Toyohiko Morishima

Atherosclerosis in carotid artery of young IDDM patients monitored by ultrasound high-resolution B-mode imaging

Ultrasound high-resolution B-mode imaging was used to assess the carotid arteries in 105 patients with insulin-dependent diabetes mellitus (IDDM), 4–25 years of age, with duration of diabetes ranging from 0.5–17 years, 529 patients with non-insulin-dependent diabetes (NIDDM), 31–86 years of age, with duration of diabetes ranging from 0.5–49 years, and 104 nondiabetic healthy subjects, 7–76 years of age, to determine the intimal plus medial thickness (IMT) of the arterial wall. The IMT values for IDDM patients 10–19 years of age (0.525 ± 0.123 mm, n = 68) or 20–25 years of age (0.696 ± 0.124 mm, n = 14) were significantly > those in age-matched nondiabetic subjects (0.444 ± 0.057 mm, n = 12, P = 0.01169; 0.538 ± 0.098 mm, n = 34, P < 0.00006). NIDDM patients showed IMT values equivalent to those in normal adults ≥ 20 years of age. Multiple regression analysis showed that IMT in IDDM patients was positively related to the duration of diabetes (P = 0.00061) as well as to age (P = 0.00046). No other possible risk factors, such as serum total cholesterol level, serum high-density lipoprotein (HDL)-cholesterol level, serum low-density lipoprotein-cholesterol level, serum triglycerides, serum lipoprotein(a) level, or systolic or diastolic blood pressure, have shown significant correlations with IMT in IDDM patients. However, non-HDL-cholesterol, smoking, and systolic hypertension were independently responsible for increases in IMT values of NIDDM patients as well as age and duration of diabetes. The partial regression coefficient of IMT for duration of diabetes (0.00978 mm/year) consistent with that of IMT for age (0.00848–0.00909 mm/year) in nondiabetic and diabetic subjects indicated that diabetes led to carotid atherosclerosis that was twice as advanced in children and adolescents with IDDM. Ultrasound high-resolution B-mode imaging revealed atherosclerosis in the carotid arteries of young IDDM patients on in vivo examination. Diabetes as well as aging can advance atherosclerosis in the carotid arteries of young diabetic patients. The IMT of carotid arteries, which can be measured noninvasively and frequently, may be an important indicator of atherosclerosis, even in young IDDM patients.

1,5-Anhydro-D-glucitol Evaluates Daily Glycemic Excursions in Well-Controlled NIDDM

OBJECTIVE To evaluate the usefulness of plasma 1,5-anhydro-D-glucitol (1,5-AG) as a possible marker for daily glycemic excursion, we measured plasma 1,5-AG, HbA1c, fasting plasma glucose (FPG) level, and daily excursion of glycemia, from which the M-value (after Schlichtkrull) was calculated as an index of daily glycemic excursion. RESEARCH DESIGN AND METHODS The subjects were 76 patients with well-controlled non-insulin-dependent diabetes mellitus (NIDDM) treated with diet therapy only (diet, n = 17), oral hypoglycemic agents (OHA, n = 28), conventional insulin therapy (CIT, n = 16), or multiple insulin injection therapy (MIT, n = 15). RESULTS HbA1c values were similar among all the groups (diet, 6.9 ± 0.6; OHA, 7.2 ± 0.5; CIT, 7.1 ± 0.6; MIT, 7.2 ± 0.5%). The MIT group showed a significantly higher 1,5-AG concentration (11.5 ± 5.3 μg/ml), a significantly lower M-value (9.2 ± 5.2), and little risk of hypoglycemia (< 4 mmol/l) and hyperglycemia (> 10 mmol/l) (1.3 ± 1.1 times/24 h) compared with the CIT group (6.9 ± 3.3μg/ml, 15.7 ± 8.9, 2.2 ± 1.6 times/24 h, respectively). Insulin doses (22.4 ± 4.5 vs. 22.0 ± 8.9 U/day), FPG (6.6 ± 2.2 vs. 7.4 ± 2.4 mmol/l), and HbA1c concentrations were not significantly different between the CIT and MIT groups. M-values significantly correlated with 1,5-AG concentrations (r = 0.414, P < 0.05), but not with HbA1c concentrations. CONCLUSIONS The findings suggest that the plasma 1,5-AG concentration can be a useful index of the daily excursion of blood glucose, especially in patients with well-controlled NIDDM.

