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.

Introduction: Many patients with type 2 diabetes mellitus (T2DM) fail to achieve the desired A1c goal because the antidiabetic medications used do not correct the underlying pathophysiologic abnormalities and monotherapy is not sufficiently potent to reduce the A1c to the 6.5 - 7.0% range. Insulin resistance and islet (beta and alpha) cell dysfunction are major pathophysiologic abnormalities in T2DM. We examine combination therapy with linagliptin plus empagliflozin as a therapeutic approach for the treatment of inadequately controlled T2DM patients.Areas covered: A literature search of all human diabetes, metabolism and general medicine journals from year 2000 to the present was conducted. Glucagon like peptide-1 (GLP-1) deficiency/resistance contributes to islet cell dysfunction by impairing insulin secretion and increasing glucagon secretion. DPP-4 inhibitors (DPP4i) improve pancreatic islet function by augmenting glucose-dependent insulin secretion and decreasing elevated plasma glucagon levels. Linagliptin, a DPP-4 inhibitor, reduces HbA1c, is weight neutral, has an excellent safety profile and a low risk of hypoglycemia. The expression of sodium-glucose cotransporter-2 (SGLT2) in the proximal renal tubule is upregulated in T2DM, causing excess reabsorption of filtered glucose. The SGLT2 inhibitor (SGLT2i), empagliflozin, improves HbA(1c) by causing glucosuria and ameliorating glucotoxicity. It also decreases weight and blood pressure, and has a low risk of hypoglycemia.Expert opinion: The once daily oral combination of linagliptin plus empagliflozin does not increase the risk of hypoglycemia and tolerability and discontinuation rates are similar to those with each as monotherapy. At HbA1c values below 8.5% linagliptin/empagliflozin treatment produces an additive effect, whereas above 8.5%, there is a less than additive reduction with combination therapy compared with the effect of each agent alone. Linagliptin/empagliflozin addition is a logical combination in patients with T2DM, especially those with an HbA1c<8.5%.

AIM:To test our hypothesis that initiating therapy with a combination of agents known to improve insulin secretion and insulin sensitivity in subjects with new-onset diabetes would produce greater, more durable reduction in glycated haemoglobin (HbA1c) levels, while avoiding hypoglycaemia and weight gain, compared with sequential addition of agents that lower plasma glucose but do not correct established pathophysiological abnormalities. METHODS:Drug-naïve, recently diagnosed subjects with type 2 diabetes mellitus (T2DM) were randomized in an open-fashion design in a single-centre study to metformin/pioglitazone/exenatide (triple therapy; n = 106) or an escalating dose of metformin followed by sequential addition of sulfonylurea and glargine insulin (conventional therapy; n = 115) to maintain HbA1c levels at <6.5% for 2 years. RESULTS:Participants receiving triple therapy experienced a significantly greater reduction in HbA1c level than those receiving conventional therapy (5.95 vs. 6.50%; p < 0.001). Despite lower HbA1c values, participants receiving triple therapy experienced a 7.5-fold lower rate of hypoglycaemia compared with participants receiving conventional therapy. Participants receiving triple therapy experienced a mean weight loss of 1.2 kg versus a mean weight gain of 4.1 kg (p < 0.01) in those receiving conventional therapy. CONCLUSION:The results of this exploratory study show that combination therapy with metformin/pioglitazone/exenatide in patients with newly diagnosed T2DM is more effective and results in fewer hypoglycaemic events than sequential add-on therapy with metformin, sulfonylurea and then basal insulin.

1 Medical Research Division, Regional Academic Health Center, 1214 W. Schunior Street, Edinburg, TX 78541, USA 2Diabetes Division, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA 3 Texas Diabetes Institute, 701 S. Zarzamora, San Antonio, TX 78207, USA 4Geriatric, Research, Education, and Clinical Center, Audie L. Murphy VA Hospital, 7400 Merton Minter Boulevard, San Antonio, TX 78229, USA

