Kuninobu Yokota

Magnesium Intake in Relation to Systemic Inflammation, Insulin Resistance, and the Incidence of Diabetes

OBJECTIVE To investigate the long-term associations of magnesium intake with incidence of diabetes, systemic inflammation, and insulin resistance among young American adults. RESEARCH DESIGN AND METHODS A total of 4,497 Americans, aged 18–30 years, who had no diabetes at baseline, were prospectively examined for incident diabetes based on quintiles of magnesium intake. We also investigated the associations between magnesium intake and inflammatory markers, i.e., high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and fibrinogen, and the homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS During the 20-year follow-up, 330 incident cases of diabetes were identified. Magnesium intake was inversely associated with incidence of diabetes after adjustment for potential confounders. The multivariable-adjusted hazard ratio of diabetes for participants in the highest quintile of magnesium intake was 0.53 (95% CI, 0.32–0.86; Ptrend < 0.01) compared with those in the lowest quintile. Consistently, magnesium intake was significantly inversely associated with hs-CRP, IL-6, fibrinogen, and HOMA-IR, and serum magnesium levels were inversely correlated with hs-CRP and HOMA-IR. CONCLUSIONS Magnesium intake was inversely longitudinally associated with incidence of diabetes in young American adults. This inverse association may be explained, at least in part, by the inverse correlations of magnesium intake with systemic inflammation and insulin resistance.

Clinical Efficacy of Magnesium Supplementation in Patients with Type 2 Diabetes

Effects of magnesium (Mg) supplementation on nine mild type 2 diabetic patients with stable glycemic control were investigated. Water from a salt lake with a high natural Mg content (7.1%) (MAG21) was used for supplementation after dilution with distilled water to 100mg/100mL; 300mL/day was given for 30 days. Fasting serum immunoreactive insulin level decreased significantly, as did HOMA□R (both p < 0.05). There was also a marked decrease of the mean triglyceride level after supplementation. The patients with hypertension showed significant reduction of systolic (p < 0.01), diastolic (p = 0.0038), and mean (p < 0.01) blood pressure. The salt lake water supplement, MAG21, exerted clinical benefit as a Mg supplement in patients with mild type 2 diabetes mellitus.

Prospective randomized study for optimal insulin therapy in type 2 diabetic patients with secondary failure

BackgroundThe large clinical trials proved that Basal-Bolus (BB) insulin therapy was effective in the prevention of diabetic complications and their progression. However, BB therapy needs multiple insulin injections per a day. In this regard, a biphasic insulin analogue needs only twice-daily injections, and is able to correct postprandial hyperglycemia. Therefore it may achieve the blood glucose control as same as that of BB therapy and prevent the diabetic complications including macroangiopathy.MethodsIn PROBE (Prospective, Randomized, Open, Blinded-Endpoint) design, forty-two type 2 diabetic patients (male: 73.8%, median(inter quartile range) age: 64.5(56.8~71.0)years) with secondary failure of sulfonylurea (SU) were randomly assigned to BB therapy with a thrice-daily insulin aspart and once-daily basal insulin (BB group) or to conventional therapy with a twice-daily biphasic insulin analogue (30 Mix group), and were followed up for 6 months to compare changes in HbA1c, daily glycemic profile, intima-media thickness (IMT) of carotid artery, adiponectin levels, amounts of insulin used, and QOL between the two groups.ResultsAfter 6 months, HbA1c was significantly reduced in both groups compared to baseline (30 Mix; 9.3(8.1~11.3) → 7.4(6.9~8.7)%, p < 0.01, vs BB;8.9(7.7~10.0) → 6.9(6.2~7.3)%, p < 0.01), with no significant difference between the groups in percentage change in HbA1c (30 Mix; -14.7(-32.5~-7.5)% vs BB -17.8(-30.1~-11.1)%, p = 0.32). There was a significant decrease in daily glycemic profile at all points except dinner time in both groups compared to baseline. There was a significant increase in the amount of insulin used in the 30 Mix group after treatment compared to baseline (30 Mix;0.30(0.17~0.44) → 0.39(0.31~0.42) IU/kg, p = 0.01). There was no significant difference in IMT, BMI, QOL or adiponectin levels in either group compared to baseline.ConclusionBoth BB and 30 mix group produced comparable reductions in HbA1c in type 2 diabetic patients with secondary failure. There was no significant change in IMT as an indicator of early atherosclerotic changes between the two groups. The basal-bolus insulin therapy may not be necessarily needed if the type 2 diabetic patients have become secondary failure.Trial registrationCurrent Controlled Trials number, NCT00348231

