Search

Aims: To investigate clusters of adipose tissue dysfunction, that is, with adipose tissue insulin resistance (ADIPO‐IR) and large waist circumference (WC), identify a worse lipidomic profile characterised by a high proportion of lipids rich in saturated fatty acids (SFA). Materials and Methods: Hierarchical clustering based on WC and ADIPO‐IR (calculated as fasting plasma non‐esterified fatty acids times fasting plasma insulin, FFA×INS), was performed in 192 adults with overweight/obesity and type 2 diabetes (T2D) treated with metformin (HbA1c = 7.8%). Free fatty acid composition and lipidomic profile were measured by mass spectrometry (GC‐MS and LC‐MSQTOF). Indexes of fatty acid desaturation (stearoyl‐coA desaturase‐1 activity, SCD116 = palmitoleic acid/palmitic acid and SCD118 = oleic acid/stearic acid) and of insulin resistance (HOMA‐IR) were also calculated. Results: Three clusters were identified: CL1 (ADIPO‐IR = 4.9 ± 2.4 and WC = 96±7 cm, mean ± SD), CL2 (ADIPO‐IR = 6.5 ± 2.5 and WC = 114 ± 7 cm), and CL3 (ADIPO‐IR = 15.0 ± 4.7 and WC = 107 ± 8 cm). Insulin concentrations, ADIPO‐IR, and HOMA‐IR significantly increased from CL1 to CL3 (all p < 0.001), while fasting glucose concentrations, HbA1c, dietary lipids and caloric intake were similar. Moreover, CL3 showed significantly higher concentrations of monounsaturated free fatty acids, oleic and palmitoleic acids, triglycerides (TAG) rich in saturated FA and associated with de novo lipogenesis (i.e., TAG 46–50), higher SCD116, SCD118, ceramide (d18:0/18:0), and phosphatidylcholine aa(36:5) compared with CL1/CL2 (all p < 0.005). Conclusions: High ADIPO‐IR and large WC identify a worse lipid profile in T2D characterised by complex lipids rich in SFA, likely due to de novo synthesis given higher plasma monounsaturated FFA and increased desaturase activity indexes. Registration Number Trial: ID NCT00700856 https://clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

Context This study addresses the development of a new glucoregulatory mechanism in type 2 diabetes (T2D) patients treated with SGLT-2 inhibitors, which is independent of glucose, insulin and glucagon. The data suggest the presence of a potential trigger factor (s) arising in the kidney that stimulates endogenous glucose production (EGP) during sustained glycosuria. Objective To investigate effects of SGLT-2 inhibitor therapy together with GLP-1 receptor agonist on EGP and glucose kinetics in patients with T2D. Our hypothesis was that increased EGP in response to SGLT2i-induced glycosuria persists for a long period and is not abolished by GLP-1 RA stimulation of insulin secretion and glucagon suppression. Methods Seventy-five patients received a 5-hour dual-tracer oral glucose tolerance test (OGTT) (intravenous 3-(3H)-glucose oral (1-14C)-glucose): (1) before/after 1 of dapagliflozin (DAPA); exenatide (EXE), or both, DAPA/EXE (acute study), and (2) after 1 and 4 months of therapy with each drug. Results In the acute study, during the OGTT plasma glucose (PG) elevation was lower in EXE (Δ = 42 ± 1 mg/dL) than DAPA (Δ = 72 ± 3), and lower in DAPA/EXE (Δ = 11 ± 3) than EXE and DAPA. EGP decrease was lower in DAPA (Δ = −0.65 ± 0.03 mg/kg/min) than EXE (Δ = −0.96 ± 0.07); in DAPA/EXE (Δ = −0.84 ± 0.05) it was lower than EXE, higher than DAPA. At 1 month, similar PG elevations (EXE, Δ = 26 ± 1 mg/dL; DAPA, Δ = 62 ± 2, DAPA/EXE, Δ = 27 ± 1) and EGP decreases (DAPA, Δ = −0.60 ± 0.05 mg/kg/min; EXE, Δ = −0.77 ± 0.04; DAPA/EXE, Δ = −0.72 ± 0.03) were observed. At 4 months, PG elevations (EXE, Δ = 55 ± 2 mg/dL; DAPA, Δ = 65 ± 6; DAPA/EXE, Δ = 46 ± 2) and lower EGP decrease in DAPA (Δ = −0.66 ± 0.04 mg/kg/min) vs EXE (Δ = −0.84 ± 0.05) were also comparable; in DAPA/EXE (Δ = −0.65 ± 0.03) it was equal to DAPA and lower than EXE. Changes in plasma insulin/glucagon could not explain higher EGP in DAPA/EXE vs EXE mg/kg/min. Conclusion Our findings provide strong evidence for the emergence of a new long-lasting, glucose-independent, insulin/glucagon-independent, glucoregulatory mechanism via which SGLT2i-induced glycosuria stimulates EGP in patients with T2D. SGLT2i plus GLP-1 receptor agonist combination therapy is accompanied by superior glycemic control vs monotherapy. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Diabetes may feature impaired insulin kinetics, which could be aggravated by altered hepatic metabolism and glycemic control. Thus, we examined insulin clearance and its possible determinants in individuals with recent-onset diabetes. RESEARCH DESIGN AND METHODS: Participants of the German Diabetes Study (GDS) with type 1 diabetes (T1D) (n = 306), type 2 diabetes (T2D) (n = 489), or normal glucose tolerance (control [CON]) (n = 167) underwent hyperinsulinemic-euglycemic clamps for assessment of whole-body insulin sensitivity (M value) and insulin clearance (ICCLAMP). Insulin clearance rates were further calculated during intravenous glucose tolerance tests (ICIVGTT) and mixed-meal tests (ICMMT). Hepatocellular lipid content (HCL) was quantified with 1H-MRS. RESULTS: Both T1D and T2D groups had lower ICCLAMP (0.12 ± 0.07 and 0.21 ± 0.06 vs. 0.28 ± 0.14 arbitrary units [a.u.], respectively, all P < 0.05) and ICMMT (0.71 ± 0.35 and 0.99 ± 0.33 vs. 1.20 ± 0.36 a.u., all P < 0.05) than CON. In T1D, ICCLAMP, ICIVGTT, and ICMMT correlated negatively with HbA1c (all P < 0.05). M value correlated positively with ICIVGTT in CON and T2D (r = 0.199 and r = 0.178, P < 0.05) and with ICMMT in CON (r = 0.176, P < 0.05). HCL negatively associated with ICIVGTT and ICMMT in T2D (r = −0.005 and r = −0.037) and CON (r = −0.127 and r = −0.058, all P < 0.05). In line, T2D or CON subjects with steatosis featured lower ICMMT than those without steatosis (both P < 0.05). CONCLUSIONS: Insulin clearance is reduced in both T1D and T2D within the first year after diagnosis but correlates negatively with liver lipid content rather in T2D. Moreover, insulin clearance differently associates with glycemic control and insulin sensitivity in each diabetes type, which may suggest specific mechanisms affecting insulin kinetics. [ABSTRACT FROM AUTHOR]

Aims: To examine the effect of pioglitazone on epicardial (EAT) and paracardial adipose tissue (PAT) and measures of diastolic function and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). Methods: Twelve patients with T2DM without clinically manifest cardiovascular disease and 12 subjects with normal glucose tolerance (NGT) underwent cardiac magnetic resonance imaging to quantitate EAT and PAT and diastolic function before and after pioglitazone treatment for 24 weeks. Whole‐body insulin sensitivity was measured with a euglycaemic insulin clamp and the Matsuda Index (oral glucose tolerance test). Results: Pioglitazone reduced glycated haemoglobin by 0.9% (P < 0.05), increased HDL cholesterol by 7% (P < 0.05), reduced triacylglycerol by 42% (P < 0.01) and increased whole‐body insulin‐stimulated glucose uptake by 71% (P < 0.01) and Matsuda Index by 100% (P < 0.01). In patients with T2DM, EAT (P < 0.01) and PAT (P < 0.01) areas were greater compared with subjects with NGT, and decreased by 9% (P = 0.03) and 9% (P = 0.09), respectively, after pioglitazone treatment. Transmitral E/A flow rate and peak left ventricular flow rate (PLVFR) were reduced in T2DM versus NGT (P < 0.01) and increased following pioglitazone treatment (P < 0.01‐0.05). At baseline normalized PLVFR inversely correlated with EAT (r = −0.45, P = 0.03) but not PAT (r = −0.29, P = 0.16). E/A was significantly and inversely correlated with EAT (r = −0.55, P = 0.006) and PAT (r = −0.40, P = 0.05). EAT and PAT were inversely correlated with whole‐body insulin‐stimulated glucose uptake (r = −0.68, P < 0.001) and with Matsuda Index (r = 0.99, P < 0.002). Conclusion: Pioglitazone reduced EAT and PAT areas and improved left ventricular (LV) diastolic function in T2DM. EAT and PAT are inversely correlated (PAT less strongly) with LV diastolic function and both EAT and PAT are inversely correlated with measures of insulin sensitivity. [ABSTRACT FROM AUTHOR]

Background: Phthalates exposure and complete edentulism are related to both low socioeconomic status. No study by far has verified if and to what extent these two conditions are related. We aimed to explore their potential association and interplay in the metabolic control and cardiovascular risk profile. Methods: In our small (n = 48) prospective pilot study twenty-four patients with type 2 diabetes (DnE) and twenty-four patients with type 2 diabetes and edentulism (DE) followed for 19 ± 2 months were treated according to best clinical standards. Phthalates' exposure was evaluated by urinary concentration of di-2-ethylhexylphthalate (DEHP), metabolites, i.e. mono 2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP) and mono 2-ethyl-5-hydroxyhexyl phthalate (MEHHP). Results: No association between phthalates and edentulism was found, nor did edentulism affect glucose control. Higher phthalates exposure was associated with a glycated haemoglobin worsening. This association was found for all the measured phthalates metabolites, both as a whole (DEHP; r = 0.33, p = 0.0209) and individually: MEHP (r = 0.41, p = 0.0033), MEHHP (r = 0.32, p = 0.028), MEOHP (r = 0.28, p = 0.0386). Conclusions: Phthalates are not associated with edentulism but predict the worsening of glucose control in subjects with type 2 diabetes. These findings might prove relevant in identifying novel biomarkers of cardiometabolic risk. Further studies are needed to validate our results and estimate the true potential of phthalates in terms of risk assessment. [ABSTRACT FROM AUTHOR]

