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Background: Low Carbohydrate Diet (LCD) and Calorie Restriction (CR) have been discussed for long. Authors have continued clinical research on LCD, CR and M value. Subjects and Methods: Subjects were 67 male patients with type 2 diabetes mellitus (T2DM). Methods were i) daily profile of blood glucose, average glucose, M value for CR meal, ii) same exam of i) after 2 days of LCD, iii) Delta and AUC ratio for 70g of carbohydrate (0 - 30 minutes) in meal tolerance test (MTT), iv) Triglyceride check for 12 days of LCD, v) analyses of correlation of biomarkers. Results: Obtained data were as follows: average age 61.2 years old, median values are HbA1c 7.8%, fasting glucose 151 mg/dL, IRI 4.4 μU/mL, HOMA-R 2.1, HOMA-β 15.9, respectively. Median values on day 2 vs 14: average glucose 198 vs 151 mg/dL, M value 134 vs 14.4, respectively. AUC ratio for Carbo70 showed more separate distribution as insulin secretion ability than Delta ratio. There were significant correlations among HbA1c, average glucose and M value. Discussion and Conclusion: These results suggested that LCD would have beneficial effects for glucose variability. Furthermore, it would become basal and reference data for the future research development in this field.

Background: Authors have continued clinical practice and research of Calorie Restriction (CR), Low Carbohydrate Diet (LCD) and Morbus (M) value for long. Subjects and Methods: Subjects were 32 type 2 diabetes mellitus (T2DM) with more than 10 μU/mL of fasting immunoreacitve insulin (IRI). Methods included fundamental tests such as glucose, IRI, homeostasis model assessment (HOMA)-R, HOMA-β, and so on. Results: Obtained data were as follows: average age 57.6 ± 12.8 years old, average HbA1c 7.6%. Median values are: average glucose 166 mg/dL, M value 46.6, fasting glucose 140 mg/dL, fasting IRI 12.4 μU/mL, HOMA-R 4.5, HOMA-β 60.3. M value showed significant correlation with HOMA-R and HOMA-β (p

Background: Diabetic nutritional treatment involves the discussion of Low Carbohydrate Diet (LCD) and Calorie Restriction (CR). Authors have initiated and developed LCD in Japan and continued clinical research. In this study, we investigated glucose variability in patients with type 2 diabetes mellitus (T2DM). Subjects and Methods: Subjects were 60 T2DM patients of 62.7 years in average with its fasting immunoreactive insulin (IRI) less than 5μU/mL. Methods include basal blood test, daily profile of blood glucose and insulinogenic index (IGI) for 70g of carbohydrate (0-30min) in CR breakfast. Correlation among these and comparison in 4 groups categorized by Morbus value were analyzed. Results: Basal data revealed HbA1c 7.9%, daily glucose 222 mg/dL in average, and Triglyceride 83 mg/dL, Morbus value 150, HOMA-R 1.1, HOMA-β 11.0 in median. Delta Ratio of IGI and AUC ratio of IGI showed significant correlations with M value and HbA1c (p

Background: There is an ongoing discussion about Low Carbohydrate Diet (LCD) and Calorie Restriction (CR). Authors and colleagues have initiated LCD in Japan, and reported clinical research studies on LCD and related biomarkers. Subjects and Methods: Subjects were 51 patients with Type 2 diabetes mellitus (T2DM) with a mean age of 62.4 ± 6.9 years old. Patients were admitted for 14 days for treatment of super LCD formula, including 12% carbohydrates, 64% lipids, 24% protein with 1400 kcal/day. Six months later, the detail of meals for 7 days, HbA1c and lifestyle items were investigated. Results: Subjects were classified into 2 groups according to the level of HbA1c at 7%. HbA1c was 6.1% vs 7.4%, and carbohydrate intake a day was 55.2g vs 123.6 g in group 1 and 2, respectively. Group 1 tended to have more usage of food and spice for LCD. There was significant correlation between HbA1c and carbohydrate intake (p

