Relation of cardiac function to insulin resistance as evaluated by hyperinsulinemic-euglycemic clamp analysis in individuals with type 2 diabetes.

AIMS: Whereas homeostasis model assessment of insulin resistance (HOMA-IR), an easily measured but limited index of insulin resistance, has been shown to correlate with impairment of cardiac function in individuals without diabetes, the pathological relevance of insulin resistance to the development of cardiac dysfunction in individuals with type 2 diabetes has remained unclear. Here we investigated the relation between left ventricular (LV) function as assessed by echocardiography and insulin resistance as evaluated by hyperinsulinemic-euglycemic clamp analysis, the gold standard for measurement of this parameter, in individuals with type 2 diabetes. METHODS: This retrospective study included 34 individuals with type 2 diabetes who underwent both hyperinsulinemic-euglycemic clamp analysis and echocardiography. Both the insulin sensitivity index (ISI) as determined by glucose clamp analysis as well as HOMA-IR were determined as measures of insulin resistance. The ratio of the peak early- to late-diastolic mitral inflow velocities (E/A) and the LV ejection fraction (LVEF) were determined as measures of diastolic and systolic function, respectively. RESULTS: The ISI was significantly correlated with both the E/A ratio and LVEF (correlation coefficients of 0.480 and 0.360, respectively), whereas HOMA-IR was not correlated with either cardiac parameter. Multivariate analysis revealed that ISI was an independent predictor for both a high log [E/A] (P = 0.031) and a high LVEF (P = 0.045). CONCLUSIONS: Insulin resistance as evaluated by hyperinsulinemic-euglycemic clamp analysis may be causally related to LV diastolic and systolic dysfunction in individuals with type 2 diabetes.

Analysis of time-dependent alterations of parameters related to erythrocytes after ipragliflozin initiation.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors often increase the hematocrit. It remains unclear whether this increase would be observed in all patients administered SGLT2 inhibitors, however. We therefore used the data from the previous study and investigated time-dependent alterations of various outcomes related to erythrocytes, erythropoiesis, and clinical outcome in type 2 diabetes subjects (n = 89) treated with ipragliflozin for 16 weeks. Among a total of 89 participants, 71 subjects (80.0% of total participants) showed the elevation of the hematocrit and 18 subjects (20.0% of total participants) did not at 16 weeks. Although the hematocrit levels at baseline were significantly lower in hematocrit-elevated group than non-elevated group, they reached the same levels 4 weeks after the onset of treatment. Binomial logistic regression analysis demonstrated that a lower baseline hematocrit level was related to the elevation of hematocrit at 16 weeks. Optimal cutoff hematocrit levels at baseline to predict hematocrit elevation were 46.9% (male) and 41.7% (female) in ROC analysis. Random intercept model analysis revealed the serum erythropoietin level increased in both hematocrit-elevated and non-elevated groups, whereas only the former group showed an increase in the percentage of reticulocytes during the first 4 weeks. These results suggest that the ipragliflozin-induced increase in hematocrit which is affected by the baseline hematocrit level is attributable to the responsiveness to, but not to the production of, erythropoietin. Collectively, Ht elevation observed in administration of SGLT2 inhibitors can result from erythropoietin-induced erythropoiesis, which is determined by the pre-treatment Ht level. Trial registration: This trial has been registered with University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR no. 000015478).

Dose-dependent accumulation of glucose in the intestinal wall and lumen induced by metformin as revealed by 18 F-labelled fluorodeoxyglucose positron emission tomography-MRI.

