Liraglutide administration improves hormonal/metabolic profile and reproductive features in women with HAIR-AN syndrome.

SUMMARY: HAIR-AN syndrome, the coexistence of Hirsutism, Insulin Resistance (IR) and Acanthosis Nigricans, constitutes a rare nosologic entity. It is characterized from clinical and biochemical hyperandrogenism accompanied with severe insulin resistance, chronic anovulation and metabolic abnormalities. Literally, HAIR-AN represents an extreme case of polycystic ovary syndrome (PCOS). In everyday practice, the management of HAIR-AN constitutes a therapeutic challenge with the available pharmaceutical agents. Specifically, the degree of IR cannot be significantly ameliorated with metformin administration, whereas oral contraceptives chronic administration is associated with worsening of metabolic profile. Liraglutide and exenatide, in combination with metformin, have been introduced in the management of significantly obese women with PCOS with satisfactory results. Based on this notion, we prescribed liraglutide in five women with HAIR-AN. In all participants a significant improvement regarding the degree of IR, fat depositions, androgen levels and the pattern of menstrual cycle was observed, with minimal weight loss. Furthermore, one woman became pregnant during liraglutide treatment giving birth to a healthy child. Accordingly, we conclude that liraglutide constitutes an effective alternative in the management of women with HAIR-AN. LEARNING POINTS: HAIR-AN management is challenging and classic therapeutic regimens are ineffective. Literally HAIR-AN syndrome, the coexistence of Hirsutism, Insulin Resistance and Acanthosis Nigricans, represents an extreme case of polycystic ovary syndrome. In cases of HAIR-AN, liraglutide constitutes an effective and safe choice.

Changes in TNM stage, reoperation and 131-I ablation rate during the use of newer methods for the preoperative diagnosis of differentiated thyroid carcinoma.

OBJECTIVE: To define and discuss the changes of important risk factors and TNM staging over the last 40 years in patients operated on for differentiated thyroid carcinoma (DTC), resulting from the introduction of newer sensitive diagnostic procedures in the preoperative evaluation of thyroid nodules. PATIENTS: We reviewed the medical records of 1251 patients with postoperative diagnosis of DTC who had undergone initial diagnosis, before surgery, at our unit, between 1971 and 2010. According to the period of diagnosis, the patients were divided into four groups (I, II, III, IV) corresponding to the four decades. RESULTS: The mean age at diagnosis was unchanged over time for both papillary (PTC) and follicular thyroid cancer (FTC). A decrease in the proportion of FTC (group I vs group IV P < 0·01) and a concomitant increase in PTC/FTC ratio was observed particularly in group IV. The significant decrease in the proportion of tumour size of PTC (group I vs group IV, P < 0·01), the increase in the proportion of microcarcinomas, from 22·4% in group I to 53·0% in group IV, P < 0·001, and the decrease in the number of cases with features of aggressiveness have changed the TNM stage towards stages I and II. The overall frequency of patients at high risk was significantly decreased, from 8·0% in group I to 1·8% in group IV. The number of patients who underwent reoperation for the completion of tumour resection and/or radioiodine therapy significantly decreased over time. CONCLUSIONS: The evaluation of thyroid nodules using the newer diagnostic methods was useful in identifying DTC early. Consequently, the reoperation and thyroid remnant ablation rates were reduced.

Coincidence of high antiislet and antithyroid autoantibody titles in first-degree relatives of patients with type 1 diabetes.

An association between thyroid and islet autoantibodies has been reported for patients with type 1 diabetes and their first-degree relatives. However no general agreement on this association has been reached since several studies reported controversial data. In the present study, sera from 429 healthy first-degree relatives of type 1 diabetic patients have been examined for the presence of thyroid and islet autoantibodies. Autoantibodies against glutamate decarboxylase (GAD65Ab) and tyrosine-phosphatase IA-2 (IA-2/ICA512Ab) have been detected by radioimmunoassay techniques with in vitro translated recombinant human 35S-autoantigens. The presence of autoantibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) has been estimated by commercial radioimmunoassay kits. An increased frequency of TgAb was found in subjects who were positive for GAD65Ab (p=0.0257). However, no significant association between TPOAb and GAD65Ab or IA-2Ab or between TgAb and IA-2Ab could be established. These data indicate an increased rate of coincidence between TgAb and GAD65Ab in healthy first-degree relatives of type 1 diabetic patients. Accordingly a common genetic background leading to the appearance of both TgAb and GAD65Ab may be suggested.

Autoantibody recognition of COOH-terminal epitopes of GAD65 marks the risk for insulin requirement in adult-onset diabetes mellitus.

