Oral Lactobacilli and salivary acidic proline-rich proteins (APRP-1/2) in dental caries.

A previous study shows that levels of acidic salivary proline-rich phosphoproteins-1/2 (APRP-1/2) increase with caries severity. The aim of this study was to examine whether this relationship also depends on the presence of H2O2-producing strains of Lactobacillus spp. Adults with severe caries (decayed, missing, and filled teeth (DMFT) > 13.9, n = 28) were compared with similarly aged adults who had minimal caries (DMFT < 5, n = 20). A total of 48 samples of whole unstimulated saliva were collected in the morning and centrifuged. Lactobacillus spp. were isolated from the sediment in Rogosa agar and peroxide (H2O2) production was determined by growing the isolates on TMB-Plus agar. Salivary APRP-1/2 content in the saliva supernatant was estimated using an enzyme-linked immunosorbent sandwich assay (ELISA). Lactobacilli were present in 67% of both caries groups but were H2O2 positive only in the minimal caries group. Irrespective of the presence of Lactobacilli, the total content of APRP-1/2 proteins was 34.5 ± 4.9 ng/ml in severe caries but just under half this in minimal caries. We conclude that Lactobacillus spp. was absent from about a third of the severe and minimal caries groups, and H2O2-producing strains were present only in the minimal caries group. The severe caries group possessed twice the content of salivary APRP 1/2 proteins as the minimal caries group. The implications of these findings for caries development are discussed.

Cytokine response in patients with chronic infections caused by Staphylococcus aureus strains and diversification of their Agr system classes.

This study aimed to describe the levels of circulating cytokine levels produced by Th lymphocytes (IFN-γ, IL-4, IL-10, IL-17A), as well as the levels of cytokines produced by monocytes/macrophages (TNF-α, IL-1ß, IL-12), in patients with chronic infections caused by Staphylococcus aureus strains, particularly in the context of the diversification of their Agr system classes. The studies were conducted on adult patients, including 50 patients with chronic suppurative dermatitis, 40 patients with chronic infections of the upper respiratory tract and 25 healthy individuals (control group). Blood serum cytokine levels were measured by enzyme-linked immunosorbent assay (ELISA). S. aureus was detected in cultures of suppurative dermal exudates or of pharyngeal smears. Classes of Agr systems in the S. aureus strains were identified using polymerase chain reaction (PCR). In both groups of patients, on average, levels of IFN-γ were doubled, while levels of IL-17A were increased by 2.5-fold, which, however, was not accompanied by increased levels of TNF-α or IL-12. The data indicate that the development of S. aureus infection among the studied patients was linked to an impoverished cytokine response of monocytes/macrophages, while that induced by the pathogen lymphocytes Th17/Th1 may be responsible for promotion of the chronic inflammatory response. In parallel, no quantitative or qualitative differences were disclosed between cytokine responses manifested by subgroups of patients infected with S. aureus strains belonging to class IV Agr, as compared to patients infected with strains of classes I to III Agr. Nevertheless, in the patients, strains belonging to class IV Agr prevailed, which points to the preferential relationship between the class and the pathogenicity of S. aureus.

Protective effect of oral Lactobacilli in pathogenesis of chronic periodontitis.

UNLABELLED: The study aimed at evaluation of IL-17 and TNF-α levels and at analysis of oral lactobacilli in patients with chronic periodontitis (CP) in the context of their protective effect on a course of the disease. The study was conducted on 14 patients with moderate CP (group 1) and 14 patients with severe CP (group 2). Control group (group 3) included 15 individuals with gingivitis. Levels of IL-17 and TNF-α were estimated using an ELISA. Strains of Lactobacillus were isolated in Rogosa agar, H(2)O(2)-production was determined in TMB-Plus agar. In group 1, the mean content of IL-17 was 19.66±6.1 pg/ml, and that of TNF-α was 4.95±0.91 pg/ml, in group 2 IL-17 content was 34.7±6.65 pg/ml, and that of TNF-α was 6.94±0.78pg/ml, in group 3 content of IL-17 was 0.65±0.58pg/ml, content of TNF-α was 0.17±0.14pg/ml. Analysis of lactobacilli manifestation in the control group and in the group with moderate CP in most of the persons demonstrated presence of H(2)O(2)-producing Lactobacillus, while in the group with severe CP presence of Lactobacillus was demonstrated in only 5 patients. CONCLUSIONS: development of CP is linked to persistent excessive cytokine response of Th17 cells, the intensity of which may affect clinical course of the disease; in parallel, H(2)O(2)-producing oral lactobacilli may prevent against progression of CP, most probably reducing secretory activity of Th17 cells and restricting growth of periodontopathogens.

