects was compared. RESEARCH DESIGN AND METHODS This was a case-control study in 15 children with type 1 diabetes, 15 children with MODY2, and 13 healthy children. Metabolic control and potential factors modifying gut microbiota were controlled. Microbiome composition was determined by 16S rRNA pyrosequencing. RESULTS Compared with healthy control subjects, type 1 diabetes was associated with a significantly lower microbiota diversity, a significantly higher relative abundance of Bacteroides, Ruminococcus, Veillonella, Blautia, and Streptococcus genera, and a lower relative abundance of Bifidobacterium, Roseburia, Faecalibacterium, and Lachnospira. Children with MODY2 showed a significantly higher Prevotella abundance and a lower Ruminococcus and Bacteroides abundance. Proinflammatory cytokines and lipopolysaccharides were increased in type 1 diabetes, and gut permeability (determined by zonulin levels) was significantly increased in type 1 diabetes and MODY2. The PICRUSt analysis found an increment of genes related to lipid and amino acid metabolism, ABC transport, lipopolysaccharide biosynthesis, arachidonic acid metabolism, antigen processing and presentation, and chemokine signaling pathways in type 1 diabetes. CONCLUSIONS Gut microbiota in type 1 diabetes differs at taxonomic and functional levels not only in comparison with healthy subjects but fundamentally with regard to a model of nonautoimmune diabetes. Future longitudinal studies should be aimed at evaluating if the modulation of gut microbiota in patients with a high risk of type 1 diabetes could modify the natural history of this autoimmune disease.

OBJECTIVE Specific autoantibodies characterize type 1 diabetes in childhood but are also found in adult-onset diabetes, even when initially non–insulin requiring, e.g., with latent autoimmune diabetes (LADA). We aimed to characterize adult-onset autoimmune diabetes. RESEARCH DESIGN AND METHODS We consecutively studied 6,156 European diabetic patients attending clinics within 5 years of diagnosis (age range, 30–70 years) examined cross-sectionally clinically and for GAD antibodies (GADA) and antibodies to insulinoma-associated antigen-2 (IA-2A) and zinc-transporter 8 (ZnT8A). RESULTS Of 6,156 patients, 541 (8.8%) had GADA and only 57 (0.9%) IA-2A or ZnT8A alone. More autoantibody-positive than autoantibody-negative patients were younger, leaner, on insulin (49.5 vs. 13.2%), and female (P < 0.0001 for each), though LADA patients (9.7% of total) did not show categorically distinct clinical features from autoantibody-negative type 2 diabetes. Similarly, more GADA patients with high (>200 World Health Organization IU) (n = 403) compared with low (n = 138) titer were female, lean, and insulin treated (54.6 vs. 39.7%) (P < 0.02 for each). Autoantibody-positive patients usually had GADA (541 of 598; 90.5%) and had LADA more often than type 1 autoimmune diabetes (odds ratio 3.3). CONCLUSIONS Adult-onset autoimmune diabetes emerges as a prevalent form of autoimmune diabetes. Our results indicate that adult-onset autoimmune diabetes in Europe encompasses type 1 diabetes and LADA in the same broad clinical and autoantibody-positive spectrum. At diagnosis, patients with adult-onset autoimmune diabetes are usually non–insulin requiring and clinically indistinguishable from patients with type 2 diabetes, though they tend to be younger and leaner. Only with screening for autoantibodies, especially GADA, can they be identified with certainty.

The Fifth International Workshop-Conference on Gestational Diabetes Mellitus (GDM) was held in Chicago, IL, 11–13 November 2005 under the sponsorship of the American Diabetes Association. The meeting provided a forum for review of new information concerning GDM in the areas of pathophysiology, epidemiology, perinatal outcome, long-range implications for mother and her offspring, and management strategies. New information and recommendations related to each of these major topics are summarized in the report that follows. The issues regarding strategies and criteria for the detection and diagnosis of GDM were not reviewed or discussed in detail, since it is anticipated that the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study will provide data in mid-2007 that will foster the development of criteria for the diagnosis of GDM that are based on perinatal outcomes. Thus, for the interim, the participants of the Fifth International Workshop-Conference on GDM endorsed a motion to continue use of the definition, classification criteria, and strategies for detection and diagnosis of GDM that were recommended at the Fourth Workshop-Conference. Those guidelines are reproduced (with minor modifications) in this article in appendix Tables 1 and 2. The invited lectures, topical discussions, and posters presented at the conference and the invited manuscripts that appear in this issue of Diabetes Care served as the basis for the following summary and recommendations. ### Pathophysiology #### General considerations. Current diagnostic criteria assign the diagnosis of GDM to women with glucose levels in the upper ∼5–10% of the population distribution. The hyperglycemia varies in severity from glucose concentrations that would be diagnostic of diabetes outside of pregnancy to concentrations that are asymptomatic and only slightly above normal, but associated with some increased risk of fetal morbidity. Like all forms of hyperglycemia, GDM is characterized by insulin levels that are insufficient to meet insulin demands. The causes of pancreatic β-cell dysfunction that …