AIM: To investigate the relationships between various clinical variables and the metformin-induced accumulation of fluorodeoxyglucose (FDG) in the intestine, with distinction between the intestinal wall and lumen, in individuals with type 2 diabetes who were receiving metformin treatment and underwent 18 F-labelled FDG ([18 F]FDG) positron emission tomography (PET)-MRI. MATERIALS AND METHODS: We evaluated intestinal accumulation of [18 F]FDG with both subjective (a five-point visual scale determined by two experienced radiologists) and objective analyses (measurement of the maximum standardized uptake value [SUVmax ]) in 26 individuals with type 2 diabetes who were receiving metformin and underwent [18 F]FDG PET-MRI. [18 F]FDG accumulation within the intestinal wall was discriminated from that in the lumen on the basis of SUVmax . RESULTS: SUVmax for the large intestine was correlated with blood glucose level (BG) and metformin dose, but not with age, body mass index, HbA1c level or estimated glomerular filtration rate (eGFR). SUVmax for the small intestine was not correlated with any of these variables. Visual scale analysis yielded essentially similar results. Metformin dose and eGFR were correlated with SUVmax for the wall and lumen of the large intestine, whereas BG was correlated with that for the wall. Multivariable analysis identified metformin dose as an explanatory factor for SUVmax in the wall and lumen of the large intestine after adjustment for potential confounders including BG and eGFR. CONCLUSIONS: Metformin dose is an independent determinant of [18 F]FDG accumulation in the wall and lumen of the large intestine in individuals treated with this drug.

Effects of insulin degludec and insulin glargine U300 on glycaemic stability in individuals with type 1 diabetes: A multicentre, randomized controlled crossover study.

To compare the effects of insulin degludec (IDeg) and insulin glargine U300 (IGlarU300) on glycaemic stability in subjects with type 1 diabetes. MATERIALS AND METHODS: In this multicentre, crossover trial, 46 individuals with type 1 diabetes and essentially undetectable circulating C-peptide were randomly assigned to either the IDeg-first/IGlarU300-second group or the IGlarU300-first/IDeg-second group, and were treated with the respective basal insulins for 4-week periods. Data were collected in the last week of each treatment period. The primary aim was to examine the potential non-inferiority of IDeg relative to IGlarU300 with regard to day-to-day variability, as evaluated by the standard deviation (SD) of fasting blood glucose (FBG) levels. Intra-day glycaemic variability and other variables were also determined by continuous glucose monitoring (CGM). RESULTS: The SD of FBG for IDeg was non-inferior to that for IGlarU300. The mean of FBG, coefficient of variation of FBG, and various glycaemic variability indexes determined by CGM did not differ between the two insulins. Whereas the administered doses of the insulins also did not differ, the mean glycaemic value was lower for IDeg than IGlarU300; the time above the target range (>180 mg/dL [10.0 mmol/L]) and the time below the target range (<70 mg/dL [3.9 mmol/L]) were shorter and longer, respectively, for IDeg than IGlarU300. CONCLUSIONS: Our data suggest that IDeg and IGlarU300 have comparable glucose-stabilizing effects in individuals with type 1 diabetes. However, the glucose-lowering effect of IDeg may be greater than that of IGlarU300 when titrated with a unit-based protocol.

Relation between HOMA-IR and insulin sensitivity index determined by hyperinsulinemic-euglycemic clamp analysis during treatment with a sodium-glucose cotransporter 2 inhibitor.

We had aimed to determine whether homeostasis model assessment-insulin resistance (HOMA-IR) reflects insulin resistance-sensitivity during treatment with a sodium-glucose cotransporter 2 inhibitor (SGLT2i). Hyperinsulinemic-euglycemic clamp analysis was performed in 22 patients with type 2 diabetic patients taking dapagliflozin (5 mg/day before or after breakfast). Propensity score matching of these individuals (SGLT2i group) for age, sex, body mass index, and clamp-derived tissue glucose uptake rate with 44 type 2 diabetic patients who had undergone clamp analysis without SGLT2i treatment (control group) identified 17 paired subjects in each group for further analysis of the relation between HOMA-IR and a clamp-derived insulin sensitivity index (ISI). Natural log-transformed HOMA-IR was negatively correlated with ISI in both SGLT2i (r = -0.527, p = 0.030) and control (r = -0.534, p = 0.027) groups. The simple regression lines for log-transformed HOMA-IR and ISI in the two groups showed similar slopes but differed in their intercepts. Multivariate analysis revealed that HOMA-IR for patients with the same ISI in the two groups was related by the formula: HOMA-IRcontrol = HOMA-IRSGLT2i × 2.45. In conclusion, HOMA-IR was well correlated with ISI during SGLT2i treatment, but values corresponding to the same ISI were lower in the SGLT2i group than in the control group.

