Serum titres of anti-glutamic acid decarboxylase-65 and anti-IA-2 autoantibodies are associated with different immunoregulatory milieu in newly diagnosed type 1 diabetes patients.

Several studies correlated genetic background and pancreatic islet-cell autoantibody status (type and number) in type 1A diabetes mellitus (T1AD), but there are no data evaluating the relationship among these markers with serum cytokines, regulatory T cells and ß cell function. This characterization has a potential importance with regard to T1AD patients' stratification and follow-up in therapeutic prevention. In this study we showed that peripheral sera cytokines [interleukin (IL)-12, IL-6, II-1ß, tumour necrosis factor (TNF)-α, IL-10] and chemokines (CXCL10, CXCL8, CXCL9, CCL2) measured were significantly higher in newly diagnosed T1AD patients when compared to healthy controls (P < 0·001). Among T1AD, we found a positive correlation between CXCL10 and CCL-2 (r = 0·80; P = 0·000), IL-8 and TNF-α (r = 0·60; P = 0·000); IL-8 and IL-12 (r = 0·57; P = 0·001) and TNF-α and IL-12 (r = 0·93; P = 0·000). Glutamic acid decarboxylase-65 (GAD-65) autoantibodies (GADA) were associated negatively with CXCL10 (r = -0·45; P = 0·011) and CCL2 (r = -0·65; P = 0·000), while IA-2A showed a negative correlation with IL-10 (r = -0·38; P = 0·027). Human leucocyte antigen (HLA) DR3, DR4 or DR3/DR4 and PTPN22 polymorphism did not show any association with pancreatic islet cell antibodies or cytokines studied. In summary, our results revealed that T1AD have a proinflammatory cytokine profile compared to healthy controls and that IA-2A sera titres seem to be associated with a more inflammatory peripheral cytokine/chemokine profile than GADA. A confirmation of these data in the pre-T1AD phase could help to explain the mechanistic of the well-known role of IA-2A as a more specific marker of beta-cell damage than GADA during the natural history of T1AD.

Periodontal disease in gestational and type 1 diabetes mellitus pregnant women.

OBJECTIVE: The present study evaluated the relationship between periodontal disease and its clinical variables in Brazilian non-diabetic pregnant women (C), gestational diabetes mellitus (GDM), or type 1 diabetes mellitus (T1DM). SUBJECTS AND METHODS: A periodontal exam was performed in one hundred and sixty-one pregnant women (GDM:80; T1DM:31; C:50) by a single-blinded calibrated examiner who recorded plaque index (PI), gingival index (GI), bleeding index (BI), gingival margin location (GM), probing depth (PD), clinical attachment level (CAL), bleeding on probing (BOP), and tooth mobility index (MI). The medical variables were age, pregestational body mass index (pre-BMI), fasting plasma glucose (FPG), and glycated hemoglobin (HbA(1c) ). RESULTS: The GI, GM, PD, CAL, BOP, and MI were significantly higher (P < 0.01) among GDM and T1DM than for C. The PI was higher in GDM and similar between C and T1DM. The Adjusted Final Model for medical variables to evaluate the effects of groups on periodontal parameters confirmed these results. CONCLUSIONS: The presence of periodontal disease was significantly higher in Brazilian diabetic pregnancies (GDM and T1DM) when compared to non-diabetic pregnant women (C). The degree of periodontal disease was similar between the GDM and T1DM groups. Age, pregestational BMI, and HbA(1c) were factors related to CAL development in these two types of diabetes mellitus.

Extreme subcutaneous, intramuscular and inhaled insulin resistance treated by pancreas transplantation alone.

Diabetes mellitus with resistance to insulin administered subcutaneously or intramuscularly (DRIASM) is a rare syndrome and is usually treated with continuous intravenous insulin infusion. We present here two cases of DRIASM in 16 and 18 years female patients that were submitted to pancreas transplantation alone (PTA). Both were diagnosed with type 1 diabetes as young children and had labile glycemic control with recurrent episodes of diabetic ketoacidosis. They had prolonged periods of hospitalization and complications related to their central venous access. Exocrine and endocrine drainages were in the bladder and systemic, respectively. Both presented immediate graft function. In patient 1, enteric conversion was necessary due to reflux pancreatitis. Patient 2 developed mild postoperative hyperglycemia in spite of having normal pancreas allograft biopsy and that was attributed to her immunosuppressive regimen. Patient 1 died 9 months after PTA from septic shock related to pneumonia. In 8 months of follow-up, Patient 2 presented optimal glycemic control without the use of antidiabetic agents. In conclusion, PTA may be an alternative treatment for DRIASM patients.

