Useful Measurement of Glucose Variability by Flash Glucose Monitoring (FGM) with the Efficacy of Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor

Diabetes has been a crucial medical and social problem worldwide. For adequate nutritional therapy, there have been discussions concerning Calorie Restriction (CR) and Low Carbohydrate Diet (LCD). We have investigated glucose variability of diabetic patients applying CR, LCD, continuous glucose monitoring (CGM) and applied FreeStyle Libre which is flash glucose monitoring (FGM). The patient is a 40-year-old female with type 2 diabetes mellitus (T2DM), who showed BMI 20.7, postprandial blood glucose 257 mg/dL. HbA1c 12.1%, Glycoalbumin 31.6% (11.6-16.4), serum C-peptide 2.0 ng/ml and unremarkable data of liver function, renal, lipids. She was provided the intervention of three stages, which are i) CR with 60% carbohydrate in Day 1-2, ii) LCD meal with 12% carbohydrate in Day 3-5; iii) LCD + Sodium-glucose cotransporter 2 (SGLT2) inhibitor (Ipragliflozin L-Proline 50mg) in Day 6-12. The glucose profile was measured by FreeStyle Libre Pro (Abbott) for 14 days. The daily profile of blood glucose was abruptly decreased on Day 6. Time percentage of satisfactory blood glucose 70-180 mg/dL (/24h) was 0%, 0%, 2%, 14%, 0%, 54%, 100% in Day 1-7, respectively. These results suppose the acute clinical efficacy of SGLT2 inhibitor, and this report would become a reference for future diabetic practice and research

Evaluating Insulin/Glucose Ratio Using Breakfast of Calorie Restriction Meal for Type 2 Diabetes Mellitus

Background: Type 2 diabetes mellitus (T2DM) has been a medical and social problem worldwide. For nutritional therapy, Low Carbohydrate Diet (LCD) and Calorie restriction (CR) have discussed for long, where authors continued clinical research. Subjects and Methods: Subjects were 68 patients with T2DM with 62.1 years on average. Methods included i) standard CR was provided a day with 1400 kcal and 60% of carbohydrate, ii) measurement of daily profile of blood glucose, iii) insulinogenic index (IGI) (0-30 mins) exam for breakfast including 70g of carbohydrate, iv) calculation of IGI by delta and Area Under the Curves(AUC). Results: Basal data revealed that HbA1c 7.9%, fasting glucose 163 mg/dL, average glucose in a day 210 mg/dL, M value 117 in the median. Increment of glucose/IRI was 48.0 mg/dL/8.6 μU/mL, respectively. Delta or AUC ratio of IGI was 0.14[0.08-0.26] and 3.3[2.5-5.2], respectively. There were significant correlations between M value and Delta or AUC ratio, with a higher coefficient in the latter. Discussion and Conclusion: IGI study in Meal Tolerance Test (MTT) would be useful for pancreas function evaluation. AUC ratio method has superiority than Delta ratio with higher correlation coefficient. Current results could be the fundamental data for the related range of research, and further development will be expected

Proposal of Meal Tolerance Test (MTT) For Investigating Ability of Insulin Secretion for Small Carbohydrate Load

Authors and collaborators have continued clinical practice and research on diabetes for long, and begun Low Carbohydrate Diet (LCD) at first in Japan. We have proposed super-, standard-, petite-LCD methods with 12%, 26%, 40% of carbohydrate, and developed medical and social LCD movement by Japanese LCD promotion association (JLCDPA). For research protocol, subjects were 10 healthy young medical staff. Two tests were 75gOGTT and meal tolerance test (MTT) of breakfast of super-LCD with 300kcal and 6g of carbohydrate. Blood glucose and immunoreactive insulin (IRI) were measured at 0 min and 30 min. Results of glucose and IRI in median value (0-30min) showed as follows: i) OGTT; 89.5 mg/dL to 130.5 mg/dL, 5.1 μU/mL to 40.6 μU/mL, ii) MTT; 93.5 mg/dL to 84.5 mg/dL, 4.9μU/mL to 10.6 μU/mL (significant increase, p<0.05). The increments of IRI for GTT (carbo-75g) and MTT (carbo-6g) were analyzed. There was a significant correlation between increments of IRI in GTT and MTT (p<0.05). Blood glucose in MTT tended to decrease from 0 min to 30 min. These results suggested that insulin secretion would be sufficient and relatively excessive for 6g of carbohydrate amount

Index of C-peptide / glucose ratio for Carbo70 can be useful in clinical practice for diabetes