A state of subclinical systemic inflammation is characteristically present in obesity/insulin resistance and type 2 diabetes mellitus (T2DM). The aim of the study was to develop an integrated measure of the circulating cytokines involved in the subclinical systemic inflammation and evaluate its relation with whole-body insulin sensitivity and glucose metabolism in T2DM. T2DM patients (n = 17, M/F 13/4, age = 55.0 ± 1.7 years, BMI = 33.5 ± 1.5 kg/m2, HbA1c = 7.7 ± 0.3 %) and normal glucose-tolerant (NGT) subjects (n = 15, M/F 7/8, age = 49.1 ± 2.5 years, BMI = 31.8 ± 1.2 kg/m2, HbA1c = 5.6 ± 0.1 %) were studied in a cross-sectional design. Whole-body insulin sensitivity was quantified by the euglycemic clamp. Beta-cell function [disposition index (DI)] was calculated using insulin and glucose values derived from an oral glucose tolerance test and the euglycemic clamp. Body fat mass was evaluated by dual-energy X-ray absorptiometry. Plasma cytokine [TNF-α, IL-6, MCP-1, osteopontin, fractalkine and adiponectin] values were divided into quintiles. A score ranging from 0 (lowest quintile) to 4 (highest quintile) was assigned. The inflammatory score (IS) was the sum of each cytokine score from which adiponectin score was subtracted in each study subject. Inflammatory cytokine levels were all higher in T2DM. IS was higher in T2DM as compared to NGT (10.0 ± 1.1 vs. 4.8 ± 0.8; p < 0.001). IS positively correlated with fasting plasma glucose (r = 0.638, p < 0.001), 1-h plasma glucose (r = 0.483, p = 0.005), 2-h plasma glucose (r = 0.611, p < 0.001) and HbA1c (r = 0.469, p = 0.007). IS was inversely correlated with insulin sensitivity (r = −0.478, p = 0.006) and DI (r = −0.523, p = 0.002). IS did not correlate with BMI and body fat mass. IS was an independent predictor of fasting plasma glucose and had a high sensibility and sensitivity to predict insulin resistance (M/I < 4). A state of subclinical inflammation defined and quantifiable by inflammatory score including TNF-α, IL-6, MCP-1, osteopontin, fractalkine and adiponectin is associated with both hyperglycemia and whole-body insulin resistance in T2DM.

Background: FGF-19, a novel intestinal hormone, is secreted in the terminal ileum postprandially and during bile salt absorption.Non-alcoholic fatty liver disease (NAFLD) is common in obesity but the molecular mechanisms of NAFLD development in non-obese patients remain yet to be defined.FGF-19 might play a protective role in NAFLD by improving insulin sensitivity, increasing hepatic beta-oxidation and inhibiting lipogenesis.The aim of our study was to investigate FGF-19 serum concentrations in non-obese (BMI <30 kg/m 2 ) individuals with NAFLD in comparison to obese (BMI >30 kg/m 2 ) patients and healthy volunteers in a fasted state and after a defined oral fat load.Patients and Methods: In total, 14 NAFLD patients (mean BMI 27.7 kg/m 2 ), 21 obese individuals and 16 healthy controls were recruited.FGF-19 levels were determined by ELISA after 10 hours of overnight fasting.Subsequently, all individuals received 1 g fat (Calogen ® ) per kg body weight orally.FGF-19 serum concentrations were measured at baseline and after 2, 4 and 6 hours.No other food intake was permitted during this time but water was allowed ad libitum.Results: Basal serum FGF-19 levels in the fasted state do not differ between overweight NAFLD patients, obese subjects and normal controls.The oral fat load increases FGF-19 levels in all three groups.FGF-19 serum levels peak after 4 hours in all three groups and were highest in controls (378.9±202.1 pg/ml).In comparison to men, women display significantly higher FGF-19 levels after 6 hours (283.4±189.6 vs. 172.1±82.1 pg/ml, p < 0.05).Of note, non-obese NAFLD patients display the lowest FGF-19 levels at all time points.In particular, FGF-19 levels 2 hours post oral fat load are significantly lower (p = 0.004) in overweight NAFLD patients (143.7±61.4pg/ml) as compared to both healthy volunteers and obese patients (287.4±177.7 pg/ml and 281.4±235.0pg/ml respectively).Conclusions: We established an oral fat load test ("OFLT"), which demonstrated impaired FGF-19 release in non-obese NAFLD patients.The hepatic mechanisms consequences of impaired FGF-19 signaling require further investigation.

