High Incidence of Diabetes in People with Extremely High High-Density Lipoprotein Cholesterol: Results of the Kanagawa Investigation of Total Checkup Data from the National Database-1 (KITCHEN-1).

BACKGROUND: It is unknown whether extremely high high-density lipoprotein cholesterol (HDL-C) has a protective effect against diabetes, which plays a key role in cardiovascular disease. METHODS: In a community-based cohort study of 387,642 subjects (40⁻68 years old) without diabetes, the incidence of diabetes 6 years later was determined according to baseline HDL-C (≤39, 40⁻49, 50⁻59, 60⁻69, 70⁻79, 80⁻89, 90⁻99, 100⁻109, or ≥110 mg/dL). RESULTS: At baseline, HDL-C ≥100 mg/dL was present in 12,908 subjects (3.3%), who had a better lipid profile and a high prevalence of heavy alcohol consumption and habitual exercise. The incidences of diabetes according to baseline HDL-C were 14.7, 11.2, 7.7, 5.3, 3.8, 2.8, 2.7, 2.5, and 3.5 per 1000 person-years, respectively. The adjusted relative risks (ARRs) for diabetes showed concave relationships with HDL-C, with minima at 80⁻89 mg/dL. The ARR (95% CI) of the lowest HDL-C category was 1.56 (1.40⁻1.74) and of the highest HDL-C category was 1.46 (1.18⁻1.81) (both p < 0.001), regardless of alcohol consumption. The latter ARR was higher in men (n = 219,047) (2.45 (1.70⁻3.53), p < 0.0001) after adjustment for baseline glycemic index. CONCLUSION: Both extremely high and low HDL-C represent risks for diabetes, which deserves further study.

Possible Long-Term Efficacy of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, for Slowly Progressive Type 1 Diabetes (SPIDDM) in the Stage of Non-Insulin-Dependency: An Open-Label Randomized Controlled Pilot Trial (SPAN-S).

INTRODUCTION: We tested the hypothesis that dipeptidyl peptidase-4 (DPP-4) inhibitors are effective in preserving the ß-cell function for long-term periods in patients with slowly progressive type 1 diabetes (SPIDDM) or latent autoimmune diabetes in adults (LADA). METHODS: In the present open-label, randomized, controlled trial, 14 non-insulin-requiring diabetic patients with glutamic acid decarboxylase autoantibodies (GADAb) were randomly assigned to receive either sitagliptin (S group) or pioglitazone (P group). As a historical control, the Tokyo Study, in which non-insulin-dependent patients with SPIDDM were assigned to receive treatment by either insulin or sulfonylurea (SU), was used. RESULTS: On average, the ∑C-peptide values during the oral glucose tolerance test through the follow-up periods showed a nonsignificant increase in the S group (n = 6, n = 5 at 48 months) compared to the P group (n = 5, n = 2 at 48 months). In comparison to the data in the Tokyo Study, treatment by sitagliptin significantly influenced the longitudinal changes in the ∑C-peptide values with a more increased direction than insulin or SU, especially in patients with 48 months of follow-up (p = 0.014 and p = 0.007, respectively). Although the titers of GADAb were not significantly different between the S and P groups during the study, the change ratio of the GADAb titers from baseline was significantly inversely correlated with the change ratio of the ∑C-peptide values from baseline in the S group (p = 0.003); in particular, when the GADAb titers decreased from baseline, the ∑C-peptide values frequently increased. CONCLUSION: The present pilot trial suggests that treatment of SPIDDM/LADA by sitagliptin, a DPP-4 inhibitor, may be more effective in preserving the ß-cell function than insulin treatment for at least 4 years, possibly through the immune modulatory effects of DPP-4 inhibitors. CLINICAL TRIAL REGISTRATION: Japanese Clinical Trials Registry UMIN000003693.

Erratum to: Decreased glucagon levels and decreased insulin secretion after sitagliptin versus mitiglinide administration with similar glycemic levels following an oral glucose load: a randomized crossover pharmaceutical mechanistic study.

[This corrects the article DOI: 10.1007/s13340-015-0207-1.].

Decreased glucagon levels and decreased insulin secretion after sitagliptin versus mitiglinide administration with similar glycemic levels following an oral glucose load: a randomized crossover pharmaceutical mechanistic study.

