Effect of dietary fructose on portal and systemic serum fructose levels in rats and in KHK-/- and GLUT5-/- mice.

Elevated blood fructose concentrations constitute the basis for organ dysfunction in fructose-induced metabolic syndrome. We hypothesized that diet-induced changes in blood fructose concentrations are regulated by ketohexokinase (KHK) and the fructose transporter GLUT5. Portal and systemic fructose concentrations determined by HPLC in wild-type mice fed for 7 days 0% free fructose were <0.07 mM, were independent of time after feeding, were similar to those of GLUT5(-/-), and did not lead to hyperglycemia. Postprandial fructose levels, however, increased markedly in those fed isocaloric 20% fructose, causing significant hyperglycemia. Deletion of KHK prevented fructose-induced hyperglycemia, but caused dramatic hyperfructosemia (>1 mM) with reversed portal to systemic gradients. Systemic fructose in wild-type and KHK(-/-) mice changed by 0.34 and 1.8 mM, respectively, for every millimolar increase in portal fructose concentration. Systemic glucose varied strongly with systemic, but not portal, fructose levels in wild-type, and was independent of systemic and portal fructose in KHK(-/-), mice. With ad libitum feeding for 12 wk, fructose-induced hyperglycemia in wild-type, but not hyperfructosemia in KHK(-/-) mice, increased HbA1c concentrations. Increasing dietary fructose to 40% intensified the hyperfructosemia of KHK(-/-) and the fructose-induced hyperglycemia of wild-type mice. Fructose perfusion or feeding in rats also caused duration- and dose-dependent hyperfructosemia and hyperglycemia. Significant levels of blood fructose are maintained independent of dietary fructose, KHK, and GLUT5, probably by endogenous synthesis of fructose. KHK prevents hyperfructosemia and fructose-induced hyperglycemia that would markedly increase HbA1c levels. These findings explain the hyperfructosemia of human hereditary fructosuria as well as the hyperglycemia of fructose-induced metabolic syndrome.

Diabetes and anxiety were associated with insomnia among Japanese male truck drivers.

OBJECTIVE/BACKGROUND: Insomnia among truck drivers may contribute to traffic accidents. We previously reported that truck drivers had adverse lifestyle habits, including smoking and drinking alcohol, in addition to enforced sedentarism making them more vulnerable to lifestyle-related diseases. This study aimed to investigate the association between insomnia and diabetes, as well as the effect of anxiety related to driving tasks on this association. PATIENTS/METHODS: A total of 755 male truck drivers under 65 years of age who belonged to Akita prefecture Truck Association in Japan were investigated. Insomnia and State-Trait Anxiety Inventory (STAI) score were assessed using a self-administered questionnaire in 2020. Insomnia was defined in accordance with International classification of sleep disorders-third edition. Diabetes was defined as a fasting blood glucose level of ≥126 mg/dL and/or use of anti-diabetic drugs using data obtained from health checkups in 2018. RESULTS: The proportions of truck drivers with insomnia and diabetes were 13.9% and 9.7%, respectively, which were higher than those in the general working population in Japan. After adjusting for age, smoking, drinking, daily hours of driving and sleep, and hypertension, the STAI score (odds ratio [OR] for the highest quartile vs. the lowest: 3.88, 95% confidence interval [CI]: 1.84-8.18) and diabetes (OR: 2.49, 95% CI: 1.11-5.60) were found to be associated with insomnia. A statistical interaction with STAI scores was not observed between diabetes and insomnia. CONCLUSIONS: The present study demonstrated that diabetes and anxiety are independently and significantly associated with insomnia in male Japanese truck drivers.

Rats fed fructose-enriched diets have characteristics of nonalcoholic hepatic steatosis.

Nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease are increasing in adults and are likely to be increasing in children. Both conditions are hepatic manifestations of metabolic syndrome. Experimental animals fed fructose-enriched diets are widely recognized as good models for metabolic syndrome. However, few reports have described the hepatic pathology of these experimental animals. In this study, 5-wk-old Wistar specific pathogen-free rats, which are a normal strain, were fed experimental diets for 5 wk. We then evaluated the degree of steatohepatitis. The 5 diet groups were as follows: cornstarch (70% wt:wt) [control (C)], high-fructose (70%) (HFr), high-sucrose (70%) (HS), high-fat (15%) (HF), and high-fat (15%) high-fructose (50%) (HFHFr) diets. The macrovesicular steatosis grade, liver:body weight ratio, and hepatic triglyceride concentration were significantly higher in the HFr group than in the other 4 groups. However, the HFr group had a significantly lower ratio of epididymal white fat:body weight than the other 4 groups and had a lower final body weight than the HF and HFHFr groups. The HF group had a greater final body weight than the C, HFr, and HS groups, but no macrovesicular steatosis was observed. The HFr group had a significantly higher grade of lobular inflammation than the other 4 groups. The distribution of lobular inflammation was predominant over portal inflammation, which is consistent with human NASH. In conclusion, rats fed fructose-enriched diets are a better model for NASH than rats fed fat-enriched diets.

Patient health literacy and patient-physician information exchange during a visit.

BACKGROUND: Health literacy (HL), the capacity of individuals to access, understand and use health information to make informed and appropriate health-related decisions, is recognized as an important concept in patient education and disease management. OBJECTIVE: To examine the relation of three levels of HL (i.e. functional, communicative and critical HL) to patient-physician information exchange during a visit. METHODS: Participants were 134 outpatients with type 2 diabetes who were under continuous care by four attending physicians at a university-affiliated hospital. The visit communication was recorded and analysed using the Roter Interaction Analysis System. Patient HL was measured through a self-reported questionnaire using newly developed self-rated scales of functional, communicative and critical HL. Sociodemographic and clinical characteristics and patient's perception of the information exchange were assessed for each patient through self-reported questionnaires and review of electronic medical records. RESULTS: Patient HL levels were related to the information exchange process during the visit. Among the three HL scales, communicative HL (the capacity to extract information, derive meaning from different forms of communication and apply new information to changing circumstances) was related to patient's perceptions of the information exchange. Further, patient communicative HL had a modifying effect on the relationship between physician's information giving and patient's perception of it, suggesting that physician's communication may be perceived differently depending on the patient's HL. CONCLUSION: The exploration of patient HL may provide a better understanding of potential barriers to patient-physician communication and patient's self-management of disease.

The number of microvascular complications is associated with an increased risk for severity of periodontitis in type 2 diabetes patients: Results of a multicenter hospital-based cross-sectional study.

AIMS/INTRODUCTION: To explore the relationships between periodontitis and microvascular complications as well as glycemic control in type 2 diabetes patients. MATERIALS AND METHODS: This multicenter, hospital-based, cross-sectional study included 620 patients with type 2 diabetes. We compared the prevalence and severity of periodontitis between patients with ≥1 microvascular complication and those without microvascular complications. We also compared the prevalence and severity of periodontitis among patients with different degrees of glycemic control. RESULTS: After adjusting for confounding factors, multiple logistic regression analysis showed that the severity of periodontitis was significantly associated with the number of microvascular complications (odds ratio 1.3, 95% confidence interval 1.1-1.6), glycated hemoglobin ≥8.0% (64 mmol/mol; odds ratio 1.6; 95% confidence interval 1.1-2.3), and older age (≥50 years; odds ratio 1.7; 95% confidence interval 1.1-2.6). However, the prevalence of periodontitis was not significantly associated with the number of microvascular complications, but was associated with male sex, high glycated hemoglobin (≥8.0% [64 mmol/mol]), older age (≥40 years), longer duration of diabetes (≥15 years) and fewer teeth (≤25). Furthermore, propensity score matching for age, sex, diabetes duration and glycated hemoglobin showed that the incidence of severe periodontitis was significantly higher among patients with microvascular complications than among those without microvascular complications (P < 0.05). CONCLUSIONS: The number of microvascular complications is a risk factor for more severe periodontitis in patients with type 2 diabetes, whereas poor glycemic control is a risk factor for increased prevalence and severity of periodontitis.