Effect of strict metabolic control on glucose handling by the liver and peripheral tissues in non-insulin-dependent diabetes mellitus

To examine the effect of strict glycemic control on the insulin resistance of non-insulin-dependent diabetes mellitus (NIDDM), we applied euglycemic hyperinsulinemic clamp combined with an oral glucose load (OGL) to nine non-obese subjects with NIDDM and quantitated insulin-mediated glucose uptake by the liver (HGU) and peripheral tissues (PGU) simultaneously before and after 3 to 4 weeks of intimate glycemic control by preprandial regular insulin injections 3 times a day. The glucose infusion rate (GIR) required to maintain euglycemia during the clamp before OGL was considered as PGU. After OGL, the fraction of ingested glucose that is not extracted by the liver enters the systemic circulation and reduces the GIR required for the clamp. HGU was calculated from the difference between the amount of OGL and the cumulative decrements in GIR after OGL and was expressed as the ratio to the amount of OGL (%). Three to 4 weeks after initiation of strict metabolic control, FPG and HbA1c levels significantly improved (9.1 +/- 0.5 vs. 6.4 +/- 0.4 mmol/l, and 11.2 +/- 0.8 vs. 8.3 +/- 0.3%, P < 0.05). HGU significantly increased to 33.1 +/- 9.5 from 14.5 +/- 4.8%, while PGU did not change (38.2 +/- 5.2 vs. 37.4 +/- 3.9 mumol/kg.min). These data suggest that short-term strict metabolic control ameliorates insulin resistance in NIDDM mainly at the hepatic level.

Augmentation of Hepatic Glucose Uptake by a Positive Glucose Gradient Between Hepatoportal and Central Nervous Systems

To determine the role of the glucose gradient between the hepatoportal system (HPS) and the central nervous system (CNS) in regulating hepatic glucose uptake, experiments were conducted with seven conscious dogs using a hepatic venous catheterization technique. With the infusion of somatostatin (0.8 µg · kg−1 · min−1), glucagon (0.65 ng · kg−1 · min−1), and insulin (27 pmol · kg−1 · min−1), arterial glucose levels could be maintained at 8 mmol/l by adjusting the intravenous glucose infusion (Ginf) according to the following three periods: 1) peripheral glucose infusion period (PE), Ginf alone; 2) portal glucose infusion period (PO), Ginf plus constant glucose infusion into the portal vein (GIRPV, 55.6 μmol · kg−1 · min−1); 3) portal and brain glucose infusion period (PO+CNS), Ginf and GIRPV plus additional glucose infusion into the unilateral carotid and vertebral arteries to abolish the positive glucose gradient between HPS and CNS. Arterial plasma glucose levels were clamped during the three periods (8.1 ± 0.1, PE; 8.2 ± 0.1, PO; 8.2 ± 0.1 mmol/l, PO+CNS). During PO, when a positive glucose gradient was promoted between HPS and CNS, the net hepatic glucose balance (NHGB) determined by the difference between hepatic glucose inflow and outflow was significantly lower than that of PE (−41.5 ± 5.3, PO vs. −7.5 ± 3.4 µmol · kg−1 · min−1, PE; P < 0.01). However, this decrease in the NHGB significantly increased during PO+CNS, when the glucose gradient between HPS and CNS was minimized, compared with PO (−21.7 ± 3.2 µmol · kg−1 · min−1 , P < 0.05). We conclude that a positive glucose gradient between HPS and CNS is an important regulatory factor of hepatic glucose uptake, but other factors also play important roles because minimizing the glucose gradient between HPS and CNS diminished the net hepatic glucose uptake by 50%.