Aim: To compare the efficacy of triple therapy (metformin/exenatide/pioglitazone) versus stepwise conventional therapy (metformin → glipizide → glargine insulin) on liver fat content and hepatic fibrosis in newly diagnosed, drug‐naïve patients with type 2 diabetes. Methods: Sixty‐eight patients completed the 6‐year follow‐up and had an end‐of‐study (EOS) FibroScan to provide measures of steatosis (controlled attenuation parameter [CAP] in dB/m) and fibrosis (liver stiffness measurement [LSM] in kPa); 59 had magnetic resonance imaging‐proton density fat fraction (MRI‐PDFF) to measure liver fat. Results: At EOS, HbA1c was 6.8% and 6.0% in triple and conventional therapy groups, respectively (P =.0006). Twenty‐seven of 39 subjects (69%) receiving conventional therapy had grade 2/3 steatosis (CAP, FibroScan) versus nine of 29 (31%) in triple therapy (P =.0003). Ten of 39 (26%) subjects receiving conventional therapy had stage 3/4 fibrosis (LSM) versus two of 29 (7%) in triple therapy (P =.04). Conventional therapy subjects had more liver fat (MRI‐PDFF) than triple therapy (12.9% vs. 8.8%, P =.03). The severity of steatosis (CAP) (r = 0.42, P <.001) and fibrosis (LSM) (r = −0.48, P <.001) correlated inversely with the Matsuda Index of insulin sensitivity, but not with percentage body fat. Aspartate aminotransferase (AST) to Platelet Ratio Index (APRI), non‐alcoholic fatty liver disease fibrosis score (NFS), plasma AST, and alanine aminotransferase (ALT) all decreased significantly with triple therapy, but only the decrease in plasma AST and ALT correlated with the severity of steatosis and fibrosis at EOS. Conclusions: At EOS, subjects with type 2 diabetes treated with triple therapy had less hepatic steatosis and fibrosis versus conventional therapy; the severity of hepatic steatosis and fibrosis were both strongly and inversely correlated with insulin resistance; and changes in liver fibrosis scores (APRI, NFS, Fibrosis‐4, and AST/ALT ratio) have limited value in predicting response to therapy. [ABSTRACT FROM AUTHOR]

Weight loss and lifestyle intervention improve glucose tolerance delaying the onset of type 2 diabetes (T2D), but individual responses are highly variable. Determining the predictive factors linked to the beneficial effects of weight loss on glucose tolerance could provide tools for individualized prevention plans. Thus, the aim was to investigate the relationship between pre-intervention values of insulin sensitivity and secretion and the improvement in glucose metabolism after weight loss. In the DEXLIFE cohort (373 individuals at high risk of T2D, assigned 3:1 to a 12-week lifestyle intervention or a control arm, Trial Registration: ISRCTN66987085), K-means clustering and logistic regression analysis were performed based on pre-intervention indices of insulin sensitivity, insulin secretion (AUC-I), and glucose-stimulated insulin response (ratio of incremental areas of insulin and glucose, iAUC I/G). The response to the intervention was evaluated in terms of reduction of OGTT-glucose concentration. Clusters' validation was done in the prospective EGIR-RISC cohort (n = 1538). Four replicable clusters with different glycemic and metabolomic profiles were identified. Individuals had similar weight loss, but improvement in glycemic profile and β-cell function was different among clusters, highly depending on pre-intervention insulin response to OGTT. Pre-intervention high insulin response was associated with the best improvement in AUC-G, while clusters with low AUC-I and iAUC I/G showed no beneficial effect of weight loss on glucose control, as also confirmed by the logistic regression model. Individuals with preserved β-cell function and high insulin concentrations at baseline have the best improvement in glucose tolerance after weight loss. [Display omitted] • Response to weight loss and lifestyle intervention in people at risk of T2D is highly heterogeneous. • Replicable clusters based on pre-intervention insulin sensitivity and concentrations during OGTT were identified. • Clusters with preserved β-cell function showed the greatest improvement in glucose control. • Insulin response to OGTT serves as a predictive factor for the individual response to weight loss. [ABSTRACT FROM AUTHOR]

Objective: Endogenous insulin clearance (EIC) is physiologically reduced at increasing insulin secretion rate (ISR). Computing EIC at the prevailing ISR does not distinguish the effects of hypersecretion from those of other mechanisms of glucose homeostasis. We aimed to measure EIC in standardized ISR conditions (i.e., at fixed ISR levels) and to analyze its associations with relevant physiologic factors.Research Design and Methods: We estimated standardized EIC (EICISR) by mathematical modeling in nine different studies with insulin and glucose infusions (N = 2,067). EICISR association with various traits was analyzed by stepwise multivariable regression in studies with both euglycemic clamp and oral glucose tolerance test (OGTT) (N = 1,410). We also tested whether oral glucose ingestion, as opposed to intravenous infusion, has an independent effect on EIC (N = 1,555).Results: Insulin sensitivity (as M/I from the euglycemic clamp) is the strongest determinant of EICISR, approximately four times more influential than insulin resistance-related hypersecretion. EICISR independently associates positively with M/I, fasting and mean OGTT glucose or type 2 diabetes, and β-cell glucose sensitivity and negatively with African American or Hispanic race, female sex, and female age. With oral glucose ingestion, an ISR-independent ∼10% EIC reduction is necessary to explain the observed insulin concentration profiles.Conclusions: Based on EICISR, we posit the existence of two adaptive processes involving insulin clearance: the first reduces EICISR with insulin resistance (not with higher BMI per se) and is more relevant than the concomitant hypersecretion; the second reduces EICISR with β-cell dysfunction. These processes are dysregulated in type 2 diabetes. Finally, oral glucose ingestion per se reduces insulin clearance. [ABSTRACT FROM AUTHOR]

Background: We evaluate whether the Pro12Ala polymorphism of peroxisome proliferator‐activated receptor γ2 (PPARγ2) has a role in the progression of diabetes by modulating the occurrence of treatment failure to glucose‐lowering drugs. Methods: We studied 215 patients with type 2 diabetes participating in the Thiazolidinediones Or Sulphonylureas and Cardiovascular Accidents Intervention Trial study. All participants were insufficiently controlled (glycated haemoglobin [HbA1c] 7.0%‐9.0%) with metformin 2 g/day and were randomly allocated to add‐on pioglitazone or a sulfonylurea. Treatment failure was defined as HbA1c ≥8% on two consecutive visits, 3 months apart. Results: Carriers or non‐carriers of the polymorphism had similar age, body mass index, and diabetes duration. Ala carriers had lower fasting plasma insulin, better insulin sensitivity (Homeostasis Model Assessment [HOMA]2‐%S), and worse beta cell secretion (HOMA2‐%B) than non‐carriers. During 24 months of follow‐up, 32.5% among the Ala carriers and 8.6% among non‐carriers (P < 0.001) developed treatment failure with a cumulative incidence of 18.6 vs 4.6/100 person‐years. Those patients who developed treatment failure were older, had a younger age at diabetes diagnosis (48 ± 10 vs 52 ± 7 years; P = 0.032), higher HbA1c (8.1 ± 0.5 vs 7.7 ± 0.5%; P < 0.001), and lower HOMA2‐%B (30 ± 12 vs 46 ± 29; P = 0.015) at study entry, as compared to those who did not develop treatment failure. At multivariate analysis, the Pro12Ala polymorphism was significantly associated with treatment failure (hazard ratio [HR] 4.45; 95% confidence interval [CI] 1.79‐11.1; P < 0.001); HbA1c at study entry was the other independent predictor of failure in this study population. Conclusion: The Pro12Ala polymorphism is associated with a greater insulin sensitivity, reduced beta cell function and a substantially increased risk of treatment failure. [ABSTRACT FROM AUTHOR]

With the development of insulin resistance (IR), there is a compensatory increase in the plasma insulin response to offset the defect in insulin action to maintain normal glucose tolerance. The insulin response is the result of two factors: insulin secretion and metabolic clearance rate of insulin (MCRI). Subjects (104 with normal glucose tolerance [NGT], 57 with impaired glucose tolerance [IGT], and 207 with type 2 diabetes mellitus [T2DM]), divided in nonobese and obese groups, received a euglycemic insulin-clamp (40 mU/m2 ⋅ min) and an oral glucose tolerance test (OGTT) (75 g) on separate days. MCRI was calculated during the insulin-clamp performed with [3-3H]glucose and the OGTT and related to IR: peripheral (glucose uptake during the insulin clamp), hepatic (basal endogenous glucose production × fasting plasma insulin [FPI]), and adipocyte (fasting free fatty acid × FPI). MCRI during the insulin clamp was reduced in obese versus nonobese NGT (0.60 ± 0.03 vs. 0.73 ± 0.02 L/min ⋅ m2, P < 0.001), in nonobese IGT (0.62 ± 0.02, P < 0.004), and in nonobese T2DM (0.68 ± 0.02, P < 0.03). The MCRI during the insulin clamp was strongly and inversely correlated with IR (r = -0.52, P < 0.0001). During the OGTT, the MCRI was suppressed within 15-30 min in NGT and IGT subjects and remained suppressed. In contrast, suppression was minimal in T2DM. In conclusion, the development of IR in obese subjects is associated with a decline in MCRI that represents a compensatory response to maintain normal glucose tolerance but is impaired in individuals with T2DM. [ABSTRACT FROM AUTHOR]

