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Authors and colleagues have continued clinical diabetic research in the light of Continuous Glucose Monitoring (CGM) and M value. M value is calculated from the daily profile of blood glucose, and it indicates the total numerical value of two factors, which are average blood glucose and mean amplitude of glycemic excursions (MAGE). The case is 53 years old female with Type 1 diabetes mellitus (T1DM), who was on multiple daily insulin injection (MDI). Using FreeStyle Libre, blood glucose was studied for 14 days. Average blood glucose in a day was 169 mg/dL, 163 mg/dL, 164 mg/dL and 166 mg/dL in day 3,5,9,11, respectively with almost same level. In contrast, the levels of the M value distributed widely from 12.5 to 98.3. A discrepancy of HbA1c was found between estimated value and laboratory data on out clinic, which was 7.4% and 8.0%, respectively. These results suggest that there would be rather large difference in MAGE even though the average blood glucose was almost the same in the 4 days. Furthermore, this investigation would be beneficial for check the detail blood glucose variability associated with various activities, and for better and stable control of blood glucose in T1DM.

In the diabetic medical practice, continuous glucose monitoring (CGM) has been recently used with beneficial efficacy. Authors have continued women’s medical care and research on Calorie Restriction (CR) and Low Carbohydrate Diet (LCD), and developed medical and social LCD movement by Japan LCD Promotion Association (JLCDPA). In this study, a diabetic female case with remarkable improving effect is shown using CGM and LCD. The case is 27 years-old female with type 2 diabetes mellitus (T2DM). She has been pregnant and on multiple daily insulin injection (MDI) with insulin 48 units/day in the university hospital. She was on this treatment until 28th weeks with no preeclampsia symptoms, and hoped to change the treatment of LCD. She came to our women’s clinic with the current data of weight 101kg, BMI 37.1 and HbA1c 7.0%. By application of FreeStyle Libre (Abbott, USA), her glucose variability showed around 160mg/dL with some episodes of hyperglycemia. The meal was changed from CR to LCD after 29th week, then insulin administration could be discontinued in 10 days. This glucose variability showed remarkable efficacy for combination of LCD and CGM. These results would become basal and reference data and contribute to the development of future research.

Background: There have been lots of discussion and controversy concerning the difference between Low Carbohydrate Diet (LCD) and Calorie Restriction (CR). The important points include glucose variability, glucose-lowering effect, weight reduction degree and influence on lipid metabolism. Subjects and Methods: Enrolled subjects were 47 patients with T2DM. Methods included the study for providing subjects CR meal with 60% carbohydrate on day 1-2 and LCD meal with 12% on day 3-14. Daily profile of blood glucose was studied seven times a day on day 2 and day 4. Further, biomarkers including HbA1c, average blood glucose, and M value were investigated and analyzed for mutual correlations. Results: Subjects were categorized into 4 groups according to the average glucose value, which were 124mg/dL, 160mg/dL, 206mg/dL, and 281mg/dL, respectively. Data in 4 groups were as follows: Number; 12,12,12,11, Male/Female; 6/6, 3/9, 6/6, 5/6, mean age; 51.3, 60.9, 65.3, 60.6 years old, HbA1c; 6.1%, 7.1%, 8.0%, 8.9%, fasting glucose on day 2; 109 mg/dL, 136 mg/dL, 178 mg/dL, 224mg/dL, respectively. Daily profiles of blood glucose in 4 groups on day 4 were remarkably decreased than those of day 2. The levels of M value indicating average blood glucose and mean amplitude of glycemic excursions (MAGE) on day 2 vs 4 were compared in 4 groups, which are 7.1 vs 10.5, 39.7 vs 5.0, 139 vs 15.7, 367 vs88, respectively. Correlations among HbA1c, M value and average blood glucose showed significant correlations (p<0.01). Discussion and Conclusion: Obtained results showed that the distribution of daily profile of blood glucose in 4 groups is separated. Further similar tendency was observed in HbA1c and M value. There was remarkable decrease of blood glucose from CR to LCD. These findings suggested that LCD would have remarkable efficacy for improving glucose variability. Furthermore, obtained findings could become basal and reference data for the developing research for CR and LCD.

