Impaired flow-mediated vasodilatation and insulin resistance in type 2 diabetic patients with albuminuria

An elevated urinary albumin excretion is associated with an increased risk of cardiovascular disease due to atherosclerosis, but the pathophysiological mechanism underlying this association is poorly understood. We studied 217 diabetic patients, that is, 121 normoalbuminuric patients, 71 microalbuminuric patients, and 25 macroalbuminuric patients. We evaluated flow-mediated dilatation of brachial artery (%FMD, one endothelial function marker associated with endogenous NO production), von Willebrand factor (vWF, endothelial activation marker), high-sensitive CRP (hsCRP, a low-grade inflammation marker), asymmetric dimethyl arginine (ADMA, an endogenous inhibitor of NO synthesis), and insulin sensitivity by steady-state plasma glucose method. %FMD was apparently decreased in microalbuminuric and macroalbuminuric patients compared with normoalbuminuric patients (p<0.001). Moreover, %FMD was significantly correlated with the degree of albuminuria (r=-0.38, p<0.05). On the other hand, vWF and hsCRP did not show significant difference between normoalbuminuric patients and microalbuminuric patients. In diabetic patients with macroalbuminuria, ADMA was significantly elevated compared to those with normoalbuminuria. Insulin sensitivity was significantly associated with urinary albumin excretion rate. These results suggested that endothelial dysfunction which may be due to impaired NO production and insulin resistance underlie the association between diabetic nephropathy and atherosclerosis in diabetic patients.     

Impaired enhancement of insulin action in cultured skeletal muscle cells from insulin resistant type 2 diabetic patients in response to contraction using electrical pulse stimulation

AimsSkeletal muscle insulin resistance is a characteristic feature of type 2 diabetes. The aim of this study was to examine the effect of contraction on insulin action using electrical pulse stimulation (EPS) in cultured skeletal muscle cells from insulin resistant type 2 diabetic patients.MethodsSkeletal muscle cell cultures were established from 6 insulin resistant type 2 diabetic subjects and age and BMI matched non-diabetic control subjects. Day 7 differentiated myotubes were treated with or without EPS for 16 h, after which glucose uptake and AS160 phosphorylation were measured in the presence or absence of insulin.ResultsIn control myotubes, EPS resulted in increased phosphorylation of AMPKThr¹⁷² (vs no EPS; p < 0.01), and this was associated with increased glucose uptake (p < 0.05). Insulin in the absence of EPS increased glucose uptake and AS160Thr⁶⁴² phosphorylation, and both effects were significantly enhanced by prior EPS. In the absence of EPS, AMPK activation was significantly increased (p < 0.01) in the diabetic vs control myotubes. Despite a comparable degree of AMPK activation following EPS, the action of insulin on glucose uptake (p < 0.05) and AS160Thr⁶⁴² phosphorylation (p < 0.001) was decreased in the diabetic vs control myotubes.ConclusionEPS mediated AMPK activation enhances the effect of insulin on glucose uptake and AS160Thr⁶⁴² phosphorylation in control myotubes replicating key metabolic benefits of exercise on insulin action in man. Conversely, insulin mediated glucose uptake and AS160Thr⁶⁴² phosphorylation remain significantly decreased in diabetic vs control myotubes despite a comparable degree of AMPK activation following EPS.     

Islet amyloid polypeptide in pancreatic islets from type 2 diabetic subjects

Aims/hypothesis: Islet amyloid polypeptide (IAPP) is a chief constituent of amyloid deposits in pancreatic islets, characteristic histopathology for type 2 diabetes. The goal of this study was to analyze islet cell composition in diabetic islets for the process of transforming water-soluble IAPP in β-cells to water-insoluble amyloid deposits by Immunocytochemical staining using different dilutions of anti-IAPP antibody. IAPP in β-cell granules may initiate β-cell necrosis through apoptosis to form interstitial amyloid deposits in type 2 diabetic islets.

Results: Control islets revealed twice as much β-cells as α-cells whereas 15 of 18 type 2 diabetic cases (83%) revealed α- cells as major cells in larger islets. Diabetic islets consisted of more larger islets with more σ-cells than β-cells, which contribute to hyperglucagonemia. In control islets, percentage of IAPP-positive cells against β-cells was 40–50% whereas percentage for type 2 diabetic islets was about 25%. Amyloid deposits in diabetic islets were not readily immunostained for IAPP using 1: 800 diluted antibody, however, 1: 400 and 1: 200 diluted solutions provided stronger immunostaining in early stages of islet amyloidogenesis after treating the deparaffinized sections with formic acid.