Objective: Recent studies indicate that sodium-glucose cotransporter 2 (SGLT-2) inhibition increases endogenous glucose production (EGP), potentially counteracting the glucose-lowering potency, and stimulates lipid oxidation and lipolysis. However, the acute effects of SGLT-2 inhibition on hepatic glycogen, lipid, and energy metabolism have not yet been analyzed. We therefore investigated the impact of a single dose of dapagliflozin (D) or placebo (P) on hepatic glycogenolysis, hepatocellular lipid (HCL) content and mitochondrial activity (kATP).Research Design and Methods: Ten healthy volunteers (control [CON]: age 30 ± 3 years, BMI 24 ± 1 kg/m2, HbA1c 5.2 ± 0.1%) and six patients with type 2 diabetes mellitus (T2DM: age 63 ± 4 years, BMI 28 ± 1.5 kg/m2, HbA1c 6.1 ± 0.5%) were investigated on two study days (CON-P vs. CON-D and T2DM-P vs. T2DM-D). 1H/13C/31P MRS was performed before, 90-180 min (MR1), and 300-390 min (MR2) after administration of 10 mg dapagliflozin or placebo. EGP was assessed by tracer dilution techniques.Results: Compared with CON-P, EGP was higher in CON-D (10.0 ± 0.3 vs. 12.4 ± 0.5 μmol kg-1 min-1; P < 0.05) and comparable in T2DM-D and T2DM-P (10.1 ± 0.7 vs. 10.4 ± 0.5 μmol kg-1 min-1; P = not significant [n.s.]). A strong correlation of EGP with glucosuria was observed (r = 0.732; P < 0.01). The insulin-to-glucagon ratio was lower after dapagliflozin in CON-D and T2DM-D compared with baseline (P < 0.05). Glycogenolysis did not differ between CON-P and CON-D (-3.28 ± 0.49 vs. -2.53 ± 0.56 μmol kg-1 min-1; P = n.s.) or T2DM-P and T2DM-D (-0.74 ± 0.23 vs. -1.21 ± 0.33 μmol kg-1 min-1; P = n.s.), whereas gluconeogenesis was higher after dapagliflozin in CON-P compared with CON-D (6.7 ± 0.6 vs. 9.9 ± 0.6 μmol kg-1 min-1; P < 0.01) but not in T2DM. No significant changes in HCL and kATP were observed.Conclusions: The rise in EGP after SGLT-2 inhibition is due to increased gluconeogenesis, but not glycogenolysis. Changes in glucagon and the insulin-to-glucagon ratio are not associated with an increased hepatic glycogen breakdown. HCL and kATP are not significantly affected by a single dose of dapagliflozin. [ABSTRACT FROM AUTHOR]

The aim of the current study was to evaluate the effect of sustained physiologic increase of ∼50 mg/dL in plasma glucose concentration on insulin secretion in normal glucose-tolerant (NGT) subjects. Twelve NGT subjects without family history of type 2 diabetes mellitus (T2DM; FH-) and 8 NGT with family history of T2DM (FH+) received an oral glucose tolerance test and two-step hyperglycemic clamp (100 and 300 mg/dL) followed by intravenous arginine bolus before and after 72-h glucose infusion. Fasting plasma glucose increased from 94 ± 2 to 142 ± 4 mg/dL for 72 h. First-phase insulin secretion (0-10 min) increased by 70%, while second-phase insulin secretion during the first (10-80 min) and second (90-160 min) hyperglycemic clamp steps increased by 3.8-fold and 1.9-fold, respectively, following 72 h of physiologic hyperglycemia. Insulin sensitivity during hyperglycemic clamp declined by ∼30% and ∼55% (both P < 0.05), respectively, during the first and second hyperglycemic clamp steps. Insulin secretion/insulin resistance (disposition) index declined by 60% (second clamp step) and by 62% following arginine (both P < 0.005) following 72-h glucose infusion. The effect of 72-h glucose infusion on insulin secretion and insulin sensitivity was similar in subjects with and without FH of T2DM. Following 72 h of physiologic hyperglycemia, metabolic clearance rate of insulin was markedly reduced (P < 0.01). These results demonstrate that sustained physiologic hyperglycemia for 72 h 1) increases absolute insulin secretion but impairs β-cell function, 2) causes insulin resistance, and 3) reduces metabolic clearance rate of insulin. [ABSTRACT FROM AUTHOR]

In this review we have discussed how the liver plays a central role in the regulation of glucose metabolism and in insulin clearance. Both non-alcoholic fatty liver disease (NAFLD) and diabetes (T2D) are characterized by high plasma insulin concentrations, hepatic insulin resistance, high hepatic glucose production (HGP), in particular gluconeogenesis (GNG), that are increased proportionally to fasting hyperglycemia, while postprandial hyperglycemia is due to impaired suppression of HGP by insulin, and reduced hepatic glycogen storage. The liver acts also as a modulator of peripheral insulin since most of insulin secreted by the pancreas is cleared by the liver during the first pass. Hepatokines and hepatic lipids can act in either autocrine or paracrine way and can be responsible of the changes in insulin sensitivity and alterations in glucose metabolism. [ABSTRACT FROM AUTHOR]

Objective: Sodium-glucose cotransporter 2 (SGLT2) inhibition causes an increase in endogenous glucose production (EGP). However, the mechanisms are unclear. We studied the effect of SGLT2 inhibitors on EGP in subjects with type 2 diabetes (T2D) and without diabetes (non-DM) in kidney transplant recipients with renal denervation.Research Design and Methods: Fourteen subjects who received a renal transplant (six with T2D [A1C 7.2 ± 0.1%] and eight non-DM [A1C 5.6 ± 0.1%) underwent measurement of EGP with [3-3H]glucose infusion following dapagliflozin (DAPA) 10 mg or placebo. Plasma glucose, insulin, C-peptide, glucagon, and titrated glucose-specific activity were measured.Results: Following placebo in T2D, fasting plasma glucose (FPG) (143 ± 14 to 124 ± 10 mg/dL; P = 0.02) and fasting plasma insulin (12 ± 2 to 10 ± 1.1 μU/mL; P < 0.05) decreased; plasma glucagon was unchanged, and EGP declined. After DAPA in T2D, FPG (143 ± 15 to 112 ± 9 mg/dL; P = 0.01) and fasting plasma insulin (14 ± 3 to 11 ± 2 μU/mL; P = 0.02) decreased, and plasma glucagon increased (all P < 0.05 vs. placebo). EGP was unchanged from baseline (2.21 ± 0.19 vs. 1.96 ± 0.14 mg/kg/min) in T2D (P < 0.001 vs. placebo). In non-DM following DAPA, FPG and fasting plasma insulin decreased, and plasma glucagon was unchanged. EGP was unchanged from baseline (1.85 ± 0.10 to 1.78 ± 0.10 mg/kg/min) after DAPA, whereas EGP declined significantly with placebo. When the increase in EGP production following DAPA versus placebo was plotted against the difference in urinary glucose excretion (UGE) for all patients, a strong correlation (r = 0.824; P < 0.001) was observed.Conclusions: Renal denervation in patients who received a kidney transplant failed to block the DAPA-mediated stimulation of EGP in both individuals with T2D and non-DM subjects. The DAPA-stimulated rise in EGP is strongly related to the increase in UGE, blunting the decline in FPG. [ABSTRACT FROM AUTHOR]

Aim: To assess the efficacy of exenatide (EXE) once weekly + dapagliflozin once daily (DAPA) versus each drug alone in reducing biomarkers of fatty liver/steatosis and fibrosis in a post hoc analysis of DURATION‐8, a 104‐week study in 695 patients with type 2 diabetes uncontrolled by metformin monotherapy. Materials and methods: We evaluated the impact of the study treatments on non‐invasive markers of hepatic steatosis (fatty liver index [FLI] and non‐alcoholic fatty liver disease [NAFLD] liver fat score), fibrosis (fibrosis‐4 index [FIB‐4]) and severe fibrosis (NAFLD fibrosis score), along with liver enzymes and insulin resistance, at weeks 28 and 52. All outcomes in this analysis were exploratory, with nominal P values reported. Results: At week 28, biomarkers of fatty liver/steatosis and fibrosis were reduced from baseline in all treatment groups. At week 28, EXE once weekly + DAPA effects for decrease in FLI were stronger than those of EXE once weekly + placebo (PLB; −2.92, 95% confidence interval [CI] −5.11, −0.73; P = 0.0092) or DAPA+PLB (−2.77 [95% CI −4.93, −0.62]; P = 0.0119), and stronger than those of EXE once weekly + PLB at week 52 (−3.23 [95% CI −5.79, −0.68]; P = 0.0134). FIB‐4 showed reduction versus baseline only in the EXE once weekly + DAPA group at both week 28 (−0.06 [95% CI −0.11, −0.01]; P = 0.0135) and week 52 (−0.05 [95% CI −0.09, −0.004]; P = 0.0308). Conclusions: The EXE once weekly + DAPA combination showed stronger effects than EXE once weekly + PLB or DAPA + PLB in ameliorating markers of hepatic steatosis and fibrosis in patients with type 2 diabetes. Prospective trials are needed to validate these findings. [ABSTRACT FROM AUTHOR]

In the transition from normal glucose tolerance (NGT) to type 2 diabetes mellitus (T2DM), the role of β-cell dysfunction and peripheral insulin resistance (IR) is well established. However, the impact of dysfunctional adipose tissue has not been fully elucidated. The aim of this study was to evaluate the role of resistance to the antilipolytic effect of insulin (adipose tissue IR [Adipo-IR]) in a large group of subjects with NGT, impaired glucose tolerance (IGT), and T2DM. Three hundred two subjects with varying glucose tolerance received an oral glucose tolerance test (OGTT) and euglycemic insulin clamp. We evaluated Adipo-IR (fasting and mean OGTT plasma free fatty acid [FFA] × insulin concentrations), peripheral IR (1/[Matsuda index] and (M/I)-1 value), and β-cell function (calculated as the ratio of the increment in plasma insulin to glucose [OGTT/IR (ΔI/ΔG ÷ IR)]). Fasting Adipo-IR was increased twofold in obese subjects with NGT and IGT versus lean subjects with NGT (8.0 ± 1.1 and 9.2 ± 0.7 vs. 4.1 ± 0.3, respectively) and threefold in subjects with T2DM (11.9 ± 0.6; P < 0.001). Progressive decline in ΔI/ΔG ÷ IR was associated with a progressive impairment in FFA suppression during OGTT, whereas the rise in mean plasma glucose concentration only became manifest when subjects became overtly diabetic. The progressive decline in β-cell function that begins in individuals with NGT is associated with a progressive increase in FFA and fasting Adipo-IR. [ABSTRACT FROM AUTHOR]

