Diabetes, Obesity and Metabolism
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Sitagliptin and risk of fractures in type 2 diabetes: <scp>R</scp>esults from the <scp>TECOS</scp> trial Aim To examine fracture incidence among participants in the T rial E valuating C ardiovascular O utcomes with S itagliptin (TECOS ). Research design and methods We used data from 14 671 participants in the TECOS study who were randomized double‐blind to sitagliptin (n = 7332) or placebo (n = 7339). Cumulative fracture incidence rates were calculated and their association with study treatment assignment was examined using multivariable C ox proportional hazards regression. Results The baseline mean (standard deviation) participant age was 65.5 (8.0) years, diabetes duration was 11.6 (8.1) years and glycated haemoglobin level was 7.2 (0.5)% [55.2 (5.5) mmol/mol], and 29.3% of participants were women and 32.1% were non‐white. During 43 222 person‐years’ follow‐up, 375 (2.6%; 8.7 per 1000 person‐years) had a fracture; 146 were major osteoporotic fractures (hip, n = 34; upper extremity, n = 81; and clinical spine, n = 31). Adjusted analyses showed fracture risk increased independently with older age (P P P P P HR ) 1.01, 95% confidence interval (CI ) 0.82 to 1.23, P HR 1.03, P P P HR 1.40, 95% CI 1.02‐1.91; P HR 0.76, 95% CI 0.59‐0.98; P Conclusion Fractures were common among people with diabetes in the TECOS study, but were not related to sitagliptin therapy. Insulin and metformin treatment were associated with higher and lower fracture risks, respectively.
Diabetes, Obesity and Metabolism - Tập 19 Số 1 - Trang 78-86 - 2017
Metformin targets brown adipose tissue in vivo and reduces oxygen consumption in vitro Aims To test the hypothesis that brown adipose tissue (BAT) is a metformin target tissue by investigating in vivo uptake of [11 C]‐metformin tracer in mice and studying in vitro effects of metformin on cultured human brown adipocytes. Materials and methods Tissue‐specific uptake of metformin was assessed in mice by PET/CT imaging after injection of [11 C]‐metformin. Human brown adipose tissue was obtained from elective neck surgery and metformin transporter expression levels in human and murine BAT were determined by qPCR. Oxygen consumption in metformin‐treated human brown adipocyte cell models was assessed by Seahorse XF technology. Results Injected [11 C]‐metformin showed avid uptake in the murine interscapular BAT depot. Metformin exposure in BAT was similar to hepatic exposure. Non‐specific inhibition of the organic cation transporter (OCT) protein by cimetidine administration eliminated BAT exposure to metformin, demonstrating OCT‐mediated uptake. Gene expression profiles of OCTs in BAT revealed ample OCT3 expression in both human and mouse BAT. Incubation of a human brown adipocyte cell models with metformin reduced cellular oxygen consumption in a dose‐dependent manner. Conclusion These results support BAT as a putative metformin target.
Diabetes, Obesity and Metabolism - Tập 20 Số 9 - Trang 2264-2273 - 2018
Why do <scp>SGLT2</scp> inhibitors reduce heart failure hospitalization? <scp>A</scp> differential volume regulation hypothesis The effect of a sodium glucose cotransporter 2 inhibitor (SGLT2i) in reducing heart failure hospitalization in the EMPA‐REG OUTCOMES trial has raised the possibility of using these agents to treat established heart failure. We hypothesize that osmotic diuresis induced by SGLT2 inhibition, a distinctly different diuretic mechanism than that of other diuretic classes, results in greater electrolyte‐free water clearance and, ultimately, in greater fluid clearance from the interstitial fluid (IF) space than from the circulation, potentially resulting in congestion relief with minimal impact on blood volume, arterial filling and organ perfusion. We utilize a mathematical model to illustrate that electrolyte‐free water clearance results in a greater reduction in IF volume compared to blood volume, and that this difference may be mediated by peripheral sequestration of osmotically inactive sodium. By coupling the model with data on plasma and urinary sodium and water in healthy subjects who received either the SGLT2i dapagliflozin or loop diuretic bumetanide, we predict that dapagliflozin produces a 2‐fold greater reduction in IF volume compared to blood volume, while the reduction in IF volume with bumetanide is only 78% of the reduction in blood volume. Heart failure is characterized by excess fluid accumulation, in both the vascular compartment and interstitial space, yet many heart failure patients have arterial underfilling because of low cardiac output, which may be aggravated by conventional diuretic treatment. Thus, we hypothesize that, by reducing IF volume to a greater extent than blood volume, SGLT2 inhibitors might provide better control of congestion without reducing arterial filling and perfusion.
