Long-term follow-up study of the efficacy of fosravuconazole in the treatment of onychomycosis in elderly patients.

Onychomycosis is a chronic and intractable disease whose prevalence increases during aging. In elderly patients, if onychomycosis is left untreated and progresses to a severe stage it may cause functional decline of the lower limbs due to foot pain. This could lead to a decline in activities of daily living and secondary impairment such as cognitive decline. Thus, the treatment of onychomycosis in elderly patients is important. We have previously shown that fosravuconazole is relatively safe and effective for onychomycosis in elderly patients. In the present study, we continued the follow-up study and investigated the efficacy of re-administration of fosravuconazole in patients with recurrent onychomycosis. One hundred and twenty-five patients aged ≥65 years who had been initially diagnosed with onychomycosis at our hospital's dermatology department, and who had responded well to fosravuconazole at 48 weeks after the initial treatment, were followed up until 144 weeks after the start of the initial treatment. Patients who experienced a recurrence within 24 weeks after the start of the follow-up were assigned to the short-term recurrence group, and those who experienced a recurrence after 24 weeks were assigned to the long-term recurrence group. All patients in both groups were re-treated with fosravuconazole to evaluate its efficacy. The short-term and long-term recurrence groups consisted of 17 (14.3%) and 10 (8.4%) patients, respectively. There were no significant differences in mean age and sex ratio between the two groups. There were no serious adverse effects in either group, and the toenail opacity ratio was significantly reduced after 12 weeks of re-treatment in both groups. The short-term and long-term recurrence groups were significantly more likely to have wedge-shaped onychomycosis and total dystrophic onychomycosis, respectively. The results suggest that re-administration of fosravuconazole is safe and as effective as the first administration for elderly patients with recurrent onychomycosis. This study was registered at UMIN-CTR (UMIN000053516).

Moon-forming impactor as a source of Earth's basal mantle anomalies.

Seismic images of Earth's interior have revealed two continent-sized anomalies with low seismic velocities, known as the large low-velocity provinces (LLVPs), in the lowermost mantle1. The LLVPs are often interpreted as intrinsically dense heterogeneities that are compositionally distinct from the surrounding mantle2. Here we show that LLVPs may represent buried relics of Theia mantle material (TMM) that was preserved in proto-Earth's mantle after the Moon-forming giant impact3. Our canonical giant-impact simulations show that a fraction of Theia's mantle could have been delivered to proto-Earth's solid lower mantle. We find that TMM is intrinsically 2.0-3.5% denser than proto-Earth's mantle based on models of Theia's mantle and the observed higher FeO content of the Moon. Our mantle convection models show that dense TMM blobs with a size of tens of kilometres after the impact can later sink and accumulate into LLVP-like thermochemical piles atop Earth's core and survive to the present day. The LLVPs may, thus, be a natural consequence of the Moon-forming giant impact. Because giant impacts are common at the end stages of planet accretion, similar mantle heterogeneities caused by impacts may also exist in the interiors of other planetary bodies.

A wet heterogeneous mantle creates a habitable world in the Hadean.

The Hadean eon, following the global-scale melting of the mantle1-3, is expected to be a dynamic period, during which Earth experienced vastly different conditions. Geologic records, however, suggest that the surface environment of Earth was already similar to the present by the middle of the Hadean4,5. Under what conditions a harsh surface environment could turn into a habitable one remains uncertain6. Here we show that a hydrated mantle with small-scale chemical heterogeneity, created as a result of magma ocean solidification, is the key to ocean formation, the onset of plate tectonics and the rapid removal of greenhouse gases, which are all essential to create a habitable environment on terrestrial planets. When the mantle is wet and dominated by high-magnesium pyroxenites, the removal of carbon dioxide from the atmosphere is expected to be more than ten times faster than the case of a pyrolitic homogeneous mantle and could be completed within  160 million years. Such a chemically heterogeneous mantle would also produce oceanic crust rich in olivine, which is reactive with ocean water and promotes serpentinization. Therefore, conditions similar to the Lost City hydrothermal field7-9 may have existed globally in the Hadean seafloor.

Inefficient Water Degassing Inhibits Ocean Formation on Rocky Planets: An Insight from Self-Consistent Mantle Degassing Models.