Aims Basal insulin peglispro ( BIL) is a novel PEGylated basal insulin with a flat pharmacokinetic and glucodynamic profile and reduced peripheral effects, which results in a hepato-preferential action. In Phase 3 trials, patients with T1DM treated with BIL had lower prandial insulin requirements, yet improved prandial glucose control, relative to insulin glargine ( GL). We hypothesized that this may be because of an enhanced sensitivity to prandial insulin with BIL resulting from lower chronic peripheral insulin action. Materials and methods Two open-label, randomized, 2-period crossover clinical studies were conducted in 28 patients with T1DM and 24 patients with T2DM. In each study period, patients received once-daily, individualized, stable, subcutaneous doses of BIL or GL for 5 weeks before a euglycaemic 2-step hyperinsulinemic clamp procedure (with [6,6- 2H2 ]-glucose in 12 of the patients with T1DM). M-values were derived from the clamp procedure for all patients, with rate of glucose appearance ( Ra) and disappearance ( Rd) and insulin sensitivity index ( SI) determined from the clamps with [6,6- 2H2 ]-glucose. Results There were no statistically significant differences between BIL and GL in key measures of hepatic (% Ra suppression during the low-dose insulin infusion; 78.7% with BIL, 81.8% with GL) or peripheral ( M-value and M/ I during the high-dose insulin infusion, Rd and SI) insulin sensitivity in patients with T1DM or T2DM. Conclusions The need to reduce prandial insulin observed with BIL during phase 3 trials cannot be explained by the differential effects of BIL and GL on sensitivity to prandial insulin in either T1DM or T2DM. [ABSTRACT FROM AUTHOR]

To investigate the prevalence of biopsy-proven non-alcoholic steatohepatitis (NASH) in a cohort of patients with morbid obesity and with or without type 2 diabetes (T2D) and to find non-invasive predictors of NASH severity. We evaluated a cohort of 412 subjects (age 19–67 years, body mass index-BMI: 44.98 kg/m2), who underwent fine-needle liver biopsy during bariatric surgery. Thirty-six percent of the subjects were affected by T2D. Liver biopsies were classified according to the Kleiner's NAFLD Activity Score (NAS). NAFLD Fibrosis Score (NFS), AST/ALT ratio, AST to Platelet ratio (APRI), fibrosis-4 score (FIB4) were calculated. A neural network analysis (NNA) was run to predict NASH severity. The prevalence of biopsy-proven NASH was 63% and 78% in subjects with obesity and without or with T2D, respectively. T2D doubled the risk of NASH [OR 2.079 (95% IC=1.31–3.29)]. The prevalence of NAFL increased with the increase of BMI, while there was an inverse correlation between BMI and NASH (r =−0.145 p =0.003). Only mild liver fibrosis was observed. HOMA-IR was positively associated with hepatocyte ballooning (r =0.208, p <0.0001) and fibrosis (r =0.159, p =0.008). The NNA highlighted a specificity of 77.3% using HDL-cholesterol, BMI, and HOMA-IR as main determinants of NASH. Our data show a higher prevalence of NASH in patients with morbid obesity than reported in the literature and the pivotal role of T2D among the risk factors for NASH development. However, the inverse correlation observed between BMI and biopsy-proven NASH suggests that over a certain threshold adiposity can be somewhat protective against liver damage. Our model predicts NASH presence with high specificity, thus helping identifying subjects who should promptly undergo liver biopsy. [ABSTRACT FROM AUTHOR]

Aims: Statins are the main lipid-lowering treatment in both primary and secondary prevention populations. Whether statins deteriorates glycemic control, predisposing to the onset of diabetes mellitus has been a matter of recent concern. Statins may accelerate progression to diabetes via molecular mechanisms that impact insulin sensitivity and secretion. In this review, we debate the relative effect of statins in driving insulin resistance and the impairment of insulin secretion. Methods: Narrative overview of the literature synthesizing the findings of literature was retrieved from searches of computerized databases, hand searches, and authoritative texts employing the key words 'Statins', 'Randomized Clinical Trial', 'Insulin sensitivity', 'Insulin resistance', 'Insulin Secretion', 'Diabetes Mellitus' alone and/or in combination. Results: The weight of clinical evidence suggests a worsening effect of statins on insulin resistance and secretion, anyway basic science studies did not find a clear molecular explanation, providing conflicting evidence regarding both the beneficial and the adverse effects of statin therapy on insulin sensitivity. Conclusions: Although most of the clinical studies suggest a worsening of insulin resistance and secretion, the cardiovascular benefits of statin therapy outweigh the risk of developing insulin resistance, thus the data suggest the need to treat dyslipidemia and to make patients aware of the possible risk of developing type 2 diabetes or, if they already are diabetic, of worsening their metabolic control. [ABSTRACT FROM AUTHOR]

OBJECTIVE Plasma adiponectin levels are reduced in type 2 diabetes mellitus (T2DM) and other insulin-resistant states. We examined whether plasma adiponectin levels at baseline and after pioglitazone treatment in impaired glucose tolerance (IGT) subjects were associated with improved insulin sensitivity (SI) and glucose tolerance status. RESEARCH DESIGN AND METHODS A total of 602 high-risk IGT subjects in ACT NOW were randomized to receive pioglitazone or placebo with a median follow-up of 2.4 years. RESULTS Pioglitazone reduced IGT conversion to diabetes by 72% in association with improved β-cell function by 64% (insulin secretion/insulin resistance index) and increased tissue sensitivity by 88% (Matsuda index). In pioglitazone-treated subjects, plasma adiponectin concentration increased threefold from 13 ± 0.5 to 38 ± 2.5 µg/mL (P < 0.001) and was strongly correlated with the improvement in SI (r = 0.436, P < 0.001) and modestly correlated with glucose area under the curve during oral glucose tolerance test (r = 0.238, P < 0.005) and insulin secretion/ insulin resistance index (r = 0.306, P < 0.005). The increase in adiponectin was a strong predictor of reversion to normal glucose tolerance and prevention of T2DM. In the placebo group, plasma adiponectin did not change and was not correlated with changes in glucose levels. There was an inverse association between baseline plasma adiponectin concentration and progression to diabetes in the placebo group but not in the pioglitazone group. CONCLUSIONS Baseline adiponectin does not predict the response to pioglitazone. The increase in plasma adiponectin concentration after pioglitazone therapy in IGT subjects is strongly related to improved glucose tolerance status and enhanced tissue sensitivity to insulin. [ABSTRACT FROM AUTHOR]

Objective To determine the effect of chronic daily exenatide treatment on β-cell function in type 2 diabetes (T2DM). Background Glucagon-like peptide receptor agonists, such as exenatide, are commonly used to treat patients with T2 DM. Drugs in this class are insulinotropic but lower blood glucose by multiple mechanisms such that effects on β-cell function can be difficult to discern by conventional measures. Design Seventy-nine subjects with previously untreated T2DM were studied before and after 24 weeks of treatment with one of the two doses of exenatide, 5- or 10-μg twice daily, or placebo. All subjects had oral glucose tolerance tests ( OGTT) before and after randomization with measurement of plasma glucose, insulin and C-peptide concentrations. Insulin secretion rates ( ISR), peripheral insulin sensitivity ( OGIS) and hepatic insulin resistance index (Hep-IR) were calculated. Results During the trial, all three groups lost similar, small but significant, amounts of weight. Compared to placebo, 24 weeks of daily high- or low-dose exenatide treatment reduced HbA1c and improved fasting and postprandial hyperglycaemia. Exenatide was associated with improved OGIS and Hep-IR independent of changes in weight. Plasma insulin levels and ISR during the OGTT did not differ before or after treatment with exenatide or placebo. However, when considered as a function of plasma glucose and insulin sensitivity, both doses of exenatide improved ISR proportionately to the improvement in plasma glucose. The higher dose of exenatide was associated with a significant improvement in β-cell sensitivity to glucose. Conclusions These findings demonstrate that in persons with early T2DM, chronic treatment with exenatide enhanced ISR and increased β-cell sensitivity to glucose. These improvements in β-cell function were not clearly reflected in plasma insulin and C-peptide levels, but became apparent when glycemia and insulin sensitivity were accounted for. [ABSTRACT FROM AUTHOR]

Context: Hepatic steatosis, defined as increased hepatocellular lipid content (HCL), associates with visceral obesity and glucose intolerance. As exact HCL quantification by 1H-magnetic resonance spectroscopy (1H-MRS) is not generally available, various clinical indices are increasingly used to predict steatosis. Objective: The purpose of this study was to test the accuracy of NAFLD liver fat score (NAFLD-LFS), hepatic steatosis index (HSI) and fatty liver index (FLI) against 1H-MRS and their relationships with insulin sensitivity and secretion. Design, Setting and Participants: Ninety-two non-diabetic, predominantly non-obese humans underwent clinical examination, 1H-MRS and an oral glucose tolerance test (OGTT) to calculate insulin sensitivity and β-cell function. Accuracy of indices was assessed from the area under the receiver operating characteristic curve (AROC). Results: Median HCL was 2.49% (0.62;4.23) and correlated with parameters of glycemia across all subjects. NAFLD-LFS, FLI and HSI yielded AROCs of 0.70, 0.72, and 0.79, respectively, and related positively to HCL, insulin resistance, fasting and post-load β-cell function normalized for insulin resistance. Upon adjustment for age, sex and HCL, regression analysis revealed that NAFLD-LFS, FLI and HSI still independently associated with both insulin sensitivity and β-cell function. Conclusion: The tested indices offer modest efficacy to detect steatosis and cannot substitute for fat quantification by 1H-MRS. However, all indices might serve as surrogate parameters for liver fat content and also as rough clinical estimates of abnormal insulin sensitivity and secretion. Further validation in larger collectives such as epidemiological studies is needed. [ABSTRACT FROM AUTHOR]