Methods: Using commercially available rabbit antihuman IAPP antibody, immunocytochemical staining was performed on 18 cases of pancreatic tissues from type 2 diabetic subjects by systematically immunostaining for insulin, glucagon, somatostatin (SRIF) and IAPP compared with controls. Sizes of islets were measured by 1 cm scale, mounted in 10X eye piece.

Conclusions/Interpretation: α cells were major islet cells in majority of diabetic pancreas (83%) and all diabetic islets contained less IAPP-positive cells than controls, indicating that IAPP deficiency in pancreatic islets is responsible for decreased IAPP in blood. In diabetic islets, water-soluble IAPP disappeared in β-cell granules, which transformed to water-insoluble amyloid deposits. Amyloid deposits were not readily immunostained using IAPP 1: 800 diluted antibody but were stronger immunostained for IAPP in early stages of amyloid deposited islets using less diluted solutions after formic acid treatment. In early islet amyloidogenesis, dying β-cell cytoplasm was adjacently located to fine amyloid fibrils, supporting that IAPP in secretary granules from dying β cells served as nidus for islet β-sheet formation.     

Islet amyloid polypeptide in pancreatic islets from type 2 diabetic subjects

Aims/hypothesis: Islet amyloid polypeptide (IAPP) is a chief constituent of amyloid deposits in pancreatic islets, characteristic histopathology for type 2 diabetes. The goal of this study was to analyze islet cell composition in diabetic islets for the process of transforming water-soluble IAPP in β-cells to water-insoluble amyloid deposits by Immunocytochemical staining using different dilutions of anti-IAPP antibody. IAPP in β-cell granules may initiate β-cell necrosis through apoptosis to form interstitial amyloid deposits in type 2 diabetic islets. Results: Control islets revealed twice as much β-cells as α-cells whereas 15 of 18 type 2 diabetic cases (83%) revealed α- cells as major cells in larger islets. Diabetic islets consisted of more larger islets with more σ-cells than β-cells, which contribute to hyperglucagonemia. In control islets, percentage of IAPP-positive cells against β-cells was 40–50% whereas percentage for type 2 diabetic islets was about 25%. Amyloid deposits in diabetic islets were not readily immunostained for IAPP using 1: 800 diluted antibody, however, 1: 400 and 1: 200 diluted solutions provided stronger immunostaining in early stages of islet amyloidogenesis after treating the deparaffinized sections with formic acid. Methods: Using commercially available rabbit antihuman IAPP antibody, immunocytochemical staining was performed on 18 cases of pancreatic tissues from type 2 diabetic subjects by systematically immunostaining for insulin, glucagon, somatostatin (SRIF) and IAPP compared with controls. Sizes of islets were measured by 1 cm scale, mounted in 10X eye piece. Conclusions/Interpretation: α cells were major islet cells in majority of diabetic pancreas (83%) and all diabetic islets contained less IAPP-positive cells than controls, indicating that IAPP deficiency in pancreatic islets is responsible for decreased IAPP in blood. In diabetic islets, water-soluble IAPP disappeared in β-cell granules, which transformed to water-insoluble amyloid deposits. Amyloid deposits were not readily immunostained using IAPP 1: 800 diluted antibody but were stronger immunostained for IAPP in early stages of amyloid deposited islets using less diluted solutions after formic acid treatment. In early islet amyloidogenesis, dying β-cell cytoplasm was adjacently located to fine amyloid fibrils, supporting that IAPP in secretary granules from dying β cells served as nidus for islet β-sheet formation.     

Improved insulin secretory function and reduced chemotactic properties after tissue culture of islets from type 1 diabetic patients

