A functional analysis of the role of IGF2 in IDDM2-encoded susceptibility to type 1 diabetes

OBJECTIVE: The association of antioxidant nutrients and risk of nuclear opacification was evaluated in the Longitudinal Study of Cataract. DESIGN: Nutritional data were collected at baseline on the 764 participants, which included assessment of dietary intake, use of vitamin supplements, and plasma levels of vitamin E. Ophthalmologic and other data were collected at baseline and at yearly follow-up visits, including lens photographs, which were graded using the Lens Opacities Classification System III protocol. MAIN OUTCOME MEASURES: Analyses examined whether the nutritional factors at baseline were related to increases in nuclear opacification at follow-up. The MULCOX2 approach, an extension of the Cox regression model, was used. Results are presented as relative risks (RRs) and 95% confidence intervals. INTERVENTION: Intervention was not applicable. RESULTS: The risk of nuclear opacification at follow-up was decreased in regular users of multivitamin supplements (RR = 0.69; 0.48-0.99), vitamin E supplements (RR = 0.43; 0.19-0.99), and in persons with higher plasma levels of vitamin E (RR = 0.58; 0.36-0.94). CONCLUSIONS: In regular users of multivitamin supplements, the risk of nuclear opacification was reduced by one third; in regular users of vitamin E supplements and persons with higher plasma levels of vitamin E, the risk was reduced by approximately half. These results are similar to those obtained in our earlier case-control study. Because these data are based on observational studies only, the results are suggestive but inconclusive. The possible effect of nutritional supplements on the lens requires confirmation by ongoing clinical trials.     

The association between a family history of type 2 diabetes and coronary artery disease in a type 1 diabetes population

The plasma protein beta2-glycoprotein I (beta2-GPI) is a major target of autoantibodies in patients with the antiphospholipid syndrome. To understand the physiological function of beta2-GPI and its potential role in the pathophysiology of the antiphospholipid syndrome, the binding of beta2-GPI to phospholipid membranes was characterized. The interaction of beta2-GPI with unilamellar vesicles containing varying amounts of acidic phospholipids with phosphatidylcholine (PC) was measured at equilibrium via relative light scattering. Analysis of binding isotherms gave apparent Kd values ranging from approximately 5.0 to 0.5 microM over a range of 5-20 mol % anionic phospholipid. Inhibition of binding by increasing ionic strength and Ca2+ ions suggests that binding is primarily electrostatic. These data indicate that beta2-GPI binding to membranes with physiological anionic phospholipid content is relatively weak in comparison to plasma coagulation proteins, suggesting that beta2-GPI does not function as a physiological anticoagulant based on its phospholipid-binding properties.     

Metformin reduces systemic methylglyoxal levels in type 2 diabetes

Methylglyoxal (MG) is a reactive alpha-dicarbonyl that is thought to contribute to diabetic complications either as a direct toxin or as a precursor for advanced glycation end products. It is produced primarily from triose phosphates and is detoxified to D-lactate (DL) by the glyoxalase pathway. Because guanidino compounds can block dicarbonyl groups, we have investigated the effects of the diamino biguanide compound metformin and of hyperglycemia on MG and its detoxification products in type 2 diabetes. MG and DL were measured by high-performance liquid chromatography in plasma from 57 subjects with type 2 diabetes. Of these subjects, 27 were treated with diet, sulfonylureas, or insulin (nonmetformin), and 30 were treated with metformin; 28 normal control subjects were also studied. Glycemic control was determined by HbA1c. MG was significantly elevated in diabetic subjects versus the normal control subjects (189.3 +/- 38.7 vs. 123.0 +/- 37 nmol/l, P = 0.0001). MG levels were significantly reduced by high-dosage (1,500-2,500 mg/day) metformin (158.4 +/- 44.2 nmol/l) compared with nonmetformin (189.3 +/- 38.7 nmol/l, P = 0.03) or low-dosage (< or = 1,000 mg/day) metformin (210.98 +/- 51.0 nmol/l, P = 0.001), even though the groups had similar glycemic control. Conversely, DL levels were significantly elevated in both the low- and high-dosage metformin groups relative to the nonmetformin group (13.8 +/- 7.7 and 13.4 +/- 4.6 vs. 10.4 +/- 3.9 micromol/l, P = 0.03 and 0.06, respectively). MG correlated with rising HbA1c levels (R = 0.4, P = 0.03, slope = 13.2) in the nonmetformin subjects but showed no increase with worsening glycemic control in the high-dosage metformin group (R = 0.0004, P = 0.99, slope = 0.02). In conclusion, MG is elevated in diabetes and relates to glycemic control. Metformin reduces MG in a dose-dependent fashion and minimizes the effect of worsening glycemic control on MG levels. To the extent that elevated MG levels lead to their development, metformin treatment may protect against diabetic complications by mechanisms independent of its antihyperglycemic effect.     

Enhanced susceptibility of low-density lipoprotein to in vitro oxidation in type 1 and type 2 diabetic patients

Macrovascular disease represents a major cause of morbidity and mortality in patients with diabetes mellitus. Low-density lipoprotein (LDL) is involved in the pathogenesis of atherosclerotic lesions, through modifying processes such as oxidation. We examined the in vitro susceptibility to oxidation and the oxidizability of LDL isolated from the plasma of Type 1 and Type 2 diabetic patients. Two groups of diabetic patients (20 Type 1, 20 Type 2) were compared with sex- and age-matched non-diabetic control groups. In vitro oxidation of the purified LDL preparations was assessed by determination of the kinetics for the formation of conjugated dienes (lag phase duration, maximal rate and maximal dienes concentration) and by measurement of thiobarbituric acid-reacting substances (TBARS) in the presence of copper ions. LDL from both Type 1 and Type 2 diabetic patients exhibited a shorter lag phase duration for conjugated dienes formation (94 +/- 14 vs. 108 +/- 20 and 97 +/- 26 vs. 112 +/- 18 min for Type 1 and Type 2 diabetic groups vs. respective control groups, P < 0.05). We also observed an increase in maximal rate of conjugated dienes formation (2.21 +/- 0.55 vs. 1.52 +/- 0.31 and 2.02 +/- 0.55 vs. 1.52 +/- 0.31 nmol/mg LDL/min, P < 0.01) and of maximal production of TBARS (77.9 +/- 11.8 vs. 65.5 +/- 10.4 and 76.7 +/- 9.9 vs. 65.3 +/- 9.4 nmol/mg LDL protein, P < 0.05) in diabetic groups. Our results demonstrate both a higher susceptibility to oxidation and a higher oxidizability of LDL from diabetic patients, as much for Type 1 as Type 2 diabetic subjects with or without pre-existent vascular complications. This enhanced propensity of LDL oxidation in patients with diabetes mellitus could at least partly be attributable to quantitative and qualitative alterations in the chemical composition of LDL and to the glycoxidation process occurring on these lipoproteins.     

Comparison of granulocyte function in diabetes mellitus type 1 and type 2

The phagocytosis rate of polymorphonuclear leucocytes was measured by flow-cytometry. Vital bacteria were incubated in whole blood. 111 blood samples were measured, 54 in diabetic patients (14 type 1 and 40 type 2), the rest of 57 samples in healthy controls. Results showed firstly, that a decompensation in glucose metabolism in diabetic patients correlated with a decrease in phagocytosis. The HbA1 level was more closely correlated than the glucose level. The second result was, that despite a similar grade of decompensation in type 1 and type 2 diabetic patients, the phagocytosis was significantly lower in type 1 diabetes. No correlation was found concerning age and sex. These findings show, that the impact on granulocytic function in diabetes is of multifactorial origin, not only a shorter or longer elevation of the serum glucose level can explain it solely.     

Genetic susceptibility factors in type 1 diabetes: linkage, disequilibrium and functional analyses

Rehabilitation after soft-tissue autograft reconstructions is controversial because there is indirect evidence that some grafts fail by creeping over time. The vulnerability of soft-tissue grafts to creep over healing time and the effects of the load environment during healing on this vulnerability have never been studied specifically. We hypothesized that immobilization would decrease the magnitude of the vulnerability of ligament grafts to creep. Thirty-nine skeletally mature New Zealand White rabbits underwent a standardized medial collateral ligament autograft procedure to the right hindlimb, and 19 of the rabbits also had the limb rigidly pinned into flexion. Subgroups were killed at 3 or 8 weeks, and all isolated tibia/medial collateral ligament/femur complexes were tested for creep at 4.1 MPa under a standardized protocol. Eight normal medial collateral ligament controls were tested similarly. Results showed that all grafts were quantitatively more susceptible to cyclic and static creep than were normal medial collateral ligament controls (p < 0.05). By 3 weeks of healing, immobilization significantly increased the magnitude of the vulnerability of the grafts to cyclic, static, and total creep (all: p < 0.05). Furthermore, the grafts had more unrecovered creep strain than did the controls following a 20-minute recovery period. Contrary to our hypothesis, immobilization resulted in increased vulnerability of these ligament autografts to creep even with this relatively nonprovocative test of short duration and low stress. We postulate that following immobilization, this increase in the magnitude of susceptibility of the grafts to creep will result in functionally significant elongation of the graft if it is exposed to higher loads and over longer periods of time in vivo.     

Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies

The aim of the study was 1) to establish the prevalence of GAD antibodies (GADab) in a population-based study of type 2 diabetes in western Finland, 2) to genetically and phenotypically characterize this subgroup, and 3) to provide a definition for latent autoimmune diabetes in adults (LADA). The prevalence of GADab was 9.3% among 1,122 type 2 diabetic patients, 3.6% among 558 impaired glucose tolerance (IGT) subjects, and 4.4% among 383 nondiabetic control subjects. Islet antigen 2 antibodies (IA2ab) or islet cell antibodies were detected in only 0.5% of the GADab- patients. The GADab+ patients had lower fasting C-peptide concentrations (median [interquartile range]: 0.46 [0.45] vs. 0.62 [0.44] nmol/l, P = 0.0002) and lower insulin response to oral glucose compared with GADab- patients. With respect to features of the metabolic syndrome, the GADab+ patients had lower systolic (140 [29.1] vs. 148 [26.0] mmHg, P = 0.009) and diastolic (79.2 [17.6] vs. 81.0 [13.1] mmHg, P = 0.030) blood pressure values, as well as lower triglyceride concentrations (1.40 [1.18] vs. 1.75 [1.25] mmol/l, P = 0.003). GADab+ men had a lower waist-to-hip ratio compared with GADab- patients. Compared with GADab- patients and control subjects, the GADab+ patients had an increased frequency HLA-DQB1*0201/0302 (13 vs. 4%; P = 0.002) and other genotypes containing the *0302 allele (22 vs. 12%; P = 0.010). However, the frequency of these high-risk genotypes was significantly lower in GADab+ type 2 patients than in type 1 diabetes of young or adult onset (0201/0302 or 0302/X: 36 vs. 66 vs. 64%, P < 0.001). The GADab+ type 2 group did not differ from control subjects with respect to genotypes containing the protective DQB1-alleles *0602 or *0603, nor with respect to the type 1 high-risk genotype in the IDDM1 (Hph1 +/+). We conclude that GADab+ patients differ from both GADab- type 2 diabetic patients and type 1 diabetic patients with respect to beta-cell function, features of the metabolic syndrome, and type 1 diabetes susceptibility genes. Further, we propose that LADA be defined as GADab positivity (>5 relative units) in patients older than 35 years at onset of type 2 diabetes.     

HLA-C genes and susceptibility to type 1 autoimmune hepatitis

Susceptibility to autoimmune hepatitis (AIH) is associated with the HLA A1-B8-DR3 haplotype, DR4 antigen, and, more specifically, the HLA DRB3*0101, DRB1*0301, and DRB1*0401 alleles. Few investigators, however, have examined the HLA C locus in AIH, which warrants detailed study in view of its recently described roles in immunoregulation. Eighty-seven adult, white patients with well-characterized type 1 AIH and 100 controls were studied. HLA C and HLA DRB1 alleles were assigned by polymerase chain reaction (PCR)-based genotyping. HLA A and B antigens were determined by standard microlymphocytotoxicity assay. Extended haplotypes were constructed according to known patterns of linkage disequilibrium. Only one HLA C locus allele, Cw*0701, which was present in 54% of patients versus 34% of controls (P = .006; relative risk [RR] = 1.54) was associated with AIH. The overall increase in the frequency of the Cw*07 gene (70.1% of patients vs. 54% of controls; P = .024; RR = 1.3) was due entirely to inheritance of the Cw*0701 allele rather than the other Cw*07 alleles, Cw*0702, *0703, and *0704. The RR for Cw*0701 (RR = 1.54) is greater than that for HLA A1 (RR = 1.33) and DRB1*0301 (RR = 1.49), but less than that for HLA-B8 (RR = 1.75). The present findings suggest that the gene or genes conferring susceptibility to AIH lie in the region centromeric to the HLA A locus between HLA C and DRB1. Although linkage disequilibrium with both B8 and DRB1*0301 may account for our finding of an increased frequency of Cw*0701, it is also possible that this allele contributes to disease susceptibility, perhaps by interaction with natural killer cells or cytotoxic T lymphocytes.     

Using behavioral interventions to assist children with type 1 diabetes manage blood glucose levels.

Treatment and management of chronic disease processes on children occurs across multiple settings, placing demands for consultation and expertise on school personnel, including school psychologists. One such chronic condition in children is type I diabetes. Children with type I insulin dependent diabetes mellitus exhibit high rates of noncompliance to treatment, which can lead to a variety of medical problems. This study examined the effectiveness of a specific behavioral intervention using behavioral consultation (BC) and conjoint behavioral consultation (CBC) to reduce uncontrolled blood glucose levels in medically at-risk children. An intermittent reward procedure was utilized to reinforce individualized target behaviors associated with treatment noncompliance. Specific target behaviors were individually established for six patients ages 8-12 through behavioral consultation interviews. Each child was randomly assigned to a reward + BC or reward + CBC condition. Results of the study showed that all participants improved; with slightly greater gains shown in the CBC condition. Follow-up data for 3 of the 4 participants completing the study showed improved compliance and mental health status. Treatment acceptability date indicate the intervention was viewed positively by parents and school based nurses. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

GLP-1 tablet in type 2 diabetes in fasting and postprandial conditions

OBJECTIVE: To examine the absorption of glucagon-like peptide (GLP)-1(7-36) amide from the buccal mucosa of type 2 diabetic patients. Previously, the effects of the peptide have been studied following intravenous and subcutaneous injection. Now, a mucoadhesive, biodegradable buccal GLP-1 tablet (9 mm) containing 119 nmol has been developed as a possible alternative to injection. RESEARCH DESIGN AND METHODS: A total of 10 type 2 diabetic patients received a single tablet under fasting conditions and before a standard meal in this randomized placebo-controlled study. RESULTS: The mean peak GLP-1 concentration was 125.1 pmol/l and occurred 30 min after application. The mean placebo-adjusted area under the curve was 5,334 min pmol/l, consistent with a relative bioavailability of 6% vs. intravenous injection and 42% vs. subcutaneous injection. The half-life of total peptide activity after buccal administration was 17 min. The placebo-adjusted glucose concentrations decreased by 1.4 mmol/l in fasting experiments and by 4.2 mmol/l after a standard mixed meal. In the fasting state at 30 min, plasma insulin increased by 185% and glucagon decreased by 20%, consistent with the increase in plasma GLP-1 concentrations. The peptide exerted a significant insulinotropic effect during meals (calculated as an insulinogenic index, 0-120 min; 84.1 vs. 45.7 in placebo experiments). CONCLUSIONS: Potentially therapeutic plasma levels of GLP-1 were achieved after administration of a single buccal tablet in type 2 diabetic patients. The peptide had a marked glucose-lowering effect during the first 2 h. This new GLP-1 tablet may become a feasible alternative treatment for type 2 diabetic patients, although a more prolonged pharmacokinetic profile is required.     

Differential susceptibility of type 1 and type 4 gonococci to chlorhexidine (Hibitane)

Virulent Type 1 gonococci have been shown to be much more suceptible to the killing action of Hibitane gluconate than the avirulent Type 4. Those exploring the possibility of genital prophylaxis as a means of controlling gonorrhoea might find Hibitane worthy of consideration.     

Ketosis-onset diabetes in young adults with subsequent non-insulin-dependency, a link between IDDM and NIDDM?

Reactivation of infections with herpes viruses is a frequent and major cause of morbidity after bone marrow transplantation. In this case report we stress that HSV infections of the colon and small intestine should be considered in the differential diagnosis of diarrhea and intestinal bleeding in the early post-transplantation period. Severe acute GVHD and subsequent intensive immunosuppressive treatment may increase the risk for reactivation of HSV infection particularly in situations in which acyclovir prophylaxis has been omitted.     

Affected-sib-pair mapping of a novel susceptibility gene to insulin-dependent diabetes mellitus (IDDM8) on chromosome 6q25-q27

Affected-sib-pair analyses were performed using 104 Caucasian families to map genes that predispose to insulin-dependent diabetes mellitus (IDDM). We have obtained linkage evidence for D6S446 (maximum lod score [MLS] = 2.8) and for D6S264 (MLS = 2.0) on 6q25-q27. Together with a previously reported data set, linkage can be firmly established (MLS = 3.4 for D6S264), and the disease locus has been designated IDDM8. With analysis of independent families, we confirmed linkage evidence for the previously identified IDDM3 (15q) and DDM7 (2q). We also typed additional markers in the regions containing IDDM3, IDDM4, IDDM5, and IDDM8. Preliminary linkage evidence for a novel region on chromosome 4q (D4S1566) has been found in 47 Florida families (P < .03). We also found evidence of linkage for two regions previously identified as potential linkages in the Florida subset: D3S1303 on 3q (P < .04) and D7S486 on 7q (P < .03). We could not confirm linkage with eight other regions (D1S191, D1S412, D4S1604, D8S264, D8S556, D10S193, D13S158, and D18S64) previously identified as potential linkages.     

Comparison of genetic susceptibility to experimental allergic/immune-mediated blepharoconjunctivitis between Lewis and Fischer rats

BACKGROUND: Changes in hepatic architecture in cirrhosis and chronic active hepatitis affect liver vascular haemodynamics. OBJECTIVE: To determine the criteria for the diagnosis of liver cirrhosis using Doppler US. MATERIALS AND METHODS: Twenty-two children with liver disease of unknown histology were prospectively examined and compared with eight normal children. Doppler US of portal vein velocity, arterio-portal velocity ratio, loss of reverse flow component in the hepatic vein and hepatic artery visualisation were examined prior to liver biopsy. Doppler results were compared with histological activity indices. Twelve patients had cirrhosis and ten had chronic active hepatitis. RESULTS: The most sensitive method (83%) for the assessment of cirrhosis was portal vein velocity less than 20 cm/sec. Arterio-portal velocity ratio (greater than 3) and hepatic artery visualisation were less sensitive (75% and 33% respectively) but specificity was 100% for all three methods. When these three methods were evaluated together, sensitivity increased to 91% and accuracy to 96%. Loss of reverse flow component was less specific (77%) but was sensitive (75%). CONCLUSIONS: Portal vein velocity, arterio-portal vein ratio and hepatic artery visualisation together were reliable in diagnosis of cirrhosis in the paediatric age group.