Effects of metformin on the glycemic control, lipid profile, and arterial blood pressure of type 2 diabetic patients with metabolic syndrome already on insulin.

Fifty-seven type 2 diabetic patients with metabolic syndrome and on insulin were assessed by a paired analysis before and 6 months after addition of metformin as combination therapy to evaluate the impact of the association on glycemic control, blood pressure, and lipid profile. This was a historical cohort study in which the files of type 2 diabetic patients with metabolic syndrome on insulin were reviewed. The body mass index (BMI), waist circumference, lipid profile, A1C level, fasting blood glucose level, daily dose of NPH insulin, systolic blood pressure, and diastolic blood pressure were assessed in each patient before the start of metformin and 6 months after the initiation of combination therapy. Glycemic control significantly improved (P < 0.001) after the addition of metformin (1404.4 +/- 565.5 mg/day), with 14% of the 57 patients reaching A1C levels up to 7%, and 53% reaching values up to 8%. There was a statistically significant reduction (P < 0.05) of total cholesterol (229.0 +/- 29.5 to 214.2 +/- 25.0 mg/dL), BMI (30.7 +/- 5.4 to 29.0 +/- 4.0 kg/m2), waist circumference (124.6 +/- 11.7 to 117.3 +/- 9.3 cm), and daily necessity of insulin. The reduction of total cholesterol occurred independently of the reductions of A1C (9.65 +/- 1.03 to 8.18 +/- 1.01%) and BMI and the reduction of BMI and WC did not interfere with the improvement of A1C. In conclusion, our study showed the efficacy of the administration of metformin and insulin simultaneously without negative effects. No changes were detected in HDL-cholesterol or blood pressure.

Effects of metformin on the glycemic control, lipid profile, and arterial blood pressure of type 2 diabetic patients with metabolic syndrome already on insulin

Fifty-seven type 2 diabetic patients with metabolic syndrome and on insulin were assessed by a paired analysis before and 6 months after addition of metformin as combination therapy to evaluate the impact of the association on glycemic control, blood pressure, and lipid profile. This was a historical cohort study in which the files of type 2 diabetic patients with metabolic syndrome on insulin were reviewed. The body mass index (BMI), waist circumference, lipid profile, A1C level, fasting blood glucose level, daily dose of NPH insulin, systolic blood pressure, and diastolic blood pressure were assessed in each patient before the start of metformin and 6 months after the initiation of combination therapy. Glycemic control significantly improved (P < 0.001) after the addition of metformin (1404.4 ± 565.5 mg/day), with 14 percent of the 57 patients reaching A1C levels up to 7 percent, and 53 percent reaching values up to 8 percent. There was a statistically significant reduction (P < 0.05) of total cholesterol (229.0 ± 29.5 to 214.2 ± 25.0 mg/dL), BMI (30.7 ± 5.4 to 29.0 ± 4.0 kg/m²), waist circumference (124.6 ± 11.7 to 117.3 ± 9.3 cm), and daily necessity of insulin. The reduction of total cholesterol occurred independently of the reductions of A1C (9.65 ± 1.03 to 8.18 ± 1.01 percent) and BMI and the reduction of BMI and WC did not interfere with the improvement of A1C. In conclusion, our study showed the efficacy of the administration of metformin and insulin simultaneously without negative effects. No changes were detected in HDL-cholesterol or blood pressure.

The hypothalamus-pituitary-ovary axis and type 1 diabetes mellitus: a mini review.

A high prevalence of menstrual cycle and fertility disturbances has long been associated with diabetes mellitus. However, rationalization of the intrinsic mechanisms of these alterations is controversial and even contradictory. This review considers (i) the relationship between diabetes mellitus, especially type 1 diabetes mellitus (T1DM), and the hypothalamus-pituitary-ovary (HPO) axis, (ii) the state of our knowledge concerning neuroendocrine control and its relationship with dopaminergic and opioid tonus, and (iii) the influence of the hypothalamus-pituitary-adrenal axis on ovarian function. Functional disturbances that occur as a consequence of diabetes are also discussed, but some T1DM-related diseases of autoimmune origin, such as oophoritis, are not further analysed. Although there are clear indications of a relationship between menstrual and fertility alterations and glycaemic control, in many instances the improvement of the latter is not sufficient to reverse such alterations. It appears that the oligoamenorrhoea and amenorrhoea associated with T1DM is mainly of hypothalamic origin (i.e. failure of the GnRH pulse generator) and may be reversible. The importance of the evaluation of the HPO axis in T1DM women with menstrual irregularities, even in the presence of adequate metabolic control, is emphasized.