Objective: To i) compare incretin responses to oral glucose and mixed meal of diabetic patients with the normoglycaemic population and ii) to investigate whether incretin responses are associated with hypertriglyceridaemia and alanine aminotransferase (ALT) as liver fat marker. Design: A population-based study. Methods: A total of 163 persons with normal glucose metabolism (NGM), 20 with intermediate hyperglycaemia and 20 with type 2 diabetes aged 40-65 years participated. Participants received a mixed meal and oral glucose load on separate occasions. Glucagon-like peptide 1 (GLP-1), glucosedependent insulinotropic polypeptide (GIP) and glucagon profiles were analysed as total area under the curve (tAUC) and incremental area under the curve. Results: In diabetic patients compared with persons with NGM, we found increased GLP-1 secretion (tAUC per hour) following oral glucose (23.2 pmol/l (95% CI 17.7-28.7) vs 18.0 (95% CI 16.9-19.1), P<0.05) but not after the mixed meal. GIP secretion among diabetic patients was increased on both occasions (82.9 pmol/l (55.9-109.8) vs 47.1 (43.8-50.4) for oral glucose and 130.6 (92.5-168.7) vs 83.2 (77.5-88.9) for mixed meal, both P<0.05). After oral glucose, GLP-1 (tAUC per hour) was inversely related to fasting triglycerides. GIP (tAUC per hour) was positively related to fasting and postprandial triglycerides. Higher fasting GIP levels were related to higher fasting and postprandial triglyceride levels and ALT. Conclusion: This study confirms that in type 2 diabetes, GLP-1 secretion is generally preserved and that GIP secretion is exaggerated. The mechanism underlying the divergent associations of GLP-1 and GIP metabolism with fat metabolism and liver fat accumulation warrants further study. [ABSTRACT FROM AUTHOR]

Background and Aims: Determinants of fatty liver (FL) might be predictive for further deterioration in insulin resistance (IR) in women with previous gestational diabetes (pGDM). The aim was to evaluate the association between pGDM, FL and future manifestation of type 2 diabetes (T2DM) by a detailed pathophysiological characterization early after pregnancy. Methods: 68 pGDM and 29 healthy controls were included 3-6 months after delivery and underwent specific metabolic assessments: status of IR was determined via oral- and intravenous-glucose-tolerance-tests with analysis of proinflammatory factors and kinetics of free-fatty-acids (FFA). According to the fatty-liver-index (FLI), pGDMs were categorized into three groups with low (FLI≤20), intermediate (20

OBJECTIVE -- Dicarboxylic acids are natural products with the potential of being an alternate dietary source of energy. We aimed to evaluate the effect of sebacic acid (a 10-carbon dicarboxylic acid; C10) ingestion on postprandial glycemia and glucose rate of appearance (R[sub a]) in healthy and type 2 diabetic subjects. Furthermore, the effect of C10 on insulin-mediated glucose uptake and on GLUT4 expression was assessed in L6 muscle cells in vitro. RESEARCH DESIGN AND METHODS -- Subjects ingested a mixed meal (50% carbohydrates, 15% proteins, and 35% lipids) containing 0 g (control) or 10 g C10 in addition to the meal or 23 g C10 as a substitute of fats. RESULTS -- In type 2 diabetic subjects, the incremental glucose area under the curve (AUC) decreased by 42% (P < 0.05) and 70% (P < 0.05) in the 10 g C10 and 23 g C10 groups, respectively. At the largest amounts used, C10 reduced the glucose AUC in healthy volunteers also. When fats were substituted with 23 g C10, AUC of R[sub a] was significantly reduced on the order of 18% (P < 0.05) in both healthy and diabetic subjects. The insulin-dependent glucose uptake by L6 cells was increased in the presence of C10 (38.7 ± 10.3 vs. 11.4 ± 5.4%; P = 0.026). This increase was associated with a 1.7-fold raise of GLUT4. CONCLUSIONS -- Sebacic acid significantly reduced hyperglycemia after a meal in type 2 diabetic subjects. This beneficial effect was associated with a reduction in glucose R[sub a], probably due to lowered hepatic glucose output and increased peripheral glucose disposal. [ABSTRACT FROM AUTHOR]

Objectives By using tracer techniques, we explored the metabolic mechanisms by which pioglitazone treatment for 16 weeks improves oral glucose tolerance in patients with type 2 diabetes when compared to subjects without diabetes. Methods In all subjects, before and after treatment, we measured rates of tissue glucose clearance (MCR), oral glucose appearance (RaO) and endogenous glucose production (EGP) during a (4-h) double tracer oral glucose tolerance test (OGTT) (1-14C-glucose orally and 3-3H-glucose intravenously). Basal hepatic insulin resistance index (HepIR) was calculated as EGPxFPI. β-cell function was assessed as the incremental ratio of insulin to glucose (ΔI/ΔG) during the OGTT. Results Pioglitazone decreased fasting plasma glucose concentration (10·5 ± 0·7 to 7·8 ± 0·6 mm, P < 0·0003) and HbA1c (9·7 ± 0·7 to 7·5 ± 0·5%, P < 0·003) despite increased body weight and no change in plasma insulin concentrations. This was determined by a decrease both in fasting EGP (20·0 ± 1·1 to 17·3 ± 0·8 μmol/kgffm min, P < 0·005) and HepIR (from 8194 declined by 49% to 3989, P < 0·002). During the OGTT, total glucose Ra during the 0- to 120-min time period following glucose ingestion decreased significantly because of a reduction in EGP. During the 0- to 240-min time period, pioglitazone caused only a modest increase in MCR ( P < 0·07) but markedly increased ΔI/ΔG ( P = 0·003). The decrease in 2h-postprandial hyperglycaemia correlated closely with the increase in ΔI/ΔG ( r = −0·76, P = 0·004) and tissue clearance ( r = −0·74, P = 0·006) and with the decrease in HepIR ( r = 0·62, P = 0·006). Conclusions In diabetic subjects with poor glycaemic control, pioglitazone improves oral glucose tolerance mainly by enhancing the suppression of EGP and improving β-cell function. [ABSTRACT FROM AUTHOR]

Pioglitazone has been shown to reduce fasting triglyceride levels. The mechanisms of this effect have not been fully elucidated, but decreased lipolysis may contribute to blunt the hypertriglyceridemic response to a meal. To test this hypothesis, we studied 27 type 2 diabetes mellitus (T2DM) patients and 7 sex-, age-, and body mass index-matched nondiabetic controls. Patients were randomized to pioglitazone (45 mg/day) or placebo for 16 wk. Whole body lipolysis was measured [as the [[sup2]H[sub5]glycerol rate of appearance (Rn)] in the fasting state and for 6 h following a mixed meal. Compared with controls, T2DM had higher postprandial profiles of plasma triglycerides, free fatty acid (FFA), and β-hydroxybutyrate, and a decreased suppression of glycerol R[suba] (P < 0.04) despite higher insulin levels [268 (156) vs. 190 (123) pmol/l, median (interquartile range)]. Following pioglitazone, triglycerides and FFA were reduced (P = 0.05 and P < 0.04, respectively), and glycerol R was more suppressed [-40 (137) vs. +7 (202) p.mol/min of placebo, P < 0.05] despite a greater fall in insulin [-85 (176) vs. -20 (58) pmol/l, P = 0.05]. We conclude that, in well-controlled T2DM patients, whole body lipolysis is insulin resistant, and pioglitazone improves the insulin sensitivity of lipolysis. [ABSTRACT FROM AUTHOR]

OBJECTIVE--To quantitate the separate impact of obesity and hyperlycemia on the incretin effect (i.e., the gain in β-cell function after oral glucose versus intravenous glucose). RESEARCH DESIGN AND METHODS--Isoglycemic oral (75 g) and intravenous glucose administration was performed in 51 subjects (24 with normal glucose tolerance [NGT], 17 with impaired glucose tolerance [IGT], and 10 with type 2 diabetes) with a wide range of BMI (20-61 kg/m[sup 2]). C-peptide deconvolution was used to reconstruct insulin secretion rates, and β-cell glucose sensitivity (slope of the insulin secretion/glucose concentration doseresponse curve) was determined by mathematical modeling. The incretin effect was defined as the oral-to-intravenous ratio of responses. In 8 subjects with NGT and 10 with diabetes, oral glucose appearance was measured by the double-tracer technique. RESULTS--The incretin effect on total insulin secretion and β-cell glucose sensitivity and the GLP-1 response to oral glucose were significantly reduced in diabetes compared with NGT or IGT (P ≤ 0.05). The results were similar when subjects were stratified by BMI tertile (P ≤ 0.05). In the whole dataset, each manifestation of the incretin effect was inversely related to both glucose tolerance (2-h plasma glucose levels) and BMI (partial r = 0.27-0.59, P ≤ 0.05) in an independent, additive manner. Oral glucose appearance did not differ between diabetes and NGT and was positively related to the GLP-1 response (r = 0.53, P < 0.01). Glucagon suppression during the oral glucose tolerance test was blunted in diabetic patients. CONCLUSIONS--Potentiation of insulin secretion, glucose sensing, glucagon-like peptide-1 release, and glucagon suppression are physiological manifestations of the incretin effect. Glucose tolerance and obesity impair the incretin effect independently of one another. Diabetes 57:1340-1348, 2008 [ABSTRACT FROM AUTHOR]

Elevated plasma FFA cause β-cell lipotoxicity and impair insulin secretion in nondiabetic subjects predisposed to type 2 diabetes mellitus [T2DM; i.e., with a strong family history of T2DM (FH+)] but not in nondiabetic subjects without a family history of T2DM. To determine whether lowering plasma FFA with acipimox, an antilipolytic nicotinic acid derivative, may enhance insulin secretion, nine FH+ volunteers were admitted twice and received in random order either acipimox or placebo (double-blind) for 48 h. Plasma glucose/insulin/C-peptide concentrations were measured from 0800 to 2400. On day 3, insulin secretion rates (ISRs) were assessed during a +125 mg/dl hyperglycemic clamp. Acipimox reduced 48-h plasma FFA by 36% (P < 0.001) and increased the plasma C-peptide relative to the plasma glucose concentration or ΔC-peptide/Δglucose AUC (+ 177%, P = 0.02), an index of improved β-cell function. Acipimox improved insulin sensitivity (M/I) 26.1 ± 5% (P <0.04). First- (+ 19 ± 6%, P = 0.1) and second-phase (+31 ± 6%, P = 0.05) ISRs during the hyperglycemic clamp also improved. This was particularly evident when examined relative to the prevailing insulin resistance [1/(M/I)], as both first- and second-phase ISR markedly increased by 29 ± 7 (P < 0.05) and 41 ± 8% (P = 0.02). There was an inverse correlation between fasting FFA and first-phase ISR (r² = 0.31, P < 0.02) and acute (2-4 min) glucose-induced insulin release after acipimox (r² 0.52, P < 0.04). In this proof-of-concept study in FH+ individuals predisposed to T2DM, a 48-h reduction of plasma FFA improves day-long meal and glucose-stimulated insulin secretion. These results provide additional evidence for the important role that plasma FFA play regarding insulin secretion in FH+ subjects predisposed to T2DM. [ABSTRACT FROM AUTHOR]

