Continual evolution of type 2 diabetes: an update on pathophysiology and emerging treatment options.

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Abstract

Diabetes is a complex and progressive disease that has a major societal and economic impact. The most common form of diabetes, type 2 diabetes mellitus (T2DM), is a multifactorial disease, the pathophysiology of which involves not only the pancreas but also the liver, skeletal muscle, adipose tissue, gastrointestinal tract, brain, and kidney. Novel therapies with mechanisms of action that are different from most existing drugs are emerging. One such class consists of compounds that inhibit renal sodium-glucose cotransporter 2, which is responsible for the bulk of glucose reabsorption by the kidneys. This new class of compounds improves glycemic control independently of insulin and promotes weight reduction, providing an additional tool to treat patients with T2DM. This review discusses the underlying pathophysiology of T2DM, clinical guidelines, and available and emerging treatment options, with particular emphasis on sodium-glucose cotransporter 2 inhibitors.

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Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans.

Véronique Ouellet, Sébastien M. Labbé, Denis Blondin … (2012)

Brown adipose tissue (BAT) is vital for proper thermogenesis during cold exposure in rodents, but until recently its presence in adult humans and its contribution to human metabolism were thought to be minimal or insignificant. Recent studies using PET with 18F-fluorodeoxyglucose (18FDG) have shown the presence of BAT in adult humans. However, whether BAT contributes to cold-induced nonshivering thermogenesis in humans has not been proven. Using PET with 11C-acetate, 18FDG, and 18F-fluoro-thiaheptadecanoic acid (18FTHA), a fatty acid tracer, we have quantified BAT oxidative metabolism and glucose and nonesterified fatty acid (NEFA) turnover in 6 healthy men under controlled cold exposure conditions. All subjects displayed substantial NEFA and glucose uptake upon cold exposure. Furthermore, we demonstrated cold-induced activation of oxidative metabolism in BAT, but not in adjoining skeletal muscles and subcutaneous adipose tissue. This activation was associated with an increase in total energy expenditure. We found an inverse relationship between BAT activity and shivering. We also observed an increase in BAT radio density upon cold exposure, indicating reduced BAT triglyceride content. In sum, our study provides evidence that BAT acts as a nonshivering thermogenesis effector in humans.

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Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin.

Jan Bolinder, Östen Ljunggren, Joel Kullberg … (2012)

Dapagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, reduces hyperglycemia in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion, and weight loss is a consistent associated finding. Our objectives were to confirm weight loss with dapagliflozin and establish through body composition measurements whether weight loss is accounted for by changes in fat or fluid components. This was a 24-wk, international, multicenter, randomized, parallel-group, double-blind, placebo-controlled study with ongoing 78-wk site- and patient-blinded extension period at 40 sites in five countries. Included were 182 patients with T2DM (mean values: women 63.3 and men 58.6 yr of age; hemoglobin A1c 7.17%, body mass index 31.9 kg/m2, and body weight 91.5 kg) inadequately controlled on metformin. Dapagliflozin 10 mg/d or placebo was added to open-label metformin for 24 wk. Primary endpoint was total body weight (TBW) change from baseline at wk 24. Key secondary endpoints were waist circumference and dual-energy x-ray absorptiometry total-body fat mass (FM) changes from baseline at wk 24, and patient proportion achieving body weight reduction of at least 5% at wk 24. In a subset of patients, magnetic resonance assessment of visceral adipose tissue (VAT) and sc adipose tissue (SAT) volume and hepatic lipid content were also evaluated. At wk 24, placebo-corrected changes with dapagliflozin were as follows: TBW, -2.08 kg [95% confidence interval (CI)=-2.84 to -1.31; P<0.0001]; waist circumference, -1.52 cm (95% CI=-2.74 to -0.31; P=0.0143); FM, -1.48 kg (95% CI=-2.22 to -0.74; P=0.0001); proportion of patients achieving weight reduction of at least 5%, +26.2% (95% CI=15.5 to 36.7; P<0.0001); VAT, -258.4 cm3 (95% CI=-448.1 to -68.6; nominal P=0.0084); SAT, -184.9 cm3 (95% CI=-359.7 to -10.1; nominal P=0.0385). In the dapagliflozin vs. placebo groups, respectively, serious adverse events were reported in 6.6 vs. 1.1%; events suggestive of vulvovaginitis, balanitis, and related genital infection in 3.3 vs. 0%; and lower urinary tract infections in 6.6 vs. 2.2%. Dapagliflozin reduces TBW, predominantly by reducing FM, VAT and SAT in T2DM inadequately controlled with metformin.

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SGLT2 inhibition--a novel strategy for diabetes treatment.

Edward Chao, Robert Henry (2010)

Inhibiting sodium-glucose co-transporters (SGLTs), which have a key role in the reabsorption of glucose in the kidney, has been proposed as a novel therapeutic strategy for diabetes. Genetic mutations in the kidney-specific SGLT2 isoform that result in benign renal glycosuria, as well as preclinical and clinical studies with SGLT2 inhibitors in type 2 diabetes, support the potential of this approach. These investigations indicate that elevating renal glucose excretion by suppressing SGLT2 can reduce plasma glucose levels, as well as decrease weight. Although data from ongoing Phase III trials of these agents are needed to more fully assess safety, results suggest that the beneficial effects of SGLT2 inhibition might be achieved without exerting significant side effects--an advantage over many current diabetes medications. This article discusses the role of SGLT2 in glucose homeostasis and the evidence available so far on the therapeutic potential of blocking these transporters in the treatment of diabetes.

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Author and article information

Journal

Journal ID (iso-abbrev): Ther Clin Risk Manag

Title: Therapeutics and clinical risk management

Publisher: Informa UK Limited

ISSN: 1176-6336

ISSN (Print): 1176-6336

Publication date (Electronic): 2015

Volume: 11

Affiliations

[1 ] Chicago College of Pharmacy, Midwestern University, Downers Grove, IL, USA.

Article

Publisher Item ID: tcrm-11-621

DOI: 10.2147/TCRM.S67387

PMC ID: 4404882

PubMed ID: 25931824

SO-VID: ae09cccf-d3a9-47dc-9443-ab0ac2996f02

History

Keywords: oral antidiabetic therapies,diabetes,hyperglycemia,sodium-glucose cotransporter 2,pharmacotherapy

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Keywords: oral antidiabetic therapies, diabetes, hyperglycemia, sodium-glucose cotransporter 2, pharmacotherapy

Continual evolution of type 2 diabetes: an update on pathophysiology and emerging treatment options.

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Abstract

Most cited references 84

Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans.

Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin.

SGLT2 inhibition--a novel strategy for diabetes treatment.

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