BACKGROUND: Type 1 diabetes results from the destruction of pancreatic beta-cell as a consequence of an autoimmune process. To date, information on the properties of islets isolated from type 1 diabetic patients is very scant. METHODS: Some immunological and functional properties of islets prepared from the pancreas of type 1 diabetic patients were studied shortly after the isolation and after a period of culture in euglycemic condition. RESULTS: Compared to control islets, freshly prepared type 1 diabetic islets released a significantly higher amount of cytokines (pg/mL) into the culture medium (TNF-alpha: 112.9 +/- 5.6 vs 75.6 +/- 24.4; INF-gamma: 286.9 +/- 26.9 vs 58.6 +/- 6.2; IL-10: 41.8 +/- 4.3 vs 10.1 +/- 3.2; TGF-1 beta: 294.0 +/- 20.6 vs 45.1 +/- 3.5); had a significantly higher chemotactic index (1.9 +/- 0.2 vs 1.2 +/- 0.1); showed reduced insulin release (% of insulin content) in response to glucose (2.8 +/- 0.7 vs 5.3 +/- 1.9), arginine (3.0 +/- 0.6 vs 5.6 +/- 1.0), and glibenclamide (2.9 +/- 0.7 vs 5.4 +/- 0.9); and exhibited decreased glucose oxidation capability and diminished mRNA expression of glucokinase, aldolase, pyruvate kinase, and mitochondrial glycerolphosphate dehydrogenase. Ten days after isolation, a normalization of cytokine release (TNF-alpha: 55.7 +/- 2.3; INF-gamma: 53.9 +/- 4.3; IL-10: 8.6 +/- 0.7; TGF-1 beta: 60.7 +/- 12.4) and chemotactic index (1.3 +/- 0.2) were observed. Moreover, there was an improvement of insulin secretion (3.8 +/- 0.3, 4.7 +/- 0.6 and 3.5 +/- 0.2 respectively in response to glucose, arginine, and glibenclamide) and glucose oxidation, and a partial recovery of the measured mRNA expressions. CONCLUSIONS: These novel results, obtained with islets prepared from patients with type 1 diabetes, demonstrate that even after months after diabetes diagnosis, a period of culture of the islets in a more favorable environment has beneficial effects on the islet function.     

老年糖尿病患者的胰岛功能变化

目的　探讨年龄对老年糖尿病患者胰岛分泌功能的影响。方法　 2型糖尿病患者 61 0例 ,按年龄分为 4组 :A组 <44岁 ;B组 45～ 59岁 ;C组 60～ 74岁 ;D组 75岁。并收集同期 NGT和 IGT患者共 1 92例作为对照。结果　 (1 )方差分析显示 ,随年龄增加老年糖尿病患者的体重、BMI、PINS、HOMA- IS明显增加 ,FBG、PBG、Hb A1 c显著降低 ,而 FINS、HOMA- IR、IAI各年龄组间差异无显著性。 (2 )协方差分析表明 ,仅控制 FBG的影响时 ,糖尿病患者各年龄组的 HOMA- IS仍有显著性差异 ,老年糖尿病患者的 HOMA- IS明显增加 ,而控制 BMI的影响后 ,各年龄组 HOMA- IS差异无显著性。 (3)糖尿病病程对 FINS、PINS、HOMA- IS的影响未达到显著性水平。 (4)决定 FINS的主要变量是 BMI,决定 PINS的主要变量是 BMI和 PBG。结论　老年糖尿病患者的胰岛素分泌功能主要决定于 BMI。年龄和糖尿病病程虽然对胰岛素分泌有负性影响但作用较弱 ,因此表现为伴随增龄的 BMI逐渐增加 ,胰岛素分泌功能也逐渐加强。校正 BMI的影响后 ,胰岛素分泌功能与年龄的关系不明显 ,但随糖尿病病程延长而逐渐减弱。     

Impaired autonomic function in type 2 diabetic patients during upper gastrointestinal endoscopy

BACKGROUND: Cardiac autonomic neuropathy, representing decreased parasympathetic nerve activity and predominance of sympathetic tone, is often encountered in diabetic patients, and leads to an increased risk of cardiovascular events including arrhythmia. To evaluate the potential cardiovascular risk of diabetics in performing esophagogastroduodenoscopy (EGD), we compared the autonomic function and cardiovascular parameters during EGD between diabetic and nondiabetic patients. METHODS: The autonomic nervous responses in 86 consecutive outpatients (42 type 2 diabetics and 44 nondiabetics) were determined by power spectral analysis (PSA) of heart-rate variations on an electrocardiogram. PSA data were based on two peaks in the low-frequency (LF) and high-frequency (HF) ranges. HF power and the ratio of LF power/HF power represented parasympathetic and sympathetic nerve activities, respectively. RESULTS: Diabetic patients showed significantly lower DeltaHF power and significantly higher DeltaLF power/HF power than nondiabetics, suggesting enhanced predominance of sympathetic activity and marked suppression of parasympathetic function. Significant correlations were found between these autonomic parameters and the diabetic duration. A slightly higher incidence of ventricular premature contractures was observed in diabetics during EGD. However, no significant difference was found in pulse or blood pressure increments during EGD between the two groups. CONCLUSIONS: This is the first study demonstrating an imbalance of autonomic function in diabetics during EGD, which may be linked to a slightly higher risk of arrhythmia.     