OBJECTIVE—In Spanish women with gestational diabetes mellitus (GDM), we aimed to study the progression to diabetes and abnormal glucose tolerance (AGT) and identify predictive factors. RESEARCH DESIGN AND METHODS—In 696 women with GDM and 70 control women, glucose tolerance was evaluated postpartum and at 5-year intervals. RESULTS—In the GDM group, the cumulative risk for diabetes and AGT was 13.8 and 42.4% after 11 years compared with 0 and 2.8% in control women, respectively (P < 0.05). Independent predictive factors for diabetes were previous hyperglycemia, four abnormal glucose values on the diagnostic oral glucose tolerance test (OGTT) or overt diabetes during pregnancy, 2-h blood glucose on the diagnostic OGTT ≥11.7 mmol/l, gestational age at diagnosis CONCLUSIONS—Spanish women with GDM have an increased risk of diabetes and AGT. Predictive factors display a nonlinear relationship. The strongest predictive factor for diabetes was four abnormal glucose values on the diagnostic OGTT or overt diabetes during pregnancy; the factor with the highest attributable fraction in the whole group was prepregnancy BMI.

OBJECTIVE—To compare the rate of insulin treatment and perinatal outcome in women with gestational diabetes mellitus (GDM) under endocrinologist-based versus diabetes nurse-based metabolic management. RESEARCH DESIGN AND METHODS—In a retrospective analysis, maternal characteristics, rate of insulin treatment, and perinatal outcome of patients with GDM delivering between 1 January 1995 and 30 June 1997 (n = 244) receiving endocrinologist-based care were compared with those delivering between 1 July 1997 and 31 December 1999 (n = 283) who received diabetes nurse-based care. The diabetes nurse’s role was similar to that of an advanced practice nurse in the U.S. There were no changes in the metabolic goals and instruments or in obstetric and neonatal management. Quantitative data were compared with the Mann-Whitney U test and categorical data, with Fisher’s exact test. RESULTS—Maternal characteristics (age, BMI, family history of diabetes, prior glucose intolerance, gestational age, and blood glucose at diagnosis of GDM) did not differ between groups treated during the two periods. Rates of insulin treatment and perinatal outcome (hypertension, preterm delivery, cesarean section, low Apgar score, macrosomia, small- and large-for-gestational-age newborns, obstetric trauma, major malformations, hypoglycemia, hypocalcemia, polycythemia, jaundice, respiratory distress, and mortality) were also similar in both groups. CONCLUSIONS—Comparison of periods of endocrinologist-based and diabetes nurse-based metabolic management of women with GDM showed no differences in the rate of insulin treatment and perinatal outcome. This supports a more active role of nurses in the management of women with GDM.

OBJECTIVE To assess the insulin antibody (IA) response to human insulin (HI) therapy in women with gestational diabetes. RESEARCH DESIGN AND METHODS IAs were measured by a competitive radiobinding assay in 50 women with gestational diabetes before and during treatment with HI and after delivery. At delivery, 15 maternal-cord blood sample pairs were analyzed for IA. As a reference, we searched for IA in 25 new-onset type I diabetic patients, before and at 3, 6, and 12 months after insulin therapy. RESULTS Insulin autoantibodies (IAAs) were detected in 1 of 50 women with gestational diabetes and 4 of 16 type I diabetic patients (P < 0.05). At the end of pregnancy after 9.3 ± 6.8 weeks on insulin therapy, 22 of 50 (44%) women with gestational diabetes became IA+ and 4 additional women were found to be positive 2 months postpartum. After 3 months on insulin, type I diabetic patients showed a higher rate of IA positivity (92%, P < 0.001). IA titers at the end of pregnancy were associated with the cumulative insulin dose (r = 0.29, P < 0.05). Postpartum, IA disappeared slowly in most IA+ women, but two women still showed IA 2 years after delivery Titers in cord blood were strongly related to those in maternal blood (r = 0.74, P < 0.01). The rate of adverse fetal outcome did not differ in IA− and IA+ mothers (27 vs. 40%, NS). CONCLUSIONS HI is immunogenic, and a short course of HI therapy induces IA in ∼ 50% of women with gestational diabetes and 92% of type I diabetic patients. In women with gestational diabetes, insulin dose is slightly associated with IA titers. These IAs apparently cross the placenta. Fetal outcome does not differ according to the maternal IA status, and IAs disappear gradually after delivery but may remain positive for 2 years after delivery.

