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OBJECTIVE: To investigate the association of the promoter region -3826 A to G polymorphism of the uncoupling protein 1 (UCP1) gene with autonomic nervous system (ANS) activity and the interaction of the polymorphism with the Trp64Arg polymorphism of the β3 adrenergic receptor (β3AR). SUBJECTS: Three-hundred and forty-nine young (mean age 20.4 ± 2.1 y old), healthy Japanese males. MEASUREMENTS: DNA was extracted from whole blood and genotyped by polymerase chain reaction restriction fragment length polymorphism. Plasma glucose, plasma insulin and body mass index (BMI) were measured. Frequency of family history of diabetes or obesity was determined by interview. Subjects randomly chosen from each genotype were examined for ANS activity during supine rest and standing by electrocardiogram power spectral analysis of heart rate variability. RESULTS: UCP1 or β3AR polymorphism was not associated with BMI, plasma glucose, plasma insulin and frequency of family history of diabetes or obesity. The inhibitory effect of UCP1 polymorphism on ANS activity was observed only with occurrence of the variant of β3AR. The very low frequency component associated with thermoregulation in the sympathetic nervous system of homozygotes of UCP1 (GG) at supine rest was significantly lower than normal (AA, 203 ± 50.3 vs 462.2 ± 83.6 ms²; mean ± s.e., P=0.021). A higher response to postural change to standing was also observed in both sympathetic and parasympathetic nervous activities of AA than of GG. CONCLUSION: While UCP1 polymorphism alone does not affect ANS activity, it has a synergistic effect with β3AR polymorphism in decreasing sympathetic nervous system activity. [ABSTRACT FROM AUTHOR]

We report a 19-year-old woman who had a history of type 1 diabetes with recurrent glycogen accumulation in the liver. During her infantile period she presented with no hepatomegaly nor growth retardation. On admission she was diagnosed with diabetic ketoacidosis (DKA). She also had hepatomegaly and elevated transaminase levels, but these abnormalities had resolved after administration of insulin. However, 4 weeks after DKA marked hepatomegaly and elevated transaminases were reappeared with simultaneous hypoglycemia which suggested an impaired glycogenolysis in the extraordinary conditions. We supposed the partial deficiency of liver glycogen phosphorylase activity in this patient and analyzed the liver glycogen phosphorylase gene (PYGL). Deduced amino acid sequence of the PYGL in this patient was completely identical to that reported by Burwinkel et al. (Y15233), however, the nucleotide sequence of PYGL cDNA was heterozygous for substitutions at positions Asp339 (GAT to GAC) on exon 9 and Ala703 (GCT to GCC on exon 17, respectively. These SNPs were also screened in 51 Japanese normal subjects by PCR-based direct sequencing or PCR-RFLP method. The same genotype observed in this patient was detected in 2 of 51(3.9%) normal subjects. These results suggest that the structure of PYGL coding sequence in this patient is unlikely to account for her excessive liver glycogen accumulation. Further studies including genetic analysis on the promoter region of the gene are necessary to clarify the etiology of susceptibility to excessive liver glycogen storage in patients with type 1 diabetes. [ABSTRACT FROM AUTHOR]

Aim: The purpose of this study was to develop a scale to assess daily time management capabilities among working patients with diabetes and to test this scale's reliability and validity., Methods: A self-administered questionnaire survey was conducted among 277 diabetes outpatients, and data from 220 participants (mean age = 54.3 ± 10.2 years, 76.8% male) were analyzed. Questionnaire items were selected through exploratory factor analysis. During the process of developing the questionnaire, opinions were solicited from experts on education for patients with diabetes, and Cronbach's α was calculated as a coefficient of reliability. Correlations with the Instrument of Diabetes Self-Care Agency (IDSCA) were examined and confirmatory factor analysis was performed to check for validity., Results: Adequacy of a 4-factor, 16-item scale was confirmed. Cronbach's α coefficient was ≥.7 for the entire scale and for the subscale items. There was a significant correlation between total IDSCA scores and various factors (r = .280-.469). However, there was no correlation between the "adjustment of life rhythms" and parts of the IDSCA subscale., Conclusion: Although some aspects warrant further investigation, the developed scale provides a reliable and valid means of assessing daily time management capabilities among working patients with diabetes, and can thus be applied to help diabetes patients to manage their daily lives., (© 2019 Japan Academy of Nursing Science.)

