Type 2 diabetes (T2D)

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Impact of bariatric surgery on type 2 diabetes: contribution of inflammation and gut microbiome?

Impact of bariatric surgery on type 2 diabetes: contribution of inflammation and gut microbiome?

Abstract Obesity is a chronic low-grade inflammatory disease (both at the systemic and adipose tissue level) that continues to rise worldwide. It is associated with an abundance of co- morbidities, including type 2 diabetes (T2D). Bariatric surgery, which induces modifications of the intestinal tract, is to date the most successful treatment for obesity. Its use has dramatically increased in number as it enables both weight reduction and metabolic improvements, with 60% of patients even achieving diabetes remission. Several mechanisms are actually demonstrated to be involved in those clinical improvements. Importantly, both obesity and T2D share many phenotypic characteristics, including increased systemic and adipose tissue inflammation, as well as gut microbiota dysbiosis. These characteristics are deeply modulated after bariatric surgery. This review will specifically focus on the host metabolic changes induced by bariatric surgery in regards of the induced gut architectural changes, as well as on the modifications in the inflammatory tone and gut microbiota observed subsequently to bariatric surgery induced weight loss.
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An integrated approach for the identification of predictive markers of type 2 diabetes

An integrated approach for the identification of predictive markers of type 2 diabetes

The trajectory and underlying mechanisms of health are determined by a complex interplay between intrinsic and extrinsic factors. There is a need for more accurate assessment of the inputs and their consequences to health (Panagiotou, 2009). Therefore, our objective was to identify accurate and robust multidimensional markers, predictive of type 2 diabetes (T2D). A case-control approach was used within the French cohort GAZEL (n~20,000). Male overweight subjects (n=112, 25≤BMI<30 kg/m², 52-64 y.o.), free of T2D at baseline, were selected and compared for several parameters (clinical, biochemical parameters, and food habits) with Cases defined as having developed T2D at follow-up (5 years later; BMI, age, sex matched). Baseline serum samples were analyzed using mass spectrometry-based untargeted metabolomics. Data mining methods were used to select the best candidate for prediction. Models were built using linear logistic regressions on the reduced dataset and their performances were determined by calculating the area under the receiver operating characteristics curve (AUC) with their 95% confidence intervals (CI), sensitivity and specificity values. Metabolomic data were integrated with the different parameters from the database to determine whether multidimensional models improve prediction. Clinical data and consumption frequencies of vegetables and sugar showed significant differences between Cases and Controls. The metabolomics approach allowed the identification of 5 predictive biomarkers. The resulting metabolite-only model showed better performances than the one built with clinical data: a lower misclassification rate (18% vs 26%) and higher AUC (0.82
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Canagliflozin: A Review in Type 2 Diabetes.

Canagliflozin: A Review in Type 2 Diabetes.

1 Introduction Type 2 diabetes (T2D) is a chronic progressive metabolic disease characterized by hyperglycaemia, due to insulin resistance/insufficient insulin production [ 1 ]. Patients are often obese, have lipid disturbances and elevated BP, and are at an increased risk of microvascular and macrovascular complications [ 1 ]. Achieving good glycaemic control [e.g. HbA 1C level <7%] is a key management goal, for which numerous antihyperglycaemic agents (AHAs) with varying mechanisms of action are now available [ 2 ]. Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a relatively recent AHA class. By inhibiting SGLT2 (a key protein in glucose resorption in the kidney), these drugs increase urinary glucose excretion (UGE), causing blood glucose levels to decline independently of insulin. One of the most widely available SGLT2 inhibitors is canagliflozin (Invokana ® ), which is approved for the treatment of T2D in various countries worldwide, including the USA and EU. This article reviews data relevant to the use of canagliflozin in T2D in the EU; fixed-dose canagliflozin/metformin tablets are also now available but are beyond the scope of this article.
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‘Treatment-resistant’ type 2 diabetes: Which definition for clinical practice?

‘Treatment-resistant’ type 2 diabetes: Which definition for clinical practice?