Gestational diabetes mellitus (GDM) has long been recognized as a heterogeneous disorder (1,2), with autoimmunity against the β-cell contributing in a small subset of patients (3). Autoimmune diabetes is caused by the destruction of β-cells of pancreatic islets by an immune-mediated process, promoted by the interaction of genetic and environmental factors (4). Autoantibodies (AAs) against pancreatic β-cell antigens precede the clinical onset of type 1 diabetes (4). Circulating islet cell antibodies, originally described by indirect immunofluorescence in 1974 (5), have been demonstrated in the great majority of individuals with type 1 diabetes, both at the preclinical state and at the onset of clinically overt diabetes, and they persist in the circulation for a long time. Islet cell AAs include autoantibodies to islet cell cytoplasm (islet cell autoantibodies [ICAs]), to native insulin (insulin autoantibodies [IAAs]), to GAD (GADA) (6–8), and to tyrosine phosphatases (insulinoma-associated antigens IA-2A and IA-2β) (9,10). Age not only modifies the risk of autoimmune diabetes, but also the presence of AAs, the intensity of β-cell destruction, the rate of progression to overt diabetes, and the degree of residual insulin secretion. Approximately 30% of subjects with classic autoimmune diabetes (type 1A diabetes) present after age 35 years (11). Childhood autoimmune diabetes is associated with an increased prevalence of alleles DR3, DQB1*0201 and DR4, and DQB1*0302, with the proportion of heterozygotes declining with age at diagnosis (12). Children with the allele HLA DR2, DQB1*0602, almost never develop diabetes, whereas this allele confers a much lower protection for adult-onset autoimmune diabetes (13). Since the discovery of AAs against islet cell antigens, it has been recognized that a fraction of adults considered to have type 2 diabetes probably have autoimmune diabetes and that the presence of GADAs indicates a strong possibility of requiring …

Type 1 diabetes and autoimmune thyroid diseases (AITDs) often coexist in the same individual and in the same family. In the general population, AITD is more frequent in female subjects and prevalence increases with age. In diabetic patients, age and sex distributions are similar, but the prevalence is higher and increases with duration of the disease (1–3,4). Thyroid dysfunction can affect metabolic control in type 1 diabetes, and some studies (3) have shown a higher severity of diabetes when it is associated with AITD, although other studies (4) did not find these differences. Nevertheless, there is general agreement (5,6) on the utility of systematic screening of AITD in the type 1 diabetes population given its high prevalence, but procedure and frequency remain controversial. The aim of the present study was to determine the presence of thyroid autoantibodies at type 1 diabetes onset and its predictive capacity for the future development of thyroid dysfunction. Between September 1987 and January 1994, 204 patients were consecutively diagnosed with type 1 diabetes at our institution. One patient had developed primary hypothyroidism 3 years before the development of type 1 diabetes, 10 patients were not followed up after a few months from diagnosis, and thyroid autoimmunity at diagnosis was not determined in 17 patients. The remaining 176 patients were included in the study. The mean age at diabetes diagnosis was 24.4 ± 9.4 years, 65% were male …

OBJECTIVE To evaluate the effect of glycemic control improvement with insulin therapy on lipoprotein(a) [Lp(a)] levels in patients with NIDDM. RESEARCH DESIGN AND METHODS We performed a longitudinal study in a tertiary referral center to compare lipid and Lp(a) levels before and after 3 months of insulin therapy in 60 poorly controlled NIDDM patients (32 men, 28 women). Patients previously treated with oral hypoglycemic agents (n = 50) received one to two insulin doses, and those previously treated with insulin (n = 10) received multiple insulin doses. Lp(a) levels were measured by the Terumo method. Differences between the two periods were assessed by the paired t test and Wilcoxon's test. RESULTS After 3 months of insulin therapy, HbA1c decreased from 9.6 ± 1.9 to 6.0 ± 1.4% (P < 0.0005) in all patients and from 9.1 ± 2.1 to 6.1 ± 2.9% (P < 0.05) in patients under multiple insulin doses, being ≤ 6.0% in 59% of patients. Total triglyceride and VLDL cholesterol levels decreased (P < 0.01) and HDL cholesterol increased significantly (P < 0.0005). However, no changes in Lp(a) levels were observed in all patients (25.3 ± 25.0 vs 25.7 ± 27.2% mg/dl) and in patients with baseline Lp(a) levels above (63.5 ± 15.5 vs. 65.1 ± 23.1 mg/dl) or below 30 mg/dl (11.5 ± 7.5 vs. 11.5 ± 7.3 mg/dl). In addition, patients reaching HbA1c levels ≤ 6.0% or > 6.0% presented similar Lp(a) levels (26.0 ± 29.1 vs 25.3 ± 25.0 mg/dl). Moreover, no correlations were observed between changes in Lp(a) levels and in the glycemic control parameters. CONCLUSIONS This study shows that the improvement of glycemic control by insulin therapy does not influence plasma Lp(a) levels, measured by the Terumo method, in NIDDM patients, independently of baseline values and the degree of glycemic control reached.

In the print version of the article cited above, the affiliation for Didac Mauricio and Alberto De …

The metabolic goal of therapy in gestational diabetes (GD) is to maintain euglycemia, and when it is not achieved with diet alone, insulin therapy is added (1). Physical training has both acute and long-term effects on insulin sensitivity, insulin secretion, and glucose metabolism in both nondiabetic and diabetic subjects (2), and the benefit of training has also been shown in patients with GD, where controlled training achieves euglycemia with no need for insulin treatment (3). Nevertheless, physical exercise of moderate intensity has been associated with uterine contractions unless performed with the arms (4). The clinical observation that light postprandial exercise …