help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-1825
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints, Permissions and Rights
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Juurinen, L.
Right arrow Articles by Yki-Järvinen, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Juurinen, L.
Right arrow Articles by Yki-Järvinen, H.
Related Collections
Right arrow Diabetes and Insulin
Right arrow Metabolism
The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 1 118-124
Copyright © 2008 by The Endocrine Society

Rosiglitazone Reduces Liver Fat and Insulin Requirements and Improves Hepatic Insulin Sensitivity and Glycemic Control in Patients with Type 2 Diabetes Requiring High Insulin Doses

Leena Juurinen, Anna Kotronen, Marit Granér and Hannele Yki-Järvinen

Department of Medicine (L.J., A.K., H.Y.-J.), Division of Diabetes, University of Helsinki, Minerva Medical Research Institute (L.J., A.K.), and Department of Internal Medicine (M.G.), Division of Cardiology, Helsinki University Central Hospital, FIN-00290 Helsinki, Finland

Address all correspondence and requests for reprints to: Anna Kotronen, M.B., Department of Medicine, Division of Diabetes, University of Helsinki, P.O. Box 700, Room C418B, FIN-00029 HUCH Helsinki, Finland. E-mail: anna.kotronen{at}helsinki.fi.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Background: Liver fat is an important determinant of insulin requirements during insulin therapy. Peroxisome proliferator-activated receptor (PPAR)-{gamma} agonists reduce liver fat. We therefore hypothesized that type 2 diabetic patients using exceptionally high doses of insulin might respond well to addition of a PPAR{gamma} agonist.

Methods: We determined the effect of the PPAR{gamma} agonist rosiglitazone on liver fat and directly measured hepatic insulin sensitivity in 14 patients with type 2 diabetes (aged 51 ± 3 yr, body mass index 36.7 ± 1.1 kg/m2), who were poorly controlled (glycosylated hemoglobin A1c (HbA1c) 8.9 ± 0.4%) despite using high doses of insulin (218 ± 22 IU/d) in combination with metformin. Liver fat content (1H-magnetic resonance spectroscopy), hepatic insulin sensitivity [6 h hyperinsulinemic euglycemic clamp (insulin 0.3 mU/kg·min) combined with [3-3H]glucose], body composition (magnetic resonance imaging), substrate oxidation rates (indirect calorimetry), clinical parameters, and liver enzymes were measured before and after rosiglitazone treatment (8 mg/d) for 8 months.

Results: During rosiglitazone, HbA1c decreased from 8.9 ± 0.4% to 7.8 ± 0.3% (P = 0.007) and insulin requirements from 218 ± 22 to 129 ± 20 IU/d (P = 0.002). Liver fat content decreased by 46 ± 9% from 20 ± 3% to 11 ± 3% (P = 0.0002). Hepatic insulin sensitivity, measured from the percent suppression of endogenous glucose production by insulin, increased from –40 ± 7% to –89 ± 12% (P = 0.001). The percent change in liver fat correlated with the percent decrease in HbA1c (r = 0.53, P = 0.06), insulin dose (r = 0.66, P = 0.014), and suppression of endogenous glucose production (r = 0.76, P = 0.003).

Conclusions: Our results suggest that rosiglitazone may be particularly effective in type 2 diabetic patients who are poorly controlled despite using high insulin doses. The mechanism is likely to involve reduced liver fat and enhanced hepatic insulin sensitivity.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
A key action of insulin is to inhibit hepatic glucose production (1). Once fatty, the liver is insulin resistant to this action of insulin both in normal subjects (2) and patients with type 2 diabetes (3). Although the ability of insulin to stimulate glucose uptake is impaired in patients with type 2 diabetes (4, 5, 6), this defect is compensated for by hyperglycemia and glucose mass action (7, 8, 9). This maintains absolute glucose flux normal under postprandial conditions (7) and implies that inhibition of hepatic glucose production both basally and postprandially determines glucose control. Consistent with a key role of hepatic insulin sensitivity in determining the response to antihyperglycemic therapies, we have previously shown in three separate studies that the degree of fat accumulation in the liver is an important determinant of insulin requirements during insulin therapy. Two of these studies were cross-sectional (3, 10) and one prospective (11). During insulin combination therapy in patients with type 2 diabetes, the insulin doses required to achieve glucose targets have varied approximately 20-fold from 10 to 200 IU/d (11, 12, 13, 14). In our experience, once the insulin dose exceeds approximately 200 IU/d despite simultaneous use of oral agents, such as sulfonylureas and metformin, it becomes exceedingly difficult to achieve good glycemic control. This could be due to the inability of insulin to act in a fatty liver.

Peroxisome proliferator-activated receptor (PPAR)-{gamma} agonists have been shown to decrease liver fat content (15, 16, 17, 18, 19). When used in combination with insulin, these agents have had a modest insulin sparing effect (mean decrease 9% or 13 IU/d) (20, 21, 22, 23, 24, 25, 26, 27, 28) and improved glycemic control, compared with placebo (20, 22, 23, 26). Because of fear of hepatotoxicity after withdrawal of troglitazone due to idiosyncratic liver reactions, patients with elevated liver enzymes were carefully excluded from these studies (21, 22, 23, 24, 25, 28). The currently available PPAR{gamma} agonists rosi- and pioglitazone have reduced not only liver enzymes (29, 30, 31) and steatosis (15, 16, 17, 18, 19) but also inflammation, ballooning necrosis, and possibly fibrosis (19). Given the potentially harmful cardiovascular effects of rosiglitazone (32) and other side effects, nonalcoholic steatohepatitis (NASH) might become an indication for PPAR{gamma} agonists. If used for treatment of type 2 diabetes, it would be useful to identify patients who respond particularly well to these agents.