Commentaries ‘Treatment-resistant’ type 2 diabetes: Which definition for clinical practice? Despite being a common feature in clinical practice and a major challenge for healthcare providers involved in the management of Type 2 Diabetes (T2D) [1], the notion of ‘treatment-resistant diabetes’ is scarcely found in the diabetes literature, which is instead dominated by the classic term ‘insulin resistance’ [2,3]. In contrast, ‘treatment-resistant hypertension’ is a well-known concept in the field of arterial hypertension [4]. Resistant hypertension is defined as the persistence of systolic blood pressure  160 mmHg (or  150 mmHg in T2D) despite pharma- cological treatment with at least three antihypertensive drugs (one of which is a thiazide or loop diuretic) [5]. Based on this definition, a practical approach for managing resistant hypertension has been recommended [6], and the results of large-scale prospective clinical trials, such as the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), have recently been re-analyzed according to this idea [7]. Yet, there is no such precise definition for ‘treatment-resistant T2D’, despite the fact that T2D and hypertension are two diseases that share several characteristics [8]. Mimicking the definition used for arterial hypertension, it has recently been proposed that the term ‘treatment-resistant T2D’ be used to refer to patients with Persistent Poorly-controlled Diabetes Mellitus (PPDM) despite standard care with three oral glucose-lowering medications [9].
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Training-induced improvement in lipid oxidation in type 2 diabetes mellitus is related to alterations in muscle mitochondrial activity. Effect of endurance training in type 2 diabetes.

Training-induced improvement in lipid oxidation in type 2 diabetes mellitus is related to alterations in muscle mitochondrial activity. Effect of endurance training in type 2 diabetes.

Training-induced improvements in skeletal muscle mitochondrial function have already been studied in healthy subjects [28] and in insulin resistant patients, including type 2 diabetes mellitus [12] and obesity, where training induced an increase in size and content of mitochondria [9] and enhanced mitochondrial fatty acid oxidation [11]. However, to our knowledge, our study is the first that demonstrates a relationship between the improvement of whole body lipid oxidation and the enhancement of mitochondrial respiration in T2D by training who have a possible disturbed skeletal muscle mitochondrial function [7-9]. The current finding of a close relationship between mitochondrial adaptation to training and lipid oxidation during exercise in T2D is consistent with the recent report in nondiabetic subjects of a relationship between lipid oxidation and mitochondrial respiration in nondiabetic subjects [29]. However, Nordby and al. [30] reported a lack of relationship between muscle oxidative capacity and whole body peak lipid oxidation in trained and untrained nondiabetic subjects. Presumably, Nordby's paper, which investigates healthy young controls, was unable to detect this relationship because of a lack of markedly low values of these parameters, that remained between a rather narrow normal range and did not exhibit enough variability for obtaining a significant correlation. By contrast, in our study, there was an important range of variation of
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Circulating PCSK9 levels are not associated with the conversion to type 2 diabetes

Circulating PCSK9 levels are not associated with the conversion to type 2 diabetes

addition, plasma PCSK9 levels were assessed using a standardized protocol using the same assay throughout. Participants under statin therapy, an important confounding factor for PCSK9 levels, were also excluded [42]. Our study presents however some limitations. In both cohorts, there were no repeated measures of circulating PCSK9 to investigate its relationship with glucose homeostasis parameters during follow-up. In IT-DIAB, no systematic OGTT was performed during the annual visit, in addition to FPG and A1C, to diagnose NOD. In ELSA- Brasil there was no repeated measure of FPG between baseline and 4-years to draw survival curves as in IT-DIAB. The observational nature of our study only allows to draw some associations regarding PCSK9 role in conversion to type 2 diabetes, but no causation. Due to a potential lack of statistical power, the absence of a diabetogenic effect for PCSK9 in our study is not definitive evidence for the absence of a role PCSK9 in glucose homeostasis.
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Addition of incretin therapy to metformin in type 2 diabetes.

Addition of incretin therapy to metformin in type 2 diabetes.

5 Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2009; 52: 17-30. 6 Pratley RE, Nauck M, Bailey T, et al, for the 1860-LIRA-DPP-4 Study Group. Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: a 26-week, randomised, parallel-group, open-label trial. Lancet 2010; 375: 1447-56.
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DPP-4 inhibitors in the treatment of type 2 diabetes.

DPP-4 inhibitors in the treatment of type 2 diabetes.