Aim: To assess the effect of muraglitazar, a dual peroxisome proliferator‐activated receptor (PPAR)γ‐α agonist, versus placebo on metabolic parameters and body composition in subjects with type 2 diabetes mellitus (T2DM).

OBJECTIVE:Our objective was to examine the mechanisms via which exenatide attenuates postprandial hyperglycemia in type 2 diabetes mellitus (T2DM).STUDY DESIGN:Seventeen T2DM patients (44 yr; seven females, 10 males; body mass index = 33.6 kg/m(2); glycosylated hemoglobin = 7.9%) received a mixed meal followed for 6 h with double-tracer technique ([1-(14)C]glucose orally; [3-(3)H]glucose i.v.) before and after 2 wk of exenatide. In protocol II (n = 5), but not in protocol I (n = 12), exenatide was given in the morning of the repeat meal. Total and oral glucose appearance rates (RaT and RaO, respectively), endogenous glucose production (EGP), splanchnic glucose uptake (75 g - RaO), and hepatic insulin resistance (basal EGP × fasting plasma insulin) were determined.RESULTS:After 2 wk of exenatide (protocol I), fasting plasma glucose decreased (from 10.2 to 7.6 mm) and mean postmeal plasma glucose decreased (from 13.2 to 11.3 mm) (P < 0.05); fasting and meal-stimulated plasma insulin and glucagon did not change significantly. After exenatide, basal EGP decreased (from 13.9 to 10.8 μmol/kg · min, P < 0.05), and hepatic insulin resistance declined (both P < 0.05). RaO, gastric emptying (acetaminophen area under the curve), and splanchnic glucose uptake did not change. In protocol II (exenatide given before repeat meal), fasting plasma glucose decreased (from 11.1 to 8.9 mm) and mean postmeal plasma glucose decreased (from 14.2 to 10.1 mm) (P < 0.05); fasting and meal-stimulated plasma insulin and glucagon did not change significantly. After exenatide, basal EGP decreased (from 13.4 to 10.7 μmol/kg · min, P = 0.05). RaT and RaO decreased markedly from 0-180 min after meal ingestion, consistent with exenatide's action to delay gastric emptying.CONCLUSIONS:Exenatide improves 1) fasting hyperglycemia by reducing basal EGP and 2) postmeal hyperglycemia by reducing the appearance of oral glucose in the systemic circulation.

Background To test potential differences between the actions of antidiabetic medications, we examined the effects of oral hypoglycaemic agents versus glargine-apidra insulin therapy in T2DM.Methods T2DM subjects were randomized to either oral hypoglycaemic agents (pioglitazone, metformin and glipizide, n = 9) or insulin therapy (n = 12) for 6 months. Carotid intimal media thickness, vascular reactivity (flow-mediated vasodilatation; percent change in brachial artery basal diameter post-ischaemia) and sublingual nitrate were measured with ultrasonography. Euglycemic hyperinsulinemic (80 mU/m(2)) clamp with [3]-3H-glucose and muscle biopsies were performed.Results Fasting plasma glucose (similar to 257 to similar to 124 mg/dL, oral hypoglycaemic agents and similar to 256 to similar to 142 mg/dL, IT) and HbA(1c) (similar to 10.3 to similar to 6.4%, OHA and similar to 10.7 to similar to 7.1%, IT) improved comparably. Endogenous glucose production (similar to 2.1 to similar to 1.7 mg/kg/min, oral hypoglycaemic agents and similar to 2.3 to similar to 2.0 mg/kg/min, insulin therapy) and endogenous glucose production suppression by insulin (similar to 0.4 to similar to 0.3 mg/kg min, oral hypoglycaemic agents and similar to 0.5 to similar to 0.7 mg/kg min, insulin therapy) were different. Total glucose disposal x 100 increased in the oral hypoglycaemic agents group (similar to 5.2 to similar to 8.1; p = 0.03), but not in insulin therapy (similar to 6.0 to similar to 5.4 mg/kg/min/mu U/mL x 100). OHA reduced CIMT (similar to 0.080 to similar to 0.068 cm; p < 0.05), whereas insulin therapy did not (similar to 0.075 to similar to 0.072 cm). After sublingual nitrate, brachial artery basal diameter increased in the OHA group (similar to 8.7 to similar to 18.2%), but not in insulin therapy (similar to 11.2 to similar to 15.0%; p < 0.02). Except for plasma adiponectin (similar to 7 to similar to 15, oral hypoglycaemic agents versus similar to 6 to similar to 10, IT), changes in inflammatory markers in the circulation and in muscle (I kappa B alpha, super-oxidase dismutase 2, monocyte-chemo-attractant protein 1, p-ERK and JNK) were equivalent.Conclusions Oral hypoglycaemic agents and insulin therapy treated patients achieved adequate glycemic control and the effects on circulating and muscle inflammatory biomarkers were similar, but only oral hypoglycaemic agents improved insulin sensitivity, vascular function and carotid intimal media thickness. These findings in a small sample suggest that the use of oral hypoglycaemic agents provides additional benefits to patients with T2DM. Copyright (C) 2011 John Wiley & Sons, Ltd.