Background: Authors have continued research for meal tolerance test (MTT) by calorie restriction diet (CRD) and low carbohydrate diet (LCD), besides M value and glucose variability. Methods: Subjects were 38 patients of two groups. Group-1 has 19 patients (57.6±12.9 years) with type 2 diabetes mellitus (T2DM) and positive glutamic acid decarboxylase antibody (GADA), which is possible to latent autoimmune diabetes in adults (LADA). Group-2 has recruited 19 cases with T2DM and negative GADA, who showed age, sex, glucose variability-matched subjects. They were given CRD on day 1-2, and LCD day 3-14, and biomarkers were compared between Group-1 and Group-2. Results: Average values of the daily profile of blood glucose on day2(CRD)/day4(LCD) in Group-1 vs 2 were studied. Obtained data were 202/148 mg/dL vs 205/143 mg/dL, respectively with similarity. However, M value showed 174/58 vs 179/22, respectively with difference. There were significant correlations of M value between day2 and day4 in Group-1 vs Group-2. Further, both showed contrast tendency, associated with wide distribution vs narrow distribution, respectively. Conclusions: These results suggested that Group-1 with positive GADA may have insufficient pancreas secretion compared with that of Group-2, and these data may become a basal reference for future study of LADA.

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: 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.

Background: Arguments have continued about Low Carbohydrate Diet (LCD) and Calorie Restriction (CR). Authors have reported clinical research of LCD and Morbus (M) value. Subjects and Methods: Subjects enrolled are 84 patients with Type 2 diabetes mellitus (T2DM), 60.9 ± 10.9 years. The protocol were as follows: 1) CR diet on day 1, 2 with 60% carbohydrates, and LCD on day 3-14 with 12% carbohydrates, 2) Daily profile of blood glucose 7 times a day on day 2 (CR) and day 4 (LCD), 3) urinary C-Peptide radioimmunoassay (u-CPR) excretion, 4) M value calculation, 5) investigation of these data with correlation. Results: Subjects were classified into 4 groups according to M value, which were .4–21, 23–66, 29–192, 200–728, respectively. HbA1c value was 6.2, 8.0, 7.8, 9.2 %, respectively. Blood glucose in median from day 2 to day 4 were 123 to 107 mg/dL, 164 to 130 mg/dL, 193 to 156 mg/dL, 277 to 201 mg/dL, respectively. M value in median from day 2 to 4 was 6.3 to 9, 41 to 7, 108 to 16, 367 to 88, respectively. u-CPR was 88 to 58, 53 to 35, 65 to 52, 74 to 64, respectively. There were significant correlations among among glucose, M value and u-CPR. Discussion and Conclusion: Average glucose, M value and u-CPR decreased remarkably on day 4. As average glucose and M value were higher, decrease degree were larger. These results suggested that carbohydrate in meal would influence glucose variability in T2DM. Our data would become basic data for pathophysiological analysis of glucose variability research in the future.

Background: Authors have continued research concerning Low Carbohydrate Diet (LCD) and its related biomarkers. We also investigated correlation among several factors such as daily profile, fasting and average of blood glucose, Morbus value, and insulin and C-peptide. Subjects and Methods: Subjects were patients with type 2 diabetes mellitus (T2DM), classified into three groups due to HbA1c value. Methods included 1) basal blood exams, 2) intake of Calorie Restriction (CR) meal with 1400kcal/day with 60% of carbohydrates, 3) check of daily blood glucose 7 times a day, 4) calculation of average glucose and M value, 5) analyses of biomarkers. Results: Average blood glucose was 168 mg/dL, 206 mg/dL, 265mg/dL in low, middle, high group, respectively. Fasting ratio of C-peptide/glucose in 3 groups was 0.37, 0.34, 0.26, respectively period. There was significant correlation among HbA1c, M value and fasting ratio of C-peptide/glucose. Discussion and Conclusion: Among 3 groups, high group revealed lower tendency of fasting C-peptide and fasting ratio of C-peptide/glucose than other groups, suggesting that high group might has lower ability of insulin secretion. Fasting ratio of C-peptide/glucose would be useful for indicating beta cell function and predicting insulin requirement in clinical practice.