Atorvastatin lowers plasma low-density lipoprotein cholesterol and C-reactive protein in Japanese type 2 diabetic patients.

We investigated the meaning and the worth of lowering low-density lipoprotein cholesterol (LDL-C) to less than 100 mg/dL in Japanese type 2 diabetic patients using atorvastatin. As a multicenter open-labeled study, 84 type 2 diabetic Japanese patients with hypercholesterolemia were enrolled between September 2003 and April 2004. Subjects received 16 weeks of treatment with atorvastatin. High-sensitive C-reactive protein (hs-CRP), plasminogen activator inhibitor 1, monocyte chemotactic protein 1, interleukin 6, urine albumin-creatinine ratio, hemoglobin A(1c), total cholesterol, and LDL-C were measured at baseline and after 8 and 16 weeks of treatment. According to the Adult Treatment Panel III of the National Cholesterol Education Program, we divided the subjects into responders (final LDL-C <100 mg/dL) and nonresponders (final LDL-C > or =100 mg/dL). After 16 weeks of atorvastatin treatment, as well as a reduction of total cholesterol and LDL-C, a significant reduction of hs-CRP was observed. Plasminogen activator inhibitor 1, monocyte chemotactic protein 1, and interleukin 6 were not changed. After stratification, hs-CRP declined only in responders. We concluded that atorvastatin not only improved hypercholesterolemia, but also reduced CRP even in Japanese diabetic patients. The results of this stratified study suggest that achievement of the Adult Treatment Panel III treatment goal of LDL-C might assure a reduction of inflammation, which is associated with cardiovascular events.

1,5-Anhydroglucitol stimulates insulin release in insulinoma cell lines.

Concentrations of 1,5-anhydroglucitol (1,5-AG), which is a major circulating polyol, decrease in patients with diabetes mellitus. In both insulinoma-derived RINr and MIN6 cells, 1,5-AG stimulated insulin release within the range of 0.03-0.61 mM in a dose-dependent manner. Insulin release was maximally stimulated by 1,5-AG to levels that reached 25% and 100% greater than that of control (1,5-AG-free group) in RINr and MIN6 cells, respectively. A physiological concentration of 1,5-AG stimulated insulin release after a 5-min incubation and this action was maintained for 60 min. In addition, at approximately 1/200 the concentration of glucose, 1,5-AG had additive action with 20 mM glucose. The action of 1,5-AG on insulin secretion with other types of saccharides and polyol was similarly additive. Mannnoheptulose and diazoxide suppressed the stimulative action of 1,5-AG on insulin release. The secretagogue action of 1,5-AG seemed to be independent on an increase in the intracellular content of cAMP and ATP. These results suggest that 1,5-AG can stimulate insulin secretion through a mechanism that completely differs from that of glucose.

Increased fructose concentrations in blood and urine in patients with diabetes.

OBJECTIVE: To investigate fructose metabolic changes in patients with diabetes. RESEARCH DESIGN AND METHODS: Serum and urinary fructose concentrations were determined in healthy subjects (n = 23) and in nondiabetic (n = 23) and diabetic patients (n = 26). Fructose was measured using our newly developed method, and (13)C(6)-fructose was used as the internal standard. After adding sample to a fixed amount of internal standard, ion-exchange resins and high-performance liquid chromatography pretreatments were performed. Then, the amount of fructose in the sample was measured by gas chromatography-mass spectrometry. RESULTS: Serum fructose concentrations in patients with diabetes (12.0 +/- 3.8 micromol/l) were significantly higher than those in healthy subjects (8.1 +/- 1.0 micromol/l, P < 0.001) and nondiabetic patients (7.7 +/- 1.6 micromol/l, P < 0.001), and daily urinary fructose excretion was significantly greater in patients with diabetes (127.8 +/- 106.7 micromol/day) than in nondiabetic patients (37.7 +/- 23.0 micromol/day, P < 0.001). In patients with diabetes (n = 20), serum fructose concentrations (8.6 +/- 1.8 micromol/l, P < 0.001) and daily urinary fructose excretion (63.4 +/- 63.8 micromol/day, P < 0.01) significantly decreased by week 2 after admission. CONCLUSIONS: The present results differed from those of previous studies in that we found that the serum and urinary fructose concentrations decreased rapidly, concomitant with an improvement in glycemia. Therefore, hyperglycemia was associated with increased serum and urinary fructose concentrations in patients with diabetes.