Aims: To investigate predictors of the initial response of beta-hydroxybutyrate (BHB) and maximum BHB (max-BHB) values during long-term therapy with the sodium-glucose co-transporter-2 inhibitor tofogliflozin (TOFO), and to explore the association of the initial elevation of BHB with subsequent clinical effects in people with type 2 diabetes mellitus., Methods: We analysed 774 people receiving TOFO in phase 3 trials in two groups based on measurable BHB change at week 4 (initial response): the top quartile [n = 194] and the three lower quartiles [n = 579]. Multivariate analysis was used to determine baseline predictors of inclusion in the top quartile and the max-BHB values. To investigate the association of the initial response with subsequent clinical effects, adjusted changes in variables in the two groups were compared using an analysis of covariance model., Results: Of the participants, 66% were men, and the mean age, glycated haemoglobin, body mass index and estimated glomerular filtration rate were 58.5 years, 8.1%, 25.6 kg/m 2 and 83.9 mL/min/1.73 m 2 , respectively. Median changes in BHB at week 4 in the top quartile and lower three quartiles were +246.4* and +30.8* μmol/L, respectively (*P < .001 vs baseline). Lower baseline insulin secretion capacity predicted the inclusion in the top quartile and greater max-BHB levels. The top quartile was associated with greater weight loss following greater increases in free fatty acids and greater reductions in fasting C-peptide levels compared with the lower three quartiles., Conclusions: Lower basal insulin secretion capacity might predict greater initial BHB elevations and max-BHB levels during long-term TOFO therapy. Greater weight loss through lipid use might be related to high initial BHB elevations., (© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: Little is known about whether sodium intake is associated with the clinical effects of SGLT2 inhibitors (SGLT2is); however, SGLT2is may increase urinary sodium excretion. Thus, we investigated the impact of daily sodium intake on the estimated glomerular filtration rate (eGFR) via an SGLT2i, tofogliflozin (TOFO), in patients with type 2 diabetes (T2D)., Methods: Individual-level data on 775 T2D patients in TOFO Phase 3 trials were analysed. Adjusted changes in variables during 52 weeks of TOFO therapy were compared according to basal daily salt intake (DSI), which was measured based on estimated daily urinary sodium excretion using the Tanaka formula. Multivariable analysis was used to investigate the impact of basal DSI on changes in eGFR at Weeks 4 and 52., Results: Sixty-six percent of participants were men; mean age, HbA1c, body mass index, eGFR MDRD and median DSI were 58.5 years, 8.0%, 25.6 kg/m 2 , 83.9 mL/min/1.73 m 2 and 9.3 g/d, respectively. In all participants, eGFR MDRD sharply dipped during Week 4, and gradually increased by Week 52, showing a significant increase overall from baseline to Week 52. Multivariable analysis showed that basal DSI and HbA1c levels were independently correlated with eGFR MDRD changes at Weeks 4 and 52. Additionally, lower baseline HbA1c and DSI levels were significantly correlated with a greater increase in eGFR MDRD at Week 52., Conclusions: Dietary salt intake, in addition to glycaemic control, correlates with changed eGFR MDRD via TOFO. Thus, an appropriate dietary approach to therapy should be considered before treatment of T2D patients with an SGLT2i., (© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: Little is known of the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on the renal tubules. We investigated the effect of the SGLT2 inhibitor, tofogliflozin (TOFO) on renal tubular indices, according to the degree of albuminuria, in type 2 diabetes mellitus (T2DM) patients with preserved renal function., Materials and Methods: A total of 988 patients, receiving TOFO, were enroled and divided into 3 groups, based on the urine albumin-to-creatinine ratio (UACR). The tubular indices (urinary N -acetyl-beta-d-glucosaminidase [NAG]-to-creatinine and urinary beta-2 microglobulin [beta2MG]-to-creatinine ratios) and UACR were log-transformed in the correlation analysis., Results: Treatment with TOFO led to similar reductions in glycated haemoglobin (HbA1c) levels, from baseline to week 24, across all groups. The NAG level increased in the normoalbuminuria group and decreased in the macroalbuminuria group significantly ( P  < .001, both), but did not change in the microalbuminuria group. Significant reductions in the UACR were observed in both microalbuminuria and macroalbuminuria groups ( P  < .001, both). Significant negative correlations between changes in the NAG and beta2MG levels and their corresponding baseline values were observed in all participants. The reduction in the UACR was negatively correlated with baseline levels. The changes in the tubular indices were positively correlated with reductions in the UACR across groups., Conclusions: Logarithmic reductions in the renal tubular indices, via SGLT2 inhibition, were observed in patients with T2DM. TOFO may not only improve the degree of albuminuria but may also have protective effects on the tubules.

Two unrelated women were hospitalized for thyrotoxic crisis complicated by multiple organ failure. Both patients were treated with antithyroid drugs and hydrocortisone, as well as insulin for hyperglycemia, and underwent mechanical ventilation with sedation. Flaccid quadriplegia became apparent after each patient completely recovered their level of consciousness once sedation was discontinued on days 6 and 15, respectively. Three to six months of rehabilitation was required for the muscle strength to fully improve in both cases. Thyrotoxicosis in addition to critical illness polyneuromyopathy and the administration of glucocorticoid therapy may have contributed to the onset of quadriplegia in these two cases. Flaccid quadriplegia is one of the serious neuromuscular conditions experienced during the treatment of thyrotoxic crisis.