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<0.05). Discussion and Conclusion: CPI-Carbo70 may be useful for evaluating pancreas function and glucose variability. These data could be basal and useful in the light of clinical evaluation and further research development.

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<0.01). Significant correlation was observed between CPI and HbA1c, CPI and M value (p<0.01). Discussion and Conclusion: CPI-Carbo70 might be useful for evaluating pancreas function and glucose variability in clinical research. Current data would become the fundamental data for the future diabetic practice and research development.

Carbohydrate and lipid metabolism were studied. Subjects were 121 patients with type 2 diabetes mellitus (T2DM), and provided Calorie restriction (CR) on day 1,2 and Low Carbohydrate Diet (LCD) from 3 to 14 days. Basal biomarkers, daily glucose profile on day 2, 4, and lipids including remnant-like particle cholesterol (RLP-C) were measured, subjects were classified into 4 groups due to average glucose with mean HbA1c 6.3%, 6.9%, 7.9%, 9.2%, respectively. Average glucose from day 2 to 4 in each group was significantly decreased. M value considerably decreased in group 2, 3, 4, indicating useful M value. Correlations were investigated among glucose, HbA1c, urinary C-Peptide and M value. As for lipids, Triglyceride from day 2 to 14 decreased considerably. RLP-C levels showed significant correlation with Triglyceride, LDL-C, atherogenic index (T-C - HDL / HDL) and TG/HDL value. These results would suggest that RLP-C may be involved in the development of arteriosclerosis of T2DM, and may have the role of further research direction in the future. In current study, our results would become the fundamental data for the further development of LCD therapy in various counties and districts, and suggest the research direction for patients with T2DM from the combined point of glucose and lipid metabolism in the future.

Background: As to nutritional therapy, continuous discussions were observed concerning calorie restriction (CR) and low-carbohydrate diet (LCD). Authors and colleagues have applied LCD for lots of diabetic patients and reported the detail relationship with ketone bodies and Morbus (M) value. Methods: Ninety-three patients with type 2 diabetes mellitus (T2DM) were considered as subjects in the study, among which 51 were male and 52 were female, 58.3±13.2 years old on average, 60 years old in median. Methods were as follows: 1) patients were admitted and provided formular diet, which included CR diet (60% carbohydrates, 1400 kcal/day) on day 1-2, and LCD (12% carbohydrate, 1400 kcal/day) on day 3-14; 2) several biomarkers on fasting were measured on day 2, 4 and 14; 3) daily profile of blood glucose were done on day 2 and day 4. Results: According to the M-value, subjects were classified into 4 groups, which were less than 25, 26-100, 101-250, more than 251, and number was 24, 24, 24, 21, respectively. The average HbA1c in 4 groups were 6.6%, 7.4%, 8.5% and 9.5% respectively. The median M-values decreased from day 2 to 4, which were 10.4 to 9.1, 53.5 to 7.7, 150 to 19.1 and 438 to 87, respectively. The average uric acid in each group revealed significant increase from day 2 to day 14. There were significant correlation between uric acid increment and creatinine increment, and among creatinine, creatinine clearance (CCr) and Cystatin C. Conclusion: LCD showed efficacy for glucose variability with significant decrease in glucose and M-value. Renal study showed increase of serum uric acid. In addition to correlations of Cystatin C and biomarkers, current results would be from some dehydrated state and/or relative decrease of total calorie intake. These findings would become the fundamental data of efficacy of LCD and its physiological influences for renal function.