Inhibitory effects of eucalyptus and banaba leaf extracts on nonalcoholic steatohepatitis induced by a high-fructose/high-glucose diet in rats.

Nonalcoholic steatohepatitis (NASH) is a liver disease associated with metabolic syndrome. The aim of this work was to examine whether eucalyptus (Eucalyptus globulus) leaf extract (ELE) and banaba (Lagerstroemia speciosa L.) leaf extract (BLE) inhibited NASH induced by excessive ingestion of fructose in rats. Wistar rats were divided into four groups according to four distinct diets: starch diet (ST), high-fructose/high-glucose diet (FG), FG diet supplemented with ELE, or FG diet supplemented with BLE. All rats were killed after 5 weeks of treatment. Serum alanine aminotransferase and total cholesterol levels were significantly lower in the BLE group than in the FG group. Liver histopathology, including steatosis, lipogranulomas, and perisinusoidal fibrosis, was significantly attenuated in the ELE and BLE groups compared with the FG group. Levels of 2-thiobarbituric acid reactive substances (TBARS), which reflect oxidative injury to the liver, were significantly suppressed by ELE and BLE. Western blotting analysis indicated that interleukin-6 expression levels were significantly lower in the ELE and BLE groups than in the FG group. These results suggest that ELE and BLE reduced lipogenesis, oxidative stress, and inflammatory cytokine expression and thus inhibited NASH induced by excessive ingestion of fructose in rats.

Effect of antidiabetic medications on microalbuminuria in patients with type 2 diabetes.

The progression of diabetes and hypertension complications is associated with microalbuminuria. Intensive glycemic control prevents or retards microalbuminuria in patients with type 2 diabetes, but little is known about the respective benefits of different antidiabetic drugs. We studied the effect of gliclazide and pioglitazone on microalbuminuria in patients with type 2 diabetes. We excluded patients with very poor glycemic control (glycated hemoglobin [HbA(1c)] >10%), impaired liver function, nondiabetic renal diseases, and those whose urine contained red blood cells, hemoglobin, or casts. Each patient received the designated drug for 12 weeks and their body weight, blood pressure (BP), fasting plasma glucose (FPG), HbA(1c), lipids (triglycerides [TG], total, and high-density lipoprotein-cholesterol [HDL-C]), 1,5 anhidroglucitol (1,5-AG), immunoreactive insulin (IRI), and urinary albumin to creatinine ratio (UACR) were measured every month. The effects of the drugs were analyzed using 2-way repeated measures analysis of variance (ANOVA). The 2 groups of patients were well matched for age, duration of diabetes, retinal status, blood pressure, body mass index (BMI), IRI, FPG, HBA(1c), 1,5-AG, lipids, and UACR, as well as the use of antihypertensive drugs. After treatment, no significant differences were seen in drug efficacy between the 2 groups. Gliclazide and pioglitazone significantly reduced FPG (F = 26.0, P <.0001), HBA(1c) (F = 48.1, P <.0001), and total cholesterol (TC) levels (F = 3.5, P <.05). Decrements in these metabolic parameters were comparable between the groups. 1,5-AG increased in both groups (F = 27.5, P <.0001), and the increment was comparable in both groups. Gliclazide and pioglitazone significantly reduced UACR (F = 15.7, P <.0001) with a comparable decrement in both groups. No other variables changed significantly throughout the 12-week treatment. These results suggest that 12 weeks of treatment with gliclazide or pioglitazone are equally effective in reducing microalbuminuria with similar improvements in blood glucose and cholesterol levels, independent of their mechanisms of actions.

