Emerging significance of butyrylcholinesterase.

Butyrylcholinesterase (BChE; EC 3.1.1.8), an enzyme structurally related to acetylcholinesterase, is widely distributed in the human body. It plays a role in the detoxification of chemicals such as succinylcholine, a muscle relaxant used in anesthetic practice. BChE is well-known due to variant forms of the enzyme with little or no hydrolytic activity which exist in some endogamous communities and result in prolonged apnea following the administration of succinylcholine. Its other functions include the ability to hydrolyze acetylcholine, the cholinergic neurotransmitter in the brain, when its primary hydrolytic enzyme, acetylcholinesterase, is absent. To assess its potential roles, BChE was studied in relation to insulin resistance, type 2 diabetes mellitus, cognition, hepatic disorders, cardiovascular and cerebrovascular diseases, and inflammatory conditions. Individuals who lack the enzyme activity of BChE are otherwise healthy, until they are given drugs hydrolyzed by this enzyme. Therefore, BChE is a candidate for the study of loss-of-function mutations in humans. Studying individuals with variant forms of BChE can provide insights into whether they are protected against metabolic diseases. The potential utility of the enzyme as a biomarker for Alzheimer's disease and the response to its drug treatment can also be assessed.

Long-term Effects of a Collaborative Care Model on Metabolic Outcomes and Depressive Symptoms: 36-Month Outcomes from the INDEPENDENT Intervention.

BACKGROUND: Collaborative care (CC) is a multicomponent team-based approach to providing mental health care with systematic integration into outpatient medical settings. The 12-month INDEPENDENT CC intervention improved joint disease control measures in patients with both depression and diabetes at 12 and 24 months following randomization. OBJECTIVE: This study investigated the durability of intervention effects on patient outcomes at 36 months following randomization. PARTICIPANTS: Adult patients with poorly controlled T2D and depression in India randomized to CC or usual care. DESIGN: Post hoc analyses of between-group differences in patient outcomes at 36 months post-randomization (N = 331) and maintenance of outcomes from 12 to 36 months (N = 314). MAIN MEASURES: We evaluated combined risk factor improvement since baseline, defined as ≥ 50.0% reduction in Symptom Checklist Depression Scale (SCL-20) scores along with reduction of at least 0.5 percentage point hemoglobin A1C, 5 mmHg systolic blood pressure, or 10 mg/dL low-density lipoprotein cholesterol. Improvements in single risk factors were also examined. KEY RESULTS: There were no between-group differences in improvements since baseline in multiple or single risk factors at 36 months. Patients in the CC group with improved outcomes at 12 months were more likely to maintain a ≥ 50.0% reduction since baseline in SCL-20 scores (CC [54.9%] vs. UC [40.9%]; RR: 1.27 [95% CI: 1.04, 1.56]) and 0.5 percentage point reduction since baseline in hemoglobin A1C (CC [31.9%] vs. UC [19.5%]; RR: 1.64 [95% CI: 1.11, 2.41]) at 36 months. CONCLUSIONS: While improvements since baseline in patient outcomes did not differ between the collaborative care and usual care groups at 36 months, patients who received CC were more likely to maintain improvements in depressive symptoms and glucose levels at 36 months if they had achieved these improvements at the end of active intervention. TRIAL REGISTRATION NUMBER: NCT02022111.

Cost-Effectiveness of a Collaborative Care Model Among Patients With Type 2 Diabetes and Depression in India.