Background: Authors and colleagues have undertaken clinical research on Carbohydrate (CR) and Low Carbohydrate Diet (LCD) for years. We have proposed new evaluation method of insulinogenic index-carbohydrate 70g (IGI-carbo70). In similar way, C-peptide index for Carbohydrate-70 (CPI-Carbo70) is proposed in this report. Subjects and methods: The subjects were 37 patients with Type 2 diabetes mellitus (T2DM) and admitted for further evaluation and treatment. CR diet was provided on day 1 and 2, including 60% carbohydrates, 25% lipids and 15% protein with 1400 kcal/day. On day 2, breakfast with 70g of carbohydrate was provided, and glucose and C-peptide values were measured at 0 and 30 minutes. Results: Average HbA1c was 8.1 %, and Morbus (M) value was 70.5 in median. Glucose and C-peptide on 0--30min significantly increased as 163--195 mg/dL, 1.1--1.5μU/mL, respectively. CPI-Carbo70 was 1.94 in average and 1.54 in median. There were significant correlations between increments of glucose and C-peptide, and between HbA1c and CPI-Carbo70. Discussion and conclusion: CPI-Carbo70 was investigated and proposed. It may be useful for evaluating the function of the pancreas. This research would give the fundamental data for this field, and further research development will be expected in the future

Normalized glucose variability by Low Carbohydrate Diet (LCD) in CGM study

In diabetic practice, continuous glucose monitoring (CGM) has been more used for glucose variability. Authors have reported and developed the clinical study of Low Carbohydrate Diet (LCD) and Calorie Restriction (CR) through Japan LCD Promotion Association (JLCDPA). A diabetic case is presented with normalizing glucose variability by LCD meal checked by CGM. Case is 51 years female with type 2 diabetes mellitus (T2DM). At first visit, HbA1c was 10.0%, glucose was 288mg/dL, BMI 39.1, GOT 16IU/mL, HDL-C 33mg/dL, Triglyceride 152mg/dL. CR meal was provided on day-1 to day-5 and LCD meal with 12% carbohydrate on day-6 to day-13. Average glucose value from CGM was 292mg/dL, 235mg/dL, 160mg/dL, 140mg/dL, 124mg/dL in day 3,5,7,9,11 respectively. On day-13, total Ketone bodies (T-KB) 540μmol/L (-131), Acetoacetic acid (AcAc) 86μmol/L (-55) and 3-hydroxybutyric acid (3-OHBA) 454μmol/L (-85). Weight reduction was 5kg on day-14 and 11.2kg on day-70 with BMI 34.6. Thus, LCD showed a remarkable glucose-lowering effect in short term. FreeStyle Libre (Abbott, USA) seems to be a useful apparatus for monitoring the detailed fluctuation of blood glucose. These results would become fundamental and reference data and contribute to the LCD research development in the future

ERK2 phosphorylation of serine 77 regulates Bmf pro-apoptotic activity

B-cell lymphoma 2 (Bcl-2) homology 3 (BH3)-only proteins represent a class of pro-apoptotic factors that neutralize pro-survival Bcl-2 proteins, and, in some cases, directly activate Bax. The mechanisms of control and the role of BH3-only proteins, such as Bcl-2 like protein 11 extra large and Bad are well studied. By contrast, relatively little is known about the regulation and role of Bcl-2 modifying factor (Bmf). The B-RAF oncogene is mutated in ∼8% of human tumors. We have previously shown that Bmf is upregulated at the transcript level and is required for apoptosis induced by targeting B-RAF signaling in tumor cells harboring mutant B-RAF. In this study, we show that Bmf is regulated at the post-translational level by mutant B-RAF-MEK-ERK2 signaling. Extracellular signal-regulated kinase (ERK2) directly phosphorylates Bmf on serine 74 and serine 77 residues with serine 77 being the predominant site. In addition, serine 77 phosphorylation reduces Bmf pro-apoptotic activity likely through a mechanism independent of altering Bmf localization to the mitochondria and/or interactions with dynein light chain 2 and the pro-survival proteins, B-cell lymphoma extra large, Bcl-2 and Mcl-1. These data identify a novel mode of regulation in Bmf that modulates its pro-apoptotic activity in mutant B-RAF tumor cells

Detailed Analysis of <em>ITPR1 </em>Missense Variants Guides Diagnostics and Therapeutic Design

