RARE POMC MUTATION IN A PATIENT WITH MYOTONIC DYSTROPHY TYPE 1 AND ADRENOCORTICOTROPIN HYPERRESPONSE TO CORTICOTROPIN-RELEASING HORMONE

Objective: Myotonic dystrophy (DM) is a monogenic disorder. It is caused by expansion of a cytosine-thymineguanine triplet in the DMPK gene which encodes for myotonic dystrophy protein kinase (DMPK). Methods: A 24-year-old man with DM and the DMPK mutation presented with elevated adrenocorticotropic hormone (ACTH) levels twice (152 and 185 pg/mL; normal value is 10 to 52 pg/mL) with normal cortisol levels (134.6 and 113.0 ng/mL, or 371.3 and 311.7 nmol/L; normal values are 67 to 226 ng/mL or 184.8 to 623.5 nmol/L). ACTH, corticotropin-releasing hormone (CRH) and insulin tolerance test (ITT) demonstrated normal cortisol response to ACTH and partial response to CRH and ITT tests, and ACTH hyperresponse to CRH and ITT. We suspected ACTH and/or ACTH receptor (ACTHR) mutations and evaluated the genetic profile for pro-opiomelanocortin (POMC), melanocortin 2 receptor (MC2R) and follicle-stimulating hormone receptor (FSHR) genes. Results: No mutations were found in either the MC2R or FSHR genes. The patient was heterozygous for the c.614A>G mutation corresponding to a p.53D>G substitution with a glycine instead of an aspartate in position 53 in POMC gene. This mutation was outside the sequence for ACTH (which spans amino acids 138 to 176) but was included in the part originating the N-terminal peptide of pro-opiomelanocortin (also called pro-γ-melanocyte stimulating hormone) which spans amino acids 27 to 102 and is involved in the regulation of adrenal steroidogenesis. Conclusion: The pathologic expansion of the cytosine-thymine-guanine triplet repeat in the 3' noncoding region of DMPK could explain the hyperresponse of ACTH typical of DM. The mutation of pro-γ-melanocyte-stimulating hormone could be associated with the abnormal response of cortisol, compatible with a partial adrenal insufficiency. Other studies are necessary to demonstrate this hypothesis

Feasibility, Adherence and Efficacy of Liraglutide Treatment in a Sample of Individuals With Mood Disorders and Obesity

Background: Liraglutide is a once-daily injectable medication approved for the treatment of obesity. Hereby we report the feasibility, adherence and efficacy of liraglutide treatment in a sample of individuals with mood disorders and obesity.Methods and Sample: Twenty-nine patients with Bipolar or Major Depressive Disorder received liraglutide once daily subcutaneously at a dose gradually titrated from 0.6 to 3 mg. All patients were obese and had previously failed multiple healthy lifestyle interventions, including exercise and diet programs. Patients' weight was recorded before liraglutide treatment (T0) and then 1 (T1), 3 (T3), and 6 months (T6) following T0.Results: Mean baseline (T0) weight was 110.54 Kg (±24.95). Compared to baseline, the percentage of weight loss was 3.37% at T1, 7.85% at T3, and 10.20% at T6. Thirty-one percent (n = 9) of patients had no side effects, 34.48% (n = 10) had one, 24.14% (n = 7) had two, and 10.34% (n = 3) had three side effects. All 29 subjects were still on liraglutide at T1; 79.31 and 48.28% were on liraglutide at T3 and T6. No significant relationship was found between liraglutide dose and likelihood to continue the medication. No patient showed a worsening of the psychiatric condition due to liraglutide treatment. Acceptability and satisfaction with treatment were good for the 48% that completed the study.Conclusions: Liraglutide treatment was efficacious, accepted and tolerated by ~50% of our sample, followed up for a period of 180 days. Larger, longer, controlled, prospective studies are warranted

From immunohistological to anatomical alterations of human pancreas in type 1 diabetes: New concepts on the stage