OBJECTIVE: To assess the cost-effectiveness of collaborative versus usual care in adults with poorly controlled type 2 diabetes and depression in India. RESEARCH DESIGN AND METHODS: We performed a within-trial cost-effectiveness analysis of a 24-month parallel, open-label, pragmatic randomized clinical trial at four urban clinics in India from multipayer and societal perspectives. The trial randomly assigned 404 patients with poorly controlled type 2 diabetes (HbA1c ≥8.0%, systolic blood pressure ≥140 mmHg, or LDL cholesterol ≥130 mg/dL) and depressive symptoms (9-item Patient Health Questionnaire score ≥10) to collaborative care (support from nonphysician care coordinators, electronic registers, and specialist-supported case review) for 12 months, followed by 12 months of usual care or 24 months of usual care. We calculated incremental cost-effectiveness ratios (ICERs) in Indian rupees (INR) and international dollars (Int'l-$) and the probability of cost-effectiveness using quality-adjusted life-years (QALYs) and depression-free days (DFDs). RESULTS: From a multipayer perspective, collaborative care costed an additional INR309,558 (Int'l-$15,344) per QALY and an additional INR290.2 (Int'l-$14.4) per DFD gained compared with usual care. The probability of cost-effectiveness was 56.4% using a willingness to pay of INR336,000 (Int'l-$16,654) per QALY (approximately three times per-capita gross domestic product). The willingness to pay per DFD to achieve a probability of cost-effectiveness >95% was INR401.6 (Int'l-$19.9). From a societal perspective, cost-effectiveness was marginally lower. In sensitivity analyses, integrating collaborative care in clinical workflows reduced incremental costs by ∼47% (ICER 162,689 per QALY, cost-effectiveness probability 89.4%), but cost-effectiveness decreased when adjusting for baseline values. CONCLUSIONS: Collaborative care for patients with type 2 diabetes and depression in urban India can be cost-effective, especially when integrated in clinical workflows. Long-term cost-effectiveness might be more favorable. Scalability across lower- and middle-income country settings depends on heterogeneous contextual factors.

Can the management of depression in type 2 diabetes be democratized?

Both type 2 diabetes and depression are common and are projected to increase. There is increasing evidence for a bidirectional relationship between the two. Diabetes is a risk factor for depression; contrariwise, individuals with depression are at greater risk of developing diabetes. They are a burden for both the individual and the society. Co-existent depression worsens diabetic control because of obesity, insulin resistance and the adverse metabolic effects of anti-diabetes medicines. In addition, compliance to lifestyle measures required for diabetes is also compromised such as following a specific diet, taking proper medications on time, getting metabolic parameters assessed and maintaining a sleep cycle. Depression occurs in many grades; mild depression is more common in diabetes than frank or full-blown depression leading to suicide. Unfortunately, there are not enough trained and accessible mental health professionals such as psychologists or psychiatrists to deal with the increasing burden of depression in diabetes. Therefore, alternate models for management of mild to moderate depression are required. There is evidence that a team-approach by employing health care assistants can lower the risk of cardiac risk factors. INtegrating DEPrEssioN and Diabetes treatmENT study was carried out to determine whether the team-approach using non-health care professionals could be effective in managing mild to moderate depression and to study its effects on metabolic parameters among subjects with type 2 diabetes mellitus. The international study, carried out in four independent centers in India assessed the impact of a trained but not qualified non-psychiatrist in coordinating and forming a fulcrum between the patient, the family and the consultant endocrinologist/diabetologist. The interventions were fine-tuned to be culturally appropriate by qualitative interviews before they began. It was shown that the outcomes of both depression and diabetes could be improved by the employment of a clinical care coordinator. It is possible to scale up the studies to wider geographical areas and health-care organizations.

Effect of a collaborative care model on anxiety symptoms among patients with depression and diabetes in India: The INDEPENDENT randomized clinical trial.

OBJECTIVE: We assessed the impact of a collaborative care intervention on anxiety symptoms among participants in India with comorbid depression, poorly controlled diabetes, and moderate to severe anxiety symptoms. METHOD: We analyzed data from a randomized controlled trial conducted at four diabetes clinics in India. Participants received either collaborative care or usual care. We included only participants who scored ⩾10 on the Generalized Anxiety Disorder-7 (GAD-7) at baseline. We estimated the effect of the intervention on clinically significant reduction in anxiety symptoms; we considered several potential baseline moderators and mediation by anti-depressant use. RESULTS: One hundred and seventy-two participants scored 10 or above on the GAD-7 at baseline. Collaborative care participants were more likely than control participants to achieve a clinically significant reduction in anxiety symptoms at 6 and 12 months (65.7% vs. 41.4% at 12 months, p = 0.002); these differences were not sustained at 18 or 24 months. There was little evidence of moderation by participant characteristics at baseline, and effects were not mediated by anti-depressant use. CONCLUSIONS: Collaborative care for the treatment of depression and type 2 diabetes can lead to clinically significant reductions in anxiety symptoms among patients with anxiety. Effects were notable during the active intervention period but not over the year post-intervention.