Glucagon secretions are impaired in patients with fulminant type 1 diabetes.

Arginine-challenge test in various types of diabetes.

Effects of ipragliflozin on glycemic control, appetite and its related hormones: A prospective, multicenter, open-label study (SOAR-KOBE Study).

AIMS/INTRODUCTION: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors improve blood glucose control, as well as reducing bodyweight by promoting urinary glucose excretion. The weight loss is less than expected from urinary glucose loss, however, likely because of an increase in food intake. To investigate whether SGLT-2 inhibitors might increase appetite by affecting related hormones, we examined the effects of the SGLT-2 inhibitor, ipragliflozin, including those on appetite-regulating hormones, in individuals with suboptimally controlled type 2 diabetes. MATERIALS AND METHODS: The present prospective, multicenter, open-label study was carried out with 96 patients with a body mass index of ≥22 kg/m2 who were treated with ipragliflozin (50 mg/day) for 16 weeks. Parameters including glycated hemoglobin level, bodyweight, circulating leptin and active ghrelin concentrations, and appetite as assessed with a visual analog scale were measured before and during treatment. RESULTS: Both glycated hemoglobin level (from 7.9 ± 0.8 to 7.1 ± 0.7%) and bodyweight (from 75.2 ± 12.6 to 72.6 ± 12.4 kg) were significantly decreased after treatment for 16 weeks. The fasting serum leptin level was significantly decreased after 2 weeks (from 19.5 ± 13.1 to 18.1 ± 12.4 ng/mL) and remained decreased up to 16 weeks, even after adjustment for bodyweight, whereas the plasma active ghrelin level showed no significant change. The visual analog scale score for hunger was significantly increased at 2 and 8 weeks. CONCLUSIONS: The present results suggest that ipragliflozin improved glycemic control and reduced bodyweight, but also reduced serum leptin levels and might thereby have increased appetite.

Impaired glucagon secretion in patients with fulminant type 1 diabetes mellitus.

PURPOSE: Fulminant type 1 diabetes mellitus (FT1DM), characterized by rapid and almost complete destruction of pancreatic ß-cells, is a newly identified subtype of type 1 diabetes mellitus. Although, the pathophysiology of this condition remains still unclear, histological evidence suggests that not only ß-cells but also α-cells of pancreatic islets are reduced in number in FT1DM. However, the ability of glucagon secretion in patients with this condition has remained largely uncharacterized. We therefore examined glucagon secretion in patients with FT1DM and compared that with patients with other types of diabetes mellitus. METHODS: Fasting glucagon levels as well as glucagon secretion induced by intravenous administration of arginine were measured in hospitalized 83 patients with diabetes mellitus, including 4 with FT1DM, 18 with type 1 diabetes mellitus (T1DM), 40 with type 2 diabetes mellitus (T2DM), 5 with slowly progressive insulin-dependent diabetes mellitus (SPIDDM), and 16 with pancreatic diabetes mellitus (PDM). RESULTS: The area under the curve for serum glucagon levels after arginine infusion in FT1DM patients was significantly smaller than that in T1DM, T2DM, or SPIDDM patients but was similar to that in PDM patients. The fasting serum glucagon level of FT1DM patients was lower than that of T1DM or T2DM patients but did not significantly differ from that of SPIDDM or PDM patients. CONCLUSIONS: These results suggest that glucagon secretion is impaired in patients with FT1DM.

Effects of Insulin Degludec and Insulin Glargine U300 on Day-to-Day Fasting Plasma Glucose Variability in Individuals with Type 1 Diabetes: A Multicenter, Randomized, Crossover Study (Kobe Best Basal Insulin Study 2).

