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

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

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

The role of Arabidopsis ABA receptors from the PYR/PYL/RCAR family in stomatal acclimation and closure signal integration

Stomata are microscopic pores found on the surfaces of leaves which act to control CO2 uptake and water loss. By integrating information derived from endogenous signals with cues from the surrounding environment the guard cells, that surround the pore, ‘set’ stomatal aperture to suit the prevailing conditions. Much research has concentrated on understanding the rapid intracellular changes that result in immediate changes to stomatal aperture. In this study we look instead at how stomata acclimate to longer timescale variations in their environment. We show that the closure-inducing signals ABA, increased CO2, decreased relative air humidity (RH), and darkness each access a unique gene network made up of clusters (or modules) of common cellular processes. However, within these some gene clusters are shared among all four stimuli. All stimuli modulate the expression of members of the PYR/PYL/RCAR family of ABA receptors, however these are modulated differentially in a stimulus-specific manner. Of the six members of the PYR/PYL/RCAR family expressed in guard cells, PYL2 is sufficient for guard cell ABA-induced responses. Whereas, in the responses to CO2 PYL4 and PYL5 are essential. Overall our work shows the importance of ABA as a central regulator and integrator of long-term changes in stomatal behaviour, including sensitivity, elicited by external signals. Understanding this architecture may aid breeding of crops with improved water and nutrient efficiency

Consensus Paper: Cerebellar Development

The development of the mammalian cerebellum is orchestrated by both cell-autonomous programs and inductive environmental influences. Here, we describe the main processes of cerebellar ontogenesis, highlighting the neurogenic strategies used by developing progenitors, the genetic programs involved in cell fate specification, the progressive changes of structural organization, and some of the better-known abnormalities associated with developmental disorders of the cerebellum

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