Background: Debate between the Calorie Restriction (CR) and Low-Carbohydrate Diet (LCD) has been continued for several years. We have started LCD therapy for diabetic patients since 1999, and experienced good response to control hyperglycemia. Recently the risk of postprandial hyperglycemia for cardiovascular events is reported, and the range of glucose level is focused. Morbus (M) value is proposed to be a good index to show the range of glucose fluctuation. Usefulness of LCD and usefulness of M-value were shown by combined analysis. Methods: Twenty-six patients with Type 2 Diabetes Mellitus (T2DM), who admitted to the Takao Hospital, were the subjects. They were 12 males and 14 females, and their age ranged from 38 to 78 years old. A few patients were new patients, but mostly referred from other hospitals to receive LCD treatment. All patients started from CR therapy with 60% carbohydrate for 2 days, and then carried out LCD dietary therapy with 12% carbohydrates for 10-12 days. On day 2 and 12, blood glucose level was measured at 7 points a day to see the fluctuation from morning to night. Blood and urinary samples were corrected on the same day to get ordinary biochemical data and metabolic marker. Results: To know the effect of LCD on different level of HbA1c, the patients were grouped to low (L; 6.1±0.5%), middle (M; 7.9±0.4%) and high (H; 9.2±0.7%) by HbA1c value. The M-values after 2 day CR were 26.1 (L), 94.1 (M) and 343 (H), respectively. The LCD therapy decreased M-value to 10.4 (L), 18.8 (M) and 84.2 (H), respectively. The significant reduction of M-values was a reflection of the improved postprandial glucose level. LCD was effective even in the bad controlled diabetic patients. In addition to the decreased triacylglycerol and 24 hr urinary C-peptide, uric acid increased in all patients. Conclusion: Ten to 12 day-dietary therapy with LCD was quite effective to improve blood glucose profile. Patients with high HbA1c could be safely treated by LCD. Blood g

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 ma

Background: The discussion concerning calorie restriction (CR) and low carbohydrate diet (LCD) has been continued for long yeas. As to LCD, we have reported lots of experience and research for glucose variability and ketone bodies. Subjects and methods: Three cases with type 2 diabetes mellitus (T2DM) were on LCD and studied. Methods included 3 patterns of LCD meal which are super, standard and petit LCD, with including carbohydrate ratio 12%, 26% and 40%, respectively. Case 1 (61, M) showed hyperglycemia about 150 mg/dL to 300 mg/dL in daily profile with 12.5% in HbA1c. Starting super LCD therapy, the glucose profile decreased to less than 150 mg/dL and HbA1c decreased to 6.7% in 3 months. Case 2 (53, M) revealed HbA1c 8.3%, weight 110 kg and body mass index 34.5. By super LCD, his weight was decreased 17 kg in 5 months, with normalized HbA1c and elevated serum 3-hydroxybutyric acid (3-OHBA). Case 3 (72, M) had always extremely elevated fasting triglyceride for 5 years. Starting petit LCD for 2 years, triglyceride and weight were decreased moderately. Successively, changing to standard LCD for 1 year, weight was decreased 6 kg, and triglyceride was normalized. Discussion and conclusion: Each case suggests the characteristic beneficial effect of LCD. From our clinical experience and research, super LCD method, which is one of the very low-carbohydrate ketogenic diet (VLCKD), has evident efficacy of weight reduction. Super-LCD is characterized by strictly limitation for carbohydrate. Standard-LCD and petit-LCD method can be useful and applicable in response to the status of the patients. Thus, LCD treatment have beneficial effects for patients with various status.

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<0.05), Triglyceride and LDL-C (p<0.05). Remnant-like particle cholesterol-C showed significant positive correlation with Atherogenic Index (AI) and triglyceride (p<0.01), significant negative correlation with HDL (p<0.05). Significant correlations were shown on day 2 and 14 in Triglyceride and LDL-C/HDL-C Ratio (p<0.01). Discussion and conclusion: Decrease of blood glucose indicated short effect of low carbohydrate diet only for 2 days from calorie restriction to low carbohydrate diet. Apparent large decrease of M value would be useful for clinical management and research. Analyses of correlations among RLP-C, triglyceride, HDL-C, LDL-C, AI and LDL-C/HDL-C Ratio would become the fundamental data for clinical research and give the hint for research direction in the future.