Autoantibodies against glutamic acid decarboxylase and 21-hydroxylase in Brazilian patients with type 1 diabetes or autoimmune thyroid diseases.

Autoimmune thyroid diseases (ATD) are often associated with Type 1 diabetes mellitus (T1DM) and Addison's disease (AD), characterizing the autoimmune polyendocrine syndrome. We evaluated the frequency of autoantibodies against glutamic acid decarboxylase isoform 65 (GAD65Ab) and 21-hydroxylase (21OHAb) in the sera of 65 [58 females (F)/7 males (M), 17-70 yr] patients with Graves' disease (GD) and 47 (45 F/2 M, 12-77 yr) with Hashimoto's thyroiditis (HT), none of whom had either diabetes or AD. The sera of 30 recently diagnosed T1DM patients (16 M/14 F, 1-39 yr) and of 97 (54 F/43 M, 7-69 yr) healthy controls were also examined. GAD65Ab were detected in the sera of 18 (60%) T1DM, 8 (12%) GD and in none of the HT patients or the controls (p = 0.03 for GD vs HT, p = 0.002 for GD vs controls, and p < 0.001 for GD vs T1DM). 21OHAb were detected in the sera of 2 (3%) GD, 1 (2%) HT and in none of the T1DM patients or the controls. GAD65Ab levels were significantly lower in GD than in T1DM patients (median: -0.06 vs 0.28, p < 0.001). Six of the 8 GD GAD65Ab-positive patients submitted to an intravenous glucose tolerance test showed no diminished first phase insulin secretion. All 21OHAb positive patients had normal basal cortisol and adrenocorticotropin (ACTH), normal cortisol response after ACTH stimulation, but high plasma renin activity. In conclusion, despite the genetic diversity of the Brazilian population, the frequency of GAD65Ab and 21OHAb in our patients is similar to that observed in other countries. GAD65Ab were more prevalent in GD than in HT patients, suggesting a difference in the immune response between these disorders. Long-term follow-up is necessary to determine the clinical relevance of these autoantibodies in the Brazilian population.

Diet plus insulin compared to diet alone in the treatment of gestational diabetes mellitus: a systematic review

Fetuses of mothers with gestational diabetes mellitus are at increased risk to develop perinatal complications mainly due to macrosomia. However, in view of the marked heterogeneity of this disease, it seems difficult to set guidelines for diagnosis and treatment. This complicates the choice of assigning patients either to diet or to insulin therapy. Also of concern is how much benefit could be expected from insulin therapy in preventing fetal complications in these patients. In a systematic review of the literature assessing the efficacy of insulin in preventing macrosomia in fetuses of mothers with gestational diabetes, we found six randomized controlled trials comparing diet alone to diet plus insulin. The studies included a total of 1281 patients (644 in the diet plus insulin group and 637 in the diet group), with marked differences among trials concerning diagnostic criteria, randomization process and treatment goals. Meta-analysis of the data resulted in a risk difference of -0.098 (95 percentCI: -0.168 to -0.028), and a number-necessary-to-treat of 11 (95 percentCI: 6 to 36), which means that it is necessary to treat 11 patients with insulin to prevent one case of macrosomia. This indicates a potential benefit of insulin, but not significantly enough to set treatment guidelines. Because of the heterogeneous evidence available in the literature about this matter, we conclude that larger trials addressing the efficacy of these two therapeutic modalities in preventing macrosomia are warranted

Non-obese adult onset diabetes with oral hypoglycemic agent failure: islet cell autoantibodies or reversible beta cell refractoriness?