AIMS: Both sitagliptin (SIT) and mitiglinide (MIT) can lower postprandial hyperglycemia. The purpose of this study was to examine differences in insulin and glucagon secretion after SIT or MIT administration when similar levels of plasma glucose (PG) were achieved for both agents following an oral glucose load. PATIENTS AND METHODS: We directly compared the effects of these two agents in 16 type-2 diabetic patients (M/F = 10/6, age 66 ± 3 years old, HbA1c 6.6 ± 0.5 %). Patients received SIT (50 mg qd for 1 week and 100 mg qd for an additional week) or MIT (10 mg tid for 2 weeks). After 2 weeks, patients crossed over to the other treatment. 75-g oral glucose tolerance tests were conducted before the study and after interventions. RESULTS: The area under the curve (AUC) up to 180 min for the PG response was similar for both agents. While basal insulin secretion rates (ISR) were similar, incremental AUC of ISR was significantly lower in the SIT treatment (522 ± 108 vs 702 ± 288 pmol/min min, p < 0.01), although the difference between the SIT and MIT treatments in the Matsuda index-which reflects insulin sensitivity-remained nonsignificant. Glucose-stimulated insulin secretion was similarly increased by the MIT and SIT treatments. Suppression of the AUC for glucagon was observed in the SIT treatment, while MIT treatment failed to suppress the glucagon concentration (-432 ± 2322 vs MIT 1116 ± 2520 pg/ml min, p < 0.05). The basal proinsulin/insulin ratio was lower in the SIT treatment (0.23 ± 0.04 vs MIT 0.26 ± 0.36, p < 0.05). CONCLUSIONS: Although either SIT or MIT can be employed to reduce postprandial hyperglycemia, SIT induces changes in hormonal profiles that are more favorable to islet functions than MIT does.

Anti-hypertensive azelnidipine preserves insulin signaling and glucose uptake against oxidative stress in 3T3-L1 adipocytes.

It is known that reactive oxygen species (ROS) are involved in the development of insulin resistance as well as pancreatic ß-cell dysfunction both of which are often observed in type 2 diabetes. In this study, we evaluated the effects of azelnidipine, a calcium channel blocker, on ROS-mediated insulin resistance in adipocytes. When 3T3-L1 adipocytes were exposed to ROS, insulin-mediated glucose uptake was suppressed, but such phenomena were not observed in the presence of azelnidipine. Phosphorylation of insulin receptor and phosphorylation of Akt were suppressed by ROS, which was mitigated by azelnidipine treatment. Activation of the JNK pathway induced by ROS was also reduced by azelnidipine. Various inflammatory cytokine levels were increased by ROS, which was also suppressed by azelnidipine treatment. In contrast, adiponectin mRNA and secreted adiponectin levels were reduced by ROS, which was refilled by azelnidipine treatment. In conclusion, azelnidipine preserves insulin signaling and glucose uptake against oxidative stress in 3T3-L1 adipocytes.

Low, but physiological, concentration of GLP-1 stimulates insulin secretion independent of the cAMP-dependent protein kinase pathway.

Glucagon-like peptide-1 (GLP-1) induces pancreatic insulin secretion via the cAMP-dependent protein kinase (PKA) pathway. However, the GLP-1 concentration used in the previous in vitro experiments was far from the in vivo concentrations. Alteration of plasma GLP-1 concentration at pM order lowers blood glucose concentration. In this study, we examined the GLP-1 action mechanism at a physiological concentration on insulin secretion. A high concentration of GLP-1 (10 nM) stimulated intracellular cAMP accumulation and insulin secretion was significantly inhibited by KT5720, a selective inhibitor of PKA. Low GLP-1 concentrations (1 pM) also increased insulin secretion without significant accumulation of intracellular cAMP, and KT5720 did not affect insulin secretion. Insulin secretion stimulated by 1 pM GLP-1 was reduced by inhibitors of calcium action, including verapamil, dantrolene, and BAPTA. Thus, we concluded that relatively low GLP-1 concentrations-comparable to in vivo blood concentrations-promoted insulin secretion independent of the cAMP-PKA pathway. This effect was dependent on intracellular Ca2+ concentration. The results of the present study may further the understanding of the dose-dependent response of GLP-1 signal transducing pathways and the complicated mechanism of insulin secretion. Studies of GLP-1 at physiologic concentrations may lead to new developments in studies of pancreatic beta-cell function.