Effect of lockdown on activities of daily living in the built environment and wellbeing.

In an effort to arrest the spread of coronavirus (COVID-19) infection, a nationwide lockdown was declared in India in March 2020. To assess how personal built environments affected the citizens in the first few weeks, an explorative online survey was conducted, eliciting responses about work habits before the lockdown, psychological wellbeing, time spent in various activities, characteristics of those who worked from home, and food and sleep patterns. We received 121 (76 male and 45 female) responses with an average age of 35.5 years [max: 70 years, min: 18 years, standard deviation (SD): 12.9 years]. The major difference caused by the lockdown was a reduction in the time taken and distance travelled of the commute to workplaces, which was an average of 30 minutes and 9.5 km, respectively. In terms of diet, subjects who were vegetarian did not experience any difference, unlike those who were non-vegetarians (p < 0.05). The results show an association of the dependent variable of 'feeling in general' with predictor variables of 'energy, pep, vitality' and 'feel healthy to work' during the pandemic, whereas the predictor variables of 'energy, pep, vitality', 'happy and satisfied personal life', 'feel healthy to work' show an association with the dependent variable of 'feeling in general' before the lockdown with a significance of p < 0.02 and R2 = 0.51 and R2 = 0.60, respectively. Among those who worked from home in constrained environments, people found spaces and seemed to adapt reasonably well to the built environment with employees showing a preference for working from bedrooms and students for working from 'sit-out' (outside) spaces (p < 0.05). There was no change in the quality or quantity of sleep during the lockdown. This study in the early weeks of the lockdown documents the way in which individuals lived through it in terms of the built environment at home.

Effect of a Collaborative Care Model on Depressive Symptoms and Glycated Hemoglobin, Blood Pressure, and Serum Cholesterol Among Patients With Depression and Diabetes in India: The INDEPENDENT Randomized Clinical Trial.

Importance: Mental health comorbidities are increasing worldwide and worsen outcomes for people with diabetes, especially when care is fragmented. Objective: To assess whether collaborative care vs usual care lowers depressive symptoms and improves cardiometabolic indices among adults with diabetes and depression. Design, Setting, and Participants: Parallel, open-label, pragmatic randomized clinical trial conducted at 4 socioeconomically diverse clinics in India that recruited patients with type 2 diabetes; a Patient Health Questionnaire-9 score of at least 10 (range, 0-27); and hemoglobin A1c (HbA1c) of at least 8%, systolic blood pressure (SBP) of at least 140 mm Hg, or low-density lipoprotein (LDL) cholesterol of at least 130 mg/dL. The first patient was enrolled on March 9, 2015, and the last was enrolled on May 31, 2016; the final follow-up visit was July 14, 2018. Interventions: Patients randomized to the intervention group (n = 196) received 12 months of self-management support from nonphysician care coordinators, decision support electronic health records facilitating physician treatment adjustments, and specialist case reviews; they were followed up for an additional 12 months without intervention. Patients in the control group (n = 208) received usual care over 24 months. Main Outcomes and Measures: The primary outcome was the between-group difference in the percentage of patients at 24 months who had at least a 50% reduction in Symptom Checklist Depression Scale (SCL-20) scores (range, 0-4; higher scores indicate worse symptoms) and a reduction of at least 0.5 percentage points in HbA1c, 5 mm Hg in SBP, or 10 mg/dL in LDL cholesterol. Prespecified secondary outcomes were percentage of patients at 12 and 24 months who met treatment targets (HbA1c <7.0%, SBP <130 mm Hg, LDL cholesterol <100 mg/dL [<70 mg/dL if prior cardiovascular disease]) or had improvements in individual outcomes (≥50% reduction in SCL-20 score, ≥0.5-percentage point reduction in HbA1c, ≥5-mm Hg reduction in SBP, ≥10-mg/dL reduction in LDL cholesterol); percentage of patients who met all HbA1c, SBP, and LDL cholesterol targets; and mean reductions in SCL-20 score, Patient Health Questionnaire-9 score, HbA1c, SBP, and LDL cholesterol. Results: Among 404 patients randomized (mean [SD] age, 53 [8.6] years; 165 [40.8%] men), 378 (93.5%) completed the trial. A significantly greater percentage of patients in the intervention group vs the usual care group met the primary outcome (71.6% vs 57.4%; risk difference, 16.9% [95% CI, 8.5%-25.2%]). Of 16 prespecified secondary outcomes, there were no statistically significant between-group differences in improvements in 10 outcomes at 12 months and in 13 outcomes at 24 months. Serious adverse events in the intervention and usual care groups included cardiovascular events or hospitalizations (4 [2.0%] vs 7 [3.4%]), stroke (0 vs 3 [1.4%]), death (2 [1.0%] vs 7 [3.4%]), and severe hypoglycemia (8 [4.1%] vs 0). Conclusions and Relevance: Among patients with diabetes and depression in India, a 12-month collaborative care intervention, compared with usual care, resulted in statistically significant improvements in a composite measure of depressive symptoms and cardiometabolic indices at 24 months. Further research is needed to understand the generalizability of the findings to other low- and middle-income health care settings. Trial Registration: ClinicalTrials.gov Identifier: NCT02022111.