Two unrelated Japanese women, 41 and 27 years of age, were admitted with histories of thirst, weight loss and palpitations of a few weeks' duration. Both were diagnosed to have diabetic ketosis or ketoacidosis with acute-onset type 1 diabetes (T1D) and Graves' disease (GD) (autoimmune polyglandular syndrome type 3 variant; APS3v), and were treated with intensive insulin therapy and anti-thyroid drugs. Human leukocyte antigen examinations showed that both cases had the HLA-A2, A24, B54, and DRB1*04:05-DQA1*03:03-DQB1*04:01 haplotype, which made them susceptible not only to APS3v, but also to both acute-onset T1D and GD. The genetic background of patients strongly contributes to the simultaneous occurrence of T1D and GD.

A 53-year-old Japanese man was admitted with a 3-month history of transient headache followed by general fatigue and weight loss. He had a history of ocular myasthenia gravis which had been in remission following thymectomy 30 years ago. He had a small diffuse goiter without tenderness, and was diagnosed as having painless thyroiditis with mild thyrotoxicosis on admission. Endocrinological studies showed he had isolated adrenocorticotropin deficiency. Magnetic resonance imaging of the pituitary gland revealed no abnormalities. His symptoms improved soon after replacement of glucocorticoid. After an episode of hypothyroidism, he spontaneously became euthyroid. It is likely that thyrotoxicosis uncovered adrenal insufficiency that had developed insidiously, and hypoadrenocorticism-induced immunological changes may have triggered the development of painless thyroiditis. Moreover, thymectomy might have facilitated the development of pituitary and thyroid autoimmunity.

Unlabelled: Aims/Introduction:  To compare first-line, single-agent glimepiride and pioglitazone in Japanese patients with type 2 diabetes uncontrolled by diet and exercise with respect to glycemic control, safety and metabolic changes., Materials and Methods:   Patients with previously untreated type 2 diabetes were enrolled in a multicenter, randomized, non-blind, parallel-group trial of glimepiride (0.5-6 mg/day) or pioglitazone (15-45 mg/day) for 6 months., Results:   A total of 191 patients aged 30-75 years were randomized. Similar percentages of patients attained the primary end-point, with glycated hemoglobin < 6.9% at month 6 with glimepiride and pioglitazone, respectively (61.2 vs 56.8%, P = 0.64). At month 6, the following significant (P < 0.05) intragroup changes in mean plasma lipid concentrations were noted as compared with baseline: total cholesterol decreased from 203.5 to 195.5 mg/dL and low-density lipoprotein (LDL)-cholesterol decreased from 124.5 to 116.3 mg/dL in the glimepiride group, whereas high-density lipoprotein (HDL)-cholesterol increased from 51.6 to 56.0 mg/dL and triglycerides decreased from 167.6 to 143.6 mg/dL in the pioglitazone group. The only symptomatic adverse events were mild-to-moderate in four patients receiving pioglitazone, and constipation in one patient receiving glimepiride. Similar numbers of patients experienced asymptomatic hypoglycemia (<60 mg/dL) in the glimepiride and pioglitazone groups (n = 7 and 5, respectively)., Conclusions:   There was no statistically significant difference between glimepiride and pioglitazone with respect to glycemic control, and both agents were well tolerated. Glimepiride significantly lowered total cholesterol and LDL-cholesterol, whereas pioglitazone increased HDL-cholesterol. This trial was registered with University Hospital Medical Information Network (UMIN), Japan, UMIN000004582. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00115.x, 2011).

1. To investigate the pharmacological effects of T-1095, this novel derivative of phlorizin was administered to GK rats for 8 weeks. T-1095 treatment significantly lowered plasma glucose and glycosylated haemoglobin (HbA1c) levels, but did not significantly affect bodyweight. 2. T-1095 treatment did not affect 3.3 mmol/L glucose-induced insulin secretion in the isolated perfused pancreas of GK rats. 3. The peak insulin release in T-1095-treated GK rats was significantly higher during the first phase than in untreated GK rats (3-4 min after beginning 16.7 mmol/L glucose perfusion). The total amount of insulin secreted during the first phase in T-1095-treated GK rats was significantly higher than in untreated GK rats (35.3 +/- 1.4 vs. 27.3 +/- 2.5 ng in T-1095-treated compared with untreated rats, respectively). 4. During the second phase, insulin release in T-1095-treated GK rats was somewhat higher than in untreated GK rats (7-30 min after beginning 16.7 mmol/L glucose perfusion). The total amount of insulin secreted during the second phase in T-1095-treated GK rats was significantly higher than in untreated GK rats (88.2 +/- 6.1 vs. 68.1 +/- 5.7 ng, respectively). 5. The total amount of insulin secreted during perfusion in T-1095-treated GK rats was significantly higher than in untreated GK rats (123.5 +/- 7.3 vs. 95.4 +/- 7.7 ng, respectively). 6. These data show that the metabolic indices, plasma glucose and HbA1c levels and insulin secretion are significantly improved by T-1095 treatment in GK rats, which are spontaneously diabetic rats, suggesting its usefulness as a novel oral therapeutic antidiabetic agent.