Background: Discussion has continued concerning calorie restriction (CR) and low carbohydrate diet (LCD). LCD was developed by Bernstein, Atkins and others, and by our co-authors in Japan. In this study, we report and discuss long-term effects in 2,699 cases, and short-term effects and hyperketonemia in 51 cases. Subjects and Methods: Study 1 (long-term): Subjects were 2,699 cases with diabetes, metabolic syndrome, or both. Methods included continuing LCD and measuring weight reduction in six to twelve months. Study 2 (short-term): Twenty-four diabetics were compared on a CR diet (1,400 kcal/day, carbo-60%) and a super-LCD (1,400 kcal/day, carbo-12%). We recently tried insulinogenic index-carbo70 (IGI-carbo70) from glucose and immunoreactive insulin (IRI; 0, 30 min) for a meal of carbohydrates of 70 g. Study 3 (hyperketonemia): Blood ketone bodies and 3-hydroxybutylic acid (3-OHBA) were measured in 51 diabetics with super-LCDs. Results: Study 1: Weight reduction of more than 10% was observed in 25.6% of subjects, and more than 2.5% was observed in 78.8% of subjects. Study 2: Base data included HbA1c 7.7 ± 1.4 %, homeostasis model assessment (HOMA)-R 3.2 ± 1.9, and HOMA-β 44.5 ± 37.0. Responses of blood glucose to meals (0-120 min) were 156 → 236 mg/dL to CR and 116 → 141 mg/dL to LCD for ten days. Triglyceride value decreased from 143.4 ± 86.8 mg/dL to 93.9 ± 34.8 mg/dL on LCD for ten days. IGI-carbo70 showed less than 0.5 in 75% of cases. Study3: Total ketone bodies were measured in four groups, which were A (4 to 5 days), B (7 to 9 days), C (11 to 13 days), D (21 to 28 days), with an average value of 994 μmol/mL in C, 36 to 623 μmol/mL in A, B, and D. As 3-OHBA value increases from normal (

Background: Low carbohydrate diets (LCD) have been recently prevalent in the medical and health field, especially in diabetes mellitus. We have applied LCD on thousands of patients with metabolic diseases and reported the clinical effect of LCD so far. Through our experience and research concerning LCD, the physiological role of glucose and ketone bodies during the pre- and post-partum period was investigated in this study. Subjects and methods: Subjects were 60 normal pregnant woman who had a normal delivery in full-term, without an abnormal glucose intolerance. Methods included the measurement of the value of ketone bodies in the umbilical cord blood, placental tissue fluid and maternal blood, associated with the value of blood glucose. As ketone bodies, the value of 3-hydroxybutyric acid (3-OHBA, beta-hydroxybutyric acid) was measured. 3-OHBA and glucose values were measured by the electrode method using Precision Exceed Kit (Abbott) and the conventional enzymatic cycling method, with comparison investigation of the data from two kits. Results: The average 3-OHBA levels were as follows: 2,235.0 μmol/L in the placenta, 779.2 μmol/L in the umbilical cord blood, in which the former is significantly higher than the latter (p < 0.001), 240.4μmol/L in the newborn after four days, and 366.7μmol/L after 30 days. The standard 3-OHBA level in a healthy man is less than 85 μmol/L. Glucose levels in the umbilical cord and placenta were 78.6 mg/dL vs 74.9 mg/dL, with no significant difference, and was the same as that of the pregnant woman. Accuracy management of the two kits revealed a significant correlation (r = 0.94, p < 0.001). 3-OHBA values of the maternal blood and umbilical cord blood were extremely elevated from the standard level, with a mutual significant correlation (r = 0.724, p < 0.001, n = 416). Conclusion: This clinical study concerning ketone bodies during pre- and post-partum period was investigated, and revealed that 1) a clinically rapid useful kit for ketone bodies had high reliability and validity compared with conventional kit, 2) elevated values of 3-OHBA were shown in the placental tissue fluid, umbilical cord, newborn and maternal blood, 3) 3-OHBA would be a physiologically indispensable element in nutrition metabolism for fetus and newborn at least until 30 days, with further development of investigation for ketone bodies.