A sufficient amount of water is required at the surface to develop water oceans. A significant fraction of water, however, remains in the mantle during magma ocean solidification, and thus the existence of water oceans is not guaranteed even for exoplanets located in the habitable zone. To discuss the likelihood of ocean formation, we built two models to predict the rate of mantle degassing during the magma ocean stage and the subsequent solid-state convection stage. We find that planets with low H2O/CO2 ratios would not have a sufficient amount of surface water to develop water oceans immediately after magma ocean solidification, and the majority of the water inventory would be retained in the mantle during their subsequent evolution regardless of planetary size. This is because oceanless planets are likely to operate under stagnant lid convection, and for such planets, dehydration stiffening of the depleted lithospheric mantle would limit the rate of mantle degassing. In contrast, a significant fraction of CO2 would already be degassed during magma ocean solidification. With a strong greenhouse effect, all surface water would exist as vapor, and water oceans may be absent throughout planetary evolution. Volatile concentrations in the bulk silicate Earth are close to the threshold amount for ocean formation, so if Venus shared similar concentrations, small differences in solar radiation may explain the divergent evolutionary paths of Earth and Venus.

Visceral fat dominant distribution in male type 2 diabetic patients is closely related to hepatic insulin resistance, irrespective of body type.

BACKGROUND: All previous studies that investigated the association between abdominal fat distribution and insulin resistance evaluated subcutaneous and visceral fat area and/or volume, but these values were not related to the body type of each subject. In the present study we have examined the association between abdominal fat distribution and peripheral (muscle)/hepatic sensitivity to insulin using the visceral to abdominal subcutaneous fat area ratio (VF/SF ratio) in male patients with type 2 diabetes mellitus. This ratio defines the predominancy of visceral or subcutaneous abdominal adiposity, independent of the body type of each individual. METHODS: Thirty-six type 2 diabetic male patients underwent a euglycemic insulin clamp (insulin infusion rate = 40 mU/m2 x min) with 3-3H-glucose to measure insulin-mediated total body (primarily reflects muscle) glucose disposal (TGD) and suppression of endogenous (primarily reflects liver) glucose production (EGP) in response to a physiologic increase in plasma insulin concentration. Abdominal subcutaneous (SF) and intraabdominal visceral fat (VF) areas were quantitated with magnetic resonance imaging (MRI) at the level of L4-5. RESULTS: TGD and TGD divided by steady state plasma insulin concentration during the insulin clamp (TGD/SSPI) correlated inversely with body mass index (BMI), total fat mass (FM) measured by 3H2O, SF and VF areas, while VF/SF ratio displayed no significant relationship with TGD or TGD/SSPI. In contrast, EGP and the product of EGP and SSPI during the insulin clamp (an index hepatic insulin resistance) correlated positively with VF/SF ratio, but not with BMI, FM, VF or SF. CONCLUSION: We conclude that, independent of the individual's body type, visceral fat dominant accumulation as opposed to subcutaneous fat accumulation is associated with hepatic insulin resistance, whereas peripheral (muscle) insulin resistance is more closely related to general obesity (i.e. higher BMI and total FM, and increased abdominal SF and VF) in male patients with type 2 diabetes.

Effects of angiotensin II receptor blockade on glucose metabolism via AMP-activated protein kinase in insulin-resistant hypertensive rats.

AMP-activated protein kinase (AMPK) mediates metabolic responses of muscle to exercise and is involved in improvement of insulin resistance by endurance exercise. Recent studies have suggested that the renin-angiotensin system (RAS) might negatively modulate insulin-mediated actions, but there has been little investigation of the correlation between RAS and AMPK. To determine the correlations between insulin resistance, the RAS, and AMPK, we performed glucose clamp studies using both insulin and 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR) to investigate the effects of various hypotonics on insulin and AMPK sensitivities. Six-week-old male Sprague-Dawley rats were divided into two groups: those fed a standard chow (SD) and those fed a fructose-rich chow (fructose-fed rats [FFRs]) for 6 weeks. FFRs were treated either with a vehicle or with valsartan or hydralazine for the last 2 weeks. We also performed Western blotting for AMPK, phospho-AMPK, and stimulating glucose transporter (GLUT)-4 proteins in each group. The glucose infusion rate for insulin (GIR(I)) was significantly lower in FFRs (10.5 +/- 1.8 mg/kg/min) than in SD (15.5 +/- 0.4 mg/kg/min), and GIR(I) was improved by valsartan (13.0 +/- 1.0 mg/kg/min) but not by hydralazine (8.3 +/- 1.6 mg/kg/min). The glucose infusion rate for AICAR (GIR(A)) in FFRs (11.1 +/- 2.2 mg/kg/min) was significantly lower than that in SD (15.5 +/- 2.8 mg/kg/min), and GIR(A) was improved by valsartan (17.5 +/- 3.1 mg/kg/min) but not by hydralazine in FFRs (11.8 +/- 1.5 mg/kg/min). Serum triglyceride level was significantly higher in FFRs; however, no difference was observed in serum triglyceride level after AICAR infusion among the groups. The amounts of AMPKalpha protein and the amounts of phospho-AMPK protein in the soleus muscle in basal conditions were not different among SD, FFRs, and FFRs treated with valsartan. There was no difference in the levels of phosphorylation of AMPK in the soleus muscle by AICAR among these three groups. No difference was observed in acetyl-CoA carboxylase (ACC) protein or phospho-ACC in both the basal condition and after AICAR infusion between SD and FFRs. Treatment with valsartan significantly increased GLUT-4 content of the soleus muscle compared with that in FFRs. These results suggest that the RAS has a significant role in the AMPK system and that impairment of response to AICAR in FFRs could be downstream of AMPK or ACC phosphorylation.