Cerebral arterial pulsatility and insulin resistance in type 2 diabetic patients

Diabetic patients have a threefold risk for cerebrovascular disease compared with nondiabetic controls. The aim of the present study was to investigate the association of insulin resistance with the pulsatility index (PI) of cerebral arteries in type 2 diabetic patients. We compared a group of 90 patients with stroke-free, type 2 diabetes and an age- and sex-matched control group of 45 healthy subjects without diabetes. We then evaluated the PI of the middle cerebral artery (MCA) by transcranial Doppler ultrasonography (TCD), and insulin resistance was determined by a short insulin tolerance test. The PI was significantly higher in diabetic patients than in healthy controls (p<0.05) and also higher in patients with insulin resistance than that seen in insulin sensitive diabetic patients (p<0.05). The PI of the MCA was significantly correlated with age (R=0.465, p<0.01), duration of diabetes (R=0.264, p=0.025) and hypertension (R=0.285, p=0.015) and inversely correlated with the insulin resistance index (Kitt: R=-0.359, p=0.030). A multiple regression analysis was performed with PI as the dependent variable and insulin resistance as an independent variable along with known clinical risk factors. Age (beta=0.393, p<0.01) and duration of diabetes (beta=0.274, p=0.043) exhibited a significant independent contribution to PI. PI could be a useful marker in the detection of diabetic cerebrovascular changes, and insulin resistance showed correlations with PI, but age and the duration of diabetes contributed independently to the variability in the PI.     

Exogenous insulin therapy slows weight loss in type 2 diabetic patients

The impact of exogenous insulin therapy on the ability of obese, noninsulin dependent diabetic patients to lose weight was studied. Weight loss data from seven insulin-requiring type 2 diabetic patients, 11 sulfonylurea-treated type 2 diabetic patients and 12 non-diabetic controls on very-low-calorie diets were analyzed. Upon starting the diet, insulin doses were reduced by 50 percent and given once daily as intermediate-acting insulin. Doses were adjusted to maintain capillary blood glucoses between 6.7 and 10 mM. Sulfonylureas were stopped upon initiation of the diet. Patients were seen weekly for determination of their dietary compliance, medical status, glucose control, activity level and amount of weight loss. The insulin-treated subjects lost significantly less weight per week, whether expressed as kilograms, change in body mass index or percent of initial body weight lost. Treatment of obese type 2 diabetic patients with insulin retards their ability to lose weight independent of caloric intake.     

Efficacy of conversion from bedtime NPH insulin to morning insulin glargine in type 2 diabetic patients on basal-prandial insulin therapy

In normal subjects, approximately half of the daily insulin requirement constitutes basal insulin. We investigated whether increasing the dose of insulin glargine up to half of the total insulin requirement could lead to better glycemic control in type 2 diabetic patients who were treated on basal-prandial insulin therapy. A total of 62 patients with type 2 diabetes on mealtime rapid-acting insulin analogue and bedtime NPH were randomized to either continuation of bedtime NPH (n=31) or morning glargine (n=31) for 6 months while continuing the aspart/lispro at each meal. The two groups were matched for age, sex, diabetes duration, BMI, HbA(1C), endogenous insulin secretion, and proportion of numbers using aspart/lispro and using oral hypoglycemic agents. The dose of insulin glargine was increased by 2-4 units to meet the target fasting blood glucose, whereas the dose of NPH was principally unchanged as a control group. Mean HbA(1C) at baseline was similar between patients with glargine and NPH (7.2% versus 6.9%). The percentage of glargine dose increased significantly (31% at baseline to 48% at 6 months) without any significant changes in total insulin dose. Mean HbA(1C) at 3 months was 6.6% with glargine and 7.0% with NPH (P<0.0001, adjusted mean change between-treatment difference 0.6% [95% CI 0.3-0.9]), and the values at 6 months were 6.6% and 6.9%, respectively (P=0.007). Frequency of hypoglycemia did not differ between the groups. Increasing the dose of glargine without changing the total daily insulin dose resulted in significantly better glycemic control in type 2 diabetic patients on basal-prandial insulin therapy. Conversion from bedtime NPH to morning glargine appears efficacious with no increase in frequency of hypoglycemia.     

