Dominant PDX1 deficiency causes highly penetrant diabetes at different ages, associated with obesity and exocrine pancreatic deficiency: Lessons for precision medicine.

OBJECTIVE: Heterozygous pathogenic or likely pathogenic (P/LP) PDX1 variants cause monogenic diabetes. We comprehensively examined the phenotypes of carriers of P/LP PDX1 variants, and delineated potential treatments that could be efficient in an objective of precision medicine. METHODS: The study primarily involved a family harboring a novel P/LP PDX1 variant. We then conducted an analysis of documented carriers of P/LP PDX1 variants, from the Human Gene Mutation Database (HGMD), RaDiO study, and Type 2 Diabetes Knowledge Portal (T2DKP) including 87 K participants. RESULTS: Within the family, we identified a P/LP PDX1 variant encoding p.G232S in four relatives. All of them exhibited diabetes, albeit with very different ages of onset (10-40 years), along with caudal pancreatic agenesis and childhood-onset obesity. In the HGMD, 79 % of carriers of a P/LP PDX1 variant displayed diabetes (with differing ages of onset from eight days of life to 67 years), 63 % exhibited pancreatic insufficiency and surprisingly 40 % had obesity. The impact of P/LP PDX1 variants on increased risk of type 2 diabetes mellitus was confirmed in the T2DKP. Dipeptidyl peptidase 4 inhibitor (DPP4i) and glucagon-like peptide-1 receptor agonist (GLP1-RA), enabled good glucose control without hypoglycemia and weight management. CONCLUSIONS: This study reveals diverse clinical presentations among the carriers of a P/LP PDX1 variant, highlighting strong variations in diabetes onset, and unexpectedly high prevalence of obesity and pancreatic development abnormalities. Clinical data suggest that DPP4i and GLP1-RA may be the best effective treatments to manage both glucose and weight controls, opening new avenue in precision diabetic medicine.

Effects of a diet plus exercise program on thyroid function in patients with obesity.

BACKGROUND: Studies of thyroid function after diet-induced weight loss in patients with obesity have yielded conflicting results. It is not known whether adding exercise to diet affects thyroid function in this patient population. The aim of the study was to prospectively evaluate the effects of a rehabilitation program on weight, body composition and thyroid function in euthyroid patients with obesity. METHODS: Serum levels of thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) in euthyroid patients with severe obesity were analyzed before and at the end of a 3-month rehabilitation program. Relationships between body weight or composition and changes in thyroid function were also investigated. Each study participant acted as his/her own control. RESULTS: The study population consisted of 34 euthyroid patients with obesity (18 men and 16 women; mean ±â€¯SD age: 51 ±â€¯12). The mean BMI was 49.3 ±â€¯12.4 kg/m2 before the program and 46 ±â€¯10.8 (p < 0.005) at the end, with a mean body weight loss of 11 kg (p < 0.05) and a mean fat mass loss of 6.8 kg (p < 0.05). The weight and fat mass losses were not significantly correlated with the serum concentrations of TSH, FT3 and FT4 measured at the end of the program. CONCLUSION: A 3-month rehabilitation program combining diet and exercise produced weight and fat mass losses without inducing thyroid dysfunction in patients with obesity.

Disordered eating behaviors as a potential obesogenic factor in schizophrenia.

Whilst people with schizophrenia have high levels of obesity and metabolic disease, our understanding of their eating behaviors is still limited. Our aim was to evaluate the relationships between eating behavior and clinical data in schizophrenia. A cross-sectional study including 66 schizophrenia outpatients compared to 81 healthy controls was undertaken. Eating behavior was assessed using the shortened 21-item version of the Three-Factor Eating Questionnaire (TFEQ-R21). The patients had a mean of 44 ±â€¯11 years; a mean BMI of 30.3 ±â€¯8 kg/m2 (vs. 24 ±â€¯3.3 kg/m2 for controls) and a mean duration of illness of 7.2 ±â€¯6 years. All mean TFEQ scores were significantly higher in patients (indicating poorer eating behaviors) compared to controls after adjustment for age and sex, BMI and smoking status. Among patients, mean TFEQ scores were not significantly different between men and women samples. The "cognitive restraint" factor was significantly higher in schizophrenia patients with a BMI < 25 than in the group of overweight patients with a BMI > 25. Our findings suggest that disordered eating behaviors affect schizophrenia patients regardless of gender or duration of disease compared to controls. More research is needed to help clarify the relationships between eating behaviors and weight-related outcomes in schizophrenia.

Surgical Management of Obesity Among People with Schizophrenia and Bipolar Disorder: a Systematic Review of Outcomes and Recommendations for Future Research.