Differences in insulin action and secretion, plasma lipids and blood pressure levels between impaired fasting glucose and impaired glucose tolerance in Japanese subjects.

We examined insulin action/secretion and cardiovascular disease risk factors in Japanese subjects with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) who were not taking any medications known to affect glucose tolerance, blood pressure (BP) or plasma lipids (PLs). A total of 1,399 subjects received measurements of anthropometry, BP, PLs, and plasma glucose/insulin concentrations during 75 g-oral glucose tolerance test (OGTT). According to 2003 American Diabetes Association criteria, subjects were classified as having normal fasting glucose (NFG)/normal glucose tolerance (NGT) (n = 1,173), IFG (n = 128), IGT (n = 55), and IFG/IGT (n = 43). Insulin action was calculated using the HOMA-R (index of hepatic insulin resistance) and Matsuda index (reflects whole body insulin sensitivity). The ratio of the incremental area under the curve of insulin to that of glucose during OGTT (delta AUC(PI)/delta AUC(PG)) was used as an index of beta-cell function. HOMA-R was higher in IFG (2.3 +/- 0.1) and IFG/IGT (2.5 +/- 0.2) than in NFG/NGT (1.8 +/- 0.03). The Matsuda index was lower in IFG (6.5 +/- 0.3), IGT (5.4 +/- 0.4) and IFG/IGT (5.1 +/- 0.5) than in NFG/NGT (9.6 +/- 0.2). Delta AUC(PI)/delta AUC(PG) was lower in IGT (0.6 +/- 0.05) and IFG/IGT (0.5 +/- 0.05) than in IFG (1.4 +/- 0.12) or NFG/NGT (1.2 +/- 0.03). Mean BP was higher in IGT (100 +/- 1.7 mmHg) than in NFG/NGT (91 +/- 0.3) or IFG (95 +/- 1.1). The plasma triglyceride level was higher in IGT (155 +/- 14 mg/dL) and IGT/IFG (173 +/- 12) than in IFG (132 +/- 7) or NFG/NGT (122 +/- 2). In conclusion, 1) whole body insulin sensitivity is decreased in IFG and IGT, with a greater reduction in IGT, 2) hepatic insulin resistance and preserved beta-cell function are characteristics of IFG, and 3) higher BP and triglyceride levels are observed in IGT. IGT is more closely associated with risk factors for cardiovascular disease than is IFG.

Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects.

BACKGROUND AND AIMS: Abdominal fat accumulation (visceral/hepatic) has been associated with hepatic insulin resistance (IR) in obesity and type 2 diabetes (T2DM). We examined the relationship between visceral/hepatic fat accumulation and hepatic IR/accelerated gluconeogenesis (GNG). METHODS: In 14 normal glucose tolerant (NGT) (body mass index [BMI] = 25 +/- 1 kg/m(2)) and 43 T2DM (24 nonobese, BMI = 26 +/- 1; 19 obese, BMI = 32 +/- 1 kg/m(2)) subjects, we measured endogenous (hepatic) glucose production (3-(3)H-glucose) and GNG ((2)H(2)O) in the basal state and during 240 pmol/m(2)/min euglycemic-hyperinsulinemic clamp, and liver (LF) subcutaneous (SAT)/visceral (VAT) fat content by magnetic resonance spectroscopy/magnetic resonance imaging. RESULTS: LF was increased in lean T2DM compared with lean NGT (18% +/- 3% vs 9% +/- 2%, P < .03), but was similar in lean T2DM and obese T2DM (18% +/- 3% vs 22% +/- 3%; P = NS). Both VAT and SAT increased progressively from lean NGT to lean T2DM to obese T2DM. T2DM had increased basal endogenous glucose production (EGP) (NGT, 15.1 +/- 0.5; lean T2DM, 16.3 +/- 0.4; obese T2DM, 17.2 +/- 0.6 micromol/min/kg(ffm); P = .02) and basal GNG flux (NGT, 8.6 +/- 0.4; lean T2DM, 9.6 +/- 0.4; obese T2DM, 11.1 +/- 0.6 micromol/min/kg(ffm); P = .02). Basal hepatic IR index (EGP x fasting plasma insulin) was increased in T2DM (NGT, 816 +/- 54; lean T2DM, 1252 +/- 164; obese T2DM, 1810 +/- 210; P = .007). In T2DM, after accounting for age, sex, and BMI, both LF and VAT, but not SAT, were correlated significantly (P < .05) with basal hepatic IR and residual EGP during insulin clamp. Basal percentage of GNG and GNG flux were correlated positively with VAT (P < .05), but not with LF. LF, but not VAT, was correlated with fasting insulin, insulin-stimulated glucose disposal, and impaired FFA suppression by insulin (all P < .05). CONCLUSIONS: Abdominal adiposity significantly affects both lipid (FFA) and glucose metabolism. Excess VAT primarily increases GNG flux. Both VAT and LF are associated with hepatic IR.