Chronic hyperglycemia is known to lead to a progressively further impaired insulin response and to hasten the development of complications in patients with type 2 diabetes, a notion referred as glucose toxicity. T-1095, a derivative of phlorizin, is a newly developed oral hypoglycemic agent that acts as a specific inhibitor of renal Na(+)-glucose co-transporters, reducing circulating blood glucose levels by promoting glucose excretion into urine. The effects of glycemic improvement by T-1095 on secretory function and cytoplasmic calcium response in pancreatic beta-cells were investigated using spontaneously diabetic GK rats. After four weeks of treatment with T-1095 (age 4 to 8 week rats), serum glucose and HbA1c levels were significantly improved (serum glucose level, GK vs. GK T-1095, 277.3 +/- 11.8 vs. 204.7 +/- 6.4 mg/dl; HbA1c level, GK vs. GK T-1095, 6.2 +/- 0.2 vs. 4.8 +/- 0.1 %). Insulin secretion induced by 16.7 mM glucose was also significantly increased in the T-1095-treated group compared to the untreated group. The [Ca(2+)]i response induced by 16.7 mM glucose in GK beta-cells was characterized by the loss of the steep first peak of [Ca(2+)]i elevation, and the lost first peak of [Ca(2+)]i reappeared in T-1095-treated beta-cells in 32 of 34 observations. In T-1095-treated beta-cells, the time lag to peak [Ca(2+)]i levels in the 16.7 mM glucose stimulation was significantly reduced (259.1 +/- 15.3 sec, p < 0.01) compared to untreated GK rats (524.7 +/- 52.9 sec). Thus, improvement of hyperglycemia by T-1095 ameliorates beta-cell function by relieving [Ca(2+)]i response.

Objective: To investigate the association of the promoter region -3826 A to G polymorphism of the uncoupling protein 1 (UCP1) gene with autonomic nervous system (ANS) activity and the interaction of the polymorphism with the Trp64Arg polymorphism of the beta3 adrenergic receptor (beta3AR)., Subjects: Three-hundred and forty-nine young (mean age 20.4+/-2.1 y old), healthy Japanese males., Measurements: DNA was extracted from whole blood and genotyped by polymerase chain reaction restriction fragment length polymorphism. Plasma glucose, plasma insulin and body mass index (BMI) were measured. Frequency of family history of diabetes or obesity was determined by interview. Subjects randomly chosen from each genotype were examined for ANS activity during supine rest and standing by electrocardiogram power spectral analysis of heart rate variability., Results: UCP1 or beta3AR polymorphism was not associated with BMI, plasma glucose, plasma insulin and frequency of family history of diabetes or obesity. The inhibitory effect of UCP1 polymorphism on ANS activity was observed only with occurrence of the variant of beta3AR. The very low frequency component associated with thermoregulation in the sympathetic nervous system of homozygotes of UCP1 (GG) at supine rest was significantly lower than normal (AA, 203.2+/-50.3 vs 462.2+/-83.6 ms(2); mean+/-s.e., P=0.021). A higher response to postural change to standing was also observed in both sympathetic and parasympathetic nervous activities of AA than of GG., Conclusion: While UCP1 polymorphism alone does not affect ANS activity, it has a synergistic effect with beta3AR polymorphism in decreasing sympathetic nervous system activity.

To determine the role of phosphatidylinositol 3-kinase (PI3-kinase) in the regulation of insulin secretion, we examined the effect of wortmannin, a PI3-kinase inhibitor, on insulin secretion using the isolated perfused rat pancreas and freshly isolated islets. In the perfused pancreas, 10(-8) M wortmannin significantly enhanced the insulin secretion induced by the combination of 8.3 mM glucose and 10(-5) M forskolin. In isolated islets, cyclic AMP (cAMP) content was significantly increased by wortmannin in the presence of 3.3 mM, 8.3 mM, and 16.7 mM glucose with or without forskolin. In the presence of 16.7 mM glucose with or without forskolin, wortmannin promoted insulin secretion significantly. On the other hand, in the presence of 8.3 mM glucose with forskolin, wortmannin augmented insulin secretion significantly; although wortmannin tended to promote insulin secretion in the presence of glucose alone, it was not significant. To determine if wortmannin increases cAMP content by promoting cAMP production or by inhibiting cAMP reduction, we examined the effects of wortmannin on 10(-4) M 3-isobutyl-1-methylxantine (IBMX)-induced insulin secretion and cAMP content. In contrast to the effect on forskolin-induced secretion, wortmannin had no effect on IBMX-induced insulin secretion or cAMP content. Moreover, wortmannin had no effect on nonhydrolyzable cAMP analog-induced insulin secretion in the perfusion study. These data indicate that wortmannin induces insulin secretion by inhibiting phosphodiesterase to increase cAMP content, and suggest that PI3-kinase inhibits insulin secretion by activating phosphodiesterase to reduce cAMP content., (Copyright 2000 Academic Press.)