Increased insulin sensitivity and decreased insulin secretion in offspring of insulin-sensitive type 2 diabetic patients

To investigate the early defects of glucose metabolism in insulin-sensitive type 2 diabetes, we performed oral and frequently sampled intravenous glucose tolerance tests (OGTT and FSIGT) with minimal model analysis in 15 offspring of Japanese type 2 diabetics with normal insulin sensitivity (insulin resistance index of homeostasis model assessment [HOMA-R] < 2.0) and in 20 healthy control subjects without a family history of type 2 diabetes. The frequency of impaired glucose tolerance (IGT) was 40% (6 of 15) in the offspring and 0% (0 of 20) in the controls. Fasting plasma glucose (4.8 +/- 0.1 v4.6 +/- 0.1 mmol/L, P = .18) and immunoreactive insulin ([IRI] 29.9 +/- 2.5 v 28.3 +/- 2.5 pmol/L, P = .64) were comparable between the offspring and the controls. The rate of glucose disappearance (KG) was significantly lower in the offspring versus the control group (2.00 +/- 0.22 v 2.60 +/- 0.17 min(-1), P= .03). The insulin sensitivity index (Si) was significantly greater in the offspring versus the controls (2.68 +/- 0.41 v 1.71 +/- 0.17 x 10(-4) min(-1) x pmol/L , P = .02). First-phase insulin secretion (FPI) to intravenous glucose was significantly lower in the offspring versus the control group (886 +/- 110 v 2,296 +/- 267 min x pmol/L, P< .01). Glucose effectiveness (SG) was comparable between the offspring and control groups. The disposition index (Si x FPI) was significantly lower in the offspring versus the controls (2,106 +/- 256 v 3,652 +/- 490 x 10(-4), P = .02). When the offspring were subdivided into 2 groups by glucose tolerance status, both normal glucose tolerance (NGT) offspring and IGT offspring showed a significant decrease in FPI and increase in Si. Thus, although the offspring of insulin-sensitive type 2 diabetics had increased insulin sensitivity, the impairment in insulin secretion was more dominant. Our results suggest that the early metabolic abnormality in insulin-sensitive type 2 diabetes is an insulin secretory dysfunction despite increased insulin sensitivity.     

Insulin action and insulin secretion in newly diagnosed type 2 diabetic patients

To clarify the insulin action and insulin secretion in newly diagnosed type 2 diabetic subjects, we investigated insulin and C-peptide response to an oral glucose tolerance test (OGTT) in 15 newly diagnosed type 2 diabetic patients and 17 healthy subjects. For insulin action, we found fasting hyperinsulinemia (8.4 +/- 0.8 vs. 6.0 +/- 0.5 microIU/ml, p = 0.014), higher insulin resistance by homeostasis model assessment (HOMA) (4.33 +/- 0.2 vs. 1.34 +/- 0.1 microIU/ml.mmol/l, p < 0.001), and lower insulin sensitivity index (ISI) (51.0 +/- 0.7 vs. 104.0 +/- 0.8, p < 0.001) in newly diagnosed diabetic patients compared to normal subjects. For insulin secretion, the increments of AUCI (area under curve of insulin) and AUCC-P (area under curve of C-peptide) (increment of AUCI: 26.1 +/- 1.4 vs. 82.8 +/- 4.5 microIU/ml.hour, p < 0.001; increment of AUCC-P: 3.9 +/- 0.2 vs. 11.4 +/- 0.6 ng/ml.hour, p < 0.001), insulin secretion by HOMA model (20.7 +/- 1.2 vs. 79.1 +/- 3.8 IU/mol, p < 0.001), and ratio of 30 min increment of fasting insulin to glucose during OGTT (1.14 +/- 0.1 vs. 13.1 +/- 0.5 IU/mol, p < 0.001) were significantly lower in the newly diagnosed diabetic patients than normal subjects. In addition, body mass index (BMI) in our type 2 diabetes is relatively lower (24 +/- 0.65 kg/m2) than those in western countries. These findings revealed poor insulin action and decreased insulin secretion in relatively less obese Taiwanese with newly diagnosed type 2 diabetes.     