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.

Angiotensin II inhibits glucose uptake of skeletal muscle via the adenosine monophosphate-activated protein kinase pathway.

Adenosine monophosphate-activated protein kinase (AMPK) mediates metabolic responses of muscle to exercise and is involved in improvement of insulin resistance by endurance exercise. Recent studies have suggested that the renin-angiotensin system might negatively modulate insulin-mediated actions, but there has been little investigation of the correlation between the renin-angiotensin system and AMPK. To determine this correlation, we performed studies with glucose clamp in vivo, and glucose uptake by skeletal muscle ex vivo using 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR). Six-week-old male Sprague-Dawley rats were fed standard chow (standard-diet rats; SD) or fructose-rich chow (fructose-fed rats; FFR) for 6 weeks. At the age of 12 weeks, SD and FFR were treated by oral gavage, either with angiotensin II (Ang II) receptor blockade (ARB; valsartan 30 mg/kg) or vehicle. Thirty minutes after the treatment, we performed glucose clamp studies to measure glucose infusion rates during infusion of insulin (GIR(I)) and of AICAR (GIR(A)), which stimulates AMPK, and studied the effect of ARB on either GIR(I) or GIR(A). In an ex vivo study, we used bilateral fresh soleus muscles from 3-week-old male Sprague-Dawley rats to examine the glucose uptake (measured by (3)H-2-deoxyglucose uptake) of one side of soleus muscle incubated with AICAR with or without Ang II, or with tumor necrosis factor-alpha, in comparison with that of the other (untreated control) side of the muscle. Blood pressure of FFR was significantly higher than that of SD rats. GIR(I) was significantly lower in FFR than in SD, and treatment with ARB did not change GIR(I). GIR(A) of FFR was significantly lower than that of SD, but GIR(A) of FFR treated with ARB was significantly increased compared with that of FFR treated with vehicle. In the ex vivo study, incubation with AICAR significantly increased glucose uptake of soleus muscles, Ang II significantly decreased AICAR-activated glucose uptake in a dose-dependent manner, and ARB canceled the effect of Ang II. The results suggest that acute inhibition of the angiotensin 1 receptor improves glucose metabolism via not insulin but AMPK pathway through the angiotensin 1 receptor in FFR.

The effect of pioglitazone on the liver: role of adiponectin.

OBJECTIVE: Diabetic hyperglycemia results from insulin resistance of peripheral tissues and glucose overproduction due to increased gluconeogenesis (GNG). Thiazolidinediones (TZDs) improve peripheral insulin sensitivity, but the effect on the liver is less clear. The goal of this study was to examine the effect of TZDs on GNG. RESEARCH DESIGN AND METHODS: Twenty sulfonylurea-treated type 2 diabetic subjects were randomly assigned (double-blind study) to receive pioglitazone (PIO group; 45 mg/day) or placebo (Plc group) for 4 months to assess endogenous glucose production (EGP) (3-(3)H-glucose infusion), GNG (D2O technique), and insulin sensitivity by two-step hyperinsulinemic-euglycemic clamp (240 and 960 pmol/min per m2). RESULTS: Fasting plasma glucose (FPG) (10.0 +/- 0.8 to 7.7 +/- 0.7 mmol/l) and HbA1c (9.0 +/- 0.4 to 7.3 +/- 0.6%) decreased in the PIO and increased in Plc group (P < 0.05 PIO vs. Plc). Insulin sensitivity increased approximately 40% during high insulin clamp after pioglitazone (P < 0.01) and remained unchanged in the Plc group (P < 0.05 PIO vs. Plc). EGP did not change, while GNG decreased in the PIO group (9.6 +/- 0.7 to 8.7 +/- 0.6 micromol x min(-1) x kg(ffm)(-1)) and increased in the Plc group (8.0 +/- 0.5 to 9.6 +/- 0.8) (P < 0.05 PIO vs. Plc). Change in FPG correlated with change in GNG flux (r = 0.63, P < 0.003) and in insulin sensitivity (r = 0.59, P < 0.01). Plasma adiponectin increased after pioglitazone (P < 0.001) and correlated with delta FPG (r = -0.54, P < 0.03), delta GNG flux (r = -0.47, P < 0.05), and delta insulin sensitivity (r = 0.65, P < 0.005). Plasma free fatty acids decreased after pioglitazone and correlated with delta GNG flux (r = 0.54, P < 0.02). From stepwise regression analysis, the strongest determinant of change in FPG was change in GNG flux. CONCLUSIONS: Pioglitazone improves FPG, primarily by reducing GNG flux in type 2 diabetic subjects.