Background: There have been continuing discussion about Calorie Restriction (CR), low carbohydrate diet (LCD) and efficacy of LCD. We have treated lots of diabetic patients and reported clinical significance of LCD and ketone bodies. In current study, Morbus (M) value for blood glucose variability were investigated in CR and LCD, with proposal for usefulness of clinical and research field. Subjects and Methods: Subjects included 52 patients with Type 2 Diabetes Mellitus (T2DM), which were male 21, female 31, 58.9±12.1 y.o.in average, 60 y.o.in median. They were admitted and provided CR diet (60 % carbohydrates, 1400 kcal/day) on day 1-2, and LCD (12 % carbohydrate, 1400 kcal/day) on day 3-14. Methods were as follows:1) basal biomarkers and daily profile of blood glucose (7 times) on CR were measured on day 2, 2) similarly, glucose profile on LCD were measured on day 4, 3) Triglyceride, uric acid and other markers were measured on day 12. 4) Morbus (M) value in glucose variability was investigated. Results: By the level of M value, subjects were classified into 4 groups. M value ranged from 13.6 to 425.6 on day 2 (CR) and from 9.0 to 82.1 on day 4 (LCD). The average HbA1c in 4 groups were 6.2 %, 7.0 %, 8.1 %, 9.0 %, respectively. Blood glucose on day 4 was significantly decreased compared with those on day 2 in each group. M value was significantly decreased from day2 to day 4 in group 2, 3, 4. Triglyceride on day 14 was significantly decreased compared with those on day 2 in each group. There was significant correlation between HbA1c and M value on day 2, between average blood glucose and M value on day 2, 4, and between M value of CR and LCD on day 2, 4. Discussion and Conclusion: The efficacy of LCD was observed from day 2 to day 4, with significant decrease in glucose and M value. The carbohydrate amount was decreased from210g (CR) to 42g (LCD) per day, resulting decrease of average blood glucose and M value. These findings suggest that M-value would be useful marker for treatment of T2DM clinically and research development in glucose variability.

Background: Authors and collaborators have continued clinical research for Low Carbohydrate Diet (LCD) and Calorie Restriction Diet (CRD), glucose variability and M value. We investigated patients with Type 2 Diabetes Mellitus (T2DM) with positive Glutamic Acid Decarboxylase Antibody (GADA). Subjects and methods: Subjects were 12 patients with T2DM showing positive GADA (group 1). They were given CRD on day 1,2, and LCD on day 3-14. Daily profile of blood glucose was measured each day, and data were calculated to M value expressing average glucose and Mean Amplitude of Glycemic Excursions (MAGE). Further, 12 T2DM cases with negative GADA were recruited, who were age-, sex-glucose-related data-matched (group 2). Results: Data of group 1 were as follows: age 54.9 ± 14.3 yo, HbA1c 7.1 ± 0.9%, average blood glucose and M value on day 2 vs 4 were 187 (157-255) vs 145 (114-172), 76.9 (45.9-278) vs 27.2 (19.3-83.5), respectively. In group 2, M value on day 2 vs 4 were 69.9 (37.8-149) vs 5.8 (3.5-13.3), respectively. Group 1 showed insufficient decreased glucose in M value. Discussion and conclusion: These results suggested that cases with positive GADA would have insufficient insulin secretion in response to LCD, and may lead to Slowly Progressive Insulin-Dependent Diabetes Mellitus (SPIDDM) status in the future.

Authors have continued clinical research of Calorie Restriction (CR) and Low Carbohydrate Diet (LCD) and present a case with precise observation of continuous glucose monitoring (CGM). The patient is 38 years-old females with type 2 diabetes mellitus (T2DM), who showed BMI 19.6, postprandial blood glucose 277 mg/dL. HbA1c 12.6%, glycoalbumin 31.8% (11.6-16.4), HOMA-R 2.8, HOMA-β 8.5, urinary excretion of C-peptide 67 μg/day, and normal range of liver, renal, lipid exams. She was given three stage intervention. The protocol was • Day 1-2; CR meal with 60% carbohydrate, • Day 3-5; LCD meal with 12% carbohydrate, • Day 6-13; LCD+Sodium–glucose cotransporter 2(SGLT2) inhibitors (Suglat 50 mg, Ipragliflozin L-Proline). The glucose variability was monitored using FreeStyle Libre Pro (Abbott) for 14 days. Blood glucose was decreased as • More than 350 mg/dL, • 180-200 mg/dL, • 100-150 mg/dL in day 7-9, and 90-120 mg/dL in day 10-13. Acute decrease of blood glucose was found 3 hours after giving Suglat, which was remarkable finding. These results suggest the improving glucose variability of LCD in short term, the acute and strong efficacy of SGLT2 inhibitors for glucose metabolism, and clinical usefulness of simultaneous observation of glucose fluctuation.