INTRODUCTION: Administered basal insulin markedly influences the fasting plasma glucose (FPG) level of individuals with type 1 diabetes. Insulin degludec (IDeg) and insulin glargine U300 (IGlar U300) are now available as ultra-long-acting insulin formulations, but whether or how their glucose-stabilizing effects differ remains unclear. We will compare the effects of these basal insulins on parameters related to blood glucose control, with a focus on day-to-day glycemic variability, in individuals with type 1 diabetes treated with multiple daily injections. METHODS: A multicenter, randomized, open-label, crossover, comparative study (Kobe Best Basal Insulin Study 2) will be performed at 13 participating institutions in Japan. A total of 46 C-peptide-negative adult outpatients with type 1 diabetes will be randomly assigned 1:1 by a centralized allocation process to IGlar U300 (first period)/IDeg (second period) or IDeg (first period)/IGlar U300 (second period) groups, in which subjects will be treated with the corresponding basal insulin for consecutive 4-week periods. The basal insulin will be titrated to achieve an FPG of less than 130 mg/dL initially and then less than 110 mg/dL if feasible. In the last week of each period, plasma glucose will be determined seven times a day by self-monitoring of blood glucose (SMBG) and intraday and day-to-day glucose excursions will be determined by flash glucose monitoring (FGM). The primary end point is comparison of day-to-day glycemic variability as evaluated by the standard deviation (SD) of FPG during the last week of each treatment period. Secondary end points include the coefficient of variance of FPG, the frequency of severe hypoglycemia as evaluated by SMBG, the duration of hypoglycemia as evaluated by FGM, intraday glycemic variability calculated from both SMBG and FGM data, and the administered insulin dose. PLANNED OUTCOMES: The results of the study will be submitted for publication in a peer-reviewed journal to report differences in the effects of two ultra-long-acting basal insulins, IDeg and IGlar U300. CONCLUSION: This head-to-head comparison will be the first study to compare the effects of IDeg and IGlar U300 on day-to-day FPG variability in C-peptide-negative individuals with type 1 diabetes. TRIAL REGISTRATION: Registered in University Hospital Medical Information Network (UMIN) Clinical Trials Registry as 000029630 on 20 June 2017. FUNDING: Novo Nordisk Pharma Ltd.

Comprehensive Evaluation of Combination Therapy with Basal Insulin and Either Lixisenatide or Vildagliptin in Japanese Patients with Type 2 Diabetes: A Randomized, Open-Label, Parallel-Group, Multicenter Study.

INTRODUCTION: We comprehensively evaluated the effects of combination therapy with insulin glargine and the incretin-based drugs lixisenatide or vildagliptin in Japanese patients with type 2 diabetes. METHODS: In this 12-week, randomized, open-label, parallel-group, multicenter study (GLP-ONE Kobe), the incretin-based drug sitagliptin was randomly switched to lixisenatide (20 µg/day, n = 18) or vildagliptin (100 mg/day, n = 20) in patients with inadequate glycemic control despite combination therapy with insulin glargine and sitagliptin. The dose of insulin glargine was titrated after the switch to maintain fasting blood glucose at approximately 110 mg/dL. The primary end points of the study were the change in glycosylated hemoglobin (HbA1c) level between before and 12 weeks after the treatment switch, the proportion of patients achieving an HbA1c level below 7.0%, and the postprandial increase in glucose concentration as assessed by self-monitoring of blood glucose. RESULTS: The change in HbA1c level from baseline to 12 weeks did not differ significantly between the lixisenatide and vildagliptin groups (- 0.6 ± 0.7% and - 0.6 ± 1.2%, respectively, P = 0.920). Neither the proportion of patients achieving an HbA1c level below 7.0% nor the postprandial increase in glucose concentration was different between two groups. Body weight and serum low density lipoprotein (LDL) cholesterol level decreased significantly in the lixisenatide and vildagliptin groups, respectively. Both drugs were associated with mild gastrointestinal symptoms but not with severe hypoglycemia. Vildagliptin was associated with elevation of serum aspartate transaminase. Treatment satisfaction as assessed with the Diabetes Treatment Satisfaction Questionnaire did not differ significantly between the two groups. CONCLUSION: The combinations of basal insulin and either lixisenatide or vildagliptin have similar efficacies with regard to improvement of glycemic control. TRIAL REGISTRATION: This trial has been registered with UMIN (No. 000010769).