Spontaneously hypertensive rats (SHR) given streptozotocin (STZ) neonatally developed genetic hypertension and overt hyperglycemia after the onset of puberty. In the present study, gonadectomy was performed before puberty in both males and females of this animal model. Orchidectomy suppressed the development of hypertension in vehicle-treated and STZ-treated SHR (systolic blood pressure at 11 weeks of age: 209 +/- 5 mm Hg in the intact vehicle group v 187 +/- 6 mm Hg in the orchidectomized vehicle group, P < .01; 211 +/- 14 mm Hg in the intact STZ group v 182 +/- 4 mm Hg in the orchidectomized STZ group, P < .001). Furthermore, orchidectomy ameliorated the development of overt hyperglycemia in STZ-treated SHR (nonfasting plasma glucose at 12 weeks of age: 22.1 +/- 0.7 mmol/L in the intact group v 16.1 +/- 2.4 mmol/L in the orchidectomized group, P < .05). On the other hand, orchidectomy did not affect glucose tolerance in vehicle-treated SHR, but attenuated the insulin response to an oral glucose load (P < .05). Orchidectomy significantly decreased urinary albumin excretion and kidney weight in both the vehicle and the STZ groups. Ovariectomy significantly increased body weight gain irrespective of STZ treatment. However, ovariectomy had no effect on hypertension, hyperglycemia, albuminuria, or kidney weight in either vehicle or STZ groups. This study demonstrated that gonadectomy had protective effects against development of hypertension, hyperglycemia, and albuminuria in males but not in females. This suggests that sex hormones may be important as a link between diabetes mellitus and hypertension in males.

We compared the renoprotective effect between angiotensin-converting enzyme inhibitor, enalapril, and a dihydropyridine-type calcium channel blocker, nicardipine, in a severe form of renal injury in rats. Two-day-old spontaneously hypertensive rats (SHR) were injected with streptozotocin or vehicle as control. UNX was performed at 3 weeks of age, and enalapril or nicardipine was administered in drinking water from 7 weeks of age. Uninephrectomy (UNX) markedly exacerbated hypertension and renal injury in the nondiabetic and diabetic SHR. Enalapril and nicardipine comparably reduced blood pressure in UNX diabetic SHR. However, serum creatinine was significantly elevated in the nicardipine-treated group as compared with the enalapril-treated group at 24 weeks of age (nicardipine-treated group, 67 +/- 4 microM; enalapril-treated group, 49 +/- 3 microM; P < 0.01; untreated group 57 +/- 4 microM). Furthermore, the incidence of glomerular sclerosis was similar between untreated and nicardipine-treated groups, whereas it tended to be reduced in the enalapril-treated group. In a separate experiment of diabetic SHR without UNX, enalapril therapy significantly ameliorated hyperglycemia and albuminuria (P < 0.01). This study showed that a renoprotective effect was seen in enalapril but not in nicardipine in UNX diabetic SHR despite the comparable reduction of blood pressure. This suggests that enalapril may be more effective than nicardipine in delaying the progression of a severe form of diabetic nephropathy.

Objective: We designed this study to develop a new animal model of high-risk pregnancy complicated by hypertension and diabetes mellitus., Study Design: Female spontaneously hypertensive rats were injected intraperitoneally with 75 mg/kg streptozotocin or vehicle as control at 2 days of age. They were mated with untreated male spontaneously hypertensive rats at 4 to 5 months of age., Results: Hyperglycemia, defined as > 20 mmol/L plasma glucose level, was maintained during pregnancy in streptozotocin-treated spontaneously hypertensive rats, and systolic blood pressure was significantly higher in the streptozotocin-treated group than in controls before delivery (p < 0.01). Furthermore, urinary albumin excretion was significantly increased in the streptozotocin-treated group during and after pregnancy compared with the prepregnant level (p < 0.05), whereas in controls it remained unchanged. The incidence of low birth weight was significantly higher in male neonates from streptozotocin-treated mothers than those from control mothers (p < 0.05)., Conclusion: Neonatally streptozotocin-treated spontaneously hypertensive rats may be useful for studying the combined effect of hypertension and diabetes mellitus during pregnancy.

Although antihypertensive therapy retards the progression of diabetic nephropathy associated with hypertension, it is not known whether glycemic control reverses or arrests diabetic nephropathy under untreated hypertension. We previously reported that spontaneous remission of diabetes occurred in the neonatal streptozotocin (STZ) model of spontaneously hypertensive rats (SHR) after 28 weeks of age, whereas hypertension persisted. Thus, we studied diabetic nephropathy before and after the recovery from hyperglycemia in this model. Two-day-old male SHR were injected intraperitoneally with STZ or vehicle for control. Hypertension was developed and maintained in both STZ and control groups in a similar degree. Before the amelioration of hyperglycemia, urinary albumin excretion increased progressively in STZ-treated SHR as compared with control (24 weeks; 1.6 +/- 0.5 mg/day, 17.5 +/- 2.3 mg/day, P < 0.001), and renal and glomerular hypertrophies were seen with mesangial expansion in STZ-treated SHR. However, along the recovery from hyperglycemia, urinary albumin excretion did not increase in the STZ-treated group, while it consistently increased in the control group (52 weeks; 25.4 +/- 10.0 mg/day, 29.7 +/- 11.4 mg/day, not significant). Furthermore, there were no significant differences in renal weight, glomerular tuft area, and the incidence of glomerular sclerosis between the two groups at 52 weeks of age. This study suggests that glycemic control may be effective for diabetic nephropathy even in the coexistence of untreated hypertension.