The molecular mechanisms by which thiazolidinediones improve insulin sensitivity in type 2 diabetes are not fully understood. We hypothesised that pioglitazone would activate the adenosine 5′-monophosphate-activated protein kinase (AMPK) pathway and increase the expression of genes involved in adiponectin signalling, NEFA oxidation and mitochondrial function in human skeletal muscle.

L'exénatide diminue de façon marquée l'hyperglycémie postprandiale (PP) et plus modestement la glycémie à jeun (GAJ). Afin d'explorer les mécanismes impliqués, 6 patients diabétiques de type 2 (DT2) (45 ± 8 ans ; 2F/4H ; IMC 31 ± 2 kg/m2 ; HbA1c 8,1 ± 0,8 %) sous metformine (n = 3) ou sulfamide (n = 3) ont reçu un repas test avant (PRE) et 2 semaines après (POST) un traitement sous-cutané par exénatide (5 μg 2/j 1 semaine puis 10 μg 2/j la 2e). Le repas contenait 600 cal, 75 g de glucose marqué ([1] -14C-glucose). 3 heures avant et 6 heures suivant le repas, les patients recevaient une perfusion continue de 3- [3H] -glucose. Le débit total d'apparition du glucose dans la circulation systémique (RaT), le débit d'apparition du glucose oral (RaO), la production endogène du glucose (EGP) et l'utilisation splanchnique du glucose alimentaire (SGU = 75 g - RaO[0-360 mn]) étaient mesurés par double marquage isotopique. La sensibilité hépatique à l'insuline (HIS) était calculée [100/EGPxFPI]. Glycémie, insulinémie et glucagonémie étaient mesurés AJ et durant 6 heures après le repas test (PRT). Avant traitement, la GAJ (moyenne ± SD 171 ± 18 mg/dl) augmentait à 225 ± 23 mg/dl PRT, l'insuline AJ de 11 ± 2 à 15 ± 3 μU/ml, le glucagon ne changeait pas (58 ± ± 8 à 57 ± 7 pg/ml). Après exénatide, la GAJ (132 ± 13 mg/ dl) et la G PRT (173 ± 16 mg/dl) diminuaient (p < 0,01 PRE vs POST). L'insuline augmentait de 7 ± 3 à 18 ± 4 μU/ml, le glucagon diminuait de 66 ± 6 à 60 ± 8 pg/ml (p < 0,01 PRE vs POST). L'EGP basale diminuait (2,3 ± 0,1 vs 1,8 ± 0,2 mg/kg/mn, p < 0,05) et l'AUC incrémentale du RaO 6h PRT de ∼50 % (p < 0,01). La SGU augmentait de ∼60 % et la HIS de ∼50 %. Ainsi, exénatide diminue la GAJ en inhibant l'EGP basale, atténue les excursions glycémiques PP en favorisant la suppression de l'EGP lors du repas et en augmentant la SGU, augmente la sécrétion d'insuline (βInsuline/βGlucose) et supprime la production PP de glucagon. L'exénatide influence profondément l'homéostasie du glucose splanchnique en augmentant la HIS et la SGU. Le rôle du ralentissement de la vidange gastrique reste indéterminé. Le GLP-1 pourrait représenter le facteur intestinal depuis longtemps recherché.