Improved postprandial glycaemic controls with insulin Aspart in type 2 diabetic patients treated with insulin

The effect on postprandial blood glucose control of an immediately pre-meal injection of the rapid acting insulin analogue Aspart (IAsp) was compared with that of human insulin Actrapid injected immediately or 30 before a test meal in insulin-treated type 2 diabetic patients with residual β-cell function. In a double-blind, double dummy crossover design, patients attended three study days where the following insulin injections in combination with placebo were given in a random order: IAsp (0.15 IU/kg body weight) immediately before the meal, or insulin Actrapid (0.15 IU/kg) immediately (Act-₀) or 30 minutes before (Act-₃₀) a test meal. We studied 25 insulin-requiring type 2 diabetic patients, including 14 males and 11 females, with a mean age of 59.7 years (range, 43–71), body mass index 28.3 kg/m² (range, 21.9–35.0), HbA_1c 8.5% (range, 6.8–10.0), glucagon-stimulated C-peptide 1.0 nmol/l (range, 0.3–2.5) and diabetes duration 12.5 years (range, 3.0–26.0). Twenty-two patients completed the study A significantly improved postprandial glucose control was demonstrated with IAsp as compared to Act₀, based on a significantly smaller postprandial blood glucose excursion (IAsp, 899 ± 609 (SD) mmol/l · min versus Act₀, 1102 ± 497 mmol/l min, p < 0.01) and supported by a significantly lower maximum serum glucose concentration (C_max) up to 360 min after dosing (IAsp, 10.8 ± 2.2 mmol/l vs. Act₀, 12.0 ±2.4 mmol/l, p < 0.02). No difference was demonstrated with a meal and Actrapid injected 30 minutes before the meal (AUC_glucose IAsp, 899 ± 609 mmol/l min vs. Act-₃₀, 868 ± 374 mmol/l min; C_max IAsp, 10.8 ± 2.2 mmol/l vs. Act-₃₀, 11.1 ± 1.8 mmol/l). No concerns about the safety of IAsp were raised. Immediate pre-meal administration of the rapid-acting insulin analogue Aspart in patients with type 2 diabetes resulted in an improved postprandial glucose control compared to Actrapid injected immediately before the meal, but showed similar control compared to Actrapid injected 30 minutes before the meal. These results indicate that the improved glucose control previously demonstrated with insulin Aspart compared to human insulin in healthy subjects and type 1 diabetic patients also applies to insulin-treated type 2 diabetic patients. Received: 3 December 1999 / Accepted in revised form: 3 March 2000     

C-reactive protein and insulin resistance in non-obese Japanese type 2 diabetic patients

The aim of the present study was to investigate the relationship between C-reactive protein (CRP) and insulin resistance in non-obese Japanese type 2 diabetic patients. A total of 135 non-obese Japanese type 2 diabetic patients (96 men and 39 women, aged 36 to 83 years, with a body mass index [BMI] of 16.2 to 26.8 kg/m2) were studied. BMI, glycosylated hemoglobin (HbA(1c)), fasting concentrations of plasma glucose, serum lipids (triglycerides, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, and total cholesterol), CRP, and fibrinogen were measured. LDL cholesterol was calculated using the Friedewald formula. Insulin resistance was estimated by the insulin resistance index of homeostasis model assessment (HOMA-IR). Univariate regression analysis showed that CRP value was positively correlated to age (r = 0.218, P =.012), BMI (r = 0.239, P =.006), HOMA-IR (r = 0.397, P <.0001), triglycerides (r= 0.310, P <.005), LDL cholesterol (r= 0.179, P =.038), and fibrinogen (r = 0.371, P <.0001) levels and inversely correlated to HDL cholesterol (r = 0.174, P =.044) level in our diabetic patients. Multiple regression analysis showed that CRP was independently predicted by HOMA-IR (P<.0001, F = 11.6) and fibrinogen (P<.0001, F = 34.2), which explained 23.5% of the variability of CRP in our non-obese Japanese type 2 diabetic patients. These results indicate that insulin resistance and fibrinogen level are independent predictors of CRP in non-obese Japanese type 2 diabetic patients.     