We studied the effects of salt loading on glucose tolerance, blood pressure, and albuminuria in rats with mild non-insulin-dependent diabetes mellitus (NIDDM). Two-day-old male Wistar Kyoto (WKY) rats were injected intraperitoneally (IP) with either 75.0 mg/kg streptozotocin (STZ) or vehicle as control. Salt loading was performed as 1% NaCl of drinking solution from 4 weeks until 12 weeks of age (estimated sodium intake: control, 3.14 +/- 0.28 mEq/d in tap-water group, 11.9 +/- 0.95 mEq/d in salt-loaded group; NIDDM, 2.93 +/- 0.16 mEq/d in tap-water group, 12.0 +/- 2.59 mEq/d in salt-loaded group). Oral glucose tolerance, glycosylated hemoglobin (GHb), and pancreatic insulin content at 12 weeks did not differ between the salt-loaded group and tap-water group in both NIDDM and control rats. Urinary sodium excretion was increased in salt-loaded groups of control and NIDDM rats, but systolic blood pressure did not differ among the groups (control, 151 +/- 6 mm Hg in tap-water group, 150 +/- 3 mm Hg in salt-loaded group; NIDDM, 152 +/- 3 mm Hg in tap-water group, 157 +/- 2 mm Hg in salt-loaded group). Urinary albumin excretion was significantly increased in salt-loaded groups (1,790 +/- 272 micrograms/d in control, 1,617 +/- 174 micrograms/d in NIDDM rats) compared with tap-water groups (691 +/- 75 micrograms/d in control, P less than .05; 616 +/- 69 micrograms/d in NIDDM rats, P less than .001), irrespective of STZ injection, but endogenous creatinine clearance was not different among the groups. Furthermore, renal growth was more greatly increased in salt-loaded groups.(ABSTRACT TRUNCATED AT 250 WORDS)

To search for a reliable marker of medium-term integrated blood glucose level in diabetics on maintenance hemodialysis (HD), plasma fructosamine and glycosylated hemoglobin (Hb) levels were determined every week and blood glucose levels were determined four times every day over 3 weeks. The mean values of fructosamine (mol/L per 40 g of albumin) and of glycosylated Hb of other the study period correlated (r = .746, P less than .001) for combined materials of diabetic and nondiabetic subjects. However, plasma fructosamine values at the end of the study period did not correlate with the overall mean blood glucose values during the preceding 8 to 21 days (r = .372, NS). In contrast, glycosylated Hb values correlated closely with the same mean blood glucose values (r = .703, P less than .001). Fructosamine values significantly decreased during a HD, irrespective of the increases in albumin and total protein. In conclusion, glycosylated Hb was a reliable marker of long-term integrated blood glucose even in diabetics on HD. However, fructosamine was not a reliable marker of medium-term integrated blood glucose in these patients.

We studied the long-term change in glycemic level in a model of non-insulin-dependent diabetes mellitus (NIDDM) induced by neonatal streptozotocin (STZ) treatment in spontaneously hypertensive rats (SHR). Two-day-old male SHR were intraperitoneally injected with 37.5 to 75.0 mg/kg of STZ or vehicle alone as control. According to nonfasting plasma glucose levels at 12 weeks of age, rats were divided into mild (less than 16.8 mmol/L) and severe (greater than or equal to 16.8 mmol/L) diabetes groups. In the mild diabetes group (n = 5), plasma glucose decreased significantly from 14.2 +/- 1.8 mmol/L (mean +/- SEM) at 20 weeks to 7.3 +/- 0.3 mmol/L at 52 weeks (P less than .05) with progressing age. At 52 weeks, overnight fasting plasma glucose levels were significantly lower and serum immunoreactive insulin (IRI) was higher than in controls, respectively (4.1 +/- 0.3 v 5.7 +/- 0.3 mmol/L, P less than 0.01; 625 +/- 50 v 409 +/- 50 pmol/L, P less than .05), and insulinoma was found in 60% of rats. Therefore, the recovery from hyperglycemia may be attributed to the development of insulinoma. In the severe diabetes group (n = 6), plasma glucose remained high until 28 weeks (27.2 +/- 1.5 mmol/L), but thereafter decreased with age, as it did in the mild diabetes group (13.7 +/- 3.5 mmol/L at 52 weeks, P less than .005). However, no insulinoma was found, and the mechanism for the recovery was unclear. The present study demonstrates that hyperglycemia spontaneously ameliorates in a neonatal STZ diabetes model of SHR, although this phenomenon may be strain-related.

