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

Influence of dexamethasone and weight loss on the regulation of serum leptin levels in obese individuals

The adipocyte hormone leptin is thought to serve as a signal to the central nervous system reflecting the status of fat stores. Serum leptin levels and adipocyte leptin messenger RNA levels are clearly increased in obesity. Nevertheless, the factors regulating leptin production are not fully understood. The aim of this study was to determine the effects of in vivo administration of the synthetic glucocorticoid dexamethasone and weight loss on serum leptin levels in two independent protocols. Twenty-five obese subjects were studied (18 women and 7 men, mean age 26.6 + or - 6 years, BMI 31.1 + or - 2.5 kg/m², percentfat 40.3 + or - 8.3) and compared at baseline to 22 healthy individuals. Serum levels of leptin, insulin, proinsulin and glucose were assessed at baseline and after ingestion of dexamethasone, 4 mg per day (2 mg, twice daily) for two consecutive days. To study the effects of weight loss on serum leptin, 17 of the obese subjects were submitted to a low-calorie dietary intervention trial for 8 weeks and again blood samples were collected. Serum leptin levels were significantly higher in the obese group compared to the control group and a high positive correlation between leptinemia and the magnitude of fat mass was found (r = 0.88, P<0.0001). After dexamethasone, there was a significant increase in serum leptin levels (22.9 + or - 12.3 vs 51.4 + or - 23.3 ng/ml, P<0.05). Weight loss (86.1 + or - 15.1 vs 80.6 + or - 14.2 kg, P<0.05) led to a reduction in leptin levels (25.13 + or - 12.8 vs 15.9 + or - 9.1 ng/ml, P<0.05). We conclude that serum leptin levels are primordially dependent on fat mass magnitude. Glucocorticoids at supraphysiologic levels are potent secretagogues of leptin in obese subjects and a mild fat mass reduction leads to a disproportionate decrease in serum leptin levels. This suggests that, in addition to the changes in fat mass, complex nutritional and hormonal interactions may also play an important role in the regulation of leptin levels

Low levels of sex hormone-binding globulin and hyperproinsulinemia as markers of increased pancreatic Beta-cell demand in men

Low levels of sex hormone-binding globulin (SHBG) are considered to be an indirect index of hyperinsulinemia, predicting the later onset of diabetes mellitus type 2. In the insulin resistance state and in the presence of an increased pancreatic ß-cell demand (e.g. obesity) both absolute and relative increases in proinsulin secretion occur. In the present study we investigated the correlation between SHBG and pancreatic ß-cell secretion in men with different body compositions. Eighteen young men (30.0 ± 2.4 years) with normal glucose tolerance and body mass indexes (BMI) ranging from 22.6 to 43.2 kg/m2 were submitted to an oral glucose tolerance test (75 g) and baseline and 120-min blood samples were used to determine insulin, proinsulin and C-peptide by specific immunoassays. Baseline SHBG values were significantly correlated with baseline insulin (r = -0.58, P<0.05), proinsulin (r = -0.47, P<0.05), C-peptide (r = -0.55, P<0.05) and also with proinsulin at 120 min after glucose load (r = -0.58, P<0.05). Stepwise regression analysis revealed that proinsulin values at 120 min were the strongest predictor of SHBG (r = -0.58, P<0.05). When subjects were divided into obese (BMI >28 kg/m2, N = 8) and nonobese (BMI £25 kg/m2, N = 10) groups, significantly lower levels of SHBG were found in the obese subjects. The obese group had significantly higher baseline proinsulin, C-peptide and 120-min proinsulin and insulin levels. For the first time using a specific assay for insulin determination, a strong inverse correlation between insulinemia and SHBG levels was confirmed. The finding of a strong negative correlation between SHBG levels and pancreatic ß-cell secretion, mainly for the 120-min post-glucose load proinsulin levels, reinforces the concept that low SHBG levels are a suitable marker of increased pancreatic ß-cell demand

Nocturnal urinary growth hormone excretion as a criterion for growth hormone deficiency