Postprandial plasma fructose level is associated with retinopathy in patients with type 2 diabetes.

The aim of the present study was to investigate the association of fructose on microangiopathy in patients with diabetes. Postprandial plasma fructose concentrations and postprandial plasma glucose concentrations were simultaneously measured 3 times within a 24-hour period (2 hours after each meal) in 38 patients with type 2 diabetes that had been admitted to the hospital. The mean postprandial plasma fructose concentrations (MPPF) and the mean postprandial plasma glucose concentrations (MPPG) were calculated. Fructose was measured by gas chromatography-mass spectrometry (GCMS). Based solely on MPPF, we were able to divide the patients into three groups: the high MPPF (31.9 +/- 6.5 micromol/L) group (n = 12), the middle MPPF (21.2 +/- 1.8 micromol/L) group (n = 13), and the low MPPF (15.2 +/- 2.4 micromol/L) group (n = 13). Prevalence and degree of retinopathy and nephropathy were then evaluated in the 3 different groups. A significant correlation was observed in the prevalence of proliferative diabetic retinopathy (PDR) among the 3 MPPF groups (P =.024). The prevalence of PDR was higher in the high MPPF group (75.0%) than in the middle and low MPPF groups (23.1% and 38.5%, respectively). Although not significantly different statistically, the prevalence of all degrees of retinopathy showed a tendency to be higher in the high MPPF group (83.3%) than in the middle and low MPPF groups (46.2% and 46.2%, respectively) (P =.081). Nephropathy prevalence also showed a tendency to be higher in the high MPPF group (66.7%) than in the middle and low MPPF groups (38.5% and 30.8%, respectively), although the differences were not significant. The prevalence of clinical albuminuria was not significantly different among the 3 groups, but there was a tendency for it to be higher in the low MPPF group (30.8%) than in the high and middle MPPF groups (16.7% and 0%, respectively). No significant differences in glycemic indicators and mean duration of diabetes were observed among the 3 groups. The increased prevalence of retinopathy in the high MPPF group suggests that fructose is associated with retinopathy in patients with type 2 diabetes.

The role of fructose-enriched diets in mechanisms of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) currently affects 20%-30% of adults and 10% of children in industrialized countries, and its prevalence is increasing worldwide. Although NAFLD is a benign form of liver dysfunction, it can proceed to a more serious condition, nonalcoholic steatohepatitis (NASH), which may lead to liver cirrhosis and hepatocellular carcinoma. NAFLD is accompanied by obesity, metabolic syndrome and diabetes mellitus, and evidence suggests that fructose, a major caloric sweetener in the diet, plays a significant role in its pathogenesis. Inflammatory progression to NASH is proposed to occur by a two-hit process. The first "hit" is hepatic fat accumulation owing to increased hepatic de novo lipogenesis, inhibition of fatty acid beta oxidation, impaired triglyceride clearance and decreased very-low-density lipoprotein export. The mechanisms of the second "hit" are still largely unknown, but recent studies suggest several possibilities, including inflammation caused by oxidative stress associated with lipid peroxidation, cytokine activation, nitric oxide and reactive oxygen species, and endogenous toxins of fructose metabolites.

Markedly increased serum and urinary fructose concentrations in diabetic patients with ketoacidosis or ketosis.