On Psychology and Psychiatry in Diabetes.

Managing diabetes requires dealing with diet, medications, and self-monitoring, besides other pressures of daily living. It, therefore, requires collaboration among individuals with diabetes, their families, and significant others including the social milieu in which they reside. Psychological stress plays critical role in the cause and course of diabetes, particularly in mastering various self-management skills, which are essential for adequate management of diabetes. It is possible to measure and to resolve such stressors. Besides the patient and the family, the built environment which the person occupies must be conducive for healthy living. This is a key component in providing an appropriate physical and psychosocial environment. Lacunae in any of the built environmental parameters compromise social and psychological well-being. Psychiatric conditions are also common in diabetes. Both depression and distress are bi-directionally associated with diabetes. The presence of one condition increases the risk of developing the other. In addition, medications used for the treatment of psychiatric conditions have adverse effects on body weight and insulin sensitivity. One must carefully weigh the risk and benefit of the drug class with potential adverse effects. Therefore, identification and management of psychological and psyciatric aspects in subjects with diabetes is an integral and critical component in treating subjects with diabetes.

Emerging links between type 2 diabetes and Alzheimer's disease.

Type 2 diabetes mellitus and Alzheimer's disease are both associated with increasing age, and each increases the risk of development of the other. Epidemiological, clinical, biochemical and imaging studies have shown that elevated glucose levels and diabetes are associated with cognitive dysfunction, the most prevalent cause of which is Alzheimer's disease. Cross sectional studies have clearly shown such an association, whereas longitudinal studies are equivocal, reflecting the many complex ways in which the two interact. Despite the dichotomy, common risk and etiological factors (obesity, dyslipidemia, insulin resistance, and sedentary habits) are recognized; correction of these by lifestyle changes and pharmacological agents can be expected to prevent or retard the progression of both diseases. Common pathogenic factors in both conditions span a broad sweep including chronic hyperglycemia per se, hyperinsulinemia, insulin resistance, acute hypoglycemic episodes, especially in the elderly, microvascular disease, fibrillar deposits (in brain in Alzheimer's disease and in pancreas in type 2 diabetes), altered insulin processing, inflammation, obesity, dyslipidemia, altered levels of insulin like growth factor and occurrence of variant forms of the protein butyrylcholinesterase. Of interest not only do lifestyle measures have a protective effect against the development of cognitive impairment due to Alzheimer's disease, but so do some of the pharmacological agents used in the treatment of diabetes such as insulin (especially when delivered intranasally), metformin, peroxisome proliferator-activated receptors γ agonists, glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes must be recognized as a risk for development of Alzheimer's disease; clinicians must ensure preventive care be given to control and postpone both conditions, and to identify cognitive impairment early to manage it appropriately.

Butyrylcholinesterase in metabolic syndrome.