The relationship between fasting hyperglycemia and insulin secretion in subjects with normal or impaired glucose tolerance.

To assess the relationship between the fasting plasma glucose (FPG) concentration and insulin secretion in normal glucose tolerance (NGT) and impaired glucose tolerance (IGT) subjects, 531 nondiabetic subjects with NGT (n = 293) and IGT (n = 238; 310 Japanese and 232 Mexican Americans) received an oral glucose tolerance test (OGTT) with measurement of plasma glucose, insulin, and C-peptide every 30 min. The insulin secretion rate was determined by plasma C-peptide deconvolution. Insulin sensitivity (Matsuda index) was measured from plasma insulin and glucose concentrations. The insulin secretion/insulin resistance (IS/IR) or disposition index was calculated as DeltaISR/DeltaG / IR. As FPG increased in NGT subjects, the IS/IR index declined exponentially over the range of FPG from 70 to 125 mg/dl. The relationship between the IS/IR index and FPG was best fit with the equation: 28.8 exp(-0.036 FPG). For every 28 mg/dl increase in FPG, the IS/IR index declined by 63%. A similar relationship between IS/IR index and FPG was observed in IGT. However, the decay constant was lower than in NGT. The IS/IR index for early-phase insulin secretion (0-30 min) was correlated with the increase in FPG in both NGT and IGT (r = -0.43, P < 0.0001 and r = -0.20, P = 0.001, respectively). However, the correlation between late-phase insulin secretion (60-120 min) and FPG was not significant. In conclusion, small increments in FPG, within the "normal" range, are associated with a marked decline in glucose-stimulated insulin secretion and the decrease in insulin secretion with increasing FPG is greater in subjects with NGT than IGT and primarily is due to a decline in early-phase insulin secretion.

Effects of sulfonylurea drugs on adiponectin production from 3T3-L1 adipocytes: implication of different mechanism from pioglitazone.

Adiponectin is a fat-derived cytokine with anti-diabetic and anti-atherogenic properties. In this study, effects of sulfonylureas (SUs) on adiponectin production and the action mechanism were evaluated using 3T3-L1 adipocytes. The cells were incubated with glimepiride, glibenclamide, gliclazide, pioglitazone, metformin and the medium only as the control. In the control, the adiponectin level evaluated as the production rate per 24 h was not changed, while pioglitazone significantly increased the adiponectin level. SUs also increased the adiponectin level, but metformin failed to show any increase in adiponectin production. SUs induced adiponectin gene expression as well as pioglitazone. Pioglitazone significantly increased adipogenesis, but glimepiride did not. The aP2 gene expression was increased by pioglitazone, but not by glimepiride. Forskolin, a protein kinase A stimulator, reduced the adiponectin production stimulated by glimepiride but not by pioglitazone. These observations strongly suggest that SUs stimulate the adiponectin production through a different mechanism from pioglitazone, namely an interaction with protein kinase A activity. The significance of the extrapancreatic action of SUs observed in this study should be further evaluated in the clinical field.

Decreased non-insulin-dependent glucose clearance contributes to the rise in fasting plasma glucose in the nondiabetic range.