Increase in hepatic and decrease in peripheral insulin clearance characterize abnormal temporal patterns of serum insulin in diabetic subjects.

Insulin plays a central role in glucose homeostasis, and impairment of insulin action causes glucose intolerance and leads to type 2 diabetes mellitus (T2DM). A decrease in the transient peak and sustained increase of circulating insulin following an infusion of glucose accompany T2DM pathogenesis. However, the mechanism underlying this abnormal temporal pattern of circulating insulin concentration remains unknown. Here we show that changes in opposite direction of hepatic and peripheral insulin clearance characterize this abnormal temporal pattern of circulating insulin concentration observed in T2DM. We developed a mathematical model using a hyperglycemic and hyperinsulinemic-euglycemic clamp in 111 subjects, including healthy normoglycemic and diabetic subjects. The hepatic and peripheral insulin clearance significantly increase and decrease, respectively, from healthy to borderline type and T2DM. The increased hepatic insulin clearance reduces the amplitude of circulating insulin concentration, whereas the decreased peripheral insulin clearance changes the temporal patterns of circulating insulin concentration from transient to sustained. These results provide further insight into the pathogenesis of T2DM, and thus may contribute to develop better treatment of this condition.

Effect of switching from conventional continuous subcutaneous insulin infusion to sensor augmented pump therapy on glycemic profile in Japanese patients with type 1 diabetes.

AIMS: Evidence suggests that sensor augmented pump (SAP) therapy is superior to conventional continuous subcutaneous insulin infusion (CSII) for achieving glycemic control in patients with type 1 diabetes. However, the clinical benefit of SAP therapy in East Asians has not yet been demonstrated. METHODS: The effect of switching from conventional CSII to SAP therapy on glycemic profile was examined in 18 Japanese patients with type 1 diabetes. The glycemic profile of the patients was determined by retrospective continuous glucose monitoring (CGM) within 1 month before the treatment switch, whereas that at 6 and 12 months after the switch was evaluated with the CGM function of the SAP device. Hemoglobin A1c levels were also measured before and after the switch to SAP therapy. RESULTS: The duration of hypoglycemia was significantly decreased at both 6 and 12 months after the change in treatment (6.6 ± 4.5, 3.2 ± 4.1, and 3.0 ± 2.8 min/h for before and 6 and 12 months, respectively), as was the HbA1c level at 12 months (7.8 ± 1.0 and 7.4 ± 0.9%, respectively). The duration of hyperglycemia did not differ between before and after the treatment switch. The decline in HbA1c level at 12 months after the switch to SAP was negatively correlated with age. CONCLUSION: Switching from conventional CSII to SAP therapy was associated with a decrease in both the duration of hypoglycemia and the level of HbA1c in Japanese patients with type 1 diabetes.

Comparison of the relationship between multiple parameters of glycemic variability and coronary plaque vulnerability assessed by virtual histology-intravascular ultrasound.

AIMS/INTRODUCTION: Increased glycemic variability is an important contributing factor to coronary artery disease. Although various parameters of glycemic variability can be derived by continuous glucose monitoring, the clinical relevance of individual parameters has remained unclear. We have now analyzed the relationship of such parameters to coronary plaque vulnerability. MATERIALS AND METHODS: The standard deviation of glucose levels (SD glucose), mean amplitude of glycemic excursions (MAGE), continuous overlapping net glycemic action calculated every 1 h (CONGA-1) and mean of daily differences (MODD) were calculated from continuous glucose monitoring data for 53 patients hospitalized for percutaneous coronary intervention. The relationship of these parameters to the percentage necrotic core of total plaque volume (%NC) as assessed by virtual histology-intravascular ultrasound (a predictor of coronary plaque rupture) was evaluated. RESULTS: All parameters of glycemic variability were significantly correlated with %NC, with correlation coefficients of 0.593, 0.626, 0.318, and 0.388 for log(SD glucose), log(MAGE), CONGA-1 and log(MODD), respectively. Simple linear regression analysis showed that the coefficients of determination for %NC and either log(SD glucose; 0.352) or log(MAGE; 0.392) were greater than those for %NC and either CONGA-1 (0.101) or log(MODD; 0.151), whereas the residual sums of squares for the former relationships (1045.1 and 979.5, respectively) were smaller than those for the latter (1449.3 and 1369.6, respectively). CONCLUSIONS: The present data suggest that SD glucose and MAGE are more highly correlated with coronary plaque vulnerability than are CONGA-1 and MODD, and are thus likely better predictors of coronary artery disease.