Diabetes, Obesity and Metabolism - Tập 20 Số 3 - Trang 479-487 - 2018
A novel <scp>GIP</scp> analogue, <scp>ZP</scp>4165, enhances glucagon‐like peptide‐1‐induced body weight loss and improves glycaemic control in rodents Aim To investigate the effects of the novel glucose‐dependent insulinotropic polypeptide (GIP ) analogue, ZP 4165, on body weight and glycaemic control in rodents, and to investigate if ZP 4165 modulates the anti‐obesity and anti‐hyperglycaemic effects of a glucagon‐like peptide‐1 (GLP ‐1) agonist (liraglutide). Methods The acute insulinotropic effect of ZP 4165 was investigated in rats during an oral glucose tolerance test. The long‐term effects of ZP 4165 on body weight and glycaemic control, either alone or in combination with liraglutide, were assessed in diet‐induced obese mice and diabetic db/db mice. Results
ZP 4165 showed insulinotropic action in rats. The GIP analogue did not alter the body weight of obese mice but enhanced GLP ‐1‐induced weight loss. In diabetic mice, 4 weeks’ dosing with ZP 4165 reduced glycated haemoglobin levels vs vehicle by an extent similar to the GLP ‐1 agonist. Conclusions ZP 4165 potentiated the anti‐obesity effect of a GLP ‐1 agonist in obese mice and improved glycaemic control in diabetic mice. These studies support further investigation of dual‐incretin therapy as a more effective treatment option than mono GLP ‐1 medication for type 2 diabetes mellitus and obesity.
Diabetes, Obesity and Metabolism - Tập 20 Số 1 - Trang 60-68 - 2018
Incretin hormones: Their role in health and disease Incretin hormones are gut peptides that are secreted after nutrient intake and stimulate insulin secretion together with hyperglycaemia. GIP (glucose‐dependent insulinotropic polypeptide) und GLP‐1 (glucagon‐like peptide‐1) are the known incretin hormones from the upper (GIP, K cells) and lower (GLP‐1, L cells) gut. Together, they are responsible for the incretin effect: a two‐ to three‐fold higher insulin secretory response to oral as compared to intravenous glucose administration. In subjects with type 2 diabetes, this incretin effect is diminished or no longer present. This is the consequence of a substantially reduced effectiveness of GIP on the diabetic endocrine pancreas, and of the negligible physiological role of GLP‐1 in mediating the incretin effect even in healthy subjects. However, the insulinotropic and glucagonostatic effects of GLP‐1 are preserved in subjects with type 2 diabetes to the degree that pharmacological stimulation of GLP‐1 receptors significantly reduces plasma glucose and improves glycaemic control. Thus, it has become a parent compound of incretin‐based glucose‐lowering medications (GLP‐1 receptor agonists and inhibitors of dipeptidyl peptidase‐4 or DPP‐4). GLP‐1, in addition, has multiple effects on various organ systems. Most relevant are a reduction in appetite and food intake, leading to weight loss in the long term. Since GLP‐1 secretion from the gut seems to be impaired in obese subjects, this may even indicate a role in the pathophysiology of obesity. Along these lines, an increased secretion of GLP‐1 induced by delivering nutrients to lower parts of the small intestines (rich in L cells) may be one factor (among others like peptide YY) explaining weight loss and improvements in glycaemic control after bariatric surgery (e.g., Roux‐en‐Y gastric bypass). GIP and GLP‐1, originally characterized as incretin hormones, have additional effects in adipose cells, bone, and the cardiovascular system. Especially, the latter have received attention based on recent findings that GLP‐1 receptor agonists such as liraglutide reduce cardiovascular events and prolong life in high‐risk patients with type 2 diabetes. Thus, incretin hormones have an important role physiologically, namely they are involved in the pathophysiology of obesity and type 2 diabetes, and they have therapeutic potential that can be traced to well‐characterized physiological effects.