The histological analysis of human pancreatic samples in type 1 diabetes (T1D) has been proven essential to move forward in the evaluation of in situ events characterizing T1D. Increasing availability of pancreatic tissues collected from diabetic multiorgan donors by centralized biorepositories, which have shared tissues among researchers in the field, has allowed a deeper understanding of T1D pathophysiology, using novel immunohistological and high-throughput methods. In this review, we provide a comprehensive update of the main recent advancements in the characterization of cellular and molecular events involving endocrine and exocrine pancreas as well as the immune system in the onset and progression of T1D. Additionally, we underline novel elements, which provide evidence that T1D pathological changes affect not only islet β-cells but also the entire pancreas

Non-coding RNAs: novel players in insulin resistance and related diseases

The rising prevalence of metabolic diseases related to insulin resistance (IR) have stressed the urgent need of accurate and applicable tools for early diagnosis and treatment. In the last decade, non-coding RNAs (ncRNAs) have gained growing interest because of their potential role in IR modulation. NcRNAs are variable-length transcripts which are not translated into proteins but are involved in gene expression regulation. Thanks to their stability and easy detection in biological fluids, ncRNAs have been investigated as promising diagnostic and therapeutic markers in metabolic diseases, such as type 2 diabetes mellitus (T2D), obesity and non-alcoholic fatty liver disease (NAFLD). Here we review the emerging role of ncRNAs in the development of IR and related diseases such as obesity, T2D and NAFLD, and summarize current evidence concerning their potential clinical application

Effect of High- versus Low-Intensity Supervised Aerobic and Resistance Training on Modifiable Cardiovascular Risk Factors in Type 2 Diabetes; The Italian Diabetes and Exercise Study (IDES)

Background: While current recommendations on exercise type and volume have strong experimental bases, there is no clear evidence from large-sized studies indicating whether increasing training intensity provides additional benefits to subjects with type 2 diabetes. Objective: To compare the effects of moderate-to-high intensity (HI) versus low-to-moderate intensity (LI) training of equal energy cost, i.e. exercise volume, on modifiable cardiovascular risk factors. Design: Pre-specified sub-analysis of the Italian Diabetes and Exercise Study (IDES), a randomized multicenter prospective trial comparing a supervised exercise intervention with standard care for 12 months (2005-2006). Setting: Twenty-two outpatient diabetes clinics across Italy. Patients: Sedentary patients with type 2 diabetes assigned to twice-a-week supervised progressive aerobic and resistance training plus exercise counseling (n = 303). Interventions: Subjects were randomized by center to LI (n = 142, 136 completed) or HI (n = 161, 152 completed) progressive aerobic and resistance training, i.e. at 55% or 70% of predicted maximal oxygen consumption and at 60% or 80% of predicted 1-Repetition Maximum, respectively, of equal volume. Main Outcome Measure(s): Hemoglobin (Hb) A(1c) and other cardiovascular risk factors; 10-year coronary heart disease (CHD) risk scores. Results: Volume of physical activity, both supervised and non-supervised, was similar in LI and HI participants. Compared with LI training, HI training produced only clinically marginal, though statistically significant, improvements in HbA(1c) (mean difference -0.17% [95% confidence interval -0.44,0.10], P = 0.03), triglycerides (-0.12 mmol/l [-0.34,0.10], P = 0.02) and total cholesterol (-0.24 mmol/l [-0.46, -0.01], P = 0.04), but not in other risk factors and CHD risk scores. However, intensity was not an independent predictor of reduction of any of these parameters. Adverse event rate was similar in HI and LI subjects. Conclusions: Data from the large IDES cohort indicate that, in low-fitness individuals such as sedentary subjects with type 2 diabetes, increasing exercise intensity is not harmful, but does not provide additional benefits on cardiovascular risk factors

Effect of High- versus Low-Intensity Supervised Aerobic and Resistance Training on Modifiable Cardiovascular Risk Factors in Type 2 Diabetes; The Italian Diabetes and Exercise Study (IDES)

