Hisako Komada

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 β-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-β, 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.

Age‐dependent decline in β‐cell function assessed by an oral glucose tolerance test‐based disposition index

We evaluated age‐dependent changes in β‐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 β‐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)

Calcium, Phosphorus, Cardiovascular Events and All‐cause Mortality in Hemodialysis Patients: A Single‐center Retrospective Cohort Study to Reassess the Validity of the Japanese Society for Dialysis Therapy Guidelines

Abstract:  Mineral and bone disorders frequently cause cardiovascular complications and mortality in hemodialysis patients, but few observational studies of Japanese patients have investigated this matter. A retrospective cohort study of 99 patients (53 males, 46 females; mean age: 65 ± 12 year; 38% with diabetes mellitus) on maintenance hemodialysis in our dialysis center was conducted. Mean serum Ca, P and intact parathyroid hormone (iPTH) levels were 9.2 ± 0.9 mg/dL, 6.1 ± 1.7 mg/dL, and 233 ± 333 pg/mL, respectively. The cutoff values for each of these three parameter were defined according to the target ranges recommended by the Japanese Society for Dialysis Therapy (JSDT) guidelines (Ca: 8.4–10.0 mg/dL; P: 3.5–6.0 mg/dL; iPTH: 60–180 pg/mL). During a 45‐month follow up, patients with all parameters outside the target ranges showed the highest incidence of cardiovascular events and all‐cause deaths (16.6 and 29.2 per 1000 person‐years, respectively). The relative risks of cardiovascular events and all‐cause deaths were analyzed by multivariate Cox regression models. The hazard ratio (HR) for cardiovascular events was significantly lower for patients who achieved serum Ca and P objectives compared with others (HR: 2.12; 95% CI: 1.04–4.34; P < 0.05), and similar differences were observed for all‐cause deaths (HR: 3.10; 95% CI: 1.13–8.53; P < 0.05). However, the relationship between iPTH levels and each of the endpoints was less pronounced. The results of this study provide support for the JSDT guidelines, which give priority to the control of serum Ca and P levels over the control of parathyroid function.

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.

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.

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

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. 1H 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.

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.Glucose homeostasis: roles of insulin clearanceType 2 diabetes mellitus (T2DM) is one of the fastest growing public health problems, characterized by chronic hyperglycemia with the failure of glucose homeostasis. Evaluating alteration in biological functions regulating circulating glucose concentration is complicated due to the mutual relation between circulating glucose and insulin. A team led by Wataru Ogawa at Kobe University designed clinical experiments for breaking such feedback relations, and a team led by Shinya Kuroda at University of Tokyo developed mathematical models for specifically quantifying the functions from the clinical data. The estimated model parameters revealed the significant increase in hepatic and decrease in peripheral insulin clearance, which occur before and after insulin delivery into systemic circulation, respectively, from healthy to T2DM subjects. Model analysis suggested these insulin clearances centrally regulate the dynamics of circulating insulin concentration in the glucose-insulin regulatory system.

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

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.

Impaired glucagon secretion in patients with fulminant type 1 diabetes mellitus

PurposeFulminant type 1 diabetes mellitus (FT1DM), characterized by rapid and almost complete destruction of pancreatic β-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 β-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.MethodsFasting 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).ResultsThe 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.ConclusionsThese results suggest that glucagon secretion is impaired in patients with FT1DM.

Bidirectional Changes Of Hepatic And Peripheral Insulin Clearance Characterize Abnormal Temporal Patterns Of Serum Insulin Concentration 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 by glucose infusion accompany T2DM pathogenesis. However, the mechanism underlying this abnormal temporal pattern of circulating insulin concentration remains unknown. Here we show that bidirectional changes of hepatic and peripheral insulin clearance characterize this abnormal temporal pattern of circulating insulin concentration during the progression of 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, during the progression of glucose intolerance. 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 insight that may be useful in treating T2DM associated with aberrant insulin clearance.