OBJECTIVE: To assess the contribution of decreased glucose clearance to the rise in fasting plasma glucose (FPG) in the nondiabetic range. RESEARCH DESIGN AND METHODS: A total of 120 subjects with normal glucose tolerance received an oral glucose tolerance test and euglycemic insulin clamp with 3-[(3)H]glucose. The basal and insulin-stimulated rates of glucose appearance, glucose disappearance, and glucose clearance and the basal hepatic insulin resistance index were calculated. Simple Pearson's correlation was used to assess the relationship between variables. RESULTS: The increase in FPG (range 75-125 mg/dl) correlated (r = 0.32, P < 0.0001) with the increase in BMI (20-50 kg/m(2)). The fasting plasma insulin (FPI) concentration also increased progressively with the increase in BMI (r = 0.62, P < 0.0001). However, despite increasing FPI, the basal glucose clearance rate declined and correlated with the increase in BMI (r = -0.56, P < 0.0001). Basal hepatic glucose production (HGP) decreased with increasing BMI (r = -0.51, P < 0.0001) and correlated inversely with the increase in FPI (r = -0.32, P < 0.0001). The hepatic insulin resistance (basal HGP x FPI) increased with rising BMI (r = 0.52, P < 0.0001). During the insulin clamp, glucose disposal declined with increasing BMI (r = -0.64, P < 0.0001) and correlated with the basal glucose clearance (r = 0.39, P < 0.0001). CONCLUSIONS: These results demonstrate that in nondiabetic subjects, rising FPG is associated with a decrease (not an increase) in basal hepatic glucose production and is explained by a reduction in glucose clearance.

Pharmacokinetics and pharmacodynamics of glimepiride in type 2 diabetic patients: compared effects of once- versus twice-daily dosing.

To compare the pharmacokinetic and pharmacodynamic effects of glimepiride between once- and twice-daily dosing in type 2 diabetic patients. Eight Japanese type 2 diabetic patients, who had been treated with 2 mg glimepiride alone over 4 weeks (age 40-70, body mass index

[Availability of drug information on bioequivalence of generic products--findings of graduate interns at a university pharmacy].

Access to drug information (DI) needed to evaluate generic product bioequivalence was studied to identify problems with the current status of DI availability and encourage proper use of DI. Ten items were chosen from among the stock of branded products at the University Pharmacy, and five corresponding generics were selected for each item. Conditions of access to information on pharmacokinetic tests and dissolution tests were rated and the assigned ratings compared. In the case of pharmacokinetic parameters obtainable from makers of generic drugs, we also performed Welch's t-test to compare the difference between values reported for branded and generic products. From the standpoint of individual tests, the pharmacokinetic tests yielded higher scores on the whole than did the dissolution tests, and low scores were obtained for the half-life of blood drug concentration (T1/2). We observed a tendency for the adequacy of information to depend more upon the drug item itself than upon the nature of the test. The percentage of tests allowing for comparison with branded products varied from 0%-75% (average 49%). Parameter by parameter, the range of variation was from 35% of Tmax to 63% of Cmax. Factors precluding comparison included insufficient data on branded products, mismatch in assayed chemical species between branded and generic, mismatch between final sampling time in AUC(t) measurement, dosage inconsistency, and insufficient data on generic products. DI should be provided in a manner that facilitates comparison of information supplied by generic drug makers with data released by makers of branded products.

Analysis of waist circumference in Japanese subjects with type 2 diabetes mellitus: lack of propriety to define the current criteria of metabolic syndrome.

A necessary condition of advocated criteria to determine the metabolic syndrome (MetS) in Japan is waist circumference (WC), which varies among races. In this study, we measured WC and visceral fat area (VFA) in subjects with type 2 diabetes (T2DM) and assessed the propriety of new criteria of MetS in Japan. Four hundred and nineteen patients (M/F: 258/161, age: 60.4+/-0.7 years, BMI: 24.4+/-0.2 kg/m(2)) who received abdominal CT examination were analyzed, and 178 (M/F: 111/67) subjects sufficed the criteria of MetS. Average VFA was significantly larger in subjects with MetS (162+/-3 cm(2) versus 82+/-3 cm(2), p<0.01). The WC and VFA were correlated significantly in both male (r=0.78, p<0.001) and female (r=0.82, p<0.001), and corresponding VFA at 85 cm of WC in male and at 90 cm in female were 125 cm(2) and 120 cm(2). Incidence of cardio- and cerebro-vascular diseases (CVD) was not different between subjects with and without MetS. The present cross-sectional study strongly suggests that the recommended WC is not suitable to define the current criteria of MetS (VFA, > or =100 cm(2)) and its criteria is not appropriate to segregate a risk of CVD in Japanese T2DM subjects. Further prospective analysis should be required to validate the criteria and clinical significance of MetS in T2DM.

Nateglinide and mitiglinide, but not sulfonylureas, induce insulin secretion through a mechanism mediated by calcium release from endoplasmic reticulum.