Relative predispositional effects of HLA class II DRB1-DQB1 haplotypes and genotypes on type 1 diabetes: a meta-analysis.

The direct involvement of the human leukocyte antigen class II DR-DQ genes in type 1 diabetes (T1D) is well established, and these genes display a complex hierarchy of risk effects at the genotype and haplotype levels. We investigated, using data from 38 studies, whether the DR-DQ haplotypes and genotypes show the same relative predispositional effects across populations and ethnic groups. Significant differences in risk within a population were considered, as well as comparisons across populations using the patient/control (P/C) ratio. Within a population, the ratio of the P/C ratios for two different genotypes or haplotypes is a function only of the absolute penetrance values, allowing ranking of risk effects. Categories of consistent predisposing, intermediate ('neutral'), and protective haplotypes were identified and found to correlate with disease prevalence and the marked ethnic differences in DRB1-DQB1 frequencies. Specific effects were identified, for example for predisposing haplotypes, there was a statistically significant and consistent hierarchy for DR4 DQB1*0302s: DRB1*0405 =*0401 =*0402 > *0404 > *0403, with DRB1*0301 DQB1*0200 (DR3) being significantly less predisposing than DRB1*0402 and more than DRB1*0404. The predisposing DRB1*0401 DQB1*0302 haplotype was relatively increased compared with the protective haplotype DRB1*0401 DQB1*0301 in heterozygotes with DR3 compared with heterozygotes with DRB1*0101 DQB1*0501 (DR1). Our results show that meta-analyses and use of the P/C ratio and rankings thereof can be valuable in determining T1D risk factors at the haplotype and amino acid residue levels.

High frequency of abnormal glucose tolerance in DQA1*0102/DQB1*0602 relatives identified as part of the Diabetes Prevention Trial--Type 1 Diabetes.

AIMS/HYPOTHESIS: Immunological and genetic markers can be used to assess risk of developing type 1 diabetes prior to the onset of clinical symptoms. Autoantibody-positive relatives of patients with type 1 diabetes are at increased risk for disease, while the presence of HLA DQA1*0102/DQB1*0602 is thought to confer protection. Using the unique population identified by the Diabetes Prevention Trial--Type Diabetes (DPT-1), our aim was to determine if these individuals were protected from type 1 diabetes. METHODS: We described metabolic and immunological characteristics of islet cell cytoplasmic autoantibodies-positive relatives with DQB1*0602 identified as part of DPT-1. RESULTS: We found that 32% of DQB1*0602-positive relatives identified through the DPT-1 had abnormalities of glucose tolerance despite the fact that only 19% had multiple type 1 diabetes-associated autoantibodies and only 13% had abnormal insulin secretion, markers typically associated with the disease. In addition, these markers were not associated with abnormal glucose tolerance. In contrast, the DQB1*0602-positive relatives had elevated fasting insulin (117+/-10 pmol/l) and homeostasis model assessment of insulin resistance (HOMA-R) (4.90+/-0.5) values, which are more commonly associated with type 2 diabetes. The later marker of insulin resistance was associated with glucose tolerance status. CONCLUSIONS/INTERPRETATION: Our data indicate that DQA1*0102/DQB1*0602 relatives identified through DPT-1 have a high frequency of abnormal glucose tolerance and a disease phenotype with characteristics of type 1 and type 2 diabetes. Thus, multiple pathways to abnormal glucose tolerance are present within families of these type 1 patients.

Autoantibodies and human leucocyte antigen class II in first-degree family members of Mexican-American type 1 diabetic patients.