Regional cerebral blood flow was measured using N-isopropyl-123I-iodoamphetamine with single-photon emission computed tomography (CT) in 16 aged patients with noninsulin-dependent diabetes mellitus (NIDDM, average age 72.8 years, average fasting plasma glucose 7.7 mmol/L), and 12 nondiabetic subjects (71.6 years, 5.3 mmol/L). None had any history of a cerebrovascular accident. Systolic blood pressure (SBP), total cholesterol, and triglyceride levels did not differ between groups. Areas of hypoperfusion were observed in 14 diabetic patients (12 patients had multiple lesions) and in 6 nondiabetic subjects (3 had multiple lesions). Areas where radioactivity was greater than or equal to 65% of the maximum count of the slice was defined as a region with normal cerebral blood flow (region of interest A, ROI-A), and areas where the count was greater than or equal to 45% were defined as brain tissue regions other than ventricles (ROI-B). The average ROI-A/B ratio of 16 slices was used as a semiquantitative indicator of normal cerebral blood flow throughout the entire brain. Mean ROI-A/B ratio was 49.6 +/- 1.7% in the diabetic group, significantly lower than the 57.9 +/- 1.6% at the nondiabetic group (p less than 0.005). The ratio was inversely correlated with SBP (r = -0.61, p less than 0.05), total cholesterol (r = -0.51, p less than 0.05), and atherogenic index (r = -0.64, p less than 0.01), and was positively correlated with high-density lipoprotein (HDL) cholesterol (r = 0.51, p less than 0.05) in the diabetic, but not the nondiabetic group. These observations suggest that the age-related reduction in cerebral blood flow may be accelerated by a combination of hyperglycemia plus other risk factors for atherosclerosis.

We studied the long-term change in blood pressures of spontaneously hypertensive rats (SHR) treated neonatally with streptozotocin (STZ). Two-day-old male SHR were injected intraperitoneally with 37.5-75.0 mg/kg STZ or with vehicle as control. STZ-treated SHR were divided into mildly or severely diabetic groups according to the nonfasting plasma glucose level at age 12 weeks (the former less than 300 mg/dl, the latter greater than or equal to 300 mg/dl). In the mildly diabetic group (MD) (n = 5), body weight increased and nonfasting plasma glucose was normalized. At 52 weeks of age, fasting plasma glucose levels were lower than controls owing to hyperinsulinemia, and insulinomas were found in 60% of rats. The systolic blood pressure (SBP) as measured by a tail-cuff method, decreased after 40 weeks, and the mean BP from 44 to 52 weeks (188 +/- 4 mmHg) was significantly lower than that in the control group (209 +/- 3 mmHg, p less than 0.01). In the severely diabetic group (SD) (n = 6), hyperglycemia persisted until 52 weeks, although its severity became less marked. BP in the SD group increased after 36 weeks, and the mean BP from 44 weeks to 52 weeks (224 +/- 5 mmHg) was significantly higher than control (p less than 0.05). The present study demonstrated that hypertension was ameliorated in SHR associated with hyperinsulinemia, and deteriorated with long-standing diabetes mellitus.

In an effort to clarify the regulation of contractions in cardiac muscle, we performed ultracentrifugation studies on the interactions between cardiac troponin and tropomyosin-actin complex in the presence of Ca2+ or Sr2+. When troponin C and troponin I were centrifuged with tropomyosin-actin complex, troponin I was not removed from tropomyosin-actin complex in the presence of bivalent-cation. Troponin C was observed to bind very weakly to troponin T-tropomyosin-actin complex in either the presence of absence of bivalent-cation. When troponin C was replaced by calmodulin, troponin I was not removed from tropomyosin-actin complex in the presence of bivalent-cation. Calmodulin bound to the troponin I-troponin T-tropomyosin-actin complex only in the presence of bivalent-cation. These results suggest that the inhibitory action of troponin I is neutralized by troponin C or calmodulin upon binding of bivalent-cation while troponin I binds to tropomyosin-actin complex in cardiac muscle. Therefore cardiac muscle seems to differ from skeletal muscle in regard to regulation of its contraction.

We examined the prevalence of orthostatic hypotension and its association with glycemic control, as assessed by hemoglobin A1 (HbA1) concentration, in type 2 diabetic patients. The prevalence of orthostatic hypotension in 886 diabetics who were referred to our study and in 587 diabetics who were not given any antihypertensive drugs was 7% and 6%, respectively. The relationship between orthostatic hypotension and HbA1 levels was evaluated only in subjects not receiving antihypertensive drugs, since antihypertensive agents might induce orthostatic hypotension. HbA1 levels were 11.0 +/- 2.1% in the diabetic patients with orthostatic hypotension, which was significantly higher than the HbA1 levels of 9.9 +/- 2.2% in the diabetic patients without orthostatic hypotension. Multivariate analysis also revealed that the association remained significant after adjustment for the treatment and duration of diabetes, age, sex and body mass index. These findings suggest that glycemic control contributes to the development of orthostatic hypotension in type 2 diabetic patients.