Nateglinide and mitiglinide (glinides) are characterized as rapid-onset and short-acting insulinotropic agents. Although both compounds do not have a sulfonylurea structure, it has been postulated that insulin secretion is preceded by their binding to Kir6.2/SUR1 complex, and a mechanism of insulin secretion of glinides has been accounted for by this pathway. However, we hypothesized the involvement of additional mechanisms of insulin secretion enhanced by glinides, and we analyzed the pattern of time course of insulin secretion from MIN6 cells with the existence of agents that have specific pharmacologic actions. Dose-dependent effects of tolbutamide, glibenclamide, nateglinide, and mitiglinide were observed. Insulin secretion induced by 3 microM tolbutamide and 1 nM glibenclamide was completely inhibited by 10 microM diazoxide and 3 microM verapamil, although the latter half-component of insulin secretion profile induced by 3 microM nateglinide or 30 nM mitiglinide remained with the existence of those agents. Glinides enhanced insulin secretion even in Ca2+-depleted medium, and its pattern of secretion was same as the pattern with existence of verapamil. The latter half was suppressed by 1 microM dantrolene, and concomitant addition of verapamil and dantrolene completely suppressed the entire pattern of insulin secretion enhanced by nateglinide. Thus, we conclude that glinide action is demonstrated through two pathways, dependently and independently, from the pathway through K(ATP) channels. We also demonstrated that the latter pathway involves the intracellular calcium release from endoplasmic reticulum via ryanodine receptor activation.

Thiazolidinediones improve beta-cell function in type 2 diabetic patients.

Thiazolidinediones (TZDs) improve glycemic control and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). There is growing evidence from in vivo and in vitro studies that TZDs improve pancreatic beta-cell function. The aim of this study was to determine whether TZD-induced improvement in glycemic control is associated with improved beta-cell function. We studied 11 normal glucose-tolerant and 53 T2DM subjects [age 53+/-2 yr; BMI 29.4+/-0.8 kg/m2; fasting plasma glucose (FPG) 10.3+/-0.4 mM; Hb A1c 8.2+/-0.3%]. Diabetic patients were randomized to receive placebo or TZD for 4 mo. Subjects received 1) 2-h OGTT with determination of plasma glucose, insulin, and C-peptide concentrations and 2) two-step euglycemic insulin (40 and 160 mU.m-2.min-1) clamp with [3-(3)H]glucose. T2DM patients were then randomized to receive 4 mo of treatment with pioglitazone (45 mg/day), rosiglitazone (8 mg/day), or placebo. Pioglitazone and rosiglitazone similarly improved FPG, mean plasma glucose during OGTT, Hb A1c, and insulin-mediated total body glucose disposal (Rd) and decreased mean plasma FFA during OGTT (all P<0.01, ANOVA). The insulin secretion/insulin resistance (disposition) index [DeltaISR(AUC)/Deltaglucose(AUC)/IR] was significantly improved in all TZD-treated groups: +1.8+/-0.7 (PIO+drug-naïve diabetics), +0.7+/-0.3 (PIO+sulfonylurea-treated diabetics), and 0.7+/-0.2 (ROSI+sulfonylurea-withdrawn diabetics) vs. -0.2+/-0.3 in the two placebo groups (P<0.01, all TZDs vs. placebo, ANOVA). Improved insulin secretion correlated positively with increased body weight, fat mass, and Rd and inversely with decreased plasma glucose and FFA during the OGTT. In T2DM patients, TZD treatment leads to improved beta-cell function, which correlates strongly with improved glycemic control.

Muscle and liver insulin resistance indexes derived from the oral glucose tolerance test.