To investigate fructose concentrations in diabetic patients with ketoacidosis or ketosis, serum fructose concentrations and daily urinary fructose excretion were measured in 23 patients with ketoacidosis (n = 16) and ketosis (n = 7) on the first day of admission. Seventeen patients were diagnosed with type 1, one patient with mitochondrial, and 4 patients with atypical diabetes. In 16 of the 23 patients, serum and urinary fructose could be assessed after starting treatments. Mean serum fructose concentration was 71.6 ± 108.1 µmol/l, and mean daily urinary fructose excretion was 352.1 ± 473.7 µmol/day. Serum fructose levels in patients with atypical diabetes were much higher (205.0 ± 213.3 µmol/l) than those in patients with type 1 diabetes (45.1 ± 44.5 µmol/l), while urinary fructose levels in atypical diabetes (249.7 ± 92.4 µmol/day) tended to be lower than those in type 1 diabetes (382.6 ± 533.2 µmol/day). Serum fructose concentrations decreased significantly (P < 0.05) from 88.1 ± 126.3 to 18.0 ± 11.0 µmol/l, and daily urinary fructose excretion also decreased significantly (P < 0.05) from 459.8 ± 530.9 to 75.1 ± 62.0 µmol/day in accordance with glycemic normalization after treatment. Marked and reversible increases in serum and urinary fructose concentrations were observed in diabetics with ketoacidosis and ketosis.

Glycemic Profiles of Healthy Individuals with Low Fasting Plasma Glucose and HbA1c.

Scant data exists on glucose profile variability in healthy individuals. Twenty-nine healthy subjects without diabetes (86% male; mean age, 38 years) were measured by a CGM system and under real-life conditions. The median percentage of time spent on the blood glucose >7.8 mmol/L for 24 hrs was greater than 10% in both NFG and IFG groups. When subjects were divided into either NFG group (i.e., FPG levels of <5.6 mmol/L; n = 22) or IFG group (FPG levels of 5.6-6.9 mmol/L; n = 7), all CGM indicators investigated but GRADE scores, including glucose variability measures, monitoring excursions, hyperglycemia, hypoglycemia, and 24-hour AUC, did not differ significantly between the two groups. GRADE score and its euglycemia% were significantly different between the two groups. Among various CGM indicators, GRADE score may be a sensitive indicator to discriminate glucose profiles between subjects with NFG and those with IFG.

Regulation of adipocytokine secretion and adipocyte hypertrophy by polymethoxyflavonoids, nobiletin and tangeretin.

AIMS: The polymethoxyflavonoids nobiletin and tangeretin possess several important biological properties such as neuroprotective, antimetastatic, anticancer, and anti-inflammatory properties. The present study was undertaken to examine whether nobiletin and tangeretin could modulate adipocytokine secretion and to evaluate the effects of these flavonoids on the hypertrophy of mature adipocytes. MAIN METHODS: All experiments were performed on the murine preadipocyte cell line 3T3-L1. We studied the formation of intracellular lipid droplets in adipocytes and the apoptosis-inducing activity to evaluate the effects of polymethoxyflavonoids on adipocyte differentiation and hypertrophy, respectively. The secretion of adipocytokines was measured using ELISA. KEY FINDINGS: We demonstrated that the combined treatment of differentiation reagents with nobiletin or tangeretin differentiated 3T3-L1 preadipocytes into adipocytes possessing less intracellular triglyceride as compared to vehicle-treated differentiated 3T3-L1 adipocytes. Both flavonoids increased the secretion of an insulin-sensitizing factor, adiponectin, but concomitantly decreased the secretion of an insulin-resistance factor, MCP-1, in 3T3-L1 adipocytes. Furthermore, nobiletin was found to decrease the secretion of resistin, which serves as an insulin-resistance factor. In mature 3T3-L1 adipocytes, nobiletin induced apoptosis; tangeretin, in contrast, did not induce apoptosis, but suppressed further triglyceride accumulation. SIGNIFICANCE: Our results suggest that nobiletin and tangeretin are promising therapeutic candidates for the prevention and treatment of insulin resistance by modulating the adipocytokine secretion balance. We also demonstrated the different effects of nobiletin and tangeretin on mature adipocytes.