As part of a genetic study of type 1 diabetes in Mexican-Americans, 360 first-degree relatives of 108 type 1 diabetic probands were studied. Islet cell antibody (ICA), insulin autoantibody, glutamic acid decarboxylase (GAD(65)), and protein tyrosine phosphatase autoantibodies were measured and human leucocyte antigen (HLA) class II alleles DRB1 and DQB1 genotyping was performed. ICA was positive in 37% of the probands and 5.8% of the relatives. A subgroup of 26 probands (12 ICA+, 14 ICA-) was tested for GAD(65) and was found positive. 4/14 ICA+ first-degree relatives were GAD(65) positive. Four relatives, positive for two antibodies, subsequently developed type 1 diabetes. Life-Table analysis of first-degree relatives with autoantibodies indicated an 80% disease-free survival at 3.5 yr. HLA-DRB1 was found to be associated with the presence of ICA in both probands and relatives, whereas HLA-DPB1 was associated with autoantibody in relatives of type 1 diabetic probands. These results suggest that autoimmunity occurs in type 1 diabetes families of Mexican descent in similar frequencies to that of non-Hispanic, Caucasian families. The presence of autoantibodies appears to be regulated in part by HLA class II genes, even in the absence of overt diabetes.

Genetic and physical mapping of a type 1 diabetes susceptibility gene (IDDM12) to a 100-kb phagemid artificial chromosome clone containing D2S72-CTLA4-D2S105 on chromosome 2q33.

Polymorphic markers within the CTLA4 gene on chromosome 2q33 have been shown to be associated with type 1 diabetes. Therefore, a gene responsible for the disease (IDDM12) most likely lies within a region of <1-2 cM of CTLA4. To define more precisely the IDDM12 interval, we genotyped a multiethnic (U.S. Caucasian, Mexican-American, French, Spanish, Korean, and Chinese) collection of 178 simplex and 350 multiplex families for 10 polymorphic markers within a genomic interval of approximately 300 kb, which contains the candidate genes CTLA4 and CD28. The order of these markers (D2S346, CD28, GGAA19E07, D2S307, D2S72, CTLA4, D2S105, and GATA52A04) was determined by sequence tagged site content mapping of bacterial artificial chromosome (BAC) and yeast artificial chromosome (YAC) clones. The transmission disequilibrium test (TDT) analyses of our data revealed significant association/linkage with three markers within CTLA4 and two immediate flanking markers (D2S72 and D2S105) on each side of CTLA4 but not with more distant markers including the candidate gene CD28. Tsp analyses revealed significant association only with the three polymorphic markers within the CTLA4 gene. The markers linked and associated with type 1 diabetes are contained within a phagemid artificial chromosome clone of 100 kb, suggesting that the IDDM12 locus is either CTLA4 or an unknown gene in very close proximity.

Islet cell antibody-positive relatives with human leukocyte antigen DQA1*0102, DQB1*0602: identification by the Diabetes Prevention Trial-type 1.

The presence of human leukocyte antigen (HLA) haplotype DQA1*0102, DQB1*0602 is associated with protection from type 1 diabetes. The Diabetes Prevention Trial-type 1 has identified 100 islet cell antibody (ICA)-positive relatives with this protective haplotype, far exceeding the number of such subjects reported in other studies worldwide. Comparisons between ICA+ relatives with and without DQB1*0602 demonstrated no differences in gender or age; however, among racial groups, African-American ICA+ relatives were more likely to carry this haplotype than others. The ICA+ DQB1*0602 individuals were less likely to have additional risk factors for diabetes [insulin autoantibody (IAA) positive or low first phase insulin release (FPIR)] than ICA+ relatives without DQB1*0602. However, 29% of the ICA+ DQB1*0602 relatives did have IAA or low FPIR. Although half of the ICA+ DQB1*0602 relatives had a high risk second haplotype, this was not associated with the additional risk factors for diabetes. Hispanic ICA+ individuals with DQB1*0602 were more likely to be IAA positive or to have low FPIR than other racial groups. In conclusion, the presence of ICA in the relatives described here suggests that whatever the mechanism that protects DQB1*0602 individuals from diabetes, it is likely to occur after the diabetes disease process has begun. In addition, there may be different effects of DQB1*0602 between ethnic groups.