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 β-cell function. The aim of this study was to determine whether TZD-induced improvement in glycemic control is associated with improved β-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-2min-1) clamp with [3-³H]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 [ΔSR(AUC)/Δglucose(AUC) ÷ IR] was significantly improved in all TZD-treated groups: + 1.8 ± 0.7 (PlO + drug-naive diabetics), +0.7 ± 0.3 (PlO + 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 β-cell function, which correlates strongly with improved glycemic control. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- We sought to examine the mechanisms by which the addition of glargine insulin or rosiglitazone improves glycemic control in type 2 diabetic subjects poorly controlled on maximally effective doses of metformin plus sulfonylurea. RESEARCH DESIGN AND METHODS -- Subjects (aged 47 ± 11 years, BMI 31 ± 5 kg/m², HbA[sub 1c] [A1C] 9.4 ± 1.3%) received bedtime glargine insulin (titrated based on the fasting plasma glucose [FPG], n = 10) or rosiglitazone (4 mg twice daily, n = 10). At baseline and after 4 months, A1C was measured and an oral glucose tolerance test and a 3-h euglycemic insulin (80 mU/m² per min) clamp with [3-³H] glucose were performed. RESULTS -- A1C and FPG decreased similarly in the glargine insulin (9.1 ± 0.4 to 7.6 ± 0.3% and 212 ± 14 to 139 ± 5 mg/dl, respectively, both P < 0.0001) and rosiglitazone (9.4 ± 0.3 to 7.6 ± 0.4% and 223 ± 14 to 160 ± 19 mg/dl, respectively, both P < 0.005) groups. After 4 months, endogenous glucose production (EGP) declined similarly with glargine insulin (2.27 ± 0.10 to 1.73 ± 0.12 mg ⋅ kg-1 ⋅ min-1, P < 0.0001) and rosiglitazone (2.21 ± 0.12 to 1.88 ± 0.12 mg ⋅ kg-1 ⋅ min-1, P = 0.01). The hepatic insulin resistance index declined in the rosiglitazone group (32 ± 3 to 21 ± 1 mg ⋅ kg-1 ⋅ min-1 x µU/ml, P = 0.03 vs. baseline and P < 0.05 vs. glargine insulin) and did not change in the glargine group (22 ± 5 to 20 ± 3 mg ⋅ kg-1 ⋅ min-1 x µU/ml, P = NS). At 4 months, glargine insulin (3.6 ± 0.5 to 4.2 4- 0.4 mg ⋅ kg-1 ⋅ min-1, P < 0.01) and rosiglitazone (2.7 ± 0.3 to 3.8 ± 0.3 mg ⋅ kg-1 ⋅ min-1, P < 0.0005) increased Rd, but the increment was greater in the rosiglitazone group (P < 0.05). Diastolic blood pressure was reduced only by rosiglitazone (P < 0.01). CONCLUSIONS -- Triple therapy with glargine insulin or rosiglitazone similarly reduced A1C, primarily by suppressing basal EGP (hepatic). Glargine insulin reduced basal EGP by increasing plasma insulin levels, while rosiglitazone decreased basal hepatic glucose production by improving hepatic insulin sensitivity. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- We studied the effects of the oral insulin secretagogue nateglinide on insulin secretion using a modeling approach to obtain β-cell function parameters from a meal test and examined the impact of the β-cell improvement on glucose tolerance. RESEARCH DESIGN AND METHODS -- Mild type 2 diabetic men and women (n = 108; fasting glucose 7.0-8.3 mmol/l) on diet treatment alone randomly received 30, 60, or 120 mg nateglinide or placebo for 24 weeks. β-Cell function parameters were derived by modeling (based on C-peptide deconvolution) from a standardized meal test at baseline and after 24 weeks of treatment. RESULTS -- The baseline demographic and metabolic characteristics of the four groups were similar. Nateglinide treatment resulted in dose-dependent reductions in the mean postprandial glucose response and at the 120-mg dose in fasting glucose. Fasting or total insulin secretion during the meal were not different. In contrast, we found differences in the model parameters. Rate sensitivity (expressing early insulin secretion when glucose is rising) was significantly enhanced at 24 weeks with the lowest nateglinide dose, with no further stimulation at higher doses. Early potentiation (expressing an initial insulin secretion enhancement), glucose sensitivity (the slope of the glucose-insulin secretion relationship), and insulin secretion at a fixed-reference 7-mmol/l glucose concentration all showed a trend toward increasing, with increasing nateglinide dose, and were significantly greater than placebo at the 120-mg dose. In multiple regression analyses, changes in rate sensitivity, glucose sensitivity, and potentiation all contributed to the observed glucose changes. CONCLUSIONS -- The model-derived parameters are sensitive measures of β-cell function, showing improvements after nateglinide treatment and predicting changes in glucose tolerance. [ABSTRACT FROM AUTHOR]

Acute elevations in free fatty acids (FFAs) stimulate insulin secretion, but prolonged lipid exposure impairs β-cell function in both in vitro studies and in vivo animal studies. In humans data are limited to short-term (≤48 h) lipid infusion studies and have led to conflicting results. We examined insulin secretion and action during a 4-day lipid infusion in healthy normal glucose tolerant subjects with (FH+ group, n = 13) and without (control subjects, n = 8) a family history of type 2 diabetes. Volunteers were admitted twice to the clinical research center and received, in random order, a lipid or saline infusion. On days 1 and 2, insulin and C-peptide concentration were measured as part of a metabolic profile after standardized mixed meals. Insulin secretion in response to glucose was assessed with a +125 mg/dl hyperglycemic clamp on day 3. On day 4, glucose turnover was measured with a euglycemic insulin clamp with [3-³H]glucose. Day-long plasma FFA concentrations with lipid infusion were increased within the physiological range, to levels seen in type 2 diabetes (∼500-800 µmol/l). Lipid infusion had strikingly opposite effects on insulin secretion in the two groups. After mixed meals, day-long plasma C-peptide levels increased with lipid infusion in control subjects but decreased in the FH+ group (+28 vs. -30%, respectively, P < 0.01). During the hyperglycemic clamp, lipid infusion enhanced the insulin secretion rate (ISR) in control subjects but decreased it in the FH+ group (first phase: +75 vs. -60%, P < 0.001; second phase: +25 vs. -35%, P < 0.04). When the ISR was adjusted for insulin resistance (ISR[sub Rd] = ISR ÷ [1/R[sub d]], where R[sub d] is the rate of insulin-stimulated glucose disposal), the inadequate β-cell response in the FH+ group was even more evident. Although ISR[sub Rd] was not different between the two groups before lipid infusion, in the FH+ group, lipid infusion reduced first- and second-phase ISR[sub Rd] to 25 and 42% of that in control subjects, respectively (both P < 0.001 vs. control subjects). Lipid infusion in the FH+ group (but not in control subjects) also caused severe hepatic insulin resistance with an increase in basal endogenous glucose production (EGP), despite an elevation in fasting insulin levels, and impaired suppression of EGP to insulin. In summary, in individuals who are genetically predisposed to type 2 diabetes, a susrained physiological increase in plasma FFA impairs insulin secretion in response to mixed meals and to intravenous glucose, suggesting that in subjects at high risk of developing type 2 diabetes, β-cell lipotoxicity may play an important role in the progression from normal glucose tolerance to overt hyperglycemia. [ABSTRACT FROM AUTHOR]

We developed a mathematical model of the glucose control of insulin secretion capable of quantifying beta-cell function from a physiological meal test. The model includes a static control, i.e., a secretion component that is a function of plasma glucose concentration (the dose-response function), and a dynamic control, i.e., a secretion component that is proportional to the positive values of the glucose concentration derivative. Furthermore, the dose-response function is assumed to be modulated by a time-varying potentiation factor. To test the model, nine nondiabetic control subjects and nine type 2 diabetic patients received three standardized mixed meals over a period of 14-15 h. Blood samples were drawn for the measurement of glucose, insulin, and C-peptide concentration. The dose-response function, the parameter of the dynamic control, and the potentiation factor were determined by fitting the model to glucose and C-peptide concentrations. In diabetic patients, the dose-response function was shifted to the right (glucose concentration at a reference insulin secretion of 300 pmol.min(-1).m(-2) was 11.7 +/- 1.1 vs. 7.2 +/- 0.7 mmol/l; P < 0.05), and decreased in slope (53 +/- 15 vs. 148 +/- 38 pmol.min(-1).m(-2).mmol(-1).l; P < 0.05) and the parameter of the dynamic control was decreased (220 +/- 67 vs. 908 +/- 276 pmol.m(-2).mmol(-1).l; P < 0.05) compared with the nondiabetic control subjects. Furthermore, potentiation was markedly blunted and delayed: maximum potentiation was observed at the first meal in normal subjects and at the second meal (about 4 h later) in diabetic subjects; the mean time for the potentiation factor was higher (7.1 +/- 0.2 vs. 5.9 +/- 0.2 h; P < 0.01), and the size of potentiation was reduced (2.6 +/- 0.5 vs. 7.2 +/- 1.5 fold increase; P < 0.005). In conclusion, our model of insulin secretion extracts multiple indexes of beta-cell function from a physiological meal test. Use of the model in patients with type 2 diabetes retrieves known defects in insulin secretion but also uncovers new facets of beta-cell dysfunction. [ABSTRACT FROM AUTHOR]