<div><h3>Background</h3><p>While current recommendations on exercise type and volume have strong experimental bases, there is no clear evidence from large-sized studies indicating whether increasing training intensity provides additional benefits to subjects with type 2 diabetes.</p> <h3>Objective</h3><p>To compare the effects of moderate-to-high intensity (HI) versus low-to-moderate intensity (LI) training of equal energy cost, i.e. exercise volume, on modifiable cardiovascular risk factors.</p> <h3>Design</h3><p>Pre-specified sub-analysis of the Italian Diabetes and Exercise Study (IDES), a randomized multicenter prospective trial comparing a supervised exercise intervention with standard care for 12 months (2005–2006).</p> <h3>Setting</h3><p>Twenty-two outpatient diabetes clinics across Italy.</p> <h3>Patients</h3><p>Sedentary patients with type 2 diabetes assigned to twice-a-week supervised progressive aerobic and resistance training plus exercise counseling (n = 303).</p> <h3>Interventions</h3><p>Subjects were randomized by center to LI (n = 142, 136 completed) or HI (n = 161, 152 completed) progressive aerobic and resistance training, i.e. at 55% or 70% of predicted maximal oxygen consumption and at 60% or 80% of predicted 1-Repetition Maximum, respectively, of equal volume.</p> <h3>Main Outcome Measure(s)</h3><p>Hemoglobin (Hb) A_1c and other cardiovascular risk factors; 10-year coronary heart disease (CHD) risk scores.</p> <h3>Results</h3><p>Volume of physical activity, both supervised and non-supervised, was similar in LI and HI participants. Compared with LI training, HI training produced only clinically marginal, though statistically significant, improvements in HbA_1c (mean difference −0.17% [95% confidence interval −0.44,0.10], P = 0.03), triglycerides (−0.12 mmol/l [−0.34,0.10], P = 0.02) and total cholesterol (−0.24 mmol/l [−0.46, −0.01], P = 0.04), but not in other risk factors and CHD risk scores. However, intensity was not an independent predictor of reduction of any of these parameters. Adverse event rate was similar in HI and LI subjects.</p> <h3>Conclusions</h3><p>Data from the large IDES cohort indicate that, in low-fitness individuals such as sedentary subjects with type 2 diabetes, increasing exercise intensity is not harmful, but does not provide additional benefits on cardiovascular risk factors.</p> <h3>Trial Registration</h3><p><a href="http://www.ISRCTN.org">www.ISRCTN.org</a><a href="http://isrctn.org/ISRCTN04252749"> ISRCTN-04252749</a>.</p> </div

Physical activity, physical fitness, anthropometric, clinical and biochemical parameters and risk scores at baseline and at the end of the 12-month study period.

<p>Values are mean (SD); LI = low-intensity subgroup; HI = high-intensity subgroup; PA = physical activity; METs = metabolic equivalents; VO_2max = maximal oxygen consumption; BMI = body mass index; BP = blood pressure; HOMA-IR = Homeostasis Model Assessment-Insulin Resistance; hs-CRP = high sensitivity C-reactive protein; UKPDS = United Kingdom Prospective Diabetes Study; CHD = coronary heart disease.</p>*<p>Wilcoxon signed ranks test; † Mann Whitney U-test; ‡ Total PA = non-supervised+supervised PA.</p

Subjects on-target for traditional cardiovascular risk factors at baseline and at the end of the 12-month study period and probability of reaching targets at 12 months.

<p>Values are n (%); LI = low-intensity group; HI = high-intensity group; OR = odd ratio; CI = confidence interval; TG = triglycerides; C = cholesterol; SBP = systolic blood pressure; DBP = diastolic blood pressure.</p>*<p>Mc Nemar test; † Logistic regression adjusted for baseline status (on-target vs. not-on-target), treatment at baseline and change during the study.</p

Average monthly energy expenditure from supervised exercise.

<p>Energy expenditure data in LI (circles, dotted line; n = 136) and HI (squares, continuous line; n = 152) participants [mean values; means (SD) are reported below]. LI = low intensity; HI = high intensity.</p

Adverse events.

*<p>χ² test; † Fisher’s exact test.</p