\ua9 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.Background: The ITPR1 gene encodes the inositol 1,4,5-trisphosphate (IP3) receptor type 1 (IP3R1), a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine/cerebellar hypoplasia. The pathophysiological basis of the different phenotypes is poorly understood. Objectives: We aimed to identify novel SCA29 and GLSP cases to define core phenotypes, describe the spectrum of missense variation across ITPR1, standardize the ITPR1 variant nomenclature, and investigate disease progression in relation to cerebellar atrophy. Methods: Cases were identified using next-generation sequencing through the Deciphering Developmental Disorders study, the 100,000 Genomes project, and clinical collaborations. ITPR1 alternative splicing in the human cerebellum was investigated by quantitative polymerase chain reaction. Results: We report the largest, multinational case series of 46 patients with 28 unique ITPR1 missense variants. Variants clustered in functional domains of the protein, especially in the N-terminal IP3-binding domain, the carbonic anhydrase 8 (CA8)-binding region, and the C-terminal transmembrane channel domain. Variants outside these domains were of questionable clinical significance. Standardized transcript annotation, based on our ITPR1 transcript expression data, greatly facilitated analysis. Genotype–phenotype associations were highly variable. Importantly, while cerebellar atrophy was common, cerebellar volume loss did not correlate with symptom progression. Conclusions: This dataset represents the largest cohort of patients with ITPR1 missense variants, expanding the clinical spectrum of SCA29 and GLSP. Standardized transcript annotation is essential for future reporting. Our findings will aid in diagnostic interpretation in the clinic and guide selection of variants for preclinical studies. \ua9 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Variants of C-C Motif Chemokine 22 (CCL22) Are Associated with Susceptibility to Atopic Dermatitis: Case-Control Studies

Atopic dermatitis (AD) is a common inflammatory skin disease caused by multiple genetic and environmental factors. AD is characterized by the local infiltration of T helper type 2 (Th2) cells. Recent clinical studies have shown important roles of the Th2 chemokines, CCL22 and CCL17 in the pathogenesis of AD. To investigate whether polymorphisms of the CCL22 gene affect the susceptibility to AD, we conducted association studies and functional studies of the related variants. We first resequenced the CCL22 gene and found a total of 39 SNPs. We selected seven tag SNPs in the CCL22 gene, and conducted association studies using two independent Japanese populations (1st population, 916 cases and 1,032 controls; 2nd population 1,034 cases and 1,004 controls). After the association results were combined by inverse variance method, we observed a significant association at rs4359426 (meta-analysis, combined P = 9.6×10−6; OR, 0.74; 95% CI, 0.65–0.85). Functional analysis revealed that the risk allele of rs4359426 contributed to higher expression levels of CCL22 mRNA. We further examined the allelic differences in the binding of nuclear proteins by electrophoretic mobility shift assay. The signal intensity of the DNA-protein complex derived from the G allele of rs223821, which was in absolute LD with rs4359426, was higher than that from the A allele. Although further functional analyses are needed, it is likely that related variants play a role in susceptibility to AD in a gain-of-function manner. Our findings provide a new insight into the etiology and pathogenesis of AD

Comparing national home-keeping and the regulation of translational stem cell applications: an international perspective

A very large grey area exists between translational stem cell research and applications that comply with the ideals of randomised control trials and good laboratory and clinical practice and what is often referred to as snake-oil trade. We identify a discrepancy between international research and ethics regulation and the ways in which regulatory instruments in the stem cell field are developed in practice. We examine this discrepancy using the notion of ‘national home-keeping’, referring to the way governments articulate international standards and regulation with conflicting demands on local players at home. Identifying particular dimensions of regulatory tools – authority, permissions, space and acceleration – as crucial to national home-keeping in Asia, Europe and the USA, we show how local regulation works to enable development of the field, notwithstanding international (i.e. principally ‘western’) regulation. Triangulating regulation with empirical data and archival research between 2012 and 2015 has helped us to shed light on how countries and organisations adapt and resist internationally dominant regulation through the manipulation of regulatory tools (contingent upon country size, the state's ability to accumulate resources, healthcare demands, established traditions of scientific governance, and economic and scientific ambitions)

Consensus Paper: Cerebellum and Social Cognition.

The traditional view on the cerebellum is that it controls motor behavior. Although recent work has revealed that the cerebellum supports also nonmotor functions such as cognition and affect, only during the last 5 years it has become evident that the cerebellum also plays an important social role. This role is evident in social cognition based on interpreting goal-directed actions through the movements of individuals (social "mirroring") which is very close to its original role in motor learning, as well as in social understanding of other individuals' mental state, such as their intentions, beliefs, past behaviors, future aspirations, and personality traits (social "mentalizing"). Most of this mentalizing role is supported by the posterior cerebellum (e.g., Crus I and II). The most dominant hypothesis is that the cerebellum assists in learning and understanding social action sequences, and so facilitates social cognition by supporting optimal predictions about imminent or future social interaction and cooperation. This consensus paper brings together experts from different fields to discuss recent efforts in understanding the role of the cerebellum in social cognition, and the understanding of social behaviors and mental states by others, its effect on clinical impairments such as cerebellar ataxia and autism spectrum disorder, and how the cerebellum can become a potential target for noninvasive brain stimulation as a therapeutic intervention. We report on the most recent empirical findings and techniques for understanding and manipulating cerebellar circuits in humans. Cerebellar circuitry appears now as a key structure to elucidate social interactions