Effects of magnesium on postprandial serum lipid responses in healthy human subjects

Postprandial hyperlipidaemia has been recognised to be a risk factor for atherosclerosis development. Epidemiological and animal studies have shown that Mg intake is inversely associated with some risk factors of atherosclerosis, including lipid metabolism. The present study was performed to determine the effects of Mg supplementation on postprandial responses in serum lipid levels. We used bittern (Nigari, in Japanese), a natural MgCl(2) solution from sea or salt lake water, for Mg supplementation. In a two-way, randomised, crossover study, sixteen healthy male volunteers consumed 30 g butter with or without 5 ml bittern containing 500 mg of Mg. Fasting and postprandial blood samples were taken 2, 3, 4 and 6 h after ingestion. Postprandial lipid responses were evaluated by serum TAG, chylomicron TAG, apo-B48, remnant-like particle cholesterol (RLP-C) and NEFA concentrations. We found that the serum and the chylomicron TAG responses after the fat load were reduced and delayed by Mg supplementation. The concentrations of apo-B48 (P < 0.05), RLP-C (P < 0.05) and NEFA (P < 0.05) were significantly lower at 2 h after the fat-with-Mg meal compared with the fat-only meal. The present study indicated that Mg supplementation could inhibit fat absorption and improve postprandial hyperlipidaemia in healthy subjects.

Dietary magnesium intake and risk of metabolic syndrome: a meta-analysis

To estimate quantitatively the association between dietary magnesium intake and risk of metabolic syndrome by combining the relevant published articles using meta‐analysis.

Two- and three-dimensional ultrastructural observations of angiogenesis in juvenile hemangioma

SummaryTwo- and three-dimensional electron microscopic observations by a serial sectioning method revealed endothelial sprouts with intracytoplasmic vacuolization in rapidly growing human juvenile hemangioma. A large vacuole bounded by a single unit membrane was enclosed in the cytoplasm and on the inner aspect of the vacuolar membrane several short microvilli were demonstrated. These appearances have not been reported before. The presence of microvilli in the vacuole indicates that the endothelium has reached the point of differentiation when a vascular lumen forms. In the cytoplasm adjacent to the vacuolar membrane, a significant number of 7 to 10 nm microfilaments were identified. These intracytoplasmic microfilaments are assumed to play a mechanical role in the development of the cytoplasmic vacuole and/or the sprout. The formation of a vacuole observed in the endothelial sprout is similar to the findings of Sabin (1920) by light microscopy in endothelial sprouts in the blood island of the chick embryo. The active endothelial sprout in juvenile hemangiomas is considered to be at least partially responsible for the capillary proliferation and enlargement of the tumor.

Differences in the pathology of the metabolic syndrome with or without visceral fat accumulation