Ubiquitous, but variable, expression of two alternatively spliced mRNAs encoding mouse homologues of transcription factors E47 and E12

Two basic helix-loop-helix (bHLH) transcription factors, E47 and E12, are involved in cell-specific gene expression as part of dimeric complexes which interact with the cis-acting motif E-box. Although both generated from a single gene (E2A) by means of alternative splicing, the structural difference in these bHLH regions between the two suggests that the two bHLH proteins may differ in some of their functions. As a step toward elucidating the individual implications of E47 and E12, we investigated the mRNA expression ratios of their homologues (A1 and kA1, respectively) in mouse tissues and cell lines. Both the A1 and kA1 mRNAs were ubiquitously expressed in all tissues examined. However, their ratios varied: e.g., skeletal muscle, 2.2 +/- 0.3 (mean +/- SE); spleen, 2.0 +/- 0.2; pancreatic islet cells, 1.2 +/- 0.2. The A1/kA1 ratios in the cell lines investigated were similar to those of their original tissues. In conclusion, the ubiquity in mRNA expression observed for both the E47 and E12 homologues in mouse provides support for their involvement in a broad range of transcriptional regulation. The variation in the A1/kA1 expression ratios, on the other hand, supports the idea that A1 (E47) and kA1 (E12) each have some unique roles in the functions of these E2A gene-encoded bHLH proteins.

Increased hepatic glucose production and decreased hepatic glucose uptake at the prediabetic phase in the Otsuka Long-Evans Tokushima Fatty rar model

To investigate the time course of the hepatic glucose metabolism in non-insulin-dependent diabetes (NIDDM), we measured hepatic glucose production (HGP) and first-pass uptake of portal glucose infusion by the liver (HGU) using dual-tracer methods in a NIDDM model, Otsuka Long-Evans Tokushima Fatty (OLETF) rats, and in normal controls, Long-Evans Tokushima Otsuka (LETO) rats, at 8, 14, and 28 weeks of age (n = 5, respectively). The fasting plasma glucose level in OLETF rats was significantly higher than in LETO rats at 28 weeks of age (8.9 +/- 1.7 v 6.3 +/- 0.4 mmol/L, P < .01), while there was no significant difference at 8 and 14 weeks. Hyperinsulinemia in OLETF rats appeared at > or = 8 weeks of age. Basal HGP was significantly higher in OLETF than in LETO rats at 8 and 28 weeks (8 weeks, 12.7 +/- 1.7 v 9.4 +/- 1.8 mg x kg(-1) x min(-1), P < .05; 28 weeks, 10.9 +/- 1.6 v 7.1 +/- 1.3 mg x kg(-1) x min(-1), P < .01). At 14 weeks, basal HGP was not significantly different between OLETF and LETO rats. However, at all study points, HGU during a portal glucose infusion was significantly lower in OLETF than in LETO rats (8 weeks, 0.9 +/- 0.2 v 2.3 +/- 0.5, P < .01; 14 weeks, 0.8 +/- 0.3 v 1.4 +/- 0.3, P < .05; 28 weeks, 0.7 +/- 0.2 v 1.4 +/- 0.3 mg x kg(-1) x min(-1), P < .01). Fasting plasma free fatty acid (FFA) levels were not significantly different between OLETF and LETO, except at 8 weeks. Suppression of plasma FFA levels by endogenous insulin during a portal glucose infusion was impaired in OLETF rats compared with LETO rats. In summary, this study demonstrates that derangement of hepatic glucose handling, such as increased basal HGP and decreased HGU, is observed in obese NIDDM model OLETF rats at the prediabetic phase when hyperglycemia is still not apparent. Furthermore, these derangements may be accompanied by impaired lipid metabolism.

