Pioglitazone reduces epicardial fat and improves diastolic function in patients with type 2 diabetes.

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.

FGF21 contributes to metabolic improvements elicited by combination therapy with exenatide and pioglitazone in patients with type 2 diabetes.

Fibroblast growth factor 21 (FGF21) is increased acutely by carbohydrate ingestion and is elevated in patients with type 2 diabetes (T2D). However, the physiological significance of increased FGF21 in humans remains largely unknown. We examined whether FGF21 contributed to the metabolic improvements observed following treatment of patients with T2D with either triple (metformin/pioglitazone/exenatide) or conventional (metformin/insulin/glipizide) therapy for 3 yr. Forty-six patients with T2D were randomized to receive either triple or conventional therapy to maintain HbA1c < 6.5%. A 2-h 75-g oral glucose tolerance test (OGTT) was performed at baseline and following 3 years of treatment to assess glucose tolerance, insulin sensitivity, and ß-cell function. Plasma total and bioactive FGF21 levels were quantitated before and during the OGTT at both visits. Patients in both treatment arms experienced significant improvements in glucose control, but insulin sensitivity and ß-cell function were markedly increased after triple therapy. At baseline, FGF21 levels were regulated acutely during the OGTT in both groups. After treatment, fasting total and bioactive FGF21 levels were significantly reduced in patients receiving triple therapy, but there was a relative increase in the proportion of bioactive FGF21 compared with that observed in conventionally treated subjects. Relative to baseline studies, triple therapy treatment also significantly modified FGF21 levels in response to a glucose load. These changes in circulating FGF21 were correlated with markers of improved glucose control and insulin sensitivity. Alterations in the plasma FGF21 profile may contribute to the beneficial metabolic effects of pioglitazone and exenatide in human patients with T2D.NEW & NOTEWORTHY In patients with T2D treated with a combination of metformin/pioglitazone/exenatide (triple therapy), we observed reduced total and bioactive plasma FGF21 levels and a relative increase in the proportion of circulating bioactive FGF21 compared with that in patients treated with metformin and sequential addition of glipizide and basal insulin glargine (conventional therapy). These data suggest that FGF21 may contribute, at least in part, to the glycemic benefits observed following combination therapy in patients with T2D.

Combination therapy with pioglitazone/exenatide/metformin reduces the prevalence of hepatic fibrosis and steatosis: The efficacy and durability of initial combination therapy for type 2 diabetes (EDICT).

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.

Bromocriptine-QR Therapy Reduces Sympathetic Tone and Ameliorates a Pro-Oxidative/Pro-Inflammatory Phenotype in Peripheral Blood Mononuclear Cells and Plasma of Type 2 Diabetes Subjects.