Some type 2 diabetic subjects develop secondary failure to sulphonylurea treatment and require insulin therapy. To test the diagnostic sensitivity and specificity of epitopes of GAD65 autoantibodies (GAD65Ab) for insulin requirement, in patients with latent autoimmune diabetes of the adult, we studied 569 adult subjects with a clinical diagnosis of type 2 diabetes mellitus. All the patients had been initially treated with hypoglycemic agents and/or diet for at least 1 yr. The presence of GAD65Ab (61/569, 10.7%) depended on insulin therapy (P<0.0001), low BMI (P<0.0001), and low basal C-peptide (P = 0.01). The majority of GAD65Ab-positive subjects (47/61, 77%) had antibodies directed to both middle (GAD65-MAb) and COOH-terminal (GAD65-CAb) epitopes. However, GAD65-CAb were more frequent in insulin-treated subjects (92% of GAD65Ab+ individuals) than in subjects treated with hypoglycemic agents and/or diet (18.2% of GAD65Ab+ individuals), while the exclusive presence of GAD65-MAb was more frequent in subjects treated with hypoglycemic agents and/or diet (81.8% vs. 8%) (P<0.0001). The presence of GAD65-CAb had a diagnostic specificity for insulin requirement as high as 99.4% (compared with 96.9% of GAD65Ab as measured in the traditional radiobinding assay) and identified a subgroup of patients with low BMI, low basal C-peptide values, and a need for insulin therapy. Subjects carrying only GAD65-MAb were phenotypically indistinguishable from GAD65Ab-negative patients. Patients positive for GAD65-M+CAb, but not those positive for GAD65-MAb only, showed an increased risk for thyroid autoimmunity, as revealed by the presence of thyroid peroxidase autoantibodies. Our study demonstrates that the use of epitope-specific antibody assays improves the diagnostic specificity of GAD65Ab, and that the presence of GAD65Ab binding to COOH-terminal epitopes is strongly associated with a need for insulin requirement.

Effects of the short-acting insulin analog [Lys(B28),Pro(B29)] on postprandial blood glucose control in IDDM.

OBJECTIVE: To establish the effects of the short-acting insulin analog Lispro versus human regular insulin (Hum-R) on postprandial metabolic control in IDDM. RESEARCH DESIGN AND METHODS: Four studies were performed in 10 C-peptide-negative IDDM patients. Lispro or Hum-R (0.15 U/kg) or Lispro + NPH (0.07 U/kg) or Hum-R + NPH were injected subcutaneously 30 min (Hum-R) or 5 min (Lispro) before lunch. Preprandial plasma glucose (PG) was maintained on all four occasions at approximately 7.3 mmol/l by intravenous insulin. RESULTS: After subcutaneous Lispro injection, plasma free insulin (FIRI) was greater between 0 and 2 h (233 +/- 22 pmol/l) than after Hum-R (197 +/- 25 pmol/l) but lower between 2.25 and 7 h (81 +/- 10 vs. 104 +/- 13 pmol/l, P < 0.05). After Lispro, PG was lower versus Hum-R for 3 h (7.4 +/- 0.6 vs. 8.3 +/- 0.9 mmol/l) but subsequently increased more than after Hum-R (3.25-7h, 11.3 +/- 1 vs. 9.6 +/- 1.2 mmol/l), resulting in a 7-h postprandial PG greater than Hum-R (9.4 +/- 0.5 vs. 8.8 +/- 0.6 mmol/l) (all P < 0.05). Addition of NPH to Lispro increased the 2.5-to 7-h FIRI to 110 +/- 11 pmol/l and decreased the 3.25- to 7-h PG to 7.7 +/- 0.8 pmol/l, resulting in 0- to 7-h PG (7.3 +/- 0.3 mmol/l) lower than after Hum-R + NPH (7.9 +/- 0.5 pmol/l) (P < 0.05). CONCLUSIONS: At meals, in order for Lispro to improve postprandial blood glucose not only at 2-h, but also over a 7-h period in C-peptide-negative IDDM, basal insulin must be optimally replaced.

Pharmacokinetics, pharmacodynamics and glucose counterregulation following subcutaneous injection of the monomeric insulin analogue [Lys(B28),Pro(B29)] in IDDM.

The aim of these studies was to compare the pharmacokinetics, pharmacodynamics, counterregulatory hormone and symptom responses, as well as cognitive function during hypoglycaemia induced by s.c. injection of 0.15 IU/kg of regular human insulin (HI) and the monomeric insulin analogue [Lys(B28),Pro (B29)] (MI) in insulin-dependent-diabetic (IDDM) subjects. In these studies glucose was infused whenever needed to prevent decreases in plasma glucose below 3 mmol/l. After MI, plasma insulin increased earlier to a peak (60 vs 90 min) which was greater than after HI (294 +/- 24 vs 255 +/- 24 pmol/l), and plasma glucose decreased earlier to a 3 mmol/l plateau (60 vs 120 min) (p < 0.05). The amount of glucose infused to prevent plasma glucose falling below 3 mmol/l was approximately three times greater after MI than HI (293 +/- 26 vs 90 +/- 25 mumol.kg-1 x 60-375 min-1, p < 0.05). After MI, hepatic glucose production was more suppressed (0.7 +/- 1 vs 5.9 +/- 0.54 mumol.kg-1.min-1) and glucose utilization was less suppressed than after HI (11.6 +/- 0.65 vs 9.1 +/- 0.11 mumol.kg-1.min-1) (p < 0.05). Similarly, plasma NEFA, glycerol, and beta-OH-butyrate were more suppressed after MI than HI (p < 0.05), whereas plasma lactate increased only after MI, but not after HI. Responses of counterregulatory hormones, symptoms and deterioration in cognitive function during plasma glucose plateau of 3 mmol/l were superimposable after MI and HI (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)