Linagliptin was also evaluated as monotherapy or add-on therapy and has shown clinically meaningful improvement of glycaemic control in type 2 diabetes. Linagliptin was given as monotherapy, 5mg once daily achieving a concentration >6.4nM leading to a median >82% DPP-4 inhibition, during 24 weeks in drug-naïve patients or patients receiving oral antidiabetic agents (other than TZDs) prior to a 6-week wash-out period [74]. In this multicenter, randomized, placebo-controlled, phase III trial, linagliptin improved glycaemic control (HbA1c -0.69 % from baseline, -1.01% in the patients with a baseline HbA1c > 9%). The percentage of patients who achieved HbA1c<7% was 25.2% with linagliptin vs 11.6% in the placebo group. Fasting and 2h post-prandial glucose were significantly reduced in the linagliptin arm compared to placebo (-1.3 mM [23mg/dl] vs placebo and -3.2 mM [58mg/dl] vs placebo, respectively). Glucose excursion after a test meal was also significantly reduced. In addition, an enhancement of β-cell function was observed (differences were seen in the proinsulin/insulin ratio, the HOMA-B index and the disposition index). Linagliptin was well tolerated and the safety profile was comparable to the placebo group (no drug-related serious event) and hypoglycaemic episodes were not increased compared to the placebo group. There was no increase of body weight.
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Bariatric surgery in patients with Type 2 diabetes: benefits, risks, indications and perspectives.

Bariatric surgery in patients with Type 2 diabetes: benefits, risks, indications and perspectives.

b Division of Gastrointestinal Surgery, Department of Surgery, CHU Sart Tilman, Liège, Belgium. Abstract Obesity plays a key role in the pathophysiology of type 2 diabetes (T2DM), and weight loss is a major objective, although difficult to achieve with medical treatments. Bariatric surgery has proven its efficacy in obtaining marked and sustained weight loss, and is also associated with a significant improvement in glucose control and even diabetes remission. Roux-en-Y gastric bypass appears to be more effective in diabetic patients than the restrictive gastroplasty procedure. This may be explained not only by greater weight reduction, but also by specific hormonal changes. Indeed, increased levels of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) may lead to improved β-cell function and insulin secretion as well as reduced insulin resistance associated with weight loss. The presence of T2DM in obese individuals is a further argument to propose bariatric surgery, and even more so when diabetes is difficult to manage by medical means and other weight-related complications are present. Bariatric surgery is associated with a better cardiovascular prognosis and reduced mortality, even though acute and long-term complications may occur. The observation that surgical rerouting of nutrients triggers changes in the release of incretin hormones that, in turn, ameliorate the diabetic state in the absence of weight loss has led to the recent development of innovative surgical procedures. Thus, bariatric surgery may be said to be progressing towards so-called 'metabolic surgery', which merits further evaluation in patients with T2DM within a multidisciplinary approach that involves both surgeons and endocrinologists.
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SGLT2 versus DPP4 inhibitors for type 2 diabetes.

SGLT2 versus DPP4 inhibitors for type 2 diabetes.

Canagliflozin Compared With Sitagliptin for Patients With Type 2 Diabetes Who Do Not Have Adequate Glycemic Control With Metformin Plus Sulfonylurea: A 52-week randomized trial. Diabetes Care. 2013; Apr 5. [Epub ahead of print]. 10. Scheen AJ. Pharmacokinetic considerations for the treatment of diabetes in patients with chronic kidney disease. Expert Opin Drug Metab Toxicol. 2013; 9(5): 529-50.

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Preventing, delaying, or masking type 2 diabetes with metformin in the diabetes prevention program?

Preventing, delaying, or masking type 2 diabetes with metformin in the diabetes prevention program?

We agree that whether drug therapy with metformin, acarbose, troglitazone, estrogens, ACE inhibitors, or angiotensin II receptor blockers truly prevent diabetes or delay its onset cannot be determined completely by the existing studies. However, delaying the onset of diabetes is clearly an important goal with major individual and public health implications. From a practical standpoint, there is little difference between delay and prevention of a disease such as type 2 diabetes with variable and late onset. If an intervention could delay the onset of diabetes long enough such that a person ultimately dies without developing the disease, delay would be equivalent to prevention. Unfortunately, neither of the DPP interventions (4) was totally effective, i.e., neither reduced the diabetes incidence rate to zero. Thus they produced only partial delay or prevention. Even partial effectiveness in this regard, however, is beneficial and is cause for optimism that more effective interventions can be developed.
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The endocannabinoid system: a promising target for the management of type 2 diabetes.