Bromocriptine-QR is a sympatholytic dopamine D2 agonist for the treatment of type 2 diabetes that has demonstrated rapid (within 1 year) substantial reductions in adverse cardiovascular events in this population by as yet incompletely delineated mechanisms. However, a chronic state of elevated sympathetic nervous system activity and central hypodopaminergic function has been demonstrated to potentiate an immune system pro-oxidative/pro-inflammatory condition and this immune phenotype is known to contribute significantly to the advancement of cardiovascular disease (CVD). Therefore, the possibility exists that bromocriptine-QR therapy may reduce adverse cardiovascular events in type 2 diabetes subjects via attenuation of this underlying chronic pro-oxidative/pro-inflammatory state. The present study was undertaken to assess the impact of bromocriptine-QR on a wide range of immune pro-oxidative/pro-inflammatory biochemical pathways and genes known to be operative in the genesis and progression of CVD. Inflammatory peripheral blood mononuclear cell biology is both a significant contributor to cardiovascular disease and also a marker of the body's systemic pro-inflammatory status. Therefore, this study investigated the effects of 4-month circadian-timed (within 2 h of waking in the morning) bromocriptine-QR therapy (3.2 mg/day) in type 2 diabetes subjects whose glycemia was not optimally controlled on the glucagon-like peptide 1 receptor agonist on (i) gene expression status (via qPCR) of a wide array of mononuclear cell pro-oxidative/pro-inflammatory genes known to participate in the genesis and progression of CVD (OXR1, NRF2, NQO1, SOD1, SOD2, CAT, GSR, GPX1, GPX4, GCH1, HMOX1, BiP, EIF2α, ATF4, PERK, XBP1, ATF6, CHOP, GSK3ß, NFkB, TXNIP, PIN1, BECN1, TLR2, TLR4, TLR10, MAPK8, NLRP3, CCR2, GCR, L-selectin, VCAM1, ICAM1) and (ii) humoral measures of sympathetic tone (norepinephrine and normetanephrine), whole-body oxidative stress (nitrotyrosine, TBARS), and pro-inflammatory factors (IL-1ß, IL-6, IL-18, MCP-1, prolactin, C-reactive protein [CRP]). Relative to pre-treatment status, 4 months of bromocriptine-QR therapy resulted in significant reductions of mRNA levels in PBMC endoplasmic reticulum stress-unfolded protein response effectors [GRP78/BiP (34%), EIF2α (32%), ATF4 (29%), XBP1 (25%), PIN1 (14%), BECN1 (23%)], oxidative stress response proteins [OXR1 (31%), NRF2 (32%), NQO1 (39%), SOD1 (52%), CAT (26%), GPX1 (33%), GPX4 (31%), GCH1 (30%), HMOX1 (40%)], mRNA levels of TLR pro-inflammatory pathway proteins [TLR2 (46%), TLR4 (20%), GSK3ß (19%), NFkB (33%), TXNIP (18%), NLRP3 (32%), CCR2 (24%), GCR (28%)], mRNA levels of pro-inflammatory cellular receptor proteins CCR2 and GCR by 24% and 28%, and adhesion molecule proteins L-selectin (35%) and VCAM1 (24%). Relative to baseline, bromocriptine-QR therapy also significantly reduced plasma levels of norepinephrine and normetanephrine by 33% and 22%, respectively, plasma pro-oxidative markers nitrotyrosine and TBARS by 13% and 10%, respectively, and pro-inflammatory factors IL-18, MCP1, IL-1ß, prolactin, and CRP by 21%,13%, 12%, 42%, and 45%, respectively. These findings suggest a unique role for circadian-timed bromocriptine-QR sympatholytic dopamine agonist therapy in reducing systemic low-grade sterile inflammation to thereby reduce cardiovascular disease risk.

Antihyperglycemic Algorithms for Type 2 Diabetes: Focus on Nonglycemic Outcomes.

Type 2 diabetes management continues to increase in complexity as more pharmacologic medication classes become available and high-quality clinical trials are completed. Because many antihyperglycemic agents could be appropriate for a given patient, expert treatment guidance is indispensable. Algorithms can help to guide clinicians toward initiating more evidence-based therapy and critically thinking about patient-centered factors that may influence their medication choices. High-quality cardiovascular, renal, and heart failure outcomes trials completed in the past several years have changed the paradigm of how we think about antihyperglycemic agents. Considerations for atherosclerotic cardiovascular disease, heart failure, and renal insufficiency now figure prominently in treatment algorithms for type 2 diabetes, and the results of recent outcomes trials have significantly transformed algorithmic guidelines published by diabetes, endocrinology, and cardiology associations.

Anti-inflammatory and anti-proliferative action of adiponectin mediated by insulin signaling cascade in human vascular smooth muscle cells.

After confirmation of the presence of adiponectin (ADPN) receptors and intra-cellular binding proteins in coronary artery smooth muscle cells (VSMC), we tested the hypotheses that, in acute insulin resistance: (i) the activation/inactivation of metabolic and mitogenic insulin signaling pathways are inversely affected by ADPN and, (ii) changes in VSMC migration/proliferation rates correlate with signal activity/inactivity. In primary cultures of VSMC exposed to high glucose and palmitate plus insulin, the expression of PI-3 kinase (Akt and m-TOR), MAP-Kinase (Erk and p-38) molecules, and inflammatory markers (TLR-4 and IkB-α) were assessed with Western blot, in the absence/presence of AdipoRon (AR). Migration and proliferation rates were measured in similar experimental conditions. There were decreases of ~ 25% (p-Akt) and 40-60% (p-mTOR) expressions with high glucose/palmitate, which reversed when AR was added were. Elevations in p-Erk and p-p38 expressions were obliterated by AR. Although, no changes were detected with high glucose and palmitate, when AR was added, a decline in inflammatory activity was substantiated by a ~ 50% decrease in TLR-4 and 40-60% increase in IkBα expression. Functional assays showed 10-20% rise in VSMC proliferation with high glucose and palmitate, but addition of AR lead to 15-25% decline. The degree of VSMC migration was reduced with AR addition by ~ 15%, ~ 35% and 55%, in VSMC exposed to 5 mM, 25 mM glucose and 25 mM + 200 µM palmitate, respectively. Changes in intracellular molecular messaging in experiments mimicking acute insulin resistance suggest that anti-inflammatory and anti-atherogenic actions of ADPN in VSMC are mediated via insulin signaling pathways.