The effect of rosiglitazone on the liver: decreased gluconeogenesis in patients with type 2 diabetes.

AIMS/HYPOTHESIS: Diabetic hyperglycemia results from insulin resistance of peripheral tissues and glucose overproduction due to increased gluconeogenesis (GNG). Thiazolidinediones have been shown to improve glycemic control and increase peripheral insulin sensitivity. Whether chronic thiazolidinedione treatment is associated with a decrease in GNG has not been determined. MATERIALS AND METHODS: We studied 26 diet-treated type 2 diabetic patients randomly assigned to rosiglitazone (RSG; 8 mg/d; n = 13) or placebo (n = 13) for 12 wk. At baseline and 12 wk, we measured endogenous glucose production (by [3H]glucose infusion) and GNG (by the [2H]2O technique) after a 15-h fast. Peripheral insulin sensitivity was evaluated by a two-step (240 and 960 pmol/min/m(-2)) euglycemic insulin clamp. RESULTS: Compared with placebo, RSG reduced fasting plasma glucose (9.7 +/- 0.7 to 7.4 +/- 0.3 mmol/liter; P < 0.001), fasting fractional GNG (-15 +/- 4%; P = 0.002), and fasting GNG flux (-3.9 +/- 1.2 micromol/min/kg fat-free mass; P = 0.004), with no effect on glycogenolytic flux. Changes in GNG flux and fasting glucose were tightly correlated (r = 0.83; P < 0.0001). During both clamp steps, RSG enhanced insulin-mediated glucose clearance (by 26% and 31%; P = 0.01 and P < 0.02, respectively). In a subgroup of patients studied with magnetic resonance imaging, the reduction in GNG flux was correlated (r = 0.65; P < 0.02) with the reduction in visceral fat area. CONCLUSION/INTERPRETATION: RSG increases peripheral tissue insulin sensitivity and decreases endogenous glucose release via an inhibition of gluconeogenesis.

Low adiponectin level in young normotensive men with a family history of essential hypertension.

Circulating level of adiponectin, an adipocyte-derived protein, is reduced in states of insulin resistance such as obesity and type 2 diabetes. We have previously shown that hypoadiponectinemia is related to insulin resistance in essential hypertension. Recent studies have shown that normotensive subjects with a positive family history of essential hypertension (FH+) have decreased insulin sensitivity compared to subjects with a negative family history of essential hypertension (FH-). We here examined the association between adiponectin concentration and insulin sensitivity in FH+ and FH-. Thirty young, non-obese and normotensive men without a family history of diabetes mellitus were enrolled. A total of 15 subjects were FH+, and the remaining 15 subjects were FH-. Insulin sensitivity index (ISI) was evaluated by the euglycemic hyperinsulinemic glucose clamp technique. Concentrations of adiponectin and other metabolic variables were measured. The FH+ group had significantly lower levels of ISI and adiponectin than did the FH- group. In all of the subjects, ISI was positively correlated with adiponectin concentration and high-density lipoprotein (HDL) cholesterol level and was negatively correlated with insulin level. Adiponectin concentration was the only independent determinant of ISI in a multiple regression analysis. Our results showed that adiponectin level was significantly decreased and that this was accompanied by reduced insulin sensitivity in young, nonobese and normotensive men with a family history of essential hypertension. Phenotype of reduced adiponectin level as an earlier penetrance may be especially useful in genetic analyses of insulin resistance and essential hypertension.

beta-Cell function in subjects spanning the range from normal glucose tolerance to overt diabetes: a new analysis.

The nature of the progressive beta-cell failure occurring as normal glucose tolerant (NGT) individuals progress to type 2 diabetes (T2DM) is incompletely understood. We measured insulin sensitivity (by a euglycemic insulin clamp) and insulin secretion rate (by deconvolution of plasma C-peptide levels during an oral glucose tolerance test) in 188 subjects [19 lean NGT (body mass index [BMI]

Dose-response effect of a single administration of oral hexyl-insulin monoconjugate 2 in healthy nondiabetic subjects.