OBJECTIVE: To derive indexes for muscle and hepatic insulin sensitivity from the measurement of plasma glucose and insulin concentrations during an oral glucose tolerance test (OGTT). RESEARCH DESIGN AND METHODS: A total of 155 subjects of Mexican-American origin (58 male and 97 female, aged 18-70 years, BMI 20-65 kg/m(2)) with normal glucose tolerance (n = 100) or impaired glucose tolerance (n = 55) were studied. Each subject received a 75-g OGTT and a euglycemic insulin clamp in combination with tritiated glucose. The OGTT-derived indexes of muscle and hepatic insulin sensitivity were compared with hepatic and muscle insulin sensitivity, which was directly measured with the insulin clamp, by correlation analysis. RESULTS: The product of total area under curve (AUC) for glucose and insulin during the first 30 min of the OGTT (glucose(0-30)[AUC] x insulin(0-30)[AUC]) strongly correlated with the hepatic insulin resistance index (fasting plasma insulin x basal endogenous glucose production) (r = 0.64, P < 0.0001). The rate of decay of plasma glucose concentration from its peak value to its nadir during the OGTT divided by the mean plasma insulin concentration (dG/dt / I) strongly correlated with muscle insulin sensitivity measured with the insulin clamp (P = 0.78, P < 0.0001). CONCLUSIONS: Novel estimates for hepatic and muscle insulin resistance from OGTT data are presented for quantitation of insulin sensitivity in nondiabetic subjects.

First phase of glucose-stimulated insulin secretion from MIN 6 cells does not always require extracellular calcium influx.

To demonstrate an involvement of ATP-sensitive potassium (K(ATP)) channel-independent pathways in the first phase of glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells, the time course of GSIS from MIN6 cells was analyzed at 30-s sample intervals. GSIS was biphasic with the first phase being observed 120 to 390 s after glucose addition, peaking at 180 s, and with a shoulder at 240 to 330 s. Both 10 microM diazoxide and 3 microM verapamil completely inhibited tolbutamide- or glibenclamide-induced insulin secretion and suppressed the peak of the first phase of GSIS, but did not result in complete suppression. The shoulder following the peak was suppressed by 1 muM dantrolene. The peak, but not shoulder, disappeared under the extracellular Ca2+-free condition. A significant amount of insulin secretion remained even in the combined presence of verapamil and dantrolene. The Na+ channel blocker tetrodotoxin (30 nM) nearly completely inhibited the first phase release. These results suggest that the first phase of GSIS from MIN6 cells depends on both Ca2+-dependent and -independent mechanisms. The former mechanism includes the extracellular Ca2+ influx via L-type voltage-dependent calcium channel and intracellular Ca2+ release from endoplasmic reticulum via ryanodine receptors, and the latter mechanism involves the pathways associated with Na+ channels.

Plasma lipid levels and nutritional intake in childhood- and adolescence-onset young type 1 diabetic patients in Japan.

In recent years, the diet of the young Japanese has changed to westernized diet with high fat content. Childhood-onset type 1 diabetic patients have had good diet training since onset of the disease, but adolescence-onset type 1 diabetic patients have already established westernized diet habit at onset of the disease, which may not be easily improved. We hypothesized that a difference of the age at onset of the disease may affect nutritional status and plasma lipid levels in Japanese type 1 diabetic patients. Plasma lipid levels and nutritional intake were compared between childhood- and adolescence-onset young type 1 diabetic patients. Our research involved 9 childhood-onset type 1 diabetic patients (childhood group), 11 adolescence-onset type 1 diabetic patients (adolescent group), and 24 age-matched non-diabetic control subjects. There were no significant differences in age and body mass index (BMI), daily energy intake among the childhood group, the adolescent group, and the non-diabetic control group. There was no significant difference in HbA1c level between the childhood group and the adolescent group. The adolescent group had significantly higher plasma levels of total cholesterol, triglyceride, and low-density lipoprotein (LDL)-cholesterol than the childhood group (p<0.01, <0.05, and <0.001, respectively) or the control group (p<0.001, <0.001, and <00.001, respectively). The adolescent group had significantly lower plasma level of high-density lipoprotein (HDL)-cholesterol than the childhood group (p<0.05). The adolescent group had significantly higher percentage energy intake from fat (31.7%, p<0.001), higher saturated fatty acids intake (19.0g/day, p<0.01), and higher cholesterol intake (428mg/day, p<0.05), and significantly lower polyunsaturated fatty acids intake (13.4g/day, p<0.05) and lower fiber intake (9.5g/day, p<0.01) than the childhood group. It is concluded that young Japanese type 1 diabetic patients with onset of adolescence have lipid abnormalities, which may be mainly caused by westernized dietary habits.