Challenges of Diabetes Care in Older People With Type 2 Diabetes and the Role of Basal Insulin.

IN BRIEF The use of long-acting basal insulin analogs is a recommended strategy in older people with diabetes because of their lower risk of hypoglycemia compared to intermediate-acting insulins. In this article, we review the results from recent clinical trials of second-generation basal insulin preparations. We conclude that, although these preparations have improved the management of insulin-requiring older people with type 2 diabetes, there is a need for additional and more specific studies to address the complexities of hyperglycemia management in this population.

Initiating therapy in patients newly diagnosed with type 2 diabetes: Combination therapy vs a stepwise approach.

There is clear evidence that achieving glycaemic targets reduces the risk of developing complications as a result of type 2 diabetes (T2D). Many patients, however, continue to have suboptimal glycaemic control because of issues that include unclear advice on how to achieve these targets as well as clinical inertia. The two management approaches recommended for patients newly diagnosed with T2D are stepwise and combination therapy, each of which has advantages and disadvantages. Stepwise therapy may result in good patient adherence and allow greater individualization of therapy, and minimization of side effects and cost, and so may be appropriate for patients who are closer to goal. Stepwise therapy, however, may also lead to frequent delays in achieving glycaemic goals and longer exposure to hyperglycaemia. Combination therapy, which is now emerging as an important therapy option, has a number of potential advantages over stepwise therapy, including reduction in clinical inertia and earlier and more frequent achievement of glycated haemoglobin goals by targeting multiple pathogenic mechanisms simultaneously, which may more effectively delay disease progression. Compared with stepwise therapy, the disadvantages of combination therapy include reduced patient adherence resulting from complex, multi-drug regimens, difficulty determining the cause of poor efficacy and/or side effects, patient refusal to accept disease, and higher cost. Fixed-dose and fixed-ratio combinations are novel therapeutic approaches which may help address several issues of treatment complexity and patient burden associated with combination therapy comprising individual drugs. The choice of which drugs to administer and the decision to use stepwise vs combination therapy, however, should always be made on an individualized basis.

Exenatide improves both hepatic and adipose tissue insulin resistance: A dynamic positron emission tomography study.

Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1-RAs) act on multiple tissues, in addition to the pancreas. Recent studies suggest that GLP-1-RAs act on liver and adipose tissue to reduce insulin resistance (IR). Thus, we evaluated the acute effects of exenatide (EX) on hepatic (Hep-IR) and adipose (Adipo-IR) insulin resistance and glucose uptake. Fifteen male subjects (age = 56 ± 8 years; body mass index = 29 ± 1 kg/m2 ; A1c = 5.7 ± 0.1%) were studied on two occasions, with a double-blind subcutaneous injection of EX (5 µg) or placebo (PLC) 30 minutes before a 75-g oral glucose tolerance test (OGTT). During OGTT, we measured hepatic (HGU) and adipose tissue (ATGU) glucose uptake with [18 F]2-fluoro-2-deoxy-D-glucose/positron emission tomography, lipolysis (RaGly) with [U-2 H5 ]-glycerol, oral glucose absorption (RaO) with [U-13 C6 ]-glucose, and hepatic glucose production (EGP) with [6,6-2 H2 ]-glucose. Adipo-IR and Hep-IR were calculated as (FFA0-120min ) × (Ins0-120min ) and (EGP0-120min ) × (Ins0-120min ), respectively. EX reduced RaO, resulting in reduced plasma glucose and insulin concentration from 0 to 120 minutes postglucose ingestion. EX decreased Hep-IR (197 ± 28 to 130 ± 37; P = 0.02) and increased HGU of orally administered glucose (23 ± 4 to 232 ± 89 [µmol/min/L]/[µmol/min/kg]; P = 0.003) despite lower insulin (23 ± 5 vs. 41 ± 5 mU/L; P < 0.02). EX enhanced insulin suppression of RaGly by decreasing Adipo-IR (23 ± 4 to 13 ± 3; P = 0.009). No significant effect of insulin was observed on ATGU (EX = 1.16 ± 0.15 vs. PLC = 1.36 ± 0.13 [µmol/min/L]/[µmol/min/kg]). CONCLUSION: Acute EX administration (1) improves Hep-IR, decreases EGP, and enhances HGU and (2) reduces Adipo-IR, improves the antilipolytic effect of insulin, and reduces plasma free fatty acid levels during OGTT. (Hepatology 2016;64:2028-2037).