In recent years, continuous glucose monitoring (CGM) has been introduced and used in clinical diabetic research. Authors have investigated research about Low Carbohydrate Diet (LCD) and Calorie Restriction (CR) and developed medical and social LCD movement through Japan LCD Promotion Association (JLCDPA). In this study, a case with remarkable improving effect for change from CR to LCD is presented using CGM. The case is 41 years-old female with type 2 diabetes mellitus (T2DM). She was newly diagnosed as T2DM with HbA1c 11.0%, glucose >400 mg/dL, BMI 26.0, AST 30 IU/mL, Hb 16.3 g/dL. She was given CR meal with 60% carbohydrate on day 1 to 4, and LCD meal with 12% carbohydrate on day 5 to 7. Daily profile of blood glucose showed 200-400 mg/dL in day 1-4, 160-240 mg/dL on day 5 and 110-150 mg/dL on day 7. FreeStyle Libre (Abbott, USA) has been valid and useful medical apparatus for monitoring the the detailed fluctuation of blood glucose. Blood glucose value was immediately decreased just after starting LCD, and the short-term effect of the LCD was found. These results would become basal and reference data and contribute to the development of future research.

Background: Discussion of Low Carbohydrate Diet (LCD) and Calorie Restriction (CR) has been continued. Authors have reported research about LCD, CR and Morbus (M) value. In current study, homeostasis model assessment (HOMA) was also investigated together, with the purpose of study for insulin resistance and secretory ability. Subjects and Methods: Subjects were 56 type 2 diabetes mellitus (T2DM) patients with fasting immunoreacitve insulin (IRI) in 5-10 μU/mL. Methods included basal tests, glucose, IRI, HOMA-R, HOMA-β, daily profile of glucose on day 2 and 14 during LCD meal. Results: The obtained data were as follows: average age 63.1 ± 10.5 yo., average HbA1c 7.9 ± 1.9%. Median values are fasting glucose 150 mg/dL, HOMA-R 2.6, HOMA-β 25.9. Divided into 4 groups due to M value, HOMA-R and HOMA-β in each group were 2.3, 2.6, 2.2, 3.5, and 46.1, 40.7, 24.3, 15.9, respectively. Median values on day 2 vs. 14 were: average blood glucose 181mg/dL vs. 139mg/dL, M value 60.7 vs. 10.2, triglyceride 129 mg/dL vs. 89.5 mg/dL. The level of M value showed significant correlation to average glucose, M value, and HOMA-β (p

Background: Discussion of Low Carbohydrate Diet (LCD) and Calorie Restriction (CR) has been observed. Authors have continued clinical research on LCD, CR and Morbus (M) value for years. Subjects and Methods: Subjects were 81 female patients with type 2 diabetes mellitus (T2DM). Methods included i) basal tests on diabetes, ii) daily profile of blood glucose, average glucose, M value for CR meal, iii) same exam of ii) for 2 days of LCD, iv) Triglyceride check for 12 days of LCD, v) analyses of these biomarkers. Results: Obtained data were as follows: average age 62.4 years old, median values are HbA1c 7.2%, fasting glucose 147 mg/dL, IRI 6.8 μU/mL, HOMA-R 2.5, HOMA-β 28.7, respectively. Median values on day 2 vs 14: average glucose 173 vs 130 mg/dL, M value 62.4 vs 9.6, respectively. There was significant correlations between M value and HbA1c (p

Background: Discussion concerning Carbohydrate Restriction (CR) and Low Carbohydrate Diet (LCD) has been continued. Authors formerly proposed insulinogenic index-carbohydrate 70 g (IGI-carbo70). Along this, C-peptide index for Carbohydrate-70 g (CPI-Carbo70) is studied. Subjects and Methods: Subjects were 46 patients (62.5 yo. in average) with Type 2 diabetes mellitus (T2DM) and admitted for evaluation. CR diet was given on day 1-2 with 60% carbohydrates, 25% lipids and 15% protein with 1400 kcal/day. On day 2, breakfast with Carbo70 was given, and glucose and C-peptide (CP) were measured at 0 and 30 minutes and analyzed. Results: As basal data, average HbA1c was 8.1%, median HbA1c, average daily glucose, median M value was 7.7%, 187 mg/dL, 71, respectively. In response to Carbo70, median values of glucose-0, glucose-30, delta-glucose, CP-0, CP-30, delta-CP was 142, 186, 22 mg/dL, 0.9, 1.4, 0.4 ng/mL, respectively. CPI-Carbo70 was 1.54 in median. There were significant correlation between glucose and CP on 0, 30min, delta-0-30min (p