Two-way crossover comparison of insulin glargine and insulin detemir in basal-bolus therapy using continuous glucose monitoring.

OBJECTIVE: This study aimed to compare the glucose-lowering effect and glycemic variability of insulin glargine with those of insulin detemir. MATERIAL AND METHODS: This was an open-label, single-center, randomized, two-way crossover study in patients with diabetes on basal-bolus insulin therapy, with neutral protamine Hagedorn (NPH) insulin as basal insulin. Patients switched from NPH insulin to a course either of insulin glargine followed by insulin detemir, or insulin detemir followed by insulin glargine, continuing the same dose of the prior bolus of insulin. To evaluate the glucose-lowering effect, daily glycemic profiles were recorded for 72 hours by continuous glucose monitoring (CGM) in an outpatient setting. The mean amplitude of glycemic excursions, standard deviation (SD), and the mean of daily difference (MODD) were used to assess intraday and day-to-day glycemic variability. RESULTS: Eleven patients were enrolled and nine completed the study. Mean blood glucose calculated from CGM values was significantly lower with insulin glargine compared with insulin detemir (9.6 ± 2.4 mmol/L versus 10.4 ± 2.8 mmol/L, P = 0.038). The SD was significantly lower with insulin glargine versus insulin detemir (2.5 ± 0.9 mmol/L vs 3.5 ± 1.6 mmol/L, P = 0.011). The MODD value was significantly lower with insulin glargine than with insulin detemir (2.2 ± 1.1 mmol/L vs 3.6 ± 1.7 mmol/L, P = 0.011). There was no significant difference between the two insulin analogs in terms of hypoglycemia. CONCLUSION: This study suggests that insulin glargine leads to more effective and more stable glycemic control than the same dose of insulin detemir.

Concomitant therapy with pioglitazone and insulin for the treatment of type 2 diabetes.

To prevent hyperinsulinemia, which may cause atherosclerosis, thiazolidinediones (TZDs), also known as insulin sensitizers, are often added to the therapeutic regimen of patients with type 2 diabetes who are receiving insulin. The combination of insulin with pioglitazone, a TZD, reduces glycoated hemoglobin (HbA(1c)) by 0.6%-2.1%. The higher the HbA(1c) baseline the larger the therapeutic reduction of HbA(1c). This combination therapy has been shown to be beneficial even in lean Japanese patients with diabetes. It should be noted that such combination therapy is much more useful when the main clinical aim is lowering not postprandial, but fasting and nocturnal glycemia. The glycemic-lowering effects of pioglitazone alone occur slowly, whereas the addition of insulin to pioglitazone often shows a dramatic glucose-lowering effect. Thus, such combination therapy increases the possibility of frequent hypoglycemia within 1 to 2 months of combining the drugs. Severe hypoglycemia in patients using this therapy is rare. Patients treated with combination therapy who show a predominant reduction of glycemia often have severe edema; in 10%-20% of patients, combination therapy leads to drug-related congestive heart failure (CHF). However, this phenomenon is usually weakened if low doses of pioglitazone which are added to insulin therapy (ie, 15 mg/day or even 7.5 mg/day for women). It is well known that pioglitazone has an anti-atherosclerotic effect, although it is unclear if hyperinsulinemia induces atherogenic changes, either directly or indirectly, by the promotion of obesity. Until now, we have not confirmed whether the anti-atherosclerotic effects of pioglitazone exceed the supposed disadvantageous action of insulin when used in combination therapy. The addition of pioglitazone tends to reduce daily insulin dosages, but study findings have not been consistent. Improvement of lipid profiles has also been weak with this combination therapy. Long-term trials are needed before any conclusions can be reached concerning atherogenic effects of treatment for type 2 diabetes. Combination therapy of even small doses of pioglitazone with insulin should be primarily used for patients who achieve insufficient reduction in glycemia with insulin monotherapy.