OBJECTIVE: 1) To evaluate the effect of a single oral dose of hexyl-insulin monoconjugate 2 (HIM2) on the rate of whole-body glucose disposal (Rd) and endogenous glucose production (EGP) in healthy nondiabetic subjects, 2) to examine the reproducibility of HIM2 on glucose metabolism, and 3) to compare the results obtained with HIM2 with those using a bioequivalent dose of subcutaneous lispro insulin. RESEARCH DESIGN AND METHODS: Six healthy subjects ([means +/- SE] aged 31 +/- 5 years and BMI 23.1 +/- 3.9 kg/m2) participated in four studies performed in random order on separate days. Subjects ingested a single dose of HIM2 (0.125, 0.5, and 0.75 mg/kg) or received subcutaneous lispro insulin (0.1 units/kg). Studies were performed with [3-3H]glucose, and plasma glucose concentration was maintained at basal levels for 4 h with the euglycemic clamp technique. After 6 weeks, subjects participated in two repeat studies to examine the reproducibility of HIM2 (0.5 mg/kg) and lispro insulin (0.1 units/kg). RESULTS: Fasting plasma insulin (7 muU/ml) increased to a maximum of 102, 321, and 561 muU/ml at 60 min after all three HIM2 doses (0.125, 0.5, and 0.75 mg/kg, respectively). A dose-related decrease in basal EGP was observed as the HIM2 dosage was increased from 0 to 0.125 to 0.5 mg/kg (P <0.05 vs. each preceding dose). Suppression of EGP was similar with the 0.5- and 0.75-mg/kg HIM2 doses. A dose-related stimulation of basal Rd was observed as the HIM2 dosage was increased from 0 to 0.125 to 0.5 (P <0.05 vs. each preceding dose) to 0.75 mg/kg (P <0.10 vs. preceding dose). Rd (0-240 min) was increased by 0.5 mg/kg oral HIM2 to a value similar to 0.1 units/kg lispro insulin. The 0.125-mg/kg HIM2 dose reduced EGP (0-240 min) to a value that was similar to 0.1 units/kg lispro insulin. The variability in the effect of HIM2 and lispro on Rd (25 +/- 7 vs. 27 +/- 1%, respectively) and on suppression of EGP (19 +/- 1 vs. 19 +/- 0.7%, respectively) was similar. CONCLUSIONS: Oral HIM2 suppresses EGP and increases tissue Rd in a dose-dependent manner. The effects of HIM2 on EGP and Rd persisted at 240 min, even though plasma insulin concentration had returned to basal levels. Oral HIM2 may provide an effective and reproducible means of controlling postprandial plasma glucose excursions in diabetic patients.

Effect of pioglitazone on circulating adipocytokine levels and insulin sensitivity in type 2 diabetic patients.

We examined the effect of pioglitazone (PIO) on circulating adipocytokine levels to elucidate the mechanisms by which thiazolidinediones improve insulin resistance in type 2 diabetes mellitus (T2DM). Twenty-three subjects with T2DM (age 54 +/- 2 yr, body mass index 29 +/- 1 kg/m(2)) were randomly assigned to receive placebo (n = 11) or PIO, 45 mg/d (n = 12), for 4 months. Before and after treatment, subjects received a 75-g oral glucose tolerance test (OGTT); euglycemic insulin clamp (40 mU/m(2).min) with 3-(3)H-glucose; determination of fat mass ((3)H(2)O); and measurement of fasting glucose, free fatty acids (FFAs), leptin, adiponectin, and TNFalpha concentrations. After 4 months of PIO, fasting plasma glucose concentration (Delta = -2.7 mol/liter), mean plasma glucose during OGTT (Delta = -3.8 mol/liter), and hemoglobin A(1c) (Delta = 1.7%) decreased (P < 0.05 vs. placebo) without change in fasting or post-OGTT plasma insulin levels. Fasting FFAs (Delta = 168 micromol/liter) and TNFalpha (Delta = 0.7 pg/ml) concentrations decreased (P < 0.05 vs. placebo), whereas adiponectin (Delta = 8.7 microg/ml) increased (P < 0.01 vs. placebo). Despite the increase in body fat mass (Delta = 3.4 kg) after PIO, plasma leptin concentration did not change significantly. No changes in plasma glucose, FFAs, or adipocytokine levels were observed in placebo-treated subjects. During the insulin clamp, endogenous (hepatic) glucose production decreased (Delta = -2.67 micromol/fat-free mass.min, P < 0.05 vs. placebo), whereas metabolic clearance rate of glucose (MCR) increased (Delta = 0.58 ml/fat-free mass.min, P < 0.05 vs. placebo) after PIO. In all subjects, before and after PIO, the decrease in plasma FFA concentration was correlated with the changes in both endogenous (hepatic) glucose production (r = 0.47, P < 0.05) and MCR (r = -0.41, P < 0.05), whereas the increase in plasma adiponectin concentration was correlated with the change in endogenous (hepatic) glucose production (r = -0.70, P < 0.01) and MCR (r = 0.49, P < 0.05). These results suggest that the direct effects of PIO on adipose tissue to decrease plasma FFA levels and increase plasma adiponectin contribute to the improvements in hepatic and peripheral insulin sensitivity and glucose tolerance in patients with T2DM.