BACKGROUND: People with schizophrenia or bipolar disorder (BD) exhibit very high levels of obesity. Little is known about the potential benefits/risks of obesity surgery. We conducted a narrative review to summarize the available knowledge on bariatric surgery in people with schizophrenia or BD. METHODS: A systematic search was conducted of major electronic databases from inception to October 2016 for studies investigating bariatric surgery among people with schizophrenia or BD. Data were presented in a narrative synthesis and future research strategies proposed. RESULTS: The electronic database searches identified 44 records. Eight studies (BD, n = 265; schizophrenia: n = 14) were included with a mean study length of 15.7 months (12-24). Seven found that bariatric surgery resulted in weight loss in those with psychiatric disorders with an excess weight loss ranging -31 to -70%. Six studies found that weight loss from bariatric surgery was similar in people with schizophrenia or BD versus controls. However, most of the studies limited their outcomes to only weight loss and did not measure whether obesity surgery affected the status and treatment of psychiatric symptoms. Although few adverse events were reported among patients with BD, data from two studies demonstrated no significant deterioration of psychiatric symptoms post-surgery in people with schizophrenia. CONCLUSIONS: Growing evidence suggests that bariatric surgery may improve short-term weight status among people with BD. However, given the paucity of studies for schizophrenia, and the lack of information on medium-to long-term results, future large-scale high-quality studies are required.

Low vitamin D levels increase the risk of type 2 diabetes in older adults: A systematic review and meta-analysis.

Low serum levels of 25 hydroxyvitamin D (25OHD) (hypovitaminosis D) is common in older adults and associated with several negative outcomes. The association between hypovitaminosis D and diabetes in older adults is equivocal, however. We conducted a meta-analysis investigating if hypovitaminosis D is associated with diabetes in prospective studies among older participants. Two investigators systematically searched major electronic databases, from inception until 10/07/2016. The cumulative incidence of diabetes among groups was estimated according to baseline serum 25OHD levels. Random effect models were used to assess the association between hypovitaminosis D and diabetes at follow-up. From 4268 non-duplicate hits, 9 studies were included; these followed 28,258 participants with a mean age of 67.7 years for a median of 7.7 years. Compared with higher levels of 25OHD, lower levels of 25OHD were associated with a higher risk of developing diabetes (6 studies; n=13,563; RR=1.31; 95% CI: 1.11-1.54; I2=37%). The findings remained significant after adjusting for a median of 11 potential confounders in all the studies available (9 studies; n=28,258; RR=1.17; 95% CI: 1.03-1.33; p=0.02; I2=0%). In conclusion, our data suggest that hypovitaminosis D is associated with an elevated risk of future diabetes in older people. Future longitudinal studies are required and should seek to confirm these findings and explore potential pathophysiological underpinnings.

Skin autofluorescence (a marker for advanced glycation end products) and erectile dysfunction in diabetes.

AIM: Although diabetes-related erectile dysfunction (ED) has many etiological factors, little is known about the putative pathophysiological role of advanced glycation end products (AGEs). Skin autofluorescence is a noninvasive marker of AGEs. Recent studies have evidenced a relationship between skin autofluorescence and several complications of diabetes. We hypothesized that AGEs (assessed by skin autofluorescence) are associated with ED in diabetes patients. METHODS: Between March 2014 and April 2015, 42 patients with type 1 diabetes (T1D) and 44 patients with type 2 diabetes (T2D) were consecutively enrolled in a descriptive, cross-sectional study and compared to 54 healthy controls. ED was evaluated via the 5-item version of the International Index of Erectile Function (IIEF-5). Skin autofluorescence was measured on the volar aspect of the arm with an AGE-Reader. RESULTS: Patients with diabetes had a mean±standard deviation age of 50±15 and a mean duration of diabetes of 16±12years. Skin autofluorescence was strongly and significantly correlated with the IIEF-5 score in the T1D subgroup (r=-0.52; P=0.004), the T2D subgroup (r=-0.32; P<0.03) and in the whole group of diabetic patients (r=-0.49; P<0.0001). In multivariate analyses that controlled for potentially confounding clinical and biochemical factors, only skin autofluorescence was still significantly correlated with the IIEF-5 score (P<0.0001). A receiver operating characteristic analysis revealed that a skin autofluorescence value ≥3.2AU determined severe ED with a sensitivity of 60% and a specificity of 87% in diabetic patients. CONCLUSION: Skin autofluorescence is significantly associated with ED in diabetes, independently of classical confounding factors.

[Management of eating disorders in schizophrenia]. / Prise en charge des troubles du comportement alimentaire dans la schizophrénie.

Little known in this contexte, the association between eating disorders (EDs) and schizophrenia is however common. EDs are involved in impaired quality of life and the development of many metabolic disorders in these vulnerable patients. Antipsychotic medications may lead to EDs and should be more extensively explored. We should sensitize patients, their families and caregivers, to improve screening and management of EDs in schizophrenia.

Emerging Drugs and Indications for Cardio-Metabolic Disorders in People with Severe Mental Illness.