Diabetes, Obesity and Metabolism - Tập 20 Số S1 - Trang 5-21 - 2018
How safe is metabolic/diabetes surgery? Although recent studies have shown the impressive antidiabetic effects of laparoscopic R oux‐en‐Y gastric bypass (LRYGB ), the safety profile of metabolic/diabetes surgery has been a matter of concern among patients and physicians. Data on patients with type 2 diabetes who underwent LRYGB or one of seven other procedures between J anuary 2007 and D ecember 2012 were retrieved from the A merican C ollege of S urgeons N ational S urgical Q uality I mprovement P rogram database and compared. Of the 66 678 patients included, 16 509 underwent LRYGB . The composite complication rate of 3.4% after LRYGB was similar to those of laparoscopic cholecystectomy and hysterectomy. The mortality rate for LRYGB (0.3%) was similar to that of knee arthroplasty. Patients who underwent LRYGB had significantly better short‐term outcomes in all examined variables than patients who underwent coronary bypass, infra‐inguinal revascularization and laparoscopic colectomy. In conclusion, LRYGB can be considered a safe procedure in people with diabetes, with similar short‐term morbidity to that of common procedures such as cholecystectomy and appendectomy and a mortality rate similar to that of knee arthroplasty. The mortality risk for LRYGB is one‐tenth that of cardiovascular surgery and earlier intervention with metabolic surgery to treat diabetes may eliminate the need for some later higher‐risk procedures to treat diabetes complications.
Diabetes, Obesity and Metabolism - Tập 17 Số 2 - Trang 198-201 - 2015
Treatment with <scp>LY</scp>2409021, a glucagon receptor antagonist, increases liver fat in patients with type 2 diabetes Aims To evaluate whether treatment with LY2409021 , a novel, selective glucagon receptor antagonist, is associated with changes in hepatic fat and other safety variables related to the benefit–risk profile for chronic use in patients with type 2 diabetes (T2D ). Methods Safety and efficacy were assessed in patients with T2D taking metformin and sulphonylurea who were randomized to LY2409021 20 mg (n = 65), placebo (n = 68), or sitagliptin 100 mg (n = 41). Key endpoints included change from baseline to month 6 in hepatic fat fraction (HFF ), assessed by magnetic resonance imaging; hepatic aminotransferases; blood pressure; lipid profile; fasting plasma glucose; and glycated haemoglobin (HbA1c ). Results A significant increase in HFF was seen with LY2409021 vs sitagliptin (least squares [LS ] mean difference 3.72%; P P LY2409021 vs sitagliptin (6.8 U /L ; P U/L ; P LY2409021 treatment showed significant HbA1c reductions vs placebo (LS mean difference −0.77%; P P LY2409021 was also associated with significant increases in systolic blood pressure vs sitagliptin (4.9 mm Hg ; P mm Hg ; P LY2409021 were reversible. Conclusion In this cohort of patients with T2D , chronic glucagon receptor antagonism with LY2409021 was associated with glucose‐lowering but also demonstrated increases in hepatic fat, hepatic aminotransferases, and other adverse effects.
Diabetes, Obesity and Metabolism - Tập 19 Số 11 - Trang 1521-1528 - 2017
Physiologic action of glucagon on liver glucose metabolism Glucagon is a primary regulator of hepatic glucose production (HGP) in vivo during fasting, exercise and hypoglycaemia. Glucagon also plays a role in limiting hepatic glucose uptake and producing the hyperglycaemic phenotype associated with insulin deficiency and insulin resistance. In response to a physiological rise in glucagon, HGP is rapidly stimulated. This increase in HGP is entirely attributable to an enhancement of glycogenolysis, with little to no acute effect on gluconeogenesis. This dramatic rise in glycogenolysis in response to hyperglucagonemia wanes with time. A component of this waning effect is known to be independent of hyperglycemia, though the molecular basis for this tachyphylaxis is not fully understood. In the overnight fasted state, the presence of basal glucagon secretion is essential in countering the suppressive effects of basal insulin, resulting in the maintenance of appropriate levels of glycogenolysis, fasting HGP and blood glucose. The enhancement of glycogenolysis in response to elevated glucagon is critical in the life‐preserving counterregulatory response to hypoglycaemia, as well as a key factor in providing adequate circulating glucose for working muscle during exercise. Finally, glucagon has a key role in promoting the catabolic consequences associated with states of deficient insulin action, which supports the therapeutic potential in developing glucagon receptor antagonists or inhibitors of glucagon secretion.