Nocturnal urinary growth hormone (U-hGH) levels measured by a sensitive immunoenzymometric assay were compared with hGH levels in serum before and after a clonidine test in healthy children and in children with short stature to determine whether U-hGH measurement is useful for the screening of hGH deficiency. The study was carried out on 19 healthy children (10 prepubertal and 9 pubertal subjects) and on 20 children with short stature, 10 with growth hormone deficiency (hGHD) and 10 with constitutional growth retardation. The diagnosis of hGHD was based on a blunted response to two provocative hGH tests in the appropriate clinical setting. Overnight urinary hGH secretion (mean of 3 collections) was measured by an immunoenzymometric assay. The best discrimination was obtained when the results were expressed as ng/h. Only one individual in the prepubertal group (U-hGH, 0.05 ng/h) and one patient in the growth retardation group (U-hGH, 0.08 ng/h) had a urinary hGH value below the highest value (0.17 ng/h) observed in the growth hormone deficiency group. The coefficient of correlation between urinary hGH in ng/h and post-clonidine peak was 0.50 (P = 0.0015), between urinary hGH in ng/l and post-clonidine peak was 0.48 (P = 0.0025), between urinary hGH in ng/l per hour and post-clonidine peak was 0.47 (P = 0.0027). The highest specificity (0.93), sensitivity (0.90), false negative rate (0.96) and false positive rate (0.82) were obtained when U-hGH was expressed as ng/h per night. Measurement of urinary nocturnal hGH excretion is a useful, simple, noninvasive method for the diagnosis of hGH deficiency. However, the day-to-day variability and wide normal range limit its usefulness in mild forms of hGH insufficiency

Cetoacidose diabética desencadeada por resistência imunológica à insulina / Diabetic ketoacidosis induced by immunologic insulin resistance

A cetoacidose diabética (CAD) é a emergência endocrinológica mais freqüente e de boa evoluçäo, na maior parte dos casos. Os autores apresentam evoluçäo atípica de três casos de CAD precipitada por resistência imunológica à insulina (RII). RELATO DE CASO. Três pacientes: H.M.L. (46 anos, diabetes mellitus (DM) tipo II, há 6 anos), D.R.J (39 anos, DM, secundário à pancreatopatia, há 11 anos) e D.L.S. (54 sanos, DM tipo II, há 9 anos) foram admitidos na Unidade de primeiro Atendimento do Hospital Säo Paulo em CAD: H.M.L. (glicemia: 716mg/dL, pH: 6,8), D.R.J. (glicemia: 684mg/dL, pH 6,.9) e D.L.S. (glicemia: 384mg/dL, pH: 7,2), todos apresentavam cetonúria. As necessidades de insulina para o controle metabólico foram: H.M.L.: 1.369UI, D.R.J.: 1.496UI, D.I.S. 1.369UI em, respectivamente: 212, 206 e 72 horas. Os anticorpos antiinsulina (AI) foram dosados por RE e ELISA: H.M.L.: 7.186nU/ml, 3,6IE; D.R.J.: 7,879nU/mL, 3,24IE; D.I.S: 8.377nU/mL, 2,88IE. O seguimento ambulatorial revelou queda progressiva dos níveis de AI:H.M.L.: 3.393nU/mL, 1,39, após dez meses da CAD; d.r.j.: 4,673Nu/Ml, 2,34 E d.i.s.: 1,510nU/mL, ambos após 18 meses da CAD. A queda nos níveis de anticorpos foi significativa nos três pacientes e foi acompanhada de melhor controle metabólico. Discussäo. A ausência de fator desencadeante, o elevado tempo, as altas doses de insulina empregadas para a compensaçäo metabólica levaram os autores à suspeita diagnóstica de RII. O diagnóstico foi confirmado pelos altos níveis séricos dos AI. O controle metabólico nestes pacientes foi obtido somente após a introduçäo de insulina na humanizada. CONCLUSAO. A resistência imunológica à insulina pode ser uma das causas de CAD sem fator precipitante aparente e má resposta às medidas terapêuticas habituais

Aspectos da fase näo-insulinodependente do diabetes mellitus do tipo I / Aspects of non-insulin-dependent phase of type I diabetes mellitus