To elucidate the role of visceral fat accumulation in the metabolic syndrome, differences in the pathology of the metabolic syndrome with or without visceral fat accumulation were investigated. A total of 472 prediabetic Japanese men (mean age, 47.5±7.2 yr) with impaired fasting glycemia (IFG) levels of 110–125 mg/dL were eligible for participation in the study. The study subjects were divided into the following four groups, and intergroup comparisons were made: group I without visceral fat area [VFA]≥100 cm2 but presenting with fewer than two other risk factors (i.e., TG≥150 mg/dL, HDL-C<40 mg/dL, BP≥130/≥85 mmHg, or FPG≥110 mg/dL) (n=231); group II without VFA of ≥100 cm2 but presenting with three or more other risk factors (n=57); group III with VFA of ≥100 cm2 accompanied by FPG≥110 mg/dL alone (n=27); and group IV with VFA≥100 cm2 and two or more other risk factors (n=157). The prevalence of patients who had three or more risk factors with or without VFA≥100 cm2 was 45.3% (214 out of 472 patients), while that of those with VFA≥100 cm2 who had two or more other risk factors was 33% (157 out of 472 patients). Group II had significantly higher VFA values than group I (p<0.05), and group IV had significantly higher VFA values than group II (p<0.001). While no significant differences in HOMA-R values were seen between groups I and II, these values were significantly higher in group IV compared to groups I and II (p<0.001 and p<0.05, respectively). Furthermore, group IV showed significantly higher 2-h insulin levels after glucose loading compared to group I (p<0.001). While no significant differences were seen between groups II and IV, insulin levels tended to be higher in group IV. Adiponectin levels showed an incremental fall in VFA from group I through groups II and III to group IV. Groups III and IV showed significantly lower adiponectin levels compared to group I (p<0.05, p<0.001, respectively); and group IV showed significantly lower adiponectin levels than group II (p<0.05). A logistic regression analysis using VFA, TG and HDL-C, and BP as explanatory variables showed that the relative risk for high HOMA-R values were 2.65 (p<0.001) for patients with VFA ≥100 cm2; 1.64 (p<0.05) for those with TG≥150 mg/dL and HDL<40 mg/dL; and 1.79 (p<0.01) for those with BP≥130/≥85 mmHg. These findings demonstrate that the degree of insulin resistance and the risk of arteriosclerosis vary depending on whether or not the metabolic syndrome accompanied by a clustering of risk factors has visceral fat accumulation as an underlying pathology, strongly suggesting a crucial role for visceral fat accumulation in the metabolic syndrome.

Japanese IGT subjects with high insulin response are far more frequently associated with the metabolic syndrome than those with low insulin response

Impaired glucose tolerance (IGT) represents a prediabetic state positioned somewhere between normal glucose tolerance and diabetes, which is also assumed to make individuals in this state highly susceptible to atherosclerotic disease. IGT also accounts for a highly heterogeneous population, with the condition varying from individual to individual. In this study, we stratified subjects with IGT by their insulin response and compare the pathology of IGT when it is associated with high or low insulin response to gain insight into the diverse pathology of IGT. Of the male corporate employees who underwent 75 g OGTT at the corporations healthcare center, 150 individuals diagnosed with IGT (isolated IGT, combined IGT and IFG) comprised our study subjects. The study subjects were stratified into four quartiles by percentile AUC for insulin, and those in the 25th or less percentile were defined as the low insulin response group (n=37) vs those in the 76th or greater percentile defined as the high insulin response group (n=38), and these groups were compared. There was no significant difference observed between the two groups in regard to post-OGTT glucose response and area under the glucose curve. However, the high insulin response group was associated with higher BMI, subcutanesous fat area, uric acid levels, HOMA-β cell values, and Δinsulin/Δglucose (30 min) than the low insulin response group. The number of risk factors for the metabolic syndrome detected (as defined by the ATPIII diagnostic criteria) per subject was 2.84±0.17 and 2.08±0.20, respectively, in the high insulin response group and in the low insulin response group, with the number significantly (p<0.05) higher in the high insulin response group. Furthermore, the incidence of the metabolic syndrome as defined by the ATPIII diagnostic criteria was 63.2% (24/38) in the high insulin response group vs 32.4% (12/27) in the low insulin response group, with the incidence significantly (p<0.01) higher in the high insulin response group. Likewise, the incidence of the metabolic syndrome as defined by the Japanese diagnostic criteria was found to be significantly (p<0.05) higher in the high insulin response group at 50% (19/38) compared to 27.0% (10/37) in the low insulin response group. Our study findings suggest that IGT subjects with high insulin response and those with low insulin response vary greatly in regard to the number of atherosclerotic risk factors complicated and the frequency with which they are associated with the metabolic syndrome. It is also shown in middle-aged Japanese males that of the two forms of IGT, IGT with high insulin response is more closely linked to the pathogenesis of atherosclerotic cardiovascular disease.

Role of hypoadiponectinemia in the metabolic syndrome and its association with post-glucose challenge hyper-free fatty acidemia: a study in prediabetic Japanese males.