Giant cell arteritis is more prevalent in urban than in rural populations: results of an epidemiological study of primary systemic vasculitides in Germany.

OBJECTIVE: To investigate the period prevalences of primary systemic vasculitides (PSV) in urban and rural populations in northern and southern Germany in 1994. METHODS: Questionnaires were sent to all hospital departments, all physicians, health insurance providers and pension funds, reference laboratories for autoimmune diseases, and death registries in two catchment areas in northern and southern Germany (combined population 875 983) to identify patients with PSV between 1 January and 31 December 1994. Each catchment area encompassed both an urban and a rural area. Each case was re-evaluated by the authors by applying the definitions of the 1992 Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis. RESULTS: A total of 180 PSV patients were identified. The overall prevalence of PSV was 216 cases per 1 000 000 inhabitants (95% confidence interval (CI) 173-259) in northern Germany vs 195 (95% CI 153-236) in southern Germany. The prevalence of PSV was two-fold higher in women than in men, and five-fold higher in people aged > or =50 yr than in people aged <50 yr. The most frequent type of PSV was giant cell arteritis (GCA), with 87 cases per 1 000 000 in northern and 94 in southern Germany, followed by Wegener's granulomatosis, with 58 and 42 cases respectively. In the population aged > or =50 yr the prevalence of GCA was 240 per 1 000 000 in northern and 300 in southern Germany. In both northern and southern Germany the prevalence of GCA in this older population was significantly higher in urban than in rural populations (355 per 1 000 000 vs 115 in northern Germany (P<0.01) and 395 vs 220 (P<0.05) in southern Germany). The relative risk for the older urban population having GCA was 2.25-fold higher (95% CI 1.4-3.6) than in the rural population, and for the female population it was 4.7-fold higher in the urban than in the rural areas (95% CI 2.4-9.3). CONCLUSION: In both northern and southern Germany, GCA was significantly more prevalent in urban than in rural populations, especially among people aged > or =50 yr and in women. It remains unclear whether this disparity was due to underdiagnosis of GCA in the rural regions associated with differences in the German health-care system in cities vs rural areas. Further studies must examine the role of (chronic) exposure to the environmental factors characteristic of cities.

Insulin-dependent diabetes mellitus (IDDM) is associated with CTLA4 polymorphisms in multiple ethnic groups.

Linkage disequilibrium (association) analysis was used to evaluate a candidate region near the CTLA4/CD28 genes using a multi-ethnic collection of families with one or more children affected by IDDM. In the data set unique to this study (Spanish, French, Mexican-American, Chinese and Korean), the transmission/disequilibrium test (TDT) revealed a highly significant deviation for transmission of alleles at the (AT)n microsatellite marker in the 3' untranslated region (P = 0.002) and the A/G polymorphism in the first exon (P = 0.00002) of the CTLA4 gene. The overall evidence for transmission deviation of the CTLA4 A/G alleles is also highly significant (P = 0.00005) in the combined data set (669 multiplex and 357 simplex families) from this study and a previous report on families from USA, Italy, UK, Spain and Sardinia. Significant heterogeneity was observed in these data sets. The British, Sardinian and Chinese data sets did not show any deviation for the A/G polymorphism, while the Caucasian-American data set showed a weak transmission deviation. Strong deviation for transmission was seen in the three Mediterranean-European populations (Italian, Spanish and French) (P = 10(-5)), the Mexican-American population (P = 0.002) and the Korean population (P = 0.03). These results suggest that a true IDDM susceptibility locus (designated IDDM12) is located near CTLA4.

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.

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)

Polymorphic gene markers in Mexican-Americans residing in southern California.

The gene frequencies of nine different genetic polymorphic markers [ABO, MNS and P blood groups; haptoglobin, transferrin, Gc protein, complement (C3), properdin factor B and alpha 1-antitrypsin] were determined in 94 Mexican-Americans residing in the Los Angeles, California area. Comparisons with published data on Mexican-Americans living in other areas of the United States or in Mexico itself revealed no significant differences in the gene frequencies between this and previous studies. However, data from the current study demonstrated significant differences in ABO and haptoglobin allele frequencies compared to published non-Hispanic Caucasian data. These data suggest a large degree of genetic homogeneity in the Mexican-American population residing in the United States. Additional gene marker studies will be important to test this hypothesis and further define the degree of non-Hispanic Caucasian admixture in this population.