The endocannabinoid system: a promising target for the management of type 2 diabetes.

shown to play a major role in EC degradation, the fatty acid amide hydroxylase (FAAH) and the monoacylglycerol lipase (MAGL) (figure 1) [42,45]. Mounting evidence suggests that the EC system is involved in the physiological regulation of numerous functions, many of which relate to stress-recovery systems and to the maintenance of energy balance [41]. In particular, EC system is regarded as an integrated physiological system modulating nutrient intake, transport, metabolism and storage, whose dysfunction is associated with abdominal adiposity and its associated co-morbidities [3,15,41,42]. In principle, EC system overactivity may result from increased EC synthesis, CB receptor overexpression and/or decreased EC degradation. Conversely, pharmacological modulation to correct overactivity of EC system may theoretically involve reduction of EC production, blockade of EC transport, blockade of CB1 (or CB2) receptors and/or enhancement of EC degradation [11]. As defect in ECs degradation may play a role in EC system overactivity, FAAH might represent a promising target for pharmacotherapeutic modulation [11]. However, while pharmacological agents that inhibit the activity of FAAH are still available, agents that stimulate FAAH are not in development yet. Thus EC system represents a major challenge both in our understanding of the complexity of signaling and in attempting to design drugs with selectivity of action. It does also provide an opportunity to develop therapeutic agents. Today we have drugs that bind to the CB1 receptor as agonists or antagonists, drugs that block the EC transport and drugs that inhibit the activity of FAAH. Considering the complexity and the ubiquity of the EC system [6], CB1 antagonism strategy will lead to drugs probably not with magic bullet-like specificity but more likely with multiple actions targeting different facets of the system [5]. This may be a great opportunity in the management of multifaceted diseases such as obesity and the metabolic syndrome [16] or type 2 diabetes [21,23].
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Treatment of type 2 diabetes.

Treatment of type 2 diabetes.

4. Therapy risk and benefits As the prevalence of type 2 diabetes and the risk of severe side-effects of oral antidiabetic agents are markedly increased with aging, special focus should be put on the specific group of elderly diabetic patients (9). In general, the same measures of management are appropriate in the older as in the younger patient with diabetes, but may need to be modified in the presence of comorbidities, polymedication or social isolation. In particular the risk of severe sulphonylurea-induced hypoglycaemia or biguanide-associated lactic acidosis is higher in the elderly, so that those drugs must be prescribed with caution in the older population. Meglitinide analogues (repaglinide and nateglinide) are more rapidly absorbed and have a shorter half-life than sulphonylureas (16,17). Therefore, they may exert a better control of postprandial hyperglycaemia and reduce the risk of hypoglycaemia at distance of the last meal. In addition, they are not excreted by the liver and may be safely used even in case of renal insufficiency. Recently launched glitazones (pioglitzone, rosiglitazone) appear to have a good safety profile as they do not share the liver toxicity described with troglitazone; however, glitazones, which may promote fluid retention, are contra-indicated in patients with congestive heart failure, a condition that is more frequently observed in the elderly population. Finally, acarbose can be safely used in elderly diabetic patients although it may induce intestinal side-effects.
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Survival in people with type 2 diabetes as a function of HbA(1c).

Survival in people with type 2 diabetes as a function of HbA(1c).

In The Lancet today, some light is thrown on this issue by Craig Currie and colleagues, 8 with data from the large and statistically powerful General Practice Research Database, which has gathered data electronically from general practitioners in the UK. The main result in this study of 48 000 patients with type 2 diabetes (cohort 1 changed from monotherapy to combination oral therapy with metformin and a sulphonylurea; cohort 2 changed to insulin treatment) is that the 10% of patients with lowest HbA 1c values (<6·7%) had a higher death rate than all but
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Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus

Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus

ABSTRACT Despite its position as the first‐line treatment for type 2 diabetes mellitus, the mechanisms underlying the plasma glucose level‐lowering effects of metformin (1,1‐ dimethylbiguanide) still remain incompletely understood. Metformin is thought to exert its primary antidiabetic action through the suppression of hepatic glucose production. Furthermore, the discovery that metformin inhibits the mitochondrial respiratory‐chain complex 1 has placed energy metabolism and activation of AMP‐activated protein kinase (AMPK) at the center of its mechanism of action. However, the role of AMPK has been challenged and might only account for indirect changes in hepatic insulin sensitivity. Various mechanisms involving alterations of cellular energy charge, AMP‐mediated inhibition of adenylate cyclase or fructose‐1,6‐bisphosphatase‐1 (FBP1) and modulation of the cellular redox state through direct inhibition of mitochondrial glycerol‐3‐ phosphate dehydrogenase (mG3PDH) are proposed for the acute inhibition of gluconeogenesis by metformin. Emerging evidence suggests that metformin could improve obesity‐induced meta‐inflammation via direct and indirect effects on tissue‐ resident immune cells in metabolic organs (that is, adipose tissue, the gastrointestinal tract and the liver). Furthermore, the gastrointestinal tract also has a major role in metformin action through modulation of glucose‐lowering hormone glucagon‐like peptide‐1 (GLP‐1) and intestinal bile acid pool and alterations in gut microbiota composition.
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Oxidative Stress and Obesity- and Type 2 Diabetes-Induced Heart Failure