Determinants of the increase in ketone concentration during SGLT2 inhibition in NGT, IFG and T2DM patients.

AIM: To examine metabolic factors that influence ketone production after sodium-glucose cotransport inhibitor (SGLT2) administration. RESEARCH DESIGN AND METHODS: Fasting plasma glucose (FPG), insulin, glucagon, free fatty acid and ketone concentrations were measured in 15 type 2 diabetes mellitus (T2DM) and 16 non-diabetic subjects before and at day 1 and day 14 after treatment with empagliflozin. RESULTS: Empagliflozin caused a 38 mg/dL reduction in FPG concentration in T2DM patients. However, it caused only a small but significant (7 mg/dL) reduction in the FPG concentration in impaired fasting glucose (IFG) subjects and did not affect FPG concentration in normal glucose tolerant (NGT) subjects. Empagliflozin caused a significant increase in mean plasma glucagon, free fatty acid (FFA) and ketone concentrations in T2DM subjects. However, empagliflozin did not cause a significant change in mean plasma insulin, glucagon or ketone concentrations in non-diabetic subjects. An index that integrates change in plasma glucose, insulin and FFA concentration at day 1 strongly correlates with plasma ketone concentration at day 1 (r = 0.85, P < .001) and day 14 (r = 0.63, r = 0.01) and predicts, with 86% sensitivity and 83% specificity, subjects at the top tertile for plasma ketone concentration after empagliflozin treatment. CONCLUSION: Results of the present study demonstrate that SGLT2 inhibition exerts different metabolic effects in non-diabetic individuals as compared to diabetic patients.

Use of Canagliflozin in Combination With and Compared to Incretin-Based Therapies in Type 2 Diabetes.

In Brief Sodium-glucose cotransporter 2 (SGLT2) inhibitors and incretin-based therapies (dipeptidyl peptidase-4 [DPP-4] inhibitors and glucagon-like peptide-1 [GLP-1] receptor agonists) are widely used to treat patients with type 2 diabetes. In clinical and real-world studies, canagliflozin, an SGLT2 inhibitor, has demonstrated superior A1C lowering compared to the DPP-4 inhibitor sitagliptin. Canagliflozin can also promote modest weight/fat loss and blood pressure reduction. The addition of canagliflozin to treatment regimens that include a DPP-4 inhibitor or a GLP-1 receptor agonist has been shown to further improve glycemic control, while still maintaining beneficial effects on cardiometabolic parameters such as body weight and blood pressure. Overall, the available clinical and real-world evidence suggests that canagliflozin is a safe and well-tolerated treatment option that can be considered either in addition to or instead of incretin-based therapies for patients with type 2 diabetes.

Novel Agents for the Treatment of Type 2 Diabetes.