Pancreatic beta-cell glucose hypersensitivity in hyperglycemic, athymic "nude" mice.

Male athymic "nude" mice (ANM) of the USC colony manifest spontaneous fasting hyperglycemia and reduced glucose tolerance; it has been proposed that they may represent a model of nonobese non-insulin-dependent diabetes. Following the recent demonstration that insulin secretion from the isolated, perfused pancreas of the male ANM appears to be hypersensitive to glucose, the function of individual pancreatic islet beta cells was investigated by measuring the membrane potential electrical activity. Initial studies demonstrated that the cyclic pattern of electrical activity in isolated female ANM islets is indistinguishable from that in control mouse islets. In contrast to control and female ANM beta cells, in which 11.1 mM glucose evoked approximately 50% maximal electrical activity, this concentration evoked almost 80% maximal activity in male ANM beta cells (p < 0.01). Investigating electrical responses at different glucose concentrations demonstrated that this increased sensitivity to glucose extends across the concentration range 2.8 to 22 mM. Assuming that in these islets, as in normal islets, electrical activity is associated with insulin release, these data indicate that the glucose-versus-insulin secretion dose-response is shifted to lower glucose concentrations at the level of the individual beta cell. Although this study demonstrates that altered beta-cell function occurs in the isolated islet of the male ANM, further investigation is under way to determine how the observed beta-cell glucose hypersensitivity is related to the hyperglycemia and impaired glucose tolerance that develop in these animals in vivo.

Therapeutic effects of antibodies against adhesion molecules in murine collagen type II-induced arthritis.

Adhesion molecules play important roles in immune reactions and inflammatory processes and may constitute attractive targets for immunomodulatory approaches. In this study, blocking mAbs against a series of adhesion molecules were tested for their therapeutic effect on developing arthritis in a mouse model. MAbs were given for a period of 4 weeks at the time of exspected incidence of visible disease symptoms, i.e. 4 weeks after priming with collagen type II. A significant reduction of incidence down to values of 13% and 29% of the controls was obtained with mAbs against CD44 and alpha 4-integrin, respectively, during an observation time of 13 weeks. MAbs against CD4 and LFA-1 resulted only in weaker, non-significant effects or a delay in the incidence. MAbs against other molecules including L-selectin, ICAM-1 or VCAM-1 were not effective. The development of antibodies against collagen type II, collagen type I, proteoglycans and the immunogen, bovine collagen type II was affected by mAb treatment to a different extent. In this case, the anti CD4 mAb was the most effective, followed by the anti alpha 4-antibodies in most cases, whereas anti CD44 showed less clear effects on the development of humoral responses. In a skin delayed type hypersensitivity model analyzed for comparison, mAbs against LFA-1/ICAM-1 and alpha 4-integrin showed the largest effects on ear swelling. These data show that mAbs against several adhesion molecules are able to block selectively distinct aspects of immune reactions, and that CD44 and alpha 4-integrins could be promising targets for an immunotherapy of rheumatoid arthritis with receptor-interfering agents.

Analysis of HLA-DQA1 and -DQB1 genes in Mexican Americans with insulin-dependent diabetes mellitus.

Mexican American patients (n = 35) with insulin-dependent diabetes mellitus (IDDM) and control subjects (n = 39) were HLA-DQA and DQB typed by the polymerase chain reaction technique combined with allele-specific oligonucleotide probes. Either DQB1*0302 or DQB1*0201 was present among 91% (32/35) of the patients compared to 67% (26/39) of controls. Either DQA1*0501 or DQA1*0301 was present in all patients (100% or 35/35) compared to 29/39 (74%) (OR 12.06 Pc < 0.05) of controls. All four of these genes, in cis or trans, were present in 15/35 (43%) of the patients compared to 3/39 (8%) of controls (OR 9.0; Pc < 0.01). The presence of one or more non-susceptibility alleles showed a dose-related decrease in relative risk. Presence of aspartic acid (Asp) at position 57 of the DQ beta chain did not confer protection and non-Asp homozygosity did not confer susceptibility to IDDM in this ethnic group. In conclusion, susceptibility to IDDM in Mexican Americans is associated with particular DQA and DQB combinations, illustrates dose-dependent parameters and contradicts the critical residue hypothesis.