Oxidative Stress and Obesity- and Type 2 Diabetes-Induced Heart Failure

10. Steyn, M.; Zitouni, K.; Kelly, F.J.; Cook, P.; Earle, K.A. Sex Differences in Glutathione Peroxidase Activity and Central Obesity in Patients with Type 2 Diabetes at High Risk of Cardio-Renal Disease. Antioxidants 2019, 8, 629. [ CrossRef ] [ PubMed ] 11. Hafstad, A.D.; Hansen, S.S.; Lund, J.; Santos, C.X.; Boardman, N.T.; Shah, A.M.; Aasum, E. NADPH Oxidase 2 Mediates Myocardial Oxygen Wasting in Obesity. Antioxidants 2020, 9, 171. [ CrossRef ] [ PubMed ] 12. Kar, S.; Shahshahan, H.R.; Hackfort, B.T.; Yadav, S.K.; Yadav, R.; Kambis, T.N.; Lefer, D.J.; Mishra, P.K.
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Targeting the AMPK pathway for the treatment of Type 2 diabetes.

Targeting the AMPK pathway for the treatment of Type 2 diabetes.

Benoît Viollet, Louise Lantier, Jocelyne Devin-Leclerc, Sophie Hébrard, Chloé Amouyal, et al... Tar- geting the AMPK pathway for the treatment of Type 2 diabetes...[r]

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Preventing and treating kidney disease in patients with type 2 diabetes

Preventing and treating kidney disease in patients with type 2 diabetes

1. Introduction Chronic kidney disease (CKD) is a classical complication of diabetes mellitus, which may lead to end-stage renal disease (ESRD) [ 1 ]. Its pathophysiology is more complex in type 2 diabetes (T2DM) than in type 1, especially because of the intervention of several other risk factors beyond chronic hyperglycemia: arterial hypertension, abdominal obesity, dys- lipidemia, hyperuricemia, which all are associated with insulin resistance, low-grade inflammation and oxidative stress [ 2 , 3 ]. Globally, the burden of diabetes and hypertension considered as the two leading drivers of CKD has increased dramatically worldwide over the past several decades. The number of patients with known diabetes quadrupled between 1980 and 2014 while the number of adults with elevated blood pressure almost doubled between 1975 and 2014. Globally, CKD due to diabetes and CKD due to hypertension contributed to about half and near a quarter of the overall increase in CKD disabil- ity-adjusted-life-years, respectively [ 4 ]. Hypertension and dia- betes are coexisting in the vast majority of patients with T2DM. Making a clear distinction between these two entities (patient primarily hypertensive or diabetic) might be difficult but pragmatically little relevant from a therapeutic point of view. This is illustrated by the fact that a kidney biopsy to prove diabetic nephropathy was not required in all large trials that will be discussed hereafter. The annual incidence of microalbuminuria and albuminuria in patients with T2DM
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Hyperglycemia, type 2 diabetes, and depressive symptoms: the British Whitehall II study.

Hyperglycemia, type 2 diabetes, and depressive symptoms: the British Whitehall II study.

The association between type 2 diabetes and depression, both major public health challenges, remains unclear (1-8). In a recent U. S. report, people with type 2 diabetes had an increased risk of depressive symptoms, whereas, conversely, in non-diabetic individuals higher impaired fasting glucose (IFG) appeared to confer protection against depression (7). While an

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Early life stress induces type 2 diabetes at adulthood in male mice

Early life stress induces type 2 diabetes at adulthood in male mice

Early life stress induces type 2 diabetes at adulthood in male mice Hanna Ilchmann, Maiwenn Olier, Corinne Lencina, Sandrine Ellero-Simatos, Michèle Nankap, Ambre Riba, Caroline Sommer, Hervé Guillou, Laurence Guzylack-Piriou, Vassilia Théodorou, Sandrine Ménard The incidence of metabolic disorders is increasing worldwide. Besides diet and life style habits, epidemiological studies highlighted an association between post-traumatic stress and metabolic disorders. Based on the concept of Developmental Origins of Health and Diseases our study aimed to investigate whether early life stress can trigger metabolic disorders and associated key features i.e. low-grade inflammation and microbiota dysbiosis.
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