Diabetes, Obesity and Metabolism - Tập 13 Số s1 - Trang 118-125 - 2011
Long‐term effects of exenatide therapy over 82 weeks on glycaemic control and weight in over‐weight metformin‐treated patients with type 2 diabetes mellitus Aim: The ability of the incretin mimetic exenatide to improve glycaemic control and reduce body weight was assessed over 82 weeks in patients with type 2 diabetes failing to achieve glycaemic control with maximally effective doses of metformin.Methods: In this interim 82‐week analysis, 150 (total cohort) of an eligible population of 183 patients opted to continue exenatide treatment in an uncontrolled open‐label extension of a 30‐week double‐blind, placebo‐controlled trial. Of these, 92 patients (completer cohort) achieved 82 weeks of exenatide therapy. Patients continued metformin throughout the study.Results: At the end of the placebo‐controlled trial, exenatide resulted in an haemoglobin A1c (HbA1c ) reduction from baseline of −1.0 ± 0.1% (mean ± SE) (exenatide treatment arms), with durable HbA1c reductions after 82 weeks of −1.3 ± 0.1%. The percent of patients who achieved HbA1c ≤7% at weeks 30 and 82 was 46 and 59% respectively. After 30 weeks, exenatide caused a reduction in weight from baseline of −3.0 ± 0.6 kg, with a progressive reduction in weight of −5.3 ± 0.8 kg after 82 weeks. In addition, exenatide treatment produced clinically significant improvements in cardiovascular risk factors after 82 weeks. The most frequent adverse event after 30 and 82 weeks of exenatide was nausea, which was generally of mild‐or‐moderate intensity. It decreased in incidence after initiation in the controlled trial and the uncontrolled open‐label extension. Hypoglycaemia was rare, with no severe events.Conclusion: Exenatide was generally well tolerated, producing a durable reduction in HbA1c and a progressive reduction in weight over 82 weeks in patients with type 2 diabetes failing to achieve glycaemic control with metformin.
Diabetes, Obesity and Metabolism - Tập 8 Số 4 - Trang 419-428 - 2006
Attainment of glycaemic goals in type 2 diabetes with once‐, twice‐, or thrice‐daily dosing with biphasic insulin aspart 70/30 (The 1‐2‐3 study) Aim: This observational study in patients with type 2 diabetes failing oral agent therapy with or without basal insulin was conducted to assess whether addition and self‐titration of biphasic insulin aspart 70/30 (BIAsp 30) could achieve American Association of Clinical Endocrinologists (AACE)/International Diabetes Federation (IDF) and American Diabetes Association (ADA) glycemic targets (HbA1c ≤6.5 and <7%).Methods: Enrolled patients (n = 100, HbA1c ≥7.5 and ≤10%) were ≥18 years of age, had diabetes ≥12 months and had received a stable antidiabetic regimen for at least 3 months [minimum of two oral antidiabetic drugs (OADs) or at least one OAD plus once‐daily basal insulin ≤60 U]. Patients discontinued prior basal insulin and added one injection of BIAsp 30 (12 U or 70–100% of prior basal insulin dose within 15 min of dinner initiation). Patients self‐titrated their BIAsp 30 dose with investigator guidance every 3 or 4 days to achieve pre‐breakfast fasting blood glucose (FBG) of 80–110 mg/dl. At 16 weeks, a pre‐breakfast injection of 6 U of BIAsp 30 was added if week 15 HbA1c exceeded 6.5%; the added dose was titrated to achieve pre‐dinner BG of 80–110 mg/dl. After an additional 16 weeks, 3 U of pre‐lunch BIAsp 30 was added if HbA1c exceeded 6.5%. This added dose was adjusted based on 2‐h post‐lunch BG to achieve postprandial glucose of 100–140 mg/dl. Subjects achieving an HbA1c ≤6.5% at 15 and 31 weeks completed the study at weeks 16 and 32 respectively.Results: Addition of once‐daily BIAsp 30 before dinner enabled 21% of the patients to achieve AACE and IDF targets (HbA1c ≤6.5%) and 41% to achieve ADA targets (HbA1c <7%). With two daily injections of BIAsp 30, these glycaemic goals were achieved by 52 and 70% of subjects. With three daily BIAsp 30 injections, 60% of patients achieved HbA1c ≤6.5%, and 77% achieved HbA1c <7.0%.Conclusions: This clinical trial demonstrates that initiation of once‐daily BIAsp 30 to type 2 diabetes patients poorly controlled on various OAD regimens was an effective treatment approach for achieving glycaemic goals. Additional patients safely achieved these goals by increasing the number of BIAsp 30 injections from one to two, and then, if uncontrolled, from two to three doses per day. Eventually, most patients previously uncontrolled on OADs with or without basal insulin were controlled by the addition and vigorous titration of BIAsp 30 to oral agent therapy.
Diabetes, Obesity and Metabolism - Tập 8 Số 1 - Trang 58-66 - 2006
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