HLA class II alleles and susceptibility and resistance to insulin dependent diabetes mellitus in Mexican-American families.

The role of HLA class II alleles in genetic predisposition to insulin dependent diabetes mellitus (IDDM) was examined by PCR/oligonucleotide probe typing of 42 Mexican-American IDDM families derived from Hispanic Caucasians and Native Americans. All high risk haplotypes (HLA-DR3 and DR4) were of European origin while the most strongly protective haplotype (DRB1*1402) was Native American. Of the 16 DR-DQ DR4 haplotypes identified, only those bearing DQB1*0302 conferred risk; the DRB1 allele, however, also markedly influenced IDDM risk. The general pattern of neutral and protective haplotypes indicates that the presence of Asp-57 in the HLA-DQ beta chain does not confer IDDM protection per se and indicates that both DRB1 and DQB1 influence IDDM susceptibility as well as protection.

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.(ABSTRACT TRUNCATED AT 250 WORDS)

Hyperglycemic athymic nude mice: factors affecting in vitro insulin secretion.

The strain of athymic nude male mice (ANM) developed at the University of Southern California (USC) exhibits spontaneous hyperglycemia and relative hypoinsulinemia in vivo. To investigate factors that influence insulin secretion in this animal model of non-insulin-dependent diabetes mellitus, we utilized the isolated perfused mouse pancreas of the ANM-USC and control BALB/c mice. We compared in vitro glucose-induced insulin secretion in ANM-USC and control mice, inhibition of secretion by somatostatin, and variability of insulin secretion over the two-year period it took to complete these experiments. Glucose-induced insulin secretion from the isolated pancreas was biphasic in both ANM-USC and controls. Insulin secretion was quantitatively equal to or greater than control mice, depending on the phase of secretion analyzed and the source of the control mice. In contrast to pancreases of control mice, insulin secretion from ANM-USC pancreases was relatively resistant to inhibition of insulin secretion by somatostatin. Variability in insulin secretion over the two years in which these experiments were performed was greater from pancreases of control than that observed from pancreases of the ANM-USC. The hyperglycemic ANM-USC mouse does not demonstrate diminished insulin secretion in vitro yet is relatively hypoinsulinemic in vivo. Thus circulating factors other than somatostatin might contribute to the insulinopenic stage in this animal model.

Ancestral origin of insulin-dependent diabetes in Mexican-Americans.

To test the hypothesis that insulin-dependent diabetes mellitus in the Mexican-American population is due to Spanish genetic admixture, we obtained ancestral information on 106 Mexican-American families with an insulin-dependent diabetic index case and 80 Mexican-American control families from 1987 to 1991. The Mexican states of origin were available on 395 grandparents of the insulin-dependent diabetic index cases and 291 grandparents of the controls. Analysis of the individual states of origin revealed that there were significantly more Mexican-American grandparents of diabetic index cases from the states of Jalisco and Michoacan when compared to the control families (31% and 16% diabetic versus 22% and 11% controls respectively, P less than 0.01). The states of Zacatecas and Durango had a lower frequency of diabetic grandparents as compared to controls (6% diabetic versus 12% controls, P less than 0.001). Analysis of the origin by Northern and Southern states of México revealed a significant decrease in the number of grandparents of the insulin-dependent diabetic cases from the Northern regions of México, 19.5%, versus 32% in controls, (P less than 0.001). These data indicate that the grandparents of the insulin-dependent diabetic index cases originate from states and regions of México which were those of the early entry of the Europeans. These data thus support the hypothesis that insulin-dependent diabetes mellitus in the Mexican-American population may be due in significant part to an original genetic contribution from the Spanish-European population.