Background: Authors and colleagues have reported nutritional research so far concerning Low Carbohydrate Diet (LCD). Formerly, we proposed useful method for insulin response to 70 g of carbohydrate. Similarly, C-peptide index for Carbohydrate-70 (CPI-Carbo70) is studied and proposed in this report. Subjects and Methods: Subjects enrolled were diabetic patients that were divided into three groups due to diabetic severity. Among them, average HbA1c was 6.6%, 7.8%, 10.0% in low, middle, high group, n=15, 15, 16 respectively. As in-patients, they were on Calorie Restriction meal on day 1 and 2, which has 1400kcal/day with carbohydrates 60%, lipids 25%, protein 15%. On day 2, breakfast with carbohydrate 70 g was provided, and glucose and C-peptide levels were measured at 0, 30 minutes. Results: Biomarkers were analyzed in 3 groups. Increment C-peptide (CP) and CPI-Carbo70 in 3 groups were 0.58, 0.57, 0.27 and 2.1, 3.2, 1.2, respectively. As for M value, CP increment, CP on 30 min, CPI-Carbo70 was investigated, which were lower in high group. There is significant correlation between HbA1c and CPI-Carbo70 (p

Background: Diabetes has been great problem worldwide. Continuous Glucose Monitoring (CGM) has been in focus, and useful CGM, FreeStyle Libre (Abbott) has been introduced to clinical ordinary practice of medicine. Case and results: The patient was 57 year-old female with type 1 diabetes mellitus (T1DM), who showed BMI 20.6 kg/m2, HbA1c 8.6%. She was on CGM measured glucose every 15 minutes in 24 hours for 14 days. Treatment included 3 times of Insulin Aspart and once of Insulin Glargin. She showed characteristic pattern of blood glucose profile according to the working schedule of the day. Discussion and conclusion: The beneficial points of FreeStyle Libre have been convenient and accurate for clinical use for reducing hypoglycemia episodes. Treatment using CGM associated with multiple daily insulin injection (MDI) confers similar or greater benefits for glycemic profile. When evening insulin was not injected one day, blood glucose increased 320 mg/dL, suggesting 64 g of carbohydrate ingested for supposed calculation. These results suggest that CGM could recommend the timing and doses of insulin injection according to the lifestyle of the patients with clinical merit.

Background: Discussion has continued for Calorie Restriction (CR) and low carbohydrate diet (LCD). We have investigated clinical research of LCD in various states for years. Case and results: The patient was 61 year-old female with HbA1c 10.5%, BMI 21.2 kg/m2 and normal vitals and physicals. Laboratory data were Hb 15.2 g/dl, Alb 5.0 g/dL, Triglyceride 43 mg/dL, HDL-C 89 mg/dL, LDL-C 152 mg/dL, immunoreactivity insulin (IRI) 2.9 μU/mL serum C-peptide reactivity (s-CPR) 1.0 ng/mL, total ketone bodies (T-KB) 3081 μmol/L (28-120), acetoacetic acid (AcAc) 300 μmol/L (14-68), 3-hydroxybutyric acid (3-OHBA) 2781 μmol/L (0-74) Autoantibodies were negative for Glutamate decarboxylase (GADA) or Islet cell (IA-2). She was diagnosed as type 2 diabetes mellitus (T2DM) and started super LCD formula meal with 12% of carbohydrate, and recorded carbohydrate amount about 20-40g per day. HbA1c value was 8.1% and 6.6% in 2 and 4 months, respectively. Significant relationship was shown between carbohydrate intake and hyperketonemia. AcAc/T-KB ratio was 15-20% and around 10%, when T-KB is less than 1000 μmol/L and more than 1000 μmol/L, respectively. Discussion and conclusion: Authors have proposed 3 types of LCD, which are petit, standard and super, with 40%, 26%, 12% of carbohydrate ratio. Continuing super- LCD usually brings elevated ketone bodies, which might have beneficial function for maintaining the health and anti-aging medicine. Currently obtained results would become the fundamental data and suppose future directions and recommendations for research of ketone bodies in low carbohydrate diet.