Butyrylcholinesterase may have a role in a number of metabolic functions and could affect the expression of insulin resistance syndrome. We present our integrated work using clinical, biochemical and bioinformatic approaches to delineate the possible function of this enzyme. Initially, we constructed a phylogenic tree with nucleotides and amino acid sequences and showed the existence of similar sequences in bacteria, plants and in other animals. We also demonstrated a possible pathogenic role for BChE in the common existence of insulin resistance, type 2 diabetes and Alzheimer's disease by in silico method and followed it up with a diabetic mouse study where cognition was slowed along with changes in BChE levels. In the next group of in silico studies, we employed THEMATICS method to identify the amino acids at the active site and later performed docking studies with drugs. THEMATICS predicted two clusters of ionisable amino acid residues that are in proximity: one with two residues and another with 11 showed perturbation in the THEMATICS curves. Using ISIS/Draw 2.5SP4, ARGUSLAB 4.0.1 and HEX 5.1. software. 3-D ligands were docked with BChE motif (from PDB). We did not find any of the ligands studied with significant docking distance, indicating they did not have direct interaction with the active site. Subsequently we performed in silico studies to compare the secondary structure and domain of BChE. Protein-protein interaction showed the following intersections with BChE UBE21, CHAT, APOE, AATF, DF ALDH9A1, PDHX, PONI PSME3 and ATP6VOA2. The integrative physiological roles of proteins with poorly known functions can be approached by generating leads in silico, which can be studied in vivo, setting into movement an iterative process.

Yoga practice in diabetes improves physical and psychological outcomes.

BACKGROUND: The aim of this study was to examine the effect of yoga practice on clinical and psychological outcomes in subjects with type 2 diabetes mellitus (T2DM). METHODS: In a 40-day yoga camp at the Institute of Yoga and Consciousness, ambulatory subjects with T2DM not having significant complications (n = 35) participated in a 40-day yoga camp, where yogic practices were overseen by trained yoga teachers. Clinical, biochemical, and psychological well-being were studied at baseline and at the end of the camp. RESULTS: At the end of the study, there was a reduction of body mass index (BMI) (26.514 +/- 3.355 to 25.771 +/- 3.40; P < 0.001) and anxiety (6.20 +/- 3.72 to 4.29 +/- 4.46; P < 0.05) and an improvement in total general well-being (48.6 +/- 11.13 to 52.66 +/- 52.66 +/- 12.87; P < 0.05). CONCLUSIONS: Participation of subjects with T2DM in yoga practice for 40 days resulted in reduced BMI, improved well-being, and reduced anxiety.

Bioinformatics analysis of functional protein sequences reveals a role for brain-derived neurotrophic factor in obesity and type 2 diabetes mellitus.

Using bioinformatics techniques and sequence analyses algorithms, a comparative study between human and rodents revealed similarity in the behavior of genes involved in the control of energy homeostasis. Brain-derived neurotrophic factor (BDNF) modulates the secretion and actions of insulin, leptin, ghrelin, various neurotransmitters and peptides, and pro-inflammatory cytokines involved in energy homeostasis suggesting that it (BDNF) has a significant role in the pathobiology of obesity and type 2 diabetes mellitus. Based on these evidences, we propose that obesity and type 2 diabetes could be disorders of the brain and BDNF could serve as a biomarker in predicting their development. Hence, methods developed to selectively deliver BDNF to appropriate hypothalamic neurons may form a novel approach in their treatment.

Elevated butyrylcholinesterase and acetylcholinesterase may predict the development of type 2 diabetes mellitus and Alzheimer's disease.

Plasma levels of C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and lipid peroxides are elevated and concentrations of endothelial nitric oxide (eNO) decreased in type 2 diabetes mellitus and Alzheimer's disease. This suggests that both these diseases are low-grade systemic inflammatory conditions and are closely associated with each other. Recent studies revealed that plasma and tissue concentrations of enzymes butyrylcholinesterase and acetylcholinesterase are elevated in type 2 diabetes and Alzheimer's disease. Acetylcholine has anti-inflammatory actions. Hence, elevated butyrylcholinesterase and acetylcholinesterase concentrations will lead to a decrease in the levels of acetylcholine that could trigger the onset of low-grade systemic inflammation seen in type 2 diabetes and Alzheimer's disease. In view of this, we propose that butyrylcholinesterase and acetylcholinesterase will not only serve as therapeutic targets but also may serve as markers to predict the development of type 2 diabetes mellitus and Alzheimer's disease.