Trata-se de um caso de diabetes mellitus do tipo I(DMI) no qual tivemos a oportunidade de diagnosticá-lo 23 meses antes das suas manifestaçöes clínicas mais freqüentes. Durante esse período foram observadas alteraçöes como o retorno de enurese, diminuiçäo na velocidade de crescimento e episódios de hiperglicemia e/ou glicosúria transitórios, apresentadas pela paciente, que podem näo ser devidamente valorizadas, na rotina clínica. Como, também, o aparecimento de marcadores imunológicos (ICA) e alteraçöes precoces na secreçäo de insulina (diminuiçäo na sua primeira fase de liberaçäo) vários meses antes do DMI manifesto. Esses marcadores imunológicos e essas alteraçöes endócrinas deveriam, se possível, ser pesquisados em pacientes com o quadro clínico inicial aqui apresentado, e em parentes jovens de DMI, no sentido de se detectar indivíduos com elevado risco de evoluírem para a fase manifesta dessa moléstia. O seguimento desses pacientes possibilitaria o diagnóstico precoce do DMI e a aplicaçäo de medidas no sentido de impedir a deteriorizaçäo total das células beta-pancreáticas e a evoluçäo para distúrbios metabólicos mais graves, como a cetoacidose diabética, com morbidade e mortalidade reconhecida

Inhibitory effect of calcitonin on growth hormone response to growth hormone releasing hormone in acromegaly

1. A neuroendocrine role for calcitonin (CT) has been suggested by the finding of CT receptors in the hypothalamus. We have recently shown that salmon calcitonin (sCT) inhibits growth hormone releasing hormone (GHRH)-induced GH secretion in msn by a mechanism apparently independent of changes in peripheral cortisol, glucose, calcium or parathyroid levels. 2. We have further investigated the inhibitory action of sCT on GH secretion by studying the effects of sCT (100 MRC units, im) or placebo on basal and GHRH (1-29) NH2 (50µg, iv) stimulated GH secretion in 6 acromemgalic patients with active disease. 3. Basal GH lelvels were not altered by sCT administration (placebo: 136 ñ 99 µg/1 vs sCT: 99 ñ 53 µg/1). However, the GH response to GHRH was decreased by sCT. The area under the curve was signficantly smaller when patients were treated with sCT compared to placebo controls (placebo: 77202 ñ 57036 vs sCT: 64828 ñ 51909 µg min-1 1-1; P < 0.01). No changes in glucose or calcium levels were observed. 4 These results demonstrate that sCT decresases GHRH-induced GH secretion in acromegalic patients. Although the mechanism of action of sCT on GH secretion is unknown, our results indicate that the inhibitory effect of this peptide on GH secretion is also observed in patients harboring pituitary adenomas

Relationship between insulin antibodies and metabolic control in type I diabetes mellitus

1. The objective of the presente study was to investigate whether a change in insulin therapy from bovine to purified porcine insulin would result in a decreased level of insulin antibodies (IA) in type I diabetic patients and whether there would be better metabolic control. 2. Insulin antibodies were measured by ELISA. Fifteen type I diabetic patients were prospectively followed for 8 months with monthly evaluations after changing insulin therapy from bovine to purified porcine insulin. 3. Group I patient (N = 4) had > ou = 1.5 (value obtained by dividing the ELISA absorbande of the tested serum by the absorbance of a standard serum) at the beginning of the study. For group I patients, the modification of insulin therapy caused a 57% reduction in insulin antibody levels, and this reduction was correlated with a decrease in 24-hour glycosuria (rs = 0.66, P < 0.001) and glicated protein (rs = 0.65, P < 0.01). Group II patients (N = 8) had IA < 1.5 and > ou = 0.3 and group III (N = 3 had IA < 0.3. Insulin antiblody levels were unchanged during the follow-up period in both group II and group III. 4. We also studied endogenous insulin secretion, measured as fasting C-peptide, and its relationships with metabolic control and insulin antibody levels. Patient with residual insulin secretion (C-peptide > 60 pmol/l) showed lower levels of 24-h glycosuria, glycated protein and glycated hemoglobin. Furthermore, in this group of patients a negative correlation was found between C-peptide and insulin antibody levels (rs=0.36, P < 0.01). 5. We conclude that insulin antibodies could be one of the factors having a detrimental effect on metabolic control