In Brief Impaired insulin secretion, increased hepatic glucose production, and decreased peripheral glucose utilization are the core defects responsible for the development and progression of type 2 diabetes. However, the pathophysiology of this disease also includes adipocyte insulin resistance (increased lipolysis), reduced incretin secretion/sensitivity, increased glucagon secretion, enhanced renal glucose reabsorption, and brain insulin resistance/neurotransmitter dysfunction. Although current diabetes management focuses on lowering blood glucose, the goal of therapy should be to delay disease progression and eventual treatment failure. Recent innovative treatment approaches target the multiple pathophysiological defects present in type 2 diabetes. Optimal management should include early initiation of combination therapy using multiple drugs with different mechanisms of action. This review examines novel therapeutic options that hold particular promise.

Effect of Dapagliflozin on Renal and Hepatic Glucose Kinetics in T2D and NGT Subjects.

Acute and chronic sodium-glucose cotransporter 2 (SGLT-2) inhibition increases endogenous glucose production (EGP). However, the organ-liver versus kidney-responsible for the increase in EGP has not been identified. In this study, 20 subjects with type 2 diabetes (T2D) and 12 subjects with normal glucose tolerance (NGT) received [3-3H]glucose infusion (to measure total EGP) combined with arterial and renal vein catheterization and para-aminohippuric acid infusion for determination of renal blood flow. Total EGP, net renal arteriovenous balance, and renal glucose production were measured before and 4 h after dapagliflozin (DAPA) and placebo administration. Following DAPA, EGP increased in both T2D and NGT from baseline to 240 min, while there was a significant time-related decrease after placebo in T2D. Renal glucose production at baseline was <5% of basal EGP in both groups and did not change significantly following DAPA in NGT or T2D. Renal glucose uptake (sum of tissue glucose uptake plus glucosuria) increased in both T2D and NGT following DAPA (P < 0.05 vs. placebo). The increase in renal glucose uptake was entirely explained by the increase in glucosuria. A single dose of DAPA significantly increased EGP, which primarily is explained by an increase in hepatic glucose production, establishing the existence of a novel renal-hepatic axis.

Genetic epidemiology of cardiometabolic risk factors and their clustering patterns in Mexican American children and adolescents: the SAFARI Study.

Pediatric metabolic syndrome (MS) and its cardiometabolic components (MSCs) have become increasingly prevalent, yet little is known about the genetics underlying MS risk in children. We examined the prevalence and genetics of MS-related traits among 670 non-diabetic Mexican American (MA) children and adolescents, aged 6-17 years (49 % female), who were participants in the San Antonio Family Assessment of Metabolic Risk Indicators in Youth study. These children are offspring or biological relatives of adult participants from three well-established Mexican American family studies in San Antonio, TX, at increased risk of type 2 diabetes. MS was defined as ≥3 abnormalities among 6 MSC measures: waist circumference, systolic and/or diastolic blood pressure, fasting insulin, triglycerides, HDL-cholesterol, and fasting and/or 2-h OGTT glucose. Genetic analyses of MS, number of MSCs (MSC-N), MS factors, and bivariate MS traits were performed. Overweight/obesity (53 %), pre-diabetes (13 %), acanthosis nigricans (33 %), and MS (19 %) were strikingly prevalent, as were MS components, including abdominal adiposity (32 %) and low HDL-cholesterol (32 %). Factor analysis of MS traits yielded three constructs: adipo-insulin-lipid, blood pressure, and glucose factors, and their factor scores were highly heritable. MS itself exhibited 68 % heritability. MSC-N showed strong positive genetic correlations with obesity, insulin resistance, inflammation, and acanthosis nigricans, and negative genetic correlation with physical fitness. MS trait pairs exhibited strong genetic and/or environmental correlations. These findings highlight the complex genetic architecture of MS/MSCs in MA children, and underscore the need for early screening and intervention to prevent chronic sequelae in this vulnerable pediatric population.

Emergence of a New Glucoregulatory Mechanism for Glycemic Control With Dapagliflozin/Exenatide Therapy in Type 2 Diabetes.

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.

Potential role of insulin signaling on vascular smooth muscle cell migration, proliferation, and inflammation pathways.