Pancreatic fat content assessed by 1 H magnetic resonance spectroscopy is correlated with insulin resistance, but not with insulin secretion, in Japanese individuals with normal glucose tolerance.

AIMS/INTRODUCTION: Whereas some clinical studies have shown that excessive fat accumulation in the pancreas is associated with impairment of insulin secretion, others have not found such an association. 1 H magnetic resonance spectroscopy allows quantitative fat analysis in various tissues including the pancreas. The pathological relevance of pancreatic fat content (PFC) in Japanese individuals remains unclear, however. MATERIALS AND METHODS: We analyzed PFC in 30 Japanese individuals with normal glucose tolerance by 1 H magnetic resonance spectroscopy, and then investigated the relationships between PFC and indexes of insulin secretion and insulin sensitivity-resistance determined by an oral glucose tolerance test. We also measured hepatic fat content and intramyocellular lipid content by 1 H magnetic resonance spectroscopy, as well as visceral fat area and subcutaneous fat area by magnetic resonance imaging, and we examined the relationships between these fat content measures and oral glucose tolerance test-derived parameters. RESULTS: PFC was correlated with indexes of insulin sensitivity-resistance, but not with those of insulin secretion. Hepatic fat content and visceral fat area were correlated with similar sets of parameters as was PFC, whereas subcutaneous fat area was correlated with parameters of insulin secretion, and intramyocellular lipid content was not correlated with any of the measured parameters. The correlation between PFC and homeostasis model assessment of insulin resistance remained significant after adjustment for age, body mass index and sex. Among fat content measures, PFC was most highly correlated with hepatic fat content and visceral fat area. CONCLUSIONS: PFC was correlated with indexes of insulin resistance, but not with those of insulin secretion in non-obese Japanese individuals with normal glucose tolerance.

Insulin Secretion and Insulin Sensitivity Before and After Surgical Treatment of Pheochromocytoma or Paraganglioma.

Context: Pheochromocytoma and paraganglioma are catecholamine-producing tumors that often impair glucose tolerance. The effects of these tumors on insulin sensitivity and insulin secretion in patients have remained unclear, however. Objective: To characterize the influence of pheochromocytoma or paraganglioma on glucose tolerance, we comprehensively analyzed various parameters related to insulin secretion or insulin sensitivity in patients with these tumors. Design: Hyperglycemic and hyperinsulinemic-euglycemic clamps, as well as an oral glucose tolerance test (OGTT), were performed in patients before and after tumor excision. Setting: Patients underwent metabolic analyses on admission to Kobe University Hospital. Patients: Eleven patients with pheochromocytoma and two with paraganglioma were examined. Intervention: None. Main Outcome Measures: We evaluated various parameters related to insulin secretion or insulin sensitivity as determined by an OGTT and by hyperglycemic and hyperinsulinemic-euglycemic clamp analyses. Results: Surgical treatment of the tumor reduced urinary catecholamine excretion and improved glucose tolerance. The insulinogenic index, but not total insulin secretion, measured during the OGTT as well as the first phase, but not the second phase, of insulin secretion during the hyperglycemic clamp were improved after surgery. The insulin sensitivity index determined during the hyperinsulinemic-euglycemic clamp remained unchanged after surgery. Conclusion: These results suggest pheochromocytoma and paraganglioma impair glucose tolerance primarily through impairment of insulin secretion-in particular, that of the early phase of the insulin secretory response. A prospective study with more patients is warranted to further confirm these results.

Glucose Homeostatic Law: Insulin Clearance Predicts the Progression of Glucose Intolerance in Humans.