Pancreatic ß cell function and insulin sensitivity, analyzed by the homeostasis model assessment, before and after 24 weeks of insulin therapy were studied and correlated with the presence of autoantibodies against ß cells (islet cell and anti-glutamic acid decarboxylase antibodies), in a group of 18 Brazilian lean adult non-insulin-dependent diabetes mellitus (NIDDM) patients with oral hypoglycemic agent failure (OHAF). Median fasting plasma glucose before and after insulin treatment was 19.1 and 8.5 mmol/l, respectively (P < 0.001); median HbA1c was 11.7 percent before vs 7.2 percent after insulin treatment (P < 0.001). Forty-four percent of the patients were positive (Ab+) to at least one autoantibody. Fasting C-peptide levels were lower in Ab+ than Ab- patients, both before (Ab+: 0.16 ± 0.09 vs Ab-: 0.41 ± 0.35 nmol/l, P < 0.003) and after insulin treatment (Ab+: 0.22 ± 0.13 vs Ab-: 0.44 ± 0.24 nmol/l, P < 0.03). Improvement of Hß was seen in Ab- (median before: 7.3 vs after insulin therapy: 33.4 percent, P = 0.003) but not in Ab+ patients (median before: 6.6 vs after insulin therapy: 20.9 percent). These results show that the OHAF observed in the 18 NIDDM patients studied was due mainly to two major causes: autoantibodies and ß cell desensitization. Autoantibodies against ß cells could account for 44 percent of OHAF, but Ab- patients may still present ß cell function recovery, mainly after a period of ß cell rest with insulin therapy. However, the effects of ß cell function recovery on the restoration of the response to oral hypoglycemic agents need to be determined

Diet plus insulin compared to diet alone in the treatment of gestational diabetes mellitus: a systematic review.

Fetuses of mothers with gestational diabetes mellitus are at increased risk to develop perinatal complications mainly due to macrosomia. However, in view of the marked heterogeneity of this disease, it seems difficult to set guidelines for diagnosis and treatment. This complicates the choice of assigning patients either to diet or to insulin therapy. Also of concern is how much benefit could be expected from insulin therapy in preventing fetal complications in these patients. In a systematic review of the literature assessing the efficacy of insulin in preventing macrosomia in fetuses of mothers with gestational diabetes, we found six randomized controlled trials comparing diet alone to diet plus insulin. The studies included a total of 1281 patients (644 in the diet plus insulin group and 637 in the diet group), with marked differences among trials concerning diagnostic criteria, randomization process and treatment goals. Meta-analysis of the data resulted in a risk difference of -0.098 (95%CI: -0.168 to -0.028), and a number-necessary-to-treat of 11 (95%CI: 6 to 36), which means that it is necessary to treat 11 patients with insulin to prevent one case of macrosomia. This indicates a potential benefit of insulin, but not significantly enough to set treatment guidelines. Because of the heterogeneous evidence available in the literature about this matter, we conclude that larger trials addressing the efficacy of these two therapeutic modalities in preventing macrosomia are warranted.

Non-obese adult onset diabetes with oral hypoglycemic agent failure: islet cell autoantibodies or reversible beta cell refractoriness?

Pancreatic beta cell function and insulin sensitivity, analyzed by the homeostasis model assessment, before and after 24 weeks of insulin therapy were studied and correlated with the presence of autoantibodies against beta cells (islet cell and anti-glutamic acid decarboxylase antibodies), in a group of 18 Brazilian lean adult non-insulin-dependent diabetes mellitus (NIDDM) patients with oral hypoglycemic agent failure (OHAF). Median fasting plasma glucose before and after insulin treatment was 19.1 and 8.5 mmol/l, respectively (P < 0.001); median HbA1c was 11.7% before vs 7.2% after insulin treatment (P < 0.001). Forty-four percent of the patients were positive (Ab+) to at least one autoantibody. Fasting C-peptide levels were lower in Ab+ than Ab- patients, both before (Ab+: 0.16+/-0.09 vs Ab-: 0.41+/-0.35 nmol/l, P < 0.003) and after insulin treatment (Ab+: 0.22+/-0.13 vs Ab-: 0.44+/-0.24 nmol/l, P < 0.03). Improvement of H was seen in Ab- (median before: 7.3 vs after insulin therapy: 33.4%, P = 0.003) but not in Ab+ patients (median before: 6.6 vs after insulin therapy: 20.9%). These results show that the OHAF observed in the 18 NIDDM patients studied was due mainly to two major causes: autoantibodies and beta cell desensitization. Autoantibodies against beta cells could account for 44% of OHAF, but Ab- patients may still present beta cell function recovery, mainly after a period of beta cell rest with insulin therapy. However, the effects of beta cell function recovery on the restoration of the response to oral hypoglycemic agents need to be determined.

Family-based association of HLA class II alleles and haplotypes with type I diabetes in Brazilians reveals some characteristics of a highly diversified population.