To investigate the role of insulin signaling pathways in migration, proliferation, and inflammation of vascular smooth muscle cells (VSMCs), we examined the expression of active components of the phosphatidyl inositol 3 (PI-3) kinase (p-Akt) and mitogen-activated protein kinase (MAPK) (p-Erk) in primary cultures of VSMCs from human coronary arteries. VSMCs were treated in a dose-response manner with insulin (0, 1, 10, and 100 nM) for 20 min, and Akt and Erk phosphorylation were measured by Western blot analysis. In separate experiments, we evaluated the effect of 200 µM palmitate, in the presence and absence of 8 µM pioglitazone, on insulin-stimulated (100 nM for 20 min) Akt and Erk phosphorylation. The phosphorylation of Akt and Erk in VSMCs exhibited a dose dependency with a three- to fourfold increase, respectively, at the highest dose (100 nM). In the presence of palmitate, insulin-induced Akt phosphorylation was completely abolished, and there was a threefold increase in p-Erk. With addition of pioglitazone, the phosphorylation of Akt by insulin remained unchanged, whereas insulin-stimulated Erk phosphorylation was reduced by pioglitazone. These data in VSMCs indicate that high palmitate decreases insulin-stimulated Akt phosphorylation and stimulates MAPK, whereas preexposure peroxisome proliferator-activated receptor-γ agonist pioglitazone preserves Akt phosphorylation and simultaneously attenuates MAPK signaling. Our results suggest that metabolic and mitogenic insulin signals have different sensitivity, are independently regulated, and may play a role in arterial smooth muscle cells migration, proliferation, and inflammation in conditions of acute hyperinsulinemia.

Dapagliflozin Impairs the Suppression of Endogenous Glucose Production in Type 2 Diabetes Following Oral Glucose.

OBJECTIVE: To examine the effect of SGLT2 inhibitors (SGLT2i) on endogenous glucose production (EGP) in patients with type 2 diabetes after an oral glucose load. RESEARCH DESIGN AND METHODS: Forty-eight patients with type 2 diabetes received an 8-h [3-3H]-glucose infusion (protocol I) to assess EGP response to: 1) dapagliflozin (DAPA), 10 mg; 2) exenatide (EXE), 5 µg s.c.; 3) DAPA/EXE; and 4) placebo (PCB). After 2 weeks (protocol II), patients were restudied with a 5-h double-tracer (i.v. [3-3H]-glucose and oral [1-14C]-glucose) oral glucose tolerance test (OGTT) preceded by PCB, DAPA, EXE, or DAPA/EXE. RESULTS: Protocol I: EGP decreased (P < 0.01) with PCB (2.16 ± 0.15 to 1.57 ± 0.08 mg/kg/min) and EXE (2.13 ± 0.16 to 1.58 ± 0.03) and remained unchanged (P = NS) with DAPA (2.04 ± 0.17 vs. 1.94 ± 0.18) and DAPA/EXE (2.13 ± 0.10 vs. 2.09 ± 0.03). During OGTT, EGP decreased (P < 0.01) with PCB (2.30 ± 0.05 to. 1.45 ± 0.06 mg/kg/min) and EXE (2.53 ± 0.08 to 1.36 ± 0.06); with DAPA (2.20 ± 0.04 vs. 1.71 ± 0.07) and DAPA/EXE (2.48 ± 0.05 vs. 1.64 ± 0.07), the decrease in EGP was attenuated (both P < 0.05). During OGTT, the insulin/glucagon (INS/GCN) ratio increased in PCB (0.26 ± 0.03 vs. 0.71 ± 0.06 µU/mL per pg/mL), whereas in DAPA (0.26 ± 0.02 to 0.50 ± 0.04), the increase was blunted (P < 0.05). In EXE, INS/GCN increased significantly (0.32 ± 0.03 to 1.31 ± 0.08) and was attenuated in DAPA/EXE (0.32 ± 0.03 vs. 0.78 ± 0.08) (P < 0.01). CONCLUSIONS: These findings provide novel evidence that the increase in EGP induced by SGLT2i is present during an oral glucose load. The fact that stimulation of EGP occurs despite elevated plasma insulin and glucagon suggests that additional factors must be involved.

Durability of Triple Combination Therapy Versus Stepwise Addition Therapy in Patients With New-Onset T2DM: 3-Year Follow-up of EDICT.