We studied the oncogenic action of neonatal streptozotocin (STZ) treatment in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) for 12 months. Two-day-old male neonates were intraperitoneally injected with STZ of which doses were 37.5-75.0 mg/kg for SHR and 100.0-150.0 mg/kg for WKY. The 12-month survival rate was 16 of 22 (73%) in SHR and 10 of 14 (71%) in WKY, respectively. The incidence of tumors in STZ-treated SHR was 27% in liver, 14% in kidney and 5% in liver and kidney, being related to the dose of STZ given, namely, 25% in 37.5 mg/kg, 50% in 50.0 or 62.5 mg/kg and 75% in 75.0 mg/kg. In STZ-treated WKY which survived 12 months, all had tumors, namely, 70% in liver, 20% in kidney and 10% in liver and kidney. Histological features of liver and kidney tumors were characteristic of hepatoma and nephroblastoma, respectively. Islet cell tumor was evident in 4 of 10 (40%) in SHR treated with lower doses of STZ (less than or equal to 50 mg/kg) but not in SHR and WKY treated with higher doses (62.5-150.0 mg/kg). The present study indicates that neonatal STZ treatment has the oncogenic action on liver, kidney and pancreatic islet.

We examined the sex differences in the development of diabetes due to neonatal streptozotocin (STZ) treatment in spontaneously hypertensive rats (SHR) which are more prone to diabetes than normotensive rats. Male and female SHR were intraperitoneally injected with various doses of STZ at 2 days after birth. In those treated with vehicle or 25 mg/kg of STZ, there were no sex differences in plasma glucose levels, which changed little during the 12 weeks of observation. When treated with 50 mg/kg of STZ, however, male SHR developed overt hyperglycemia greater than 300 mg/dl plasma glucose after 8 weeks of age, while females showed a minimal change in plasma glucose levels. When given 75 mg/kg of STZ, female rats developed overt hyperglycemia at 4-6 weeks of age, during which time male SHR showed no apparent hyperglycemia. At 8 weeks or later, however, both males and females had similarly high levels of plasma glucose. Glycosylated hemoglobin at 12 weeks was compatible with plasma glucose levels in each group. The present results indicate that there are sex differences in susceptibility to neonatal STZ treatment and in development of hyperglycemia.

To clarify the significance of the parameters which might indicate the abnormalities in the kidney, urinary N-acetyl-beta-D-glucosaminidase (NAG), urinary total protein (TP), urinary beta 2-microglobulin (beta 2MG) and serum NAG were determined in 61 type 1 diabetics who had neither retinopathy nor macroalbuminuria (negative albuminuria by Albustix), and in 19 age, sex-matched nondiabetic subjects. Urinary NAG, urinary TP and serum NAG levels were significantly elevated in the diabetics compared with the nondiabetic subjects, even though in the diabetics, whose duration of diabetes was not longer than 2.5 years. The relationships between these parameters and glycemic indices at different periods were studied in diabetics. Urinary NAG was correlated the strongest with the mean blood glucose level over the 7 days before the collection of urine (r = 0.47) among the 5 glycemic indices. On the other hand, urinary TP and urinary beta 2MG were correlated the strongest with the urinary glucose at the time of collection of urine (r = 0.77 and r = 0.37, respectively) among the 5 glycemic indices. No correlation of urinary NAG, urinary TP or urinary beta 2MG with stable HbA1 was observed. On the multiple regression analysis, 32% of the changes in urinary NAG, 61% of urinary TP, 19% of urinary beta 2MG and 20% of serum NAG were explained merely by the blood glucose levels, respectively. No relationship was observed among each parameter and duration of diabetes, insulin dose, urinary excretion of C-peptide or lipid levels.(ABSTRACT TRUNCATED AT 250 WORDS)

We have evaluated the residual pancreatic B cell function by glucagon load test in 28 patients with non-insulin-dependent diabetes mellitus (NIDDM) of a duration of 20 years or more. The increase in serum C-peptide at 6 minutes after glucagon administration (delta C-peptide) was used as an index of residual B cell function. There was much less delta C-peptide in patients treated with insulin than in those treated with sulfonylurea (p less than 0.05), and it was significantly correlated with the body mass index (r = 0.40, p less than 0.05). Long term metabolic control assessed by the average annual mean fasting blood glucose for the observation period (mean, 21 years) was not correlated with delta C-peptide (r = -0.13). The prevalence of retinopathy which needed photocoagulation therapy and of neuropathy in patients with poor residual B cell function (delta C-peptide less than or equal to 0.3 ng/ml) was the same as that in those with good residual B cell function (delta C-peptide greater than or equal to 1.0 ng/ml). The present study shows that the residual B cell function is not correlated with long term glycemic control and the prevalence of diabetic complications in long-standing NIDDM patients.

We compared the glucose tolerance and insulin responses to intravenous (IV) glucose administration of a dose of 1 g/kg body weight in a conscious and unrestrained state of spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) with catheters chronically indwelled into artery and vein. Both plasma glucose levels at two minutes and ten minutes following IV glucose load as well as the incremental and total areas of plasma glucose were slightly but significantly lower in SHR than in WKY. Glucose disappearance rate (K value) was 7.7 +/- 0.3%/min in SHR, being slightly but significantly higher than that of 6.8 +/- 0.3%/min in WKY. On the other hand, insulin responses to the glucose load at ten minutes and 30 minutes as well as incremental and total insulin areas were significantly lower in SHR than in WKY. There was no significant difference in insulinogenic index between SHR and WKY. Our observations suggest that in a conscious and unrestrained state, SHR have the greater glucose tolerance associated with reduced insulin secretion than do WKY.