In the present mechanistic study, we hypothesized that patients requiring high doses of insulin are particularly responsive to PPAR{gamma} agonist treatment and that PPAR{gamma} agonism would markedly reduce insulin requirements and liver fat and improve hepatic insulin sensitivity. We searched for patients who had been chronically using a stable high dose of insulin combined with metformin and then added rosiglitazone to the treatment regimen. We have previously shown that metformin has no effect on liver fat in insulin-naive patients (15) and that adding insulin to previous metformin treatment in insulin-naive patients has only a minor effect on liver fat content (10).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects and study design

This study was an investigator-initiated study not financially supported by the industry. We recruited, by contacting specialists in southern Finland, 14 patients (nine men and five women, mean duration of diabetes 12 yr) with type 2 diabetes who were poorly controlled despite high-dose insulin therapy (>100 IU/d, range 115–400 IU/d) combined with metformin (2 g/d for more than 2 yr) to be treated with additional rosiglitazone (8 mg once a day) for 8 months. The insulin treatment regiments varied from basal insulin alone (n = 5) to use of multiple insulin injection therapy (n = 9). The patients were instructed to decrease their insulin doses by 4–10 IU whenever hypoglycemia (fasting plasma glucose < 4 mmol/liter) occurred. Additional inclusion criteria were stable insulin dose for at least 2 yr and body weight and glycemic control for at least 6 months before participation. Exclusion criteria were clinical or echocardiographic evidence of heart failure, other cardiovascular disease, or any other significant disease that would make implementation of the study protocol impossible; treatment with drugs that may alter glucose metabolism (steroids, β-blockers, and thiazide diuretics); abnormal serum creatinine, macroalbuminuria, and excessive alcohol consumption (>20 g/d); and drug abuse. The inclusion and exclusion criteria were reviewed at a screening visit, during which the patients underwent a history and physical examination, and blood samples were taken for measurement of the blood count, serum creatinine, electrolytes, fasting plasma glucose, glycosylated hemoglobin (HbA1c), liver enzymes, and lipids. An electrocardiogram was recorded, and a urine sample was taken to exclude patients with infections and macroalbuminuria. Transthoracic echocardiography was performed by one of the investigators (M.G.) using Vivid 7 digital ultrasonography system (GE Vingmed Ultrasound, Horton, Norway). The left ventricular ejection fraction was calculated by M-mode echocardiography from the parasternal long-axis view. Measurements were made while the subject was lying in the left lateral recumbent position from three consecutive beats. The average of three beats was used for analysis. Subjects with left ventricular ejection fraction less than 50% were excluded.

If a patient was considered eligible after the screening visit, metabolic studies [measurement of liver fat, insulin sensitivity of the glucose rate of appearance (Ra) and rate of disappearance (Rd), body composition, and substrate oxidation rates] were performed before and after 8 months of additional treatment with rosiglitazone as detailed below. The nature and potential risks of the study were explained to all subjects before obtaining their written, informed consent. The experimental protocol was approved by the ethical committee of the Helsinki University Central Hospital.

In vivo insulin action on glucose production and use

Patients were admitted to the hospital on the evening before the study. At 1800 h, an indwelling 18-gauge catheter (Venflon; Viggo-Spectramed, Helsingborg, Sweden) equipped with an obturator was inserted in an antecubital vein. On this evening before the study, the patients did not take their bedtime insulin injection. To determine glucose Ra and Rd, a primed continuous iv infusion of [3-3H]glucose was started at 0400 h and continued for a total of 11 h. The priming dose of [3-3H]glucose was adjusted according to the fasting blood glucose concentration measured at 0400 h as follows: priming dose = [glucose (millimoles per liter) at 0400 h/5] x 20 µCi/min. This dose was infused iv over 10 min and was followed by a continuous-rate infusion of [3-3H]glucose at a rate of 0.2 µCi/min as previously described (3). Before the start of the insulin infusion, another catheter was inserted in a retrograde position in a heated dorsal hand vein for withdrawal of arterialized venous blood. Baseline blood samples were taken for measurement of fasting plasma glucose; glucose specific activity (SA); HbA1c; triglycerides; total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol; free fatty acids; and serum-free insulin concentrations. At 0900 h, after a 300-min equilibrium period, a primed continuous (0.3 mU/kg·min) infusion of insulin (Actrapid Human; Novo Nordisk, Bagsvaerd, Denmark) was started (0 min), as previously described (33).

Because hepatic glucose production is more sensitive to suppression by insulin than muscle glucose uptake (8, 34), we chose a low insulin infusion rate to be able to accurately assess hepatic insulin sensitivity. Plasma glucose was adjusted to and then maintained at approximately 8 mmol/liter (144 mg/dl) for 360 min. This was done using a variable-rate infusion of 20% glucose based on plasma glucose measurements, which were made from arterialized venous blood every 5–10 min. Blood samples for measurement of glucose SA were taken basally at –30, –20, and 0 min and at 120, 180, 240, 280, 300, 330, and 360 min during the insulin infusion. Serum-free insulin concentrations were measured every 60 min.

Insulin clearance We have previously found rosiglitazone to increase insulin clearance, possibly via a decrease in liver fat content (15). To evaluate this possibility in the present study, insulin clearance [milliliters per kilogram fat-free mass (FFM) per minute] was calculated by dividing the rate of insulin infusion (milliunits per kilogram FFM per minute) by the increment in serum insulin concentration (mean concentration measured during the insulin infusion minus fasting serum insulin).

[3-3H]glucose SA and calculation of glucose kinetics To determine glