Adina Zeidler

A functional variant of SUMO4, a new I|[kappa]|B|[alpha]| modifier, is associated with type 1 diabetes

Previous studies have suggested more than 20 genetic intervals that are associated with susceptibility to type 1 diabetes (T1D), but identification of specific genes has been challenging and largely limited to known candidate genes. Here, we report evidence for an association between T1D and multiple single-nucleotide polymorphisms in 197 kb of genomic DNA in the IDDM5 interval. We cloned a new gene (SUMO4), encoding small ubiquitin-like modifier 4 protein, in the interval. A substitution (M55V) at an evolutionarily conserved residue of the crucial CUE domain of SUMO4 was strongly associated with T1D (P = 1.9 × 10−7). SUMO4 conjugates to IκBα and negatively regulates NFκB transcriptional activity. The M55V substitution resulted in 5.5 times greater NFκB transcriptional activity and ∼2 times greater expression of IL12B, an NFκB-dependent gene. These findings suggest a new pathway that may be implicated in the pathogenesis of T1D.

Components of variance for vibratory and thermal threshold testing in normal and diabetic subjects

Quantitative sensory testing (QST) is commonly used in the assessment of diabetic neuropathy. However, little data are available on the reliability of tactile and thermal testing devices. Reproducibility of QST measures between centers has not been previously reported. This study was designed to validate QST testing procedures and determine if these devices are suitable for large scale multicenter clinical trials. Finger and toe vibratory (Vf, Vt) and thermal (Tf, Tt) thresholds were determined for ten normal individuals by a two-alternative forced-choice procedure using the Optacon Tactile Tester (OTT) and Thermal Sensitivity Tester (TST). Threshold measurements were reproducible between technologists and had a day-to-day coefficient of variation of Vf 20%, Vt 23%, Tf 41%, and Tt 95%. Thresholds were determined for 140 normal individuals at six centers. Mean threshold values between centers were not significantly different. Center-to-center coefficients of variation (CV) were Vf 44%, Vt 45%, Tf 47%, and Tt 87%. There was no significant difference in threshold measures with regard to sex, side studied, presence of calluses, or skin temperature. Vf thresholds significantly correlated with age (p < 0.01). There was no correlation between either vibratory or thermal thresholds in normal individuals, and nerve conduction velocities (NCV). Thermal and vibratory thresholds were determined for 98 diabetic patients. Diabetic subjects without clinical evidence of neuropathy were not significantly different from normal individuals, but diabetic patients with neuropathy had increased thresholds compared to normals (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities of the Migrating Motor Complex in Diabetics with Autonomic Neuropathy and Diarrhea

Diarrhea is a common symptom in long-standing diabetes. The pathogenesis of this diarrhea remains obscure, although it appears to be related to the development of autonomic neuropathy, which may cause several abnormalities including altered gut motility. We studied fasting gastrointestinal motility for a mean of 210 min in a group of 12 type-II diabetics with diarrhea. All patients had peripheral neuropathy and symptoms of autonomic neuropathy. Their motor activity was compared with that of a group of six normal volunteers. In addition, gastrointestinal transit time was assessed by the hydrogen breath test. The presence of bacterial overgrowth was assessed by the hydrogen breath test and culture of jejunal secretions. The diabetics showed grossly disordered motor activity. There was a complete absence of phase-III activity in two patients. Most phase IIIs commenced in the distal duodenum or jejunum. The phase-III component was often of short duration at each recording site. There was increased velocity of propagation between sites. Continuous phase-II activity was noted in some patients. Antral activity was absent or reduced during phase II. Gastrointestinal transit time was significantly prolonged in the diabetics. Bacterial overgrowth was demonstrated in three diabetic subjects. These motility abnormalities are nonspecific and are unlikely to play a major role in the pathogenesis of diabetic diarrhea.

High Prevalence of Diabetes in Young Adult Ethiopian Immigrants to Israel

We performed oral glucose tolerance tests in 158 Ethiopian immigrants to Israel. The subjects were <30 yr of age, had lived in Israel ≤4 yr, and originated from villages in the Gondar and Ambovar regions of Ethiopia. Most had been subjected to famine conditions in Ethiopia and/or extreme hardship in Sudan before or during immigration. All were lean. They revealed a profound change in dietary habits since their arrival in Israel, with consumption of large amounts of refined carbohydrate in place of spicy stews and injura (Ethiopian pita) that had constituted dietary staples in better times in Ethiopia. According to National Diabetes Data Group criteria, 14 (8.9%) of the subjects had diabetes, and another 14 (8.9%) had impaired glucose tolerance. In addition, 13 subjects had a dramatic increase in capillary blood glucose levels (>300 mg/dl) 1 h after ingestion of 75 g glucose, despite fasting and 2-h values well within the normal range, and they complained of associated symptoms during the 1st h of testing. Eleven of 137 men and 3 of 21 women had diabetes; 7 (5.1%) of the men and 7 (33%) of the women had impaired glucose tolerance. These results indicate a high prevalence of diabetes among young adult Ethiopian immigrants of relatively short residency in Israel, for which the factors responsible warrant further investigation.

Impaired exocrine pancreatic function in diabetics with diarrhea and peripheral neuropathy

Exocrine pancreatic insufficiency has been observed in some diabetics with peripheral neuropathy and diarrhea. Several mechanisms may be responsible for this insufficiency: (1) pancreatic atrophy, (2) disruption of the cholinergic enteropancreatic reflexes, or (3) elevated serum levels of peptides such as glucagon and pancreatic polypeptide which are known to inhibit pancreatic exocrine secretion. To clarify the mechanism(s) involved in this exocrine pancreatic impairment, we studied 10 diabetics with diarrhea and peripheral neuropathy. Their results were compared to those of eight normal volunteers. Each subject underwent a standardized pancreatic function study which assessed nonstimulated secretion, the response to intrajejunal infusion of a mixture of amino acids, and the output following intravenous administration of secretin and cholecystokinin (CCK). In separate studies, the effect of a background infusion of bethanechol and secretin on the pancreatic response to CCK was assessed in six patients and six normal controls. Compared to normals, all diabetics exhibited a significant reduction in both enzyme and bicarbonate secretion to all stimuli. This reduction was not corrected by administering bethanechol. Plasma glucagon and pancreatic polypeptide levels in diabetics were not significantly higher than those in controls. We conclude that diabetics with diarrhea and peripheral neuropathy exhibit impairment of their exocrine pancreatic secretion and possible mechanisms for this are discussed.

Association of HLA-DPB1*0301 With IDDM in Mexican-Americans

Susceptibility to IDDM has been associated with specific alleles at the HLA class II loci in a variety of human populations. Previous studies among Mexican-Americans, a group ancestrally derived from Native Americans and Hispanic whites, showed that the DR4 haplotypes (DRB1*0405-DQB1*0302 and DRB1*0402-DQB1*0302) and the DR3 haplotype (DRB1*0301-DQB1*0201) were increased among patients and suggested a role for both DR and DQ alleles in susceptibility and resistance. Based on the analysis of 42 Mexican-American IDDM families and ethnically matched control subjects by polymerase chain reaction/sequence-specific oligonucleotide probe typing, we report an association of IDDM with the DPB1 allele, *0301 (relative risk = 6.6; P = 0.0012) in this population. The analysis of linkage disequilibrium patterns in this population indicates that the observed increased frequency in DPB1*0301 among patients cannot be attributed simply to linkage disequilibrium with high-risk DR-DQ haplotypes. These data suggest that in addition to alleles at the DRB1 and DQB1 loci, polymorphism at the DPB1 locus may also influence IDDM risk.

Oral Insulin Therapy to Prevent Progression of Immune‐Mediated (Type 1) Diabetes

Abstract: Repeated ingestion of insulin has been suggested as an immune tolerization therapy to prevent immune‐mediated (type 1) diabetes. We performed a placebo‐controlled, two‐dose, oral insulin tolerance trial in newly diagnosed (< 2 years) diabetic patients who had required insulin replacement for less than 4 weeks and were found to have cytoplasmic islet cell autoantibodies (ICAs). No oral hypoglycemic agents were permitted during the trial. Endogenous insulin reserves were estimated at six‐month intervals by plasma C‐peptide responses to a mixed meal. Positive ICAs were found in 262 (31%) of the 846 patients screened. Of the 197 who agreed to participate, 187 could be followed for 6 to 36 months. Endogenous insulin retention was dependent upon initial stimulated C‐peptide response, age at diabetes onset, and numbers of specific islet cell autoantibodies found. Oral insulin improved plasma C‐peptide responses in patients diagnosed at ages greater than 20 years, best seen at the low (1 mg/day) over the high (10 mg/day) insulin dose (P= .003 and P= .01, respectively). In patients diagnosed before age 20 years, the 1 mg dose was ineffective, whereas the 10 mg dose actually accelerated C‐peptide loss (P= .003). There were no adverse effects. If confirmed, these findings suggest that diabetic patients over age 20 years with ICA evidence of late‐onset immune‐mediated diabetes should be considered for oral insulin at 1 mg/day to better retain endogenous insulin secretion.

Avoidance responding in mice with diabetes mellitus

In order to examine the behavioral concomitants of the neuroendocrine state of diabetes mellitus, the behavior of diabetic and normal male mice was compared in two behavioral paradigms. Diabetic mice were found to display significantly more passive avoidance to shock and significantly more submissive social behavior as compared to control mice. Furthermore, within the group of diabetic mice, mice showing the most passive avoidance also displayed the most submissive behavior. These findings suggest that diabetes mellitus may have effects on the neuroendocrine system that are manifested as changes in behavior.

Gallbladder dysfunction in diabetes mellitus

To further elucidate the mechanism of impaired gallbladder emptying in diabetics with and without neuropathy, gallbladder function was assessed by ultrasonography following a medium-chain triglyceride (lipomul, 1.5 mg/kg) infusion into the duodenum and compared to that during intravenous infusion of cholecystokinin in diabetic women. Results were compared with five healthy control women. Mean (±sd) maximal percent gallbladder volume in diabetics following lipomul was reduced to 49±8% and after intravenous cholecystokinin to 47±9%, which was less than those in controls, 21±9% and 24±6%, respectively, but not significantly different. Further analysis of gallbladder emptying to lipomul differentiated two subgroups of diabetics: one subgroup (N=5) had emptying comparable to controls (responders), while the other (N=5) had very modest emptying (nonresponders). Two of the patients in the latter group had normal gallbladder emptying during exogenous cholecystokinin and their response would be compatible with visceral neuropathy. Blood levels of cholecystokinin, measured by bioassay, following lipomul and exogenous cholecystokinin were similar in controls and diabetics. Presence of diabetic neuropathy did not correlate with impaired gallbladder emptying. Follow up at 6 and 12 months of the three nonresponder diabetics revealed that no gallstones had developed and that two of them became responders to exogenous cholecystokinin. We conclude that: (1) following lipomul, about 50% of diabetics in this study have impaired gallbladder emptying, which is not strictly correlated with diabetic neuropathy; (2) this was not due to abnormal cholecystokinin release; (3) in diabetic patients with impaired gallbladder emptying another abnormality may be present in the gallbladder; and (4) impaired gallbladder contraction may not lead to gallstone formation in one-year follow-up.

HLA-DRw Antigens in Mexican-American and Black-American Diabetic Patients

HLA-A, -B, and -C antigens were studied in 67 Mexican-American and 38 black-American diabetic patients who had the onset of their disease before age 31 yr. Control populations consisted of 322 Mexican-American and 367 black-American subjects for HLA-A, -B, and -C antigens. In addition, HLA-DRw antigens were studied in 60 Mexican-American and 34 black-American diabetic patients. Control populations for HLA-DRw antigens consisted of 189 Mexican-American and 145 black-American subjects. We found that juvenile-onset-diabetic patients of Mexican-American origin who had the onset of their disease before age 19 demonstrated a significant increase in HLA-DRw4. HLA-DRw4 was also significantly increased in black-American patients with juvenile-onset diabetes mellitus. HLA-DRw2 was not detected in any patient with juvenile-onset diabetes in either ethnic group. A significant association was found between HLA-B18 and HLA-DRw3 in Mexican-American juvenile-diabetic patients. These findings, which are comparable to those in similar Caucasian patients, provide additional information to support the hypothesis that HLA-DRw antigens play a major role in determining the susceptibility to juvenile-onset diabetes mellitus.