Homeostatic control of blood glucose is regulated by a complex feedback loop between glucose and insulin, of which failure leads to diabetes mellitus. However, physiological and pathological nature of the feedback loop is not fully understood. We made a mathematical model of the feedback loop between glucose and insulin using time course of blood glucose and insulin during consecutive hyperglycemic and hyperinsulinemic-euglycemic clamps in 113 subjects with variety of glucose tolerance including normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM). We analyzed the correlation of the parameters in the model with the progression of glucose intolerance and the conserved relationship between parameters. The model parameters of insulin sensitivity and insulin secretion significantly declined from NGT to IGT, and from IGT to T2DM, respectively, consistent with previous clinical observations. Importantly, insulin clearance, an insulin degradation rate, significantly declined from NGT, IGT to T2DM along the progression of glucose intolerance in the mathematical model. Insulin clearance was positively correlated with a product of insulin sensitivity and secretion assessed by the clamp analysis or determined with the mathematical model. Insulin clearance was correlated negatively with postprandial glucose at 2h after oral glucose tolerance test. We also inferred a square-law between the rate constant of insulin clearance and a product of rate constants of insulin sensitivity and secretion in the model, which is also conserved among NGT, IGT and T2DM subjects. Insulin clearance shows a conserved relationship with the capacity of glucose disposal among the NGT, IGT and T2DM subjects. The decrease of insulin clearance predicts the progression of glucose intolerance.

Effects of insulin degludec and insulin glargine on day-to-day fasting plasma glucose variability in individuals with type 1 diabetes: a multicentre, randomised, crossover study.

AIMS/HYPOTHESIS: We compared the effects of insulin degludec (IDeg; Des(B30)LysB29(γ-Glu Nε-hexadecandioyl) human insulin) and insulin glargine (IGlar; A21Gly,B31Arg,B32Arg human insulin) on the day-to-day variability of fasting plasma glucose (FPG) levels in individuals with type 1 diabetes treated with basal-bolus insulin injections. METHODS: The effects of basal-bolus insulin therapy for 4 weeks with either IDeg or IGlar as the basal insulin in adult C-peptide-negative outpatients with type 1 diabetes were investigated in an open-label, multicentre, randomised, crossover trial. Randomisation was conducted using a centralised allocation process. The primary endpoints were the SD and CV of FPG during the final week of each treatment period. Secondary endpoints included serum glycoalbumin level, daily dose of insulin, intraday glycaemic variability and frequency of severe hypoglycaemia. RESULTS: Thirty-six randomised participants (17 in the IDeg/IGlar and 19 in the IGlar/IDeg groups) were recruited, and data for 32 participants who completed the trial were analysed. The mean (7.74 ± 1.76 vs 8.56 ± 2.06 mmol/l; p = 0.04) and SD (2.60 ± 0.97 vs 3.19 ± 1.36 mmol/l; p = 0.03) of FPG were lower during IDeg treatment than during IGlar treatment, whereas the CV did not differ between the two treatments. The dose of IDeg was smaller than that of IGlar (11.0 ± 5.2 vs 11.8 ± 5.6 U/day; p < 0.01), but other secondary endpoints did not differ between the treatments. CONCLUSIONS/INTERPRETATION: IDeg yielded a lower FPG level and smaller day-to-day variability of FPG at a lower daily dose compared with IGlar in participants with type 1 diabetes. IDeg serves as a good option for basal insulin in the treatment of type 1 diabetes. TRIAL REGISTRATION: University Hospital Medical Information Network 000009965. FUNDING: This research recieved no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Postprandial serum C-peptide to plasma glucose concentration ratio correlates with oral glucose tolerance test- and glucose clamp-based disposition indexes.