Background: Continuous Glucose Monitoring (CGM) has been in focus for treatment of diabetes. Recently, a sensor-based flash glucose monitoring system, FreeStyle Libre (Abbott), has been introduced to clinical practice. Case and results: The patient was 53 year-old female with type 1 diabetes mellitus (T1DM), who showed BMI 25.1 kg/m2, HbA1c 9.5% in January, 6.0% in June and 7.7% in November, 2017 as data on outclinic. CGM measured glucose every 15 minutes in 24 hours for 14 days on June and November, and estimated HbA1c was 5.4% and 6.1%, respectively with discrepancy. Discussion and conclusion: The beneficial points of FreeStyle Libre have been accurate, convenient and small size for clinical use for lessen hypoglycemia episodes. Key benefits of CGM monitoring are frequency of testing, trends, alarms, therapy optimization. Former studies for FreeStyle Libre tended to show lower values and larger mean absolute relative difference (MARD) in lower range of glucose levels, suggesting possible cause of the discrepancy for HbA1c levels. FreeStyle Libre for CGM would lead to better balance optimization of glucose control and current results would become basal data for future investigation of CGM.

Background: The discussion has continued concerning Calorie Restriction (CR) and Low Carbohydrate Diet (LCD) for years. Authors and colleagues have continued clinical research on LCD. In this study, CR diet was given to diabetic patients and the new evaluation way of insulinogenic index-carbohydrate 70 g (IGI-carbo70) would be proposed. Subjects and methods: The subjects were 48 patients with Type 2 diabetes mellitus (T2DM) and admitted for 14 days for further evaluation and treatment. CR diet was provided on day 1 and 2, including 60% carbohydrate, 25% lipids and 15% protein with 1400 kcal/day. On the morning of day 2, breakfast with 70 g of carbohydrate was given, and blood glucose and immune reactive insulin (IRI) at 0 and 30 min and IGI were investigated. Results: Average HbA1c was 7.9% and Morbus (M) value was 108 in median. Glucose and IRI on 0-30 min significantly increased as 166-212 mg/dL, 4.3-1.9 μU/mL, respectively. Classified into 3 groups as to HbA1c level, low, middle and high group showed HbA1c 6.0%, 7.8%, 9.7%, respectively. Glucose and IRI on 0-30 min in median were 117-50, 166-203, 218-299 mg/dL, 4.4-12.8, 4.5-13.5, 4.2-9.9 μU/mL, with IGI 0.25, 0.14, 0.10, respectively. Discussion and conclusion: Newly-proposed IGI-carbo70 was investigated, and there were several correlations among 8 related biomarkers. These findings suggest that current results would become the fundamental data and IGIcarbo70 could be the useful way to evaluate diabetic status by usual meal with mixed nutrients.

Background: Arguments have continued for long concerning low carbohydrate diet and calorie restriction (calorie-restricted diet). Authors have reported clinical studies of low carbohydrate diet on ketone bodies, glucose variability and Morbus value so far. Subjects and methods: Subjects are 28 patients with Type 2 diabetes mellitus, which were 20/8 (M/F) with 48.3 ± 13.9 years old with serum triglyceride more than 250 mg/dL on blood sampling with overnight fasting. They were admitted for 14 days and the protocol was as follows: 1) calorie-restricted diet on day 1 and 2, which had 60% carbohydrates, 2) low carbohydrate diet on day 3-14 days which is so-called super-low carbohydrate diet formula with 12% carbohydrates. Results: Mean HbA1c was 8.0 ± 1.7% and mean fasting glucose was 177 ± 52 mg/dL. Median data days 2 to 4 were 208 to 147 mg/dL in average glucose, 146 to 21 in Morbus (M) value and 123 to 94.5 mg/day in urinary C-peptide. Median data days 2 to 14 were 366 to 159 mg/dL in Triglyceride, 46 to 42 mg/dL in HDL-C and 111 to 120 mg/dL in LDL-C. Remnant-like particle cholesterol on day 2 was 15.9 mg/dL in median. Significant correlations on day 2 were shown between Triglyceride and HDL-C (p