Separate contribution of diabetes, total fat mass, and fat topography to glucose production, gluconeogenesis, and glycogenolysis.

The contribution of increased gluconeogenesis (GNG) to the excessive rate of endogenous glucose production (EGP) in type 2 diabetes (T2DM) is well established. However, the separate effects of obesity (total body fat), visceral adiposity, and T2DM have not been investigated. We measured GNG (by the (2)H(2)O technique) and EGP (with 3-(3)H-glucose) after an overnight fast in 44 type 2 diabetic and 29 gender/ethnic-matched controls. Subjects were classified as obese (body mass index 30 kg/m(2) or greater) or nonobese (body mass index < 30 kg/m(2)); diabetic subjects were further subdivided according to the severity of fasting hyperglycemia [fasting plasma glucose (FPG) < 9 mm or >or= 9 mm]. EGP was similar in nondiabetic controls and T2DM with FPG less than 9 mm but was increased in T2DM with FPG >or= 9 mm (P < 0.001). Within the diabetic groups, obesity had an independent effect to further increase basal EGP (P < 0.01). In both nonobese diabetic groups, both the percent GNG and gluconeogenic flux were increased, compared with nonobese nondiabetic controls. In both diabetic groups, obesity further increased both percent GNG and gluconeogenic flux. In obese and nonobese T2DM, the increase in gluconeogenic flux was not accompanied by a reciprocal decrease in glycogenolysis, indicating a loss of hepatic autoregulation. By multivariate analysis, gluconeogenic flux was positively correlated with percent body fat, visceral fat, and the fasting plasma free fatty acid and glucose concentrations (all P

Decreased plasma adiponectin concentrations are closely related to hepatic fat content and hepatic insulin resistance in pioglitazone-treated type 2 diabetic patients.

The effect of pioglitazone (PIO) on plasma adiponectin concentration, endogenous glucose production (EGP), and hepatic fat content (HFC) was studied in 11 type 2 diabetic patients (age, 52 +/- 2 yr; body mass index, 29.6 +/- 1.1 kg/m(2); HbA(1c), 7.8 +/- 0.4%). HFC (magnetic resonance spectroscopy) and basal plasma adiponectin concentration were quantitated before and after PIO (45 mg/d) for 16 wk. Subjects received a 3-h euglycemic insulin (100 mU/m(2).min) clamp combined with 3-[(3)H] glucose infusion to determine rates of EGP and tissue glucose disappearance (Rd) before and after PIO. PIO reduced fasting plasma glucose (10.0 +/- 0.7 to 7.2 +/- 0.6 mmol/liter, P < 0.01) and HbA(1c) (7.8 +/- 0.4 to 6.5 +/- 0.3%, P < 0.01) despite increased body weight (83.0 +/- 3.0 to 86.4 +/- 3.0 kg, P < 0.01). PIO improved Rd (6.6 +/- 0.6 vs. 5.2 +/- 0.5 mg/kg.min, P < 0.005) and reduced EGP (0.23 +/- 0.04 to 0.05 +/- 0.02 mg/kg.min, P < 0.01) during the 3-h insulin clamp. After PIO treatment, HFC decreased from 21.3 +/- 4.2 to 11.0 +/- 2.4% (P < 0.01), and plasma adiponectin increased from 7 +/- 1 to 21 +/- 2 micro g/ml (P < 0.0001). Plasma adiponectin concentration correlated negatively with HFC (r = -0.60, P < 0.05) and EGP (r = -0.80, P < 0.004) and positively with Rd before (r = 0.68, P < 0.02) pioglitazone treatment; similar correlations were observed between plasma adiponectin levels and HFC (r = -0.65, P < 0.03) and Rd after (r = 0.70, P = 0.01) pioglitazone treatment. EGP was almost completely suppressed after pioglitazone treatment; taken collectively, plasma adiponectin concentration, before and after pioglitazone treatment, still correlated negatively with EGP during the insulin clamp (r = -0.65, P < 0.001). In conclusion, PIO treatment in type 2 diabetes causes a 3-fold increase in plasma adiponectin concentration. The increase in plasma adiponectin is strongly associated with a decrease in hepatic fat content and improvements in hepatic and peripheral insulin sensitivity. The increase in plasma adiponectin concentration after thiazolidinedione therapy may play an important role in reversing the abnormality in hepatic fat mobilization and the hepatic/muscle insulin resistance in patients with type 2 diabetes.

Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1.

Type 2 diabetes mellitus (DM) is characterized by insulin resistance and pancreatic beta cell dysfunction. In high-risk subjects, the earliest detectable abnormality is insulin resistance in skeletal muscle. Impaired insulin-mediated signaling, gene expression, glycogen synthesis, and accumulation of intramyocellular triglycerides have all been linked with insulin resistance, but no specific defect responsible for insulin resistance and DM has been identified in humans. To identify genes potentially important in the pathogenesis of DM, we analyzed gene expression in skeletal muscle from healthy metabolically characterized nondiabetic (family history negative and positive for DM) and diabetic Mexican-American subjects. We demonstrate that insulin resistance and DM associate with reduced expression of multiple nuclear respiratory factor-1 (NRF-1)-dependent genes encoding key enzymes in oxidative metabolism and mitochondrial function. Although NRF-1 expression is decreased only in diabetic subjects, expression of both PPAR gamma coactivator 1-alpha and-beta (PGC1-alpha/PPARGC1 and PGC1-beta/PERC), coactivators of NRF-1 and PPAR gamma-dependent transcription, is decreased in both diabetic subjects and family history-positive nondiabetic subjects. Decreased PGC1 expression may be responsible for decreased expression of NRF-dependent genes, leading to the metabolic disturbances characteristic of insulin resistance and DM.

Rosiglitazone improves downstream insulin receptor signaling in type 2 diabetic patients.

Thiazolidinediones (TZDs) improve glycemic control and insulin sensitivity in patients with type 2 diabetes. To determine whether the TZD-induced improvement in glycemic control is associated with enhanced insulin receptor signaling in skeletal muscle, 20 type 2 diabetic patients received a 75-g oral glucose tolerance test (OGTT) and euglycemic insulin (80 mU x m(-2) x min(-1)) clamp with [3-(3)H]glucose/indirect calorimetry/vastus lateralis muscle biopsies before and after 16 weeks of rosiglitazone treatment. Six age-matched nondiabetic subjects served as control subjects. RSG improved fasting plasma glucose (185 +/- 8 to 139 +/- 5 mg/dl), mean plasma glucose during the OGTT (290 +/- 9 to 225 +/- 6 mg/dl), HbA(1c) (8.5 +/- 0.3 to 7.1 +/- 0.3%), insulin-mediated total-body glucose disposal (TGD) (6.9 +/- 0.7 to 9.2 +/- 0.8 mg x kg(-1) fat-free mass x min(-1)) (all P < 0.001), and decreased fasting plasma free fatty acid (FFA) (789 +/- 59 to 656 +/- 50 micro Eq/l) and mean FFA during the OGTT (644 +/- 41 to 471 +/- 35 micro Eq/l) (both P < 0.01). Before RSG treatment, insulin infusion did not significantly increase insulin receptor tyrosine phosphorylation (0.95 +/- 0.10 to 1.08 +/- 0.13 density units; NS) but had a small stimulatory effect on insulin receptor substrate (IRS)-1 tyrosine phosphorylation (1.05 +/- 0.10 to 1.21 +/- 0.12 density units; P < 0.01) and the association of p85 with IRS-1 (0.94 +/- 0.06 to 1.08 +/- 0.06 activity units; P < 0.01). RSG therapy had no effect on basal or insulin-stimulated insulin receptor tyrosine phosphorylation but increased insulin stimulation of IRS-1 tyrosine phosphorylation (1.13 +/- 0.11 to 1.56 +/- 0.17 density units; P < 0.01 vs. prerosiglitazone) and p85 association with IRS-1 (1.00 +/- 0.06 to 1.27 +/- 0.07 activity units; P < 0.05 vs. prerosiglitazone). In control and type 2 diabetic subjects, TGD/nonoxidative glucose disposal correlated positively with the insulin-stimulated increments in IRS-1 tyrosine phosphorylation (r = 0.52/r = 0.57, P < 0.01) and inversely with the plasma FFA concentration during the insulin clamp (r = -0.55/r = -0.53, P < 0.01). However, no significant association between plasma FFA concentrations during the insulin clamp and the increment in either IRS-1 tyrosine phosphorylation or the association of p85 with IRS-1 was observed. In conclusion, in type 2 diabetic patients, rosiglitazone treatment enhances downstream insulin receptor signaling in muscle and decreases plasma FFA concentration while improving glycemic control.