Comparison of the Effects of Pioglitazone and Metformin on Hepatic and Extra-Hepatic Insulin Action in People With Type 2 Diabetes

Basu, Rita; Shah, Pankaj; Basu, Ananda; Norby, Barbara; Dicke, Betty A.; Chandramouli, Visvanathan; Cohen, Ohad; Landau, Bernard R.; Rizza, Robert A.

doi:10.2337/db07-0827

Cited by 56 publications

(48 citation statements)

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“…Glycogenolysis was calculated by subtracting the rate of gluconeogenesis from endogenous glucose production. The results from the diabetic subjects have previously been published, in part, elsewhere (19). Statistical analysis.…”

Section: Methodsmentioning

confidence: 99%

“…Details of the experimental design have been described in detail elsewhere (19). Subjects were admitted to the Mayo Clinical Research Unit on the evening before study and given a standard meal at 1700 h and 1.67 g 2 H 2 O/kg body water in divided doses at 1800, 2000, and 2200 h. Insulin was infused in the diabetic subjects during the night to maintain glucose at ϳ5.5 mmol/l.…”

Section: Methodsmentioning

confidence: 99%

“…Rates are expressed in the figures and text as micromoles per kilogram lean body mass per min. Rates of glucose appearance and disappearance and endogenous glucose production were calculated using the steady-state equations of Steele et al (22) as previously described (19). Rates of gluconeogenesis were calculated either by multiplying the plasma C5-to-C2 glucose ratio by endogenous glucose production or plasma C5 glucose-to-2 H 2 O ratio by the total rate of glucose appearance (2).…”

Section: Methodsmentioning

confidence: 99%

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Plasma C5 Glucose–to–2H2O Ratio Does Not Provide an Accurate Assessment of Gluconeogenesis During Hyperinsulinemic-Euglycemic Clamps in Either Nondiabetic or Diabetic Humans

et al. 2008

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OBJECTIVE-Measurement of plasma C2 glucose enrichment is cumbersome. Therefore, the plasma C5 glucose-to-2 H 2 O rather than the plasma C5-to-C2 glucose ratio commonly has been used to measure gluconeogenesis and glycogenolysis during hyperinsulinemic-euglycemic clamps. The validity of this approach is unknown. RESEARCH DESIGN AND METHODS-Ten nondiabetic and 10 diabetic subjects ingested2 H 2 O the evening before study. The following morning, insulin was infused at a rate of 0.6 mU ⅐ kg Ϫ1⅐ min Ϫ1 and glucose was clamped at ϳ5.3 mmol/l for 5 h. Plasma C5 glucose, C2 glucose, and 2 H 2 O enrichments were measured hourly from 2 h onward. RESULTS-Plasma C2 glucose and plasma2 H 2 O enrichment were equal in both groups before the clamp, resulting in equivalent estimates of gluconeogenesis and glycogenolysis. In contrast, plasma C2 glucose and plasma C5 glucose enrichments fell throughout the clamp, whereas plasma 2 H 2 O enrichment remained unchanged. Since the C5 glucose concentration and, hence, the C5 glucose-to-2 H 2 O ratio is influenced by both gluconeogenesis and glucose clearance, whereas the C5-to-C2 glucose ratio is only influenced by gluconeogenesis, the C5 glucose-to-2 H 2 O ratio overestimated (P Ͻ 0.01) gluconeogenesis during the clamp. This resulted in biologically implausible negative (i.e., calculated rates of gluconeogenesis exceeding total endogenous glucose production) rates of glycogenolysis in both the nondiabetic and diabetic subjects.CONCLUSIONS-Plasma C5 glucose-to-2 H 2 O ratio does not provide an accurate assessment of gluconeogenesis in nondiabetic or diabetic subjects during a traditional (i.e., 2-3 h) hyperinsulinemic-euglycemic clamp. The conclusions of studies that have used this approach need to be reevaluated. Diabetes 57:1800-1804, 2008 M easurement of gluconeogenesis in humans is difficult. The deuterated water method is widely used for this purpose (1-17). This method relies on the fact that the fifth carbon of glucose is labeled during gluconeogenesis, whereas the second carbon of glucose is labeled with deuterium during equilibration of glucose-6-phosphate and fructose-6-phoshate (1,2). Therefore, at steady state, the ratio of plasma glucose with deuterium on the fifth carbon (C5 glucose) to plasma glucose labeled on the second carbon (C2 glucose) equals the percentage of plasma glucose derived from gluconeogenesis (1,2). Measurement of C2 glucose enrichment is cumbersome. Since 2 H 2 O and C2 glucose enrichments are equal at steady state, many investigators have used the plasma C5 glucose-to-2 H 2 O ratio to calculate gluconeogenesis after an overnight fast (4 -7,9 -12,18). The C5 glucose-to-2 H 2 O ratio has also been used to measure gluconeogenesis during glucose clamps (4,6,7,11,12,18). However, the validity of this approach is uncertain. We have reported that the rate of gluconeogenesis measured during the final hour of a 3-h hyperinsulinemic-euglycemic clamp in lean nondiabetic subjects using the C5-to-C2 glucose ratio correlated with that measured in the same subjects us...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Plasma C5 Glucose–to–2H2O Ratio Does Not Provide an Accurate Assessment of Gluconeogenesis During Hyperinsulinemic-Euglycemic Clamps in Either Nondiabetic or Diabetic Humans