Stimulatory effect of serum from diabetic patients on insulin release from mouse pancreatic islets maintained in tissue culture

Summary Islets of Langerhans from NMRI-mice were kept for one week in tissue culture in medium supplemented with human serum obtained from either normal healthy subjects or newly diagnosed juvenile diabetic patients before insulin treatment. Islets cultured in diabetic serum released more inslin than islets cultured in normal serum, whether tissue culture medium 199 with 5.5–8.3 mmol/1 glucose and 10% serum, or culture medium RPMI1 640 with 11 mmol/1 glucose and 0.5% serum were used. Islets kept for one week in culture with diabetic serum did not show any decrease in DNA content or glucose induced insulin secretion and biosynthesis. It is concluded that serum from newly diagnosed insulin dependent diabetic patients stimulates insulin release from isolated mouse islets kept in tissue culture. The underlying mechanism is unknown.     

Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin

Several properties of pancreatic beta-cells in type 2 diabetes (T2D) were studied by using islets isolated from T2D subjects. Moreover, because metformin has protective effects on nondiabetic beta-cells exposed to high glucose or free fatty acid levels, we investigated its direct action on T2D islet cells. Diabetic islets were characterized by reduced insulin content, decreased amount of mature insulin granules, impaired glucose-induced insulin secretion, reduced insulin mRNA expression, and increased apoptosis with enhanced caspase-3 and -8 activity. These alterations were associated with increased oxidative stress, as shown by higher nitrotyrosine concentrations, increased expression of protein kinase C-beta2 and nicotinamide adenine dinucleotide phosphate reduced-oxidase, and changes in mRNA expression of manganese- superoxide dismutase, Cu/Zn-superoxide dismutase, catalase, and glutathione peroxidase. Twenty-four-hour incubation of T2D islets with metformin was associated with increased insulin content, increased number and density of mature insulin granules, improved glucose-induced insulin release, and increased insulin mRNA expression. Moreover, apoptosis was reduced, with concomitant decrease of caspase-3 and -8 activity. These changes were accompanied by reduction or normalization of several markers of oxidative stress. Thus, T2D islets have several functional and survival defects, which can be ameliorated by metformin; the beneficial effects of the drug are mediated, at least in part, by a reduction of oxidative stress.     

Effects of bezafibrate on insulin sensitivity and insulin secretion in non-obese Japanese type 2 diabetic patients

The aim of the present study was to investigate the effect of bezafibrate on insulin sensitivity and insulin secretion in 30 non-obese Japanese type 2 diabetic patients with hypertriglyceridemia (serum triglycerides > 150 mg/dL). Insulin sensitivity was measured with homeostasis model assessment insulin resistance (HOMA-IR) proposed by Matthews et al. HOMA-B-cell function, proposed by Matthews et al validated against minimal model-derived insulin secretion, was used to assess pancreatic insulin function. Twenty-two patients were treated with glibenclimide and the rest were treated with diet alone. All patients were treated with bezafibrate (400 mg/d) for 3 months. There were no changes in diet and the dose of any medications used throughout the study. Fasting glucose, insulin, triglycerides, HDL cholesterol, and total cholesterol levels were measured before and after treatment of bezafibrate. After treatment of bezafibrate for 3 months, serum triglyceride levels significantly decreased from 277 +/- 30 to 139 +/- 9 mg/dL (P <.001) and serum HDL cholesterol levels increased significantly from 45 +/- 2 to 52 +/- 2 mg/dL (P =.003). Serum cholesterol level was unchanged during the study (198 +/- 7 v 201 +/- 7 mg/dL, P =.383). Fasting glucose (163 +/- 8 v 139 +/- 6 mg/dL, P =.006) significantly decreased after the treatment with bezafibrate. HbA1c levels decreased, although not statistically significant (7.50 +/- 0.25 v 7.17% +/- 0.19%, P =.147). On the other hand, fasting insulin (9.3 +/- 0.7 v 7.3 +/- 0.5 microU/mL, P =.010) and HOMA-IR (3.61 +/- 0.24 to 2.53 +/- 0.20, P <.001) levels decreased significantly after the treatment with bezafibrate. In contrast, HOMA-B-cell function did not change during the study (41.4 +/- 5.5 v 41.8 +/- 4.7, P =.478). There was no significant difference in body mass index (BMI) levels before and after the therapy (23.0 +/- 0.4 v 23.1 +/- 0.4 kg/m(2), P =.483). From these results, it can be concluded that bezafibrate reduces serum triglycerides, insulin resistance, and fasting blood glucose levels in non-obese Japanese type 2 diabetic patients.