The contribution of gluconeogenesis (GNG) to endogenous glucose output (EGO) in type 2 diabetes is controversial. Little information is available on the separate influence of obesity on GNG. We measured percent GNG (by the 2H2O technique) and EGO (by 6,6-[2H]glucose) in 37 type 2 diabetic subjects (9 lean and 28 obese, mean fasting plasma glucose [FPG] 8.3 +/- 0.3 mmol/l) and 18 control subjects (6 lean and 12 obese) after a 15-h fast. Percent GNG averaged 47 +/- 5% in lean control subjects and was significantly increased in association with both obesity (P < 0.01) and diabetes (P = 0.004). By multivariate analysis, percent GNG was independently associated with BMI (partial r = 0.27, P < 0.05, with a predicted increase of 0.9% per BMI unit) and FPG (partial r = 0.44, P = 0.0009, with a predicted increase of 2.7% per mmol/l of FPG). In contrast, EGO was increased in both lean and obese diabetic subjects (15.6 +/- 0.5 micromol x min(-1) x kg(-1) of fat-free mass, n = 37, P = 0.002) but not in obese nondiabetic control subjects (13.1 0.7, NS) as compared with lean control subjects (12.4 +/- 1.4). Consequently, gluconeogenic flux (percent GNG x EGO) was increased in obesity (P = 0.01) and markedly elevated in diabetic subjects (P = 0.0004), whereas glycogenolytic flux was reduced only in association with obesity (P = 0.05). Fasting plasma glucagon levels were significantly increased in diabetic subjects (P < 0.05) and positively related to EGO, whereas plasma insulin was higher in obese control subjects than lean control subjects (P = 0.05) and unrelated to measured glucose fluxes. We conclude that the percent contribution of GNG to glucose release after a 15-h fast is independently and quantitatively related to the degree of overweight and the severity of fasting hyperglycemia. In obese individuals, reduced glycogenolysis ensures a normal rate of glucose output. In diabetic individuals, hyperglucagonemia contributes to inappropriately elevated rates of glucose output from both GNG and glycogenolysis. [ABSTRACT FROM AUTHOR]

Raised plasma triglycerides (TGs) and nonesterified fatty acid (NEFA) concentrations are thought to play a role in the pathogenesis of insulin-resistant diabetes. We report on two sisters with extreme hypertriglyceridemia and overt diabetes, in whom surgical normalization of TGs cured the diabetes. In all of the family members (parents, two affected sisters, ages 18 and 15 years, and an 11-year-old unaffected sister), we measured oral glucose tolerance, insulin sensitivity (by the euglycemic-hyperinsulinemic clamp technique), substrate oxidation (indirect calorimetry), endogenous glucose production (by the [6,6-2H2]glucose technique), and postheparin plasma lipoprotein lipase (LPL) activity. In addition, GC-clamped polymerase chain reaction-amplified DNA from the promoter region and the 10 coding LPL gene exons were screened for nucleotide substitution. Two silent mutations were found in the father's exon 4 (Glu118 Glu) and in the mother's exon 8 (Thr361 Thr), while a nonsense mutation (Ser447 Ter) was detected in the mother's exon 9. Mutations in exons 4 and 8 were inherited by the two affected girls. At 1-2 years after the appearance of hyperchylomicronemia, both sisters developed hyperglycemia with severe insulin resistance. Because medical therapy (including high-dose insulin) failed to reduce plasma TGs or control glycemia, lipid malabsorption was surgically induced by a modified biliopancreatic diversion. Within 3 weeks of surgery, plasma TGs and NEFA and cholesterol levels were drastically lowered. Concurrently, fasting plasma glucose levels fell from 17 to 5 mmol/l (with no therapy), while insulin-stimulated glucose uptake, oxidation, and storage were all markedly improved. Throughout the observation period, plasma TG levels were closely correlated with both plasma glucose and insulin concentrations, as measured during the oral glucose tolerance test. These cases provide evidence that insulin-resistant diabetes can be caused by extremely high levels of TGs. [ABSTRACT FROM AUTHOR]

Resveratrol is a biologically active diphenolic compound exerting multiple beneficial effects in the organism, including anti-diabetic properties. This action is, however, not fully elucidated. In the present study, we examined effects of resveratrol on some parameters related to insulin signaling, and also on diabetes-associated dysregulation in Goto-Kakizaki (GK) rats with congenital type 2 diabetes. Resveratrol was given at the dose of 20 mg/kg b.w. for 10 weeks. It was shown that the expression and phosphorylation levels of insulin receptor in the skeletal muscle of GK rats were significantly decreased, compared with control animals. However, these changes were totally prevented by resveratrol. Liver expression of the insulin receptor was also reduced, but in this case, resveratrol was ineffective. Resveratrol was also demonstrated to significantly influence parameters of insulin binding (dissociation constant and binding capacity) in the skeletal muscle and liver. Moreover, it was shown that the expression levels of proteins related to intracellular glucose transport (GLUT4 and TUG) in adipose tissue of GK rats were significantly decreased. However, treatment with resveratrol completely abolished these changes. Resveratrol was found to induce normalization of TUG expression in the skeletal muscle. Blood levels of insulin and GIP were elevated, whereas proinsulin and GLP-1 diminished in GK rats. However, concentrations of these hormones were not affected by resveratrol. These results indicate that resveratrol partially ameliorates diabetes-associated dysregulation in GK rats. The most relevant finding covers the normalization of the insulin receptor expression in the skeletal muscle and also GLUT4 and TUG in adipose tissue. [ABSTRACT FROM AUTHOR]

Hepatic insulin clearance, a physiological process that in response to nutritional cues clears ~50–80% of circulating insulin, is emerging as an important factor in our understanding of the pathogenesis of type 2 diabetes mellitus (T2DM). Insulin-degrading enzyme (IDE) is a highly conserved Zn2+-metalloprotease that degrades insulin and several other intermediate-size peptides. Both, insulin clearance and IDE activity are reduced in diabetic patients, albeit the cause-effect relationship in humans remains unproven. Because historically IDE has been proposed as the main enzyme involved in insulin degradation, efforts in the development of IDE inhibitors as therapeutics in diabetic patients has attracted attention during the last decades. In this review, we retrace the path from Mirsky's seminal discovery of IDE to the present, highlighting the pros and cons of the development of IDE inhibitors as a pharmacological approach to treating diabetic patients. [ABSTRACT FROM AUTHOR]

The author discusses the study "Relation of central adiposity and body mass index to the development of diabetes in the Diabetes Prevention Program," by G. A. Bray and colleagues. Topics discussed include the importance of free fatty acids as regulators of glucose metabolism, a Diabetes Prevention Program (DPP) study on metformin treatment effect, and lifestyle intervention as one of the ways to reduce diabetes incidence.

Glucagon-like peptide-1 (GLP-1) is released in response to meals and exerts important roles in the maintenance of normal glucose homeostasis. GLP-1 is also important in the regulation of neurologic and cognitive functions. These actions are mediated via neurons in the nucleus of the solitary tract that project to multiple regions expressing GLP-1 receptors (GLP-1Rs). Treatment with GLP-1R agonists (GLP-1-RAs) reduces ischemia-induced hyperactivity, oxidative stress, neuronal damage and apoptosis, cerebral infarct volume, and neurologic damage, after cerebral ischemia, in experimental models. Ongoing human trials report a neuroprotective effect of GLP-1-RAs in Alzheimer's and Parkinson's disease. In this review, we discuss the role of GLP-1 and GLP-1-RAs in the nervous system with focus on GLP-1 actions on appetite regulation, glucose homeostasis, and neuroprotection. [ABSTRACT FROM AUTHOR]

Abstract: In the natural history of type 2 diabetes (T2DM), individuals progress from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) to overt T2DM and this progression has been demonstrated in populations of diverse ethnic background. It is widely recognised that both insulin resistance and beta-cell dysfunction are important in the pathogenesis of glucose intolerance. In populations with a high prevalence of T2DM, insulin resistance is well established long before the development of any impairment in glucose homeostasis, particularly in subjects with ectopic fat accumulation. However, as long as the beta cell is able to secrete sufficient amounts of insulin to offset the severity of insulin resistance, glucose tolerance remains normal. This dynamic interaction between insulin secretion and insulin resistance is essential to the maintenance of NGT and interruption of this crosstalk between the beta cell and peripheral tissues results in the progressive deterioration of glucose homeostasis. In this paper the role of beta-cell function is reviewed, as well as the role of ectopic fat accumulation and insulin resistance in the development of type 2 diabetes. [Copyright &y& Elsevier]

A sustained physiologic elevation of plasma FFA induced by lipid infusion impairs insulin secretion in lean normal glucose-tolerant (NGT) subjects genetically predisposed to T2DM (both parents with T2DM; FH+). Whether insulin secretion is further impaired by a combined elevation of plasma FFA and glucose cone. has not been previously examined in Mexican-American (MxAm) FH+. To this end, we studied the effect of a 48-hour lipid +/- glucose infusion on insulin secretion in 8 MxAmFH+ (43±5yr, BMI=25±0.9 kg/m2, FPG=94±4 mg/dl) and 8 healthy NGT MxAm matched-controls (CON) without a family history of T2DM (35±4yr, BMI=25.5±0.9 kg/m2, FPG=93±1 mg/dl). On separate GCRC admissions, subjects received either an infusion of saline (SAL-control), low-dose lipid (LIP; 30 ml/h), combined lipid+glucose (LIP+GLU; target plasma glucose 120 mg/dl) or glucose only (GLU). On day 3, a +125 mg/dL hyperglycemic clamp was performed to assess insulin secretion rates (ISR), calculated by deconvolution analysis of plasma C-peptide cone. Mean 48-hour plasma FFA were comparable during SAL (CON vs. FH+: 311±41 vs. 350±28 mmol/L) and increased similarly with LIP (556±61 vs. 613±56 mmol/L). During LIP+GLU and GLU admissions, mean plasma glucose and FFA (420±43 vs. 414±30 mmol/L and 105±7 vs. 105±12 mmol/L, respectively; all p<0.01 vs. SAL) were well matched between groups. LIP had contrasting effects on beta-cell function in CON vs. FH+ subjects. In CON, the increase above baseline (delta) in first (0-10 min) and second (10-120 min) phase ISR was significant with LIP (1st ph= + 17%; 2nd ph= + 10%, both p<0.05 vs. SAL) and GLU+LIP (NS vs. LIP), while GLU further stimulated ISR (1st and 2nd ph vs. LIP, p=0.04; vs. SAL: <0.01). In contrast, in MxAmFH+ ISR was frankly reduced by LIP compared to SAL (1st ph: -34%; and 2nd ph - 14%, both p<0.05 vs. SAL, p<0.05-01 vs. CON). However, the 48-h hyperglycemia of LIP+GLU stimulated rather than impaired both 1st (+97%) and 2nd (+47%) ph ISR (both p<0.05 vs. LIP), as also did GLU (1st ph= +81%, p<0.02; 2nd ph= +20%, p<0.07 vs. LIP). Conclusion: In lean CON, neither elevated FFA or hyperglycemia impaired ISR. However, lean MxAmFH+ subjects displayed a unique susceptibility to a mild and physiological 48-hour increase in plasma FFA. Hyperglycemia had no deleterious effect, but rather reversed lipid-induced beta-cell dysfunction in MxAmFH+ subjects genetically predisposed to T2DM. [ABSTRACT FROM AUTHOR]