et al. 2008

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“…Data were analyzed with Sequence Detector 1.7 software (Applied Biosystems). β-actin was used as effect in adipose tissue, but also anti-inflammatory and anti-apoptotic effects [9]. Several reports show the effects of TZDs on ER stress and chronic inflammation.…”

Section: Rna Preparation and Rt-pcrmentioning

confidence: 99%

Rosiglitazone attenuates casein-induced hepatic endoplasmic reticulum stress in Sprague-Dawley rats: a novel model of endoplasmic reticulum stress

Kang

Kim

et al. 2013

Endocr J

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“…Metformin mainly acts by reducing hepatic glucose production through inhibition of gluconeogenesis and may increase glucose uptake in peripheral tissue (2,3). Although initially effective, metformin alone frequently fails to maintain glycemic control as type 2 diabetes progresses (1,4).…”

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confidence: 99%

Empagliflozin as Add-On to Metformin in Patients With Type 2 Diabetes: A 24-Week, Randomized, Double-Blind, Placebo-Controlled Trial

et al. 2014

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OBJECTIVETo investigate the efficacy and tolerability of empagliflozin as an add-on to metformin therapy in patients with type 2 diabetes. RESEARCH DESIGN AND METHODSPatients with HbA 1c levels of ‡7% to £ 10% ( ‡53 to £86 mmol/mol) while receiving metformin ( ‡1,500 mg/day) were randomized and treated with once-daily treatment with empagliflozin 10 mg (n = 217), empagliflozin 25 mg (n = 213), or placebo (n = 207) for 24 weeks. The primary end point was the change in HbA 1c level from baseline at week 24. Key secondary end points were changes from baseline in weight and mean daily glucose (MDG) at week 24. with empagliflozin 25 mg (both P < 0.001). Empagliflozin significantly reduced MDG level and systolic and diastolic blood pressure (BP) versus placebo. Adjusted mean (SE) changes from baseline in weight were 20.45 kg (0.17 kg) with placebo, 22.08 kg (0.17 kg) with empagliflozin 10 mg, and 22.46 kg (0.17 kg) with empagliflozin 25 mg (both P < 0.001). Adverse events (AEs) were similar across groups (placebo 58.7%; empagliflozin 49.5-57.1%). Confirmed hypoglycemic AEs were reported in 0.5%, 1.8%, and 1.4% of patients receiving placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Events consistent with urinary tract infections were reported in 4.9%, 5.1%, and 5.6% of patients, and events consistent with genital infections were reported in 0%, 3.7%, and 4.7% of patients, respectively. CONCLUSIONSEmpagliflozin 10 and 25 mg for 24 weeks as add-on to metformin therapy significantly improved glycemic control, weight, and BP, and were well-tolerated.

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Comparison of the Effects of Pioglitazone and Metformin on Hepatic and Extra-Hepatic Insulin Action in People With Type 2 Diabetes

Cited by 56 publications

References 53 publications

Plasma C5 Glucose–to–2H2O Ratio Does Not Provide an Accurate Assessment of Gluconeogenesis During Hyperinsulinemic-Euglycemic Clamps in Either Nondiabetic or Diabetic Humans

Plasma C5 Glucose–to–2H2O Ratio Does Not Provide an Accurate Assessment of Gluconeogenesis During Hyperinsulinemic-Euglycemic Clamps in Either Nondiabetic or Diabetic Humans

Rosiglitazone attenuates casein-induced hepatic endoplasmic reticulum stress in Sprague-Dawley rats: a novel model of endoplasmic reticulum stress

Empagliflozin as Add-On to Metformin in Patients With Type 2 Diabetes: A 24-Week, Randomized, Double-Blind, Placebo-Controlled Trial

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