OBJECTIVE: The C-peptide index (CPI), a ratio of serum C-peptide to plasma glucose levels, is a readily measured index of ß-cell function. The difference in the physiological features reflected by the index measured under fasting (F-CPI) or postprandial (PP-CPI) conditions has remained unclear, however. MATERIALS/METHODS: We investigated the relationship of the two CPIs to indexes of insulin secretion measured with an oral glucose tolerance test (OGTT) or with hyperglycemic and hyperinsulinemic-euglycemic clamp analyses as well as to disposition indexes (indexes of insulin secretion adjusted for insulin sensitivity) calculated from OGTT- or clamp-based analyses. We also examined the relationship between glucose tolerance and the clamp-based disposition index. RESULTS: The clamp-based disposition index declined progressively from normal glucose tolerance to impaired glucose tolerance to Type 2 diabetes, and it strongly correlated with the 2-h plasma glucose level during an OGTT. For patients with Type 2 diabetes, both F-CPI and PP-CPI correlated with indexes of insulin secretion including HOMA-ß, the insulinogenic index, the ratio of the area under the insulin curve to that under the glucose curve during an OGTT, the serum C-peptide level after glucagon challenge, as well as early and total insulin secretion measured with a hyperglycemic clamp. PP-CPI, but not F-CPI, was significantly correlated with clamp-based and OGTT-based disposition indexes. CONCLUSIONS: F-CPI was correlated only with unadjusted indexes of insulin secretion, whereas PP-CPI was correlated with such indexes as well as with those adjusted for insulin sensitivity. The better clinical utility of PP-CPI might be attributable to these physiological characteristics.

Correlation of serum CPR to plasma glucose ratio with various indices of insulin secretion and diseases duration in type 2 diabetes.

Evaluating insulin secretion ability and sensitivity is essential to establish an appropriate treatment for patients with type 2 diabetes. The serum C-peptide response (CPR) level is used to evaluate the quantity of endogenous insulin secretion. However, the serum CPR level alone cannot indicate insulin-secretion ability or insulin sensitivity, because plasma glucose levels influence endogenous insulin secretion and vice versa. The CPR index, a ratio of serum CPR level to plasma glucose concentration when measured simultaneously, was previously reported to be a useful marker to determine the necessity of insulin treatment in patients with type 2 diabetes, but the reasons are unknown. The aim of this study was to clarify which factors affect the CPR index in patients with type 2 diabetes. Totally, 121 subjects were included in this study; all participants were hospitalized for type 2 diabetes. On the day after admission, we calculated the CPR index from each patient's fasting blood sample and a blood sample taken 2 hours after breakfast (the postprandial sample). A detailed medical history was taken from each patient to establish the disease duration. The degree of diabetic retinopathy judged by an ophthalmologist was obtained from patients' medical records. An oral glucose tolerance test and a glucagon load test were performed after the fasting plasma glucose level decreased to 130 mg/dl, and indices of insulin secretion and sensitivity were calculated. Fasting and postprandial CPR indices were moderately correlated with total endogenous insulin secretion after oral glucose load and with the CPR level after glucagon load, insulin sensitivity, composite index, and the reciprocal index of homeostasis model assessment (HOMA-R-1). Furthermore, there was a weak but significant correlation between the postprandial CPR index and the duration of diabetes. The postprandial CPR index was inversely correlated with the degree of diabetic retinopathy, which is known to be associated with the duration of hyperglycemia. Our data clearly shows that the CPR index is a useful parameter to reflect the degree of impaired glucose tolerance.

Age-dependent decline in ß-cell function assessed by an oral glucose tolerance test-based disposition index.

We evaluated age-dependent changes in ß-cell function as assessed with an oral glucose tolerance test (OGTT)-based analog of the disposition index (oral disposition index). A total of 110 Japanese normoglycemic subjects (aged 22-59 years) was divided into decadal age groups (20, 30, 40 and 50 s) and subjected to an OGTT. The oral disposition index was calculated as the product of the Matsuda index and the ratio of the area under the insulin curve to the area under the glucose curve for 0-120 min during the OGTT (AUCins/gluc120). Although indexes of insulin secretion, including AUCins/gluc120 and the insulinogenic index, did not differ among age groups, the oral disposition index differed significantly among decadal ages and declined with age. The oral disposition index is thus a sensitive measure of ß-cell function, and a natural decline in such function likely begins in early adulthood and progresses with age. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00099.x, 2011).