The association of HLA class II haplotypes with type I diabetes was analyzed in 56 Southeastern Brazilian families using affected family-based controls (AFBAC) method. DRB1-DQA1-DQB1 alleles were determined by polymerase chain reaction/sequence-specific primer genotyping. This study first revealed the great haplotype diversity of Brazilians (65 different haplotypes even with incomplete DRB1 subtyping), probably due to the admixture of Africans genes with European and Amerindian genes in this population. The results revealed increased frequencies of the DRB1*03-DQA1*0501-DQB1*02 and DRB1*0401-DQA1*03-DQB1*0302 haplotypes in the patient group The highest risk for type I diabetes was associated with the heterozygote DRB1*03/*04 genotype as largely reported, and DRB1*03/X and DRB1*04/Y genotypes conferred a significant, but much lower disease risk. Protection from type I diabetes revealed some peculiarities in Southeastern Brazilians: a lack of significant protecting effect of the DRB1*1501-DQA1*0102-DQB1*0602 haplotype, and an apparent protection conferred by the DRB1*13-DQB1*0301, DRB1*11-DQB1*0301, and DRB1*01-DQB1*0501 two-locus haplotypes. The risk to type I diabetes in the highly diversified Southeastern Brazilians evidenced specific information to the prediction of the disease in this region of the country.

Development according to pubertal stage in Brazilian children and adolescents with short-term diabetes.

The anthropometric status and metabolic control of 51 recently diagnosed Brazilian schoolchildren with type 1 diabetes (DM1), during the first 5 years of the disease, were compared with those of normal children (60 girls and 132 boys) belonging to the same environmental condition and pubertal stage. Metabolic control was evaluated on the basis of fasting plasma glucose (FPG) and HbA1c levels. The criteria of the National Center for Health Statistics were used for anthropometric evaluation. FPG (205 +/- 51 mg/dl for girls vs 200 +/- 34 mg/dl for boys) and % above upper normal limit of median HbA1c (1.8% for girls vs 2.5% for boys with diabetes) were not significantly different during follow-up. The Z-score of the last height evaluation was lower in the girls' group (-0.14 vs -0.53, P<0.05). By forward stepwise analysis, the Z-score of the initial height was statistically significant as a determinant factor for height at the end of the study in both girls and boys with DM1. The Z-score of weight at last evaluation was not different from that at diagnosis in either sex. However, analysis according to pubertal stage showed a tendency to a weight increase in the girls. The weight recovery and height loss in girls with DM1 follows the trend of the normal Brazilian population.

Development according to pubertal stage in Brazilian children and adolescents with short-term diabetes

The anthropometric status and metabolic control of 51 recently diagnosed Brazilian schoolchildren with type 1 diabetes (DM1), during the first 5 years of the disease, were compared with those of normal children (60 girls and 132 boys) belonging to the same environmental condition and pubertal stage. Metabolic control was evaluated on the basis of fasting plasma glucose (FPG) and HbA1c levels. The criteria of the National Center for Health Statistics were used for anthropometric evaluation. FPG (205 + or - 51 mg/dl for girls vs 200 + or - 34 mg/dl for boys) and percent above upper normal limit of median HbA1c (1.8 percent for girls vs 2.5 percent for boys with diabetes) were not significantly different during follow-up. The Z-score of the last height evaluation was lower in the girls' group (-0.14 vs -0.53, P<0.05). By forward stepwise analysis, the Z-score of the initial height was statistically significant as a determinant factor for height at the end of the study in both girls and boys with DM1. The Z-score of weight at last evaluation was not different from that at diagnosis in either sex. However, analysis according to pubertal stage showed a tendency to a weight increase in the girls. The weight recovery and height loss in girls with DM1 follows the trend of the normal Brazilian population

Latent autoimmune diabetes of the adult (LADA) in a Brazilian Indian.

CONTEXT: Latent autoimmune diabetes of the adult (LADA) as originally described represents perhaps as many as 10 - 20% of adult-onset patients with diabetes. DESIGN: case report. CASE REPORT: A 38-year-old Brazilian Xavante-Jê Indian with Latent Autoimmune Diabetes of the Adult (LADA) is described, coming from the Sangradouro community in Poxoréu, Mato Grosso. The onset of diabetes after reaching 25 years of age, the evolution to insulin deficiency after a period of insulin-independence and the presence of auto-antibodies to glutamic acid decarboxylase (GAD) characteristic of LADA were present. This patient may represent the first case of LADA in a Brazilian with full Indian heritage. Further studies are necessary to verify the prevalence of this new type of diabetes in this population that does not have Caucasoid admixture and has a particular environmental background.