OBJECTIVE: To compare the long-term efficacy of initiating therapy with metformin/pioglitazone/exenatide in patients with new-onset type 2 diabetes mellitus (T2DM) versus sequential addition of metformin followed by glipizide and insulin. RESEARCH DESIGN AND METHODS: Drug-naive patients (N = 318) with new-onset T2DM were randomly assigned to receive for 3 years either 1) combination therapy with metformin, pioglitazone, and exenatide (triple therapy) or 2) sequential addition of metformin followed by glipizide and insulin (conventional therapy) to maintain HbA1c at <6.5% (48 mmol/mol). Insulin sensitivity and ß-cell function were measured at baseline and 3 years. The primary outcome was the difference in HbA1c between the groups at 3 years. RESULTS: Baseline HbA1c ± SEM values were 9.0% ± 0.2% and 8.9% ± 0.2% in the triple therapy and conventional therapy groups, respectively. The decrease in HbA1c resulting from triple therapy was greater at 6 months than that produced by conventional therapy (0.30% [95% CI 0.21-0.39]; P = 0.001), and the HbA1c reduction was maintained at 3 years in patients receiving triple therapy compared with conventional therapy (6.4% ± 0.1% and 6.9% ± 0.1%, respectively), despite intensification of antihyperglycemic therapy in the latter. Thus, the difference in HbA1c between the two treatment groups at 3 years was 0.50% (95% CI 0.39-0.61; P < 0.0001). Triple therapy produced a threefold increase in insulin sensitivity and 30-fold increase in ß-cell function. In conventional therapy, insulin sensitivity did not change and ß-cell function increased by only 34% (both P < 0.0001 vs. triple therapy). CONCLUSIONS: Triple therapy with agents that improve insulin sensitivity and ß-cell function in patients with new-onset T2DM produces greater, more durable HbA1c reduction than agents that lower glucose levels without correcting the underlying metabolic defects.

NF-κB activity in muscle from obese and type 2 diabetic subjects under basal and exercise-stimulated conditions.

NF-κB is a transcription factor that controls the gene expression of several proinflammatory proteins. Cell culture and animal studies have implicated increased NF-κB activity in the pathogenesis of insulin resistance and muscle atrophy. However, it is unclear whether insulin-resistant human subjects have abnormal NF-κB activity in muscle. The effect that exercise has on NF-κB activity/signaling also is not clear. We measured NF-κB DNA-binding activity and the mRNA level of putative NF-κB-regulated myokines interleukin (IL)-6 and monocyte chemotactic protein-1 (MCP-1) in muscle samples from T2DM, obese, and lean subjects immediately before, during (40 min), and after (210 min) a bout of moderate-intensity cycle exercise. At baseline, NF-κB activity was elevated 2.1- and 2.7-fold in obese nondiabetic and T2DM subjects, respectively. NF-κB activity was increased significantly at 210 min following exercise in lean (1.9-fold) and obese (2.6-fold) subjects, but NF-κB activity did not change in T2DM. Exercise increased MCP-1 mRNA levels significantly in the three groups, whereas IL-6 gene expression increased significantly only in lean and obese subjects. MCP-1 and IL-6 gene expression peaked at the 40-min exercise time point. We conclude that insulin-resistant subjects have increased basal NF-κB activity in muscle. Acute exercise stimulates NF-κB in muscle from nondiabetic subjects. In T2DM subjects, exercise had no effect on NF-κB activity, which could be explained by the already elevated NF-κB activity at baseline. Exercise-induced MCP-1 and IL-6 gene expression precedes increases in NF-κB activity, suggesting that other factors promote gene expression of these cytokines during exercise.

Pioglitazone improvement of fasting and postprandial hyperglycaemia in Mexican-American patients with Type 2 diabetes: a double tracer OGTT study.

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-(14)C-glucose orally and 3-(3)H-glucose intravenously). Basal hepatic insulin resistance index (HepIR) was calculated as EGPxFPI. beta-cell function was assessed as the incremental ratio of insulin to glucose (DeltaI/DeltaG) 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 micromol/kg(ffm) 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 DeltaI/DeltaG (P = 0.003). The decrease in 2h-postprandial hyperglycaemia correlated closely with the increase in DeltaI/DeltaG (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 beta-cell function.