Patients with severe mental illnesses, such as schizophrenia and bipolar disorder, are at increased risk of developing metabolic disorders including obesity, diabetes, and dyslipidemia. All of these comorbidities increase the risk of cardiovascular disease and mortality. Different approaches, including diet and lifestyle modifications, behavioral therapy and switching antipsychotic agents, have been proposed to manage these metabolic abnormalities. However, these interventions may be insufficient, impractical or fail to counteract the metabolic dysregulation. Consequently, a variety of pharmacological agents such as antidiabetic drugs, have been studied in an attempt to reverse the weight gain and metabolic abnormalities evident in these patients. Despite a significant effect, many of these treatments are used off-label. This qualitative review focuses on pharmacological agents that could offer significant benefits in the management of cardio-metabolic disorders associated with serious mental illness.

Advanced glycation end products and schizophrenia: A systematic review.

Oxidative stress has become an exciting area of research on schizophrenia, which is a highly prevalent condition that affects approximately 1% of the worldwide population. Advanced glycation end products (AGEs), which are considered metabolic biomarkers of increased oxidative stress, have a pathogenic role in the development and progression of different oxidative stress-based diseases including atherosclerosis, diabetes, neurodegenerative disorders and schizophrenia. AGE formation and accumulation as well as the activation of its receptor (RAGE) can lead to signaling through several inflammatory signaling pathways and further damaging effects. This systematic review is based on a search conducted in July 2014 in which 6 studies were identified that met our criteria. In this work, we describe how recent methodological advances regarding the role of AGEs may contribute to a better understanding of the pathophysiology of schizophrenia and provide a different approach in the comprehension of the relationship between cardiovascular disease and schizophrenia. These latest findings may lead to new directions for future research on novel diagnostic and treatment strategies.

Eating disorders in schizophrenia: implications for research and management.

Objective. Despite evidence from case series, the comorbidity of eating disorders (EDs) with schizophrenia is poorly understood. This review aimed to assess the epidemiological and clinical characteristics of EDs in schizophrenia patients and to examine whether the management of EDs can be improved. Methods. A qualitative review of the published literature was performed using the following terms: "schizophrenia" in association with "eating disorders," "anorexia nervosa," "bulimia nervosa," "binge eating disorder," or "night eating syndrome." Results. According to our literature review, there is a high prevalence of comorbidity between schizophrenia and EDs. EDs may occur together with or independent of psychotic symptoms in these patients. Binge eating disorders and night eating syndromes are frequently found in patients with schizophrenia, with a prevalence of approximately 10%. Anorexia nervosa seems to affect between 1 and 4% of schizophrenia patients. Psychopathological and neurobiological mechanisms, including effects of antipsychotic drugs, should be more extensively explored. Conclusions. The comorbidity of EDs in schizophrenia remains relatively unexplored. The clearest message of this review is the importance of screening for and assessment of comorbid EDs in schizophrenia patients. The management of EDs in schizophrenia requires a multidisciplinary approach to attain maximized health outcomes. For clinical practice, we propose some recommendations regarding patient-centered care.

Increased advanced glycation end-products (AGEs) assessed by skin autofluorescence in schizophrenia.

BACKGROUND: Oxidative stress has been intensively studied as a key biochemical system in the pathophysiology of schizophrenia. However, little is known about the implication of oxidative stress in the development of physical illnesses in schizophrenia patients, who are characterized by high cardiovascular risk and decreased life expectancy. Advanced glycation end-products (AGEs) are considered to be markers of oxidative stress and are linked to the development of atherosclerosis. METHODS: We investigated AGE levels determined by a noninvasive skin autofluorescence (skin AF) method (AGE-Reader™) in schizophrenia patients. Skin AF was assessed in 55 schizophrenia patients without diabetes or renal disease and 55 healthy controls matched for age, gender and smoking status. Nineteen of the 55 schizophrenia patients had a severe form of the disease (Kraepelinian schizophrenia). RESULTS: Skin AF was significantly higher in schizophrenia patients compared to controls (2.46 ± 0.52 and 1.90 ± 0.21, respectively, p < 0.0001). Kraepelinian schizophrenia patients had significantly higher skin AF than non-Kraepelinian schizophrenia patients (p = 0.05). CONCLUSIONS: This is the first study to demonstrate high AGE levels assessed by a noninvasive method in schizophrenia patients.

Anhedonia in Kraepelinian schizophrenia: a preliminary study.

Kraepelinian schizophrenia, defined as a severe form of the disease, is characterized by a high number of negative symptoms and less depression, respectively. The relationship between anhedonia and Kraepelinian schizophrenia was explored. Depressive and trait anticipatory and consummatory anhedonia were compared in Kraepelinian (n=10, M age 49.2 yr., SD=10.8) and non-Kraepelinian (n=23, M age=42.7 yr., SD=10.8) patients with schizophrenia. The Kraepelinian group had more anticipatory and consummatory anhedonia than the non-Kraepe-linian group. The two groups did not differ on depressive anhedonia or depression.