Background and Aims: A sustained physiologic elevation of plasma FFA induced by lipid infusion impairs insulin secretion in lean normal glucose-tolerant (NGT) subjects genetically predisposed to T2DM (both parents with T2DM; FH+), but the effect in obese pts has not been previously examined in Mexican-American (MxAm) FH+. To this end, we studied the effect of a 48-hour lipid infusion on insulin secretion in 8 obese NGT MxAmFH+ (OBFH+) (42±4yr, BMI=33.5±1.5 kg/m2, FPG=95±3 mg/dl) and 8 obese NGT MxAm matched-controls (OB-CON) without a family history of T2DM (40±5yr, BMI=30.0±0.9 kg/m2, FPG=97±:3mg/dl). We also compared results with 8 NGT lean MxAmFH+ (L-FH+) (43±5yr, BMI=25±0.9 kg/m2, FPG=94±4 mg/dl) and 8 lean MxAm matched-controls (L-CON) without a family history of T2DM (35±4yr, BMI=25.5±0.9 kg/m2, FPG=93±1mg/dl). Materials and Methods: Pts were admitted twice to the research unit and received either an infusion of saline (SAL-control) or low-dose lipid (LIP; 30 ml/h; target FFA 2-fold elevation). On day 3, a +125 mg/dL hyperglycemic clamp was performed to assess insulin sensitivity (M/I) and secretion rates (ISR) by deconvolution analysis of plasma C-peptide conc. Results: Mean 48-hour plasma FFA were comparable during SAL (NS) in obese subjects and increased similarly by ∼70% with LIP (p<0.01 vs. SAL; NS between groups).Obese FH+ and CON subjects were insulin resistant (M/I) compared to their respective lean controls (p<0.01). During SAL, both OB FH+ and CON groups had a higher increase above baseline (delta) in first (0-10 min; 1st ph) and second (10-120 min; 2nd ph) phase ISR: L-FH+ vs. OB-FH+ and L-CON vs. OB-CON (both p<0.01). When ISR was expressed taking into account insulin sensitivity, 1st ph (-19%) and 2nd ph (-16%) ISR was lower in OB-FH+ compared to OB-CON (both p<0.05). During LIP, ISR was also lower in L-FH+ and L-CON (1st ph: -60% and -32%, 2nd ph:-31% and -42%, respectively, all p<0.01 vs. the respective obese group). Insulin resistance was not further exacerbated by LIP in either OB-FH + vs. OB-CON. In OB-FH+ vs OB-CON, 1st ph (-30%) and 2nd ph (-26%) ISR remained significantly lower when taking into account insulin sensitivity during LIP (both p<0.05). LIP infusion caused a greater reduction in both 1st ph and 2nd ph ISR (both p<0.05) in L-FH+ compared to OB-FH+. Conclusion: Obesity is associated with a significant increase in ISR in OB-FH+ vs. OB-CON. ISR in L-FH+ appears to be more susceptible to lipotoxicity than in OB-FH+. [ABSTRACT FROM AUTHOR]

Non-Alcoholic Steatohepatitis (NASH) is a chronic liver disease frequently associated with insulin resistance and type 2 diabetes mellitus (T2DM), and characterized by steatosis and necroinflammation with or without perisinusoidal fibrosis. We have recently reported that 6 months treatment with pioglitazone (PIO) reverses the metabolic and histological abnormalities of patients with IGT or T2DM and NASH, but also leads to weight gain. We performed a careful evaluation to understand the nature of weight gain associated with PIO treatment in NASH, as it may be important to establish the safety of its use in this population. To this end we analyzed a subgroup of 35 patients who completed the tests for determination of whole body fat (WBF) and total body water (TBW): 21 patients received PIO (9 IGT/12 T2DM) and 14 placebo (6 IGT/8 T2DM), in a double-blind, randomized fashion for a period of 6 months. WBF and TBW were measured before and after treatment using dual energy X-ray absorptiometry (DXA, Hologic Inc, Waltham, MA), a water dilution technique using 3H20 and bioimpedance. Results: PIO increased body weight (from 93.6±19.2 to 96.1±20.8 kg, p<0.003) and WBF as measured by DXA (from 31.8±8.3 to 33.9±9.6 kg, p<0.003) while no changes were seen with placebo. Total body water measured with 3H20 was not altered significantly either after PIO (from 45.0±10.5 to 45.3±9.6) or placebo (from 44.5±9.9 to 44.6±12.5 1), p=NS. Muscle hydration [(assessed by the ratio of TBW (measured with 3H20) over fat-free mass (measured with DXA)] was unchanged both by PIO (from 0.72±0.07 to 0.73±0.07, p=NS) and placebo treatments (from 0.75±0.06 to 0.72±0.061/kg, p=NS). Extracellular water (measured with bioimpedance) was unchanged both in PIO (from 18.2±3.5 to 18.6±3.4) and in placebo (from 19.3±3.1 to 19.6±3.31), p=NS. Conclusion: Six months of PIO treatment in patients with IGT or T2DM and NASH is associated with mild to moderate weight gain that is attributable to an increase in adipose tissue mass and not to water retention. [ABSTRACT FROM AUTHOR]

Aims: Non-Alcoholic Fatty Liver Disease (NAFLD) and type 2 diabetes (T2D) share pathophysiological mechanisms and possible therapeutic strategies. We evaluated the effects of 1-year treatment with pioglitazone or sulphonylureas on indirect indices of NAFLD in people with T2D and the role of insulin-resistance and glucotoxicity in determining these effects.Methods: Patients with T2D (n = 195) aged 50-75 years, poorly controlled with metformin 2 g/day, were randomly allocated to add-on pioglitazone (n = 98) or sulphonylureas (n = 97) within the TOSCA.IT trial. Plasma insulin, glucose, and liver enzymes were measured at baseline and after 1-year. Indirect indices of NAFLD (Liver Fat Equation [LFE], Hepatic Steatosis Index [HSI], and Index of NASH [ION]), and insulin resistance (HOMA-IR, Visceral Adiposity Index [VAI] and adipose tissue Insulin Resistance [ADIPO-IR]) were calculated.Results: Indices of NAFLD improved after pioglitazone, but not after sulphonylureas; differences between changes (1-year minus baseline) were respectively: -1.76 ± 3.84 vs. 0.28 ± 3.75 for LFE; -1.35 ± 2.78 vs. -0.27 ± 2.63 for HSI; -9.75 ± 43 vs. 3.24 ± 31 for ION; p < 0.05 for all. Indices of insulin resistance decreased after pioglitazone, but not after sulphonylureas: -0.95 ± 4.57 vs. 0.37 ± 3.34 for HOMA-IR, p = 0.032; -1.25 ± 4.11 vs. 1.36 ± 5.43 for ADIPO-IR, p = 0.001; -0.53 ± 1.88 vs. 0.03 ± 2.36 for VAI, p = 0.074. Changes in NAFLD indices were similar with different doses of pioglitazone (15, 30, or 45 mg/day), and were independent of blood glucose control.Conclusions: One-year treatment with pioglitazone even at low dosage significantly improved liver steatosis and inflammation, systemic and adipose tissue insulin resistance in patients with T2D. The beneficial effects of pioglitazone on NAFLD were independent of blood glucose control. [ABSTRACT FROM AUTHOR]

Phthalates are non-persistent pollutants related to impaired metabolism and high cardiovascular risk. Their toxic metabolites are eliminated through urine and feces. Prevention policies are considered by the governments, although no therapeutic strategy to facilitate their elimination from the human body has been proposed so far. Aim of the present study was to verify, for the first time in humans, whether diuretics might be able to enhance phthalates' toxic metabolites urinary output. We conducted a two-armed, parallel-design, randomized clinical trial. Thirty patients with type 2 diabetes and hypertension received a four week-treatment with Dapagliflozin 10 mg or Hydrochlorothiazide 12.5 mg. 24-hours urine were collected to measure urinary excretion of three major 2-ethylhexyl-phthalate (DEHP) metabolites, i.e. mono 2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP) and mono 2-ethyl-5-hydroxyhexyl phthalate (MEHHP). 24-h urinary excretion of DEHP and MEHP was increased (+44%, p = 0.036; +49%, p = 0.0016) while MEOHP e MEHHP showed only a positive trend (+25%, p = 0.016; +36%, p = 0.062). Irrespective of the specific treatment, induced variations of daily urinary eliminations of MEHP metabolites were related with the 24-h urinary sodium (r = 0.42, p = 0.0226) and potassium (r = 0.54, p = 0.0026) excretion. Also, DEHP and MEOHP were related to sodium (r = 0·43, p = 0.0205; r = 0·44, p = 0.0168 respectively) but not to potassium. Urinary phthalates excretion seems to occur mainly through sodium- and potassium-related mechanisms, apparently independent from the different diuretic effect. Both thiazide diuretics and SLGT2 inhibitors are effective into the removal of phthalates metabolites from the human body, reducing the human tissues' exposure to their toxicity. • SGLT2i or thiazide increases urinary excretion of phthalates metabolites. • The effect is independent from the diuretic class. • The increase of urinary MEHP excretion is positively related to sodium one. • Through diuretics, it is possible to enhance phthalates elimination from the body. • Urine samples might lead to overestimate exposure if subjects are on diuretics. [ABSTRACT FROM AUTHOR]