A role for activin A and betacellulin in human fetal pancreatic cell differentiation and growth.

Activin A (Act.A), a member of the transforming growth factor beta family of secreted proteins, has been implicated in the regulation of growth and differentiation of various cell types. Betacellulin (BTC), a member of the epidermal growth factor family, converts exocrine AR42J cells to insulin-expressing cells when combined with Act.A. We have used primary cultures of human fetal pancreatic tissue to identify the effects of Act.A and/or BTC on islet development and growth. Exposure to Act.A resulted in a 1.5-fold increase in insulin content (P < 0.005) and a 2-fold increase in the number of cells immunopositive for insulin (P < 0.005). The formation of islet-like cell clusters, containing mainly epithelial cells, during a 5-day culture, was stimulated 1.4-fold by BTC (P < 0.05). BTC alone caused a 2.6-fold increase in DNA synthesis (P < 0.005). These data suggest that Act.A induces endocrine differentiation, whereas BTC has a mitogenic effect on human undifferentiated pancreatic epithelial cells.

Autoantibodies against recombinant human steroidogenic enzymes 21-hydroxylase, side-chain cleavage and 17alpha-hydroxylase in Addison's disease and autoimmune polyendocrine syndrome type III.

OBJECTIVE: To evaluate the frequency of autoantibodies (Ab) against 21 hydroxylase (21OH), side-chain cleavage (SCC) and 17alpha-hydroxylase (17OH), in Addison's disease (AD) and autoimmune polyendocrine syndrome type III (APSIII). DESIGN AND METHODS: We used radiobinding assays and in vitro translated recombinant human (35)S-21OH, (35)S-SCC or (35)S-17OH and studied serum samples from 29 AD (18 idiopathic, 11 granulomatous) and 18 APSIII (autoimmune thyroid disease plus type 1 diabetes mellitus, without AD) patients. Results were compared with those of adrenocortical autoantibodies obtained with indirect immunofluorescence (ACA-IIF). RESULTS: ACA-IIF were detected in 15/18 (83%) idiopathic and in 1/11 (9%) granulomatous AD subjects. 21OHAb were found in 14/18 (78%) idiopathic and in the same (9%) granulomatous AD subject. A significant positive correlation was shown between ACA-IIF and 21OHAb levels (r(2)=0.56, P<0.02). The concordance rate between the two assays was 83% (24/29) in AD patients. SCCAb were found in 5/18 (28%) idiopathic (4 of whom were also positive for 21OHAb) and in the same (9%) granulomatous AD subject. 17OHAb were found in only 2/18 (11%) idiopathic and none of the granulomatous AD patients. Two APSIII patients were positive for ACA-IIF, but only one was positive for 21OHAb and SCCAb. 17OHAb were found in another two APSIII patients. CONCLUSIONS: Measurement of 21OHAb should be the first step in immune assessment of patients with AD and individuals at risk for adrenal autoimmunity, in addition to ACA-IIF. Due to their low prevalence in AD, measurement of SCCAb and 17OHAb should be indicated only for 21OHAb negative patients and/or for those with premature ovarian failure, regardless of ACA-IIF results.

Metabolic and ultrastructural effects of cyclosporin A on pancreatic islets.

We investigated the effect of different doses of cyclosporin A (CyA) on glucose and insulin levels, as well as its residual effects on pancreatic islets ultrastructure after discontinuation of the drug. We studied four groups of Wistar rats. One control- (n = 5) and three experimental groups, n = 10 each, were treated with different doses of CyA i.m. for 14 days: group I, 5 mg/Kg; group II, 15 mg/Kg; and group III, 25 mg/Kg. Five animals of each group were sacrificed after 14 days, and the remaining five after 21 days to assess residual CyA effects. On the day of sacrifice, the rats underwent maltose absorption test, and glucose and insulin levels were measured. Pancreatic biopsies were obtained on day 21 to evaluate islets ultrastructure by electron microscopy. As a result, statistically significant, dose dependent (P < 0.05) increases in glucose and insulin levels were observed in CyA-treated groups. Groups II and III showed insulin levels significantly higher after fasting (P < 0.05) on day 14 comparing to the controls, while in groups I and II values returned to normal after CyA discontinuation. Group III showed persistently increased insulin levels on day 21. Pancreatic ultrastructural changes were observed only in group III. We can conclude that CyA effects on glucose and insulin levels were temporary and reversible at low doses. Ultrastructural changes in the pancreatic islets may occur with high doses of CyA.