Association Between Plasma LRG1 and Lower Cognitive Function in Asians With Type 2 Diabetes Mellitus.

CONTEXT: Leucine-rich α-2-glycoprotein 1 (LRG1) has been implicated in the pathogenesis of diabetic complications, but its association with cognitive function remains unclear. OBJECTIVE: Our primary objective is to investigate the longitudinal association between LRG1 and cognitive function in patients with type 2 diabetes mellitus (T2DM). Secondarily, we determine the causal relationship using Mendelian randomization (MR) and the role of arterial stiffness as a potential mediator. METHODS: T2DM patients (n = 1039; age = 64.1 ± 6.4 years) were followed-up for 5.3 ± 1.2 years. Plasma LRG1 was measured at baseline using enzyme-linked immunosorbent assay. Baseline and follow-up cognitive function was assessed using Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). One-sample MR was performed with rs4806985 as plasma LRG1-associated single-nucleotide polymorphism. Mediation analysis was performed to examine if pulse wave velocity (PWV), an arterial stiffness index, mediated the association between plasma LRG1 and follow-up cognitive function. RESULTS: Elevated baseline natural log (Ln)-transformed LRG1 was inversely associated with baseline and follow-up RBANS total score with adjusted coefficients -1.38 (95% CI -2.55 to -.21; P = .021) and -1.38 (95% CI -2.70 to -.07; P = .039), respectively. Genetically predicted higher levels of plasma LRG1 was associated with lower follow-up RBANS total score with coefficient -7.44 (95% CI -14.14 to -.74; P = .030) per unit increase in LnLRG1. Higher PWV accounted for 27.7% of the association between LnLRG1 and follow-up RBANS total score. CONCLUSION: Baseline plasma LRG1 was associated with lower cognitive function at follow-up in patients with T2DM, mediated by PWV. MR analysis provided evidence of an association between genetically influenced plasma LRG1 and lower cognitive function at follow-up.

Short-term Weight Trajectory of Severely Obese Individuals With and Without Pathogenic Satiety-Regulation Melanocortin 3/4 Receptor (MC3/4R) Mutations From a Multi-ethnic Asian Large Bariatric Surgery Program.

The melanocortin (3 or 4) receptor (MC3/4R) is involved in regulating satiety and body weight. Therefore, pathogenic mutation in MC3/4R is associated with severe obesity, for which bariatric surgery is one of the treatment options. However, there is limited data on whether individuals with MC3/4R mutation will have differential weight response to surgery, especially among the Asian populations-the epi-center of the evolving global obesity epidemic. From our large prospective Obesity-Metabolism & Intervention Cohort Study (OMICS; N = 654, recruited between 2007 and 2022), 5 individuals with pathogenic MC3/4R mutations ("case") were identified using candidate-genes panel next-generation sequencing (Illumina iSeq). These subjects were carefully propensity score-matched (baseline body mass index [BMI], age, sex, ethnicity, proportion with diabetes, type of bariatric surgery) in a 1:4 ratio to other controls. We performed linear mixed model analysis (for repeated measurements) to compare their longitudinal weight trajectories (percentage total weight loss, %TWL) over 12 months. The 5 cases with MC3/4R mutations were 48 ± 11 years, BMI 40.8 ± 11.2 kg/m2, 60% with diabetes, and all males. Their weight at baseline (pre-op), and 6 months and 12 months after surgery were 120 ± 38, 100 ± 31, and 101 ± 30 kg, respectively. Compared with propensity score-matched controls (N = 20), linear mixed model analysis suggested no difference in surgically induced %TWL (ß coefficient = -5.8 ± 3.7, P = .13) over 12 months between the groups. Therefore, we conclude that rare pathogenic MC3/4R mutations do not significantly modify weight change (%TWL) in response to bariatric surgery.

Long-Term Observation of a Man With Severe Obesity and Undiagnosed Monogenic Diabetes Serendipitously Treated With Metabolic Surgery.

A 43-year-old man, with severe obesity (43 kg/m2) and diabetes (presumed as type 2 diabetes [T2D]), underwent vertical sleeve gastrectomy in 2009 and Roux-en-Y gastric bypass in 2013. Recently, whole exome sequencing (conducted to search for monogenic obesity) serendipitously revealed that the individual harbored a heterozygous glucokinase (GCK) variant p.(Arg422Leu) that was bioinformatically strongly predicted to be likely pathogenic. Therefore, he is likely to have concomitant maturity-onset diabetes of the young (MODY) type 2 (GCK-MODY). A retrospective evaluation of the clinical data showed that the subject was diagnosed with T2D (given his severe obesity) in 2005 and was treated with oral antidiabetic monotherapy. His hyperglycemia was mostly mild (HbA1c [hemoglobin] < 8.1%), consistent with that of MODY2, despite severe obesity. After vertical sleeve gastrectomy, complete diabetes remission (HbA1c <6.0% and fasting plasma glucose <5.6 mmol/L without use of antidiabetic medication) was achieved. The percentage of maximum body weight loss attained after surgery was 23.6%. Euglycemia was maintained during the subsequent decade, up to the last follow-up in 2019, without any sign of hypoglycemia. In conclusion, we report a decade-long clinical experience of a man with severe obesity and diabetes likely due to the coexistence of GCK-MODY and T2D, serendipitously treated with metabolic surgery. Interestingly, metabolic surgery was effective and safe for him.