Portal insulin delivery is superior to peripheral delivery in handling of portally delivered glucose

It is still controversial as to whether physiological portal insulin delivery has metabolic advantages over peripheral insulin delivery. To clarify this issue, glycemic regulation during intravenous (IVGTT) and oral (OGTT) glucose tolerance tests and hyperglycemic clamp studies with either peripheral or portal glucose infusion was investigated in left-segmentally pancreatectomized dogs with portal ([PPx] n = 7) or systemic ([Tx] n = 7) venous drainage of the remaining pancreas. In Tx dogs, systemic diversion of pancreatic venous effluent was accomplished by gastroduodenal-caval shunt. Data obtained were compared with those in normal control dogs ([NC] n = 7). The loss of pancreatic beta-cell mass in PPx dogs decreased insulin responses to peripheral and portal glucose loads. In contrast, Tx dogs showed insulin responses comparable to those of NC dogs to glucose loads via both routes. Against peripheral glucose loads (IVGTT and hyperglycemic clamp with peripheral glucose infusion), PPx and Tx dogs showed deteriorated glucose handling. Against portal glucose loads (OGTT and hyperglycemic clamp with portal glucose infusion), deteriorated glucose handling was observed in Tx dogs, but not in PPx dogs. Deterioration in glycemic regulation against portal glucose loads in left-segmentally pancreatectomized dogs with peripheral insulin delivery but not in pancreatectomized dogs with portal delivery indicates that intraportal hyperglycemia and hyperinsulinemia are essential for promoting hepatic glucose handling.

Quantitative Determination of Hepatic Glucose Uptake Using an Innovative Approach

For perfect glycemic control in diabetics, therapeutic modalities which enhance impaired hepatic glucose uptake seen in diabetics should be utilized. In animal experiments, we demonstrated that factors promoting hepatic glucose uptake are the glucose gradient between the central nervous system and the hepato-portal system, portal hyperinsulinemia and normal premeal glycemia. Therefore, we investigated both the effects of intensified insulin therapy and a single bout of exercise on hepatic glucose uptake by euglycemic hyperinsulinemic clamp combined with oral glucose loading. In 56 out of 77 patients, perfect glycemic normalization was established with mean regular insulin doses of 10, 7, 7 U at breakfast, lunch and dinner, respectively. The ratio of splanchnic glucose disposal to the amount of ingested glucose increased significantly from 19.0 to 42.1%. A single bout of exercise enhanced hepatic glucose uptake from 23.4 to 50.5%. Both strict glycemic regulation and exercise enhance hepatic glucose uptake significantly in non-obese diabetic patients.

Clinical usefulness of a non-wiping type glucose meter in diabetic patients

A non-wiping type glucose meter using electrochemistry was developed. The glucose sensor strip has a sophisticated micro-structure for aspirating blood automatically. The meter compensates for drift of sensor output due to temperature change of the atmosphere. Mounting blood on the sensing site and wiping blood and precise time are no longer required. Range of measurement is 40-500 mg/dl. Reading of the meter for standard solutions of 90 or 360 mg/dl glucose showed negligible drift of measurement from 10.5 degrees C to 38.5 degrees C. The correlation between plasma glucose concentrations as determined by the meter and that by a Glucose Analyzer 2 was 0.995 with a slope of 1.00 and intercept of -0.65 (n = 48). In the case of blood glucose concentration (Y), the values were Y = 1.06X-0.91, r = 0.987, n = 62. This meter is quite easy to use and is highly accurate for glucose monitoring in patients regardless of operation skill. It should thus be readily applicable to diabetic patients.

Trials of a database constructed for diabetics. 3. An aid for physicians' rounds using a lap-top microcomputer

An aid for physicians’ rounds of diabetic patients is described that employs a laptop microcomputer. Information on each patient that is stored in the diabetics database is used during a clinical conference prior to the physicians’ rounds. Decisions from the conference are then input, a list of each patient’s medical problems is produced with severity scores, and comments are printed out for use in the subsequent physicians round. These comments are understandable by any of the attending physicians and, if the system is linked with control of a patient’s admission and discharge, ward beds can be utilized more efficiently.