We investigated the role of hypoadiponectinemia in the metabolic syndrome (MS), as well as its association with post-glucose challenge hyper-free fatty acidemia in the clinical setting. The study subjects comprised 177 corporate employees shown to have a fasting plasma glucose (FPG) level of 125 mg/dL or less in a 75 g OGTT in the corporations healthcare center. When divided into those who met the Japanese criteria for the metabolic syndrome (MS group; n=45) and those who did not (Non-MS group; n=132), the MS group was shown to have significantly lower adiponectin levels than the Non-MS group, and tended to show higher high-sensitivity C-reactive protein (CRP) values than the Non-MS group, while not achieving statistical significance. The MS group showed higher baseline glucose levels; higher baseline, 30-, 60-, and 120-min post-challenge insulin levels; higher 30-, 60- and 120-min post-challenge free fatty acid levels than the Non-MS group. Additionally, there was a significant, negative correlation between adiponectin levels, area under the free fatty acid curve, and area under the insulin curve at OGTT (r=−0.24, p<0.01; r=−0.21, p<0.01, respectively). When the patients were divided by adiponectin level into four groups to examine the number of risk factors for MS detected per patient and the incidence of MS, the lower the adiponectin level, the more risk factors were found per patient, with 68% of patients with an adiponectin level of less than 4 μg/mL found to have MS. In those with an adiponectin level of less than 4 μg/mL, BMI values, uric acid levels, HOMA-R values, and the number of risk factors for MS involved per patient were shown to be higher than in those with an adiponectin level of 4 μg/mL or greater. Furthermore, the following risk factors for MS were more frequently found in those with an adiponectin level of less than 4 μg/mL than in those with an adiponectin level of 4 μg/mL or greater; VFA≥100 cm2 (OR 12.8, p<0.001); TG≥150 mg/dL (OR 3.2, p<0.05); HDL-C<40 mg/dL (OR 1.9, p=0.29); BP≥130/85 mmHg (OR 2.2, p=0.15); and FPG≥110 mg/dL (OR 1.9, p=0.29). Again, the incidence of MS (OR 7.6, p<0.001) by the ATP III criteria, as well as that by the Japanese criteria (OR 8.6, p<0.001), was found to be higher in those with an adiponectin level of less than 4 μg/mL than in those with an adiponectin level of 4 μg/mL or greater. Our study results suggest that adiponectin is closely associated with the multiple risk factors that go to make up the MS, suggesting a role for hypoadiponectinemia as a surrogate marker for the MS and further appear to suggest that post-challenge hyper-free fatty acidemia may account in part for hypoadiponectinemia in the MS.

Magnesium intake and incidence of pancreatic cancer: the VITamins and Lifestyle study

Background:Studies document that magnesium is inversely associated with the risk of diabetes, which is a risk factor of pancreatic cancer. However, studies on the direct association of magnesium with pancreatic cancer are few and findings are inconclusive. In this study, we aimed to investigate the longitudinal association between magnesium intake and pancreatic cancer incidence in a large prospective cohort study.Method:A cohort of 66 806 men and women aged 50–76 years at baseline who participated in the VITamins And Lifestyle (VITAL) study was followed from 2000 to 2008. Multivariable-adjusted Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of pancreatic cancer incidence by magnesium intake categories.Result:During an average of 6.8-year follow-up, 151 participants developed pancreatic cancer. Compared with those who met the recommended dietary allowance (RDA) for magnesium intake, the multivariable-adjusted HRs (95% CIs) for pancreatic cancer were 1.42 (0.91, 2.21) for those with magnesium intake in the range of 75–99% RDA and 1.76 (1.04, 2.96) for those with magnesium intake <75% RDA. Every 100 mg per day decrement in magnesium intake was associated with a 24% increase in the incidence of pancreatic cancer (HR: 1.24; 95% CI: 1.02, 1.50; Ptrend=0.03). The observed inverse associations appeared not to be appreciably modified by age, gender, body mass index, and non-steroidal anti-inflammatory drug use but appeared to be limited to those taking magnesium supplementation (from multivitamins or individual supplement).Conclusions:Findings from this prospective cohort study indicate that magnesium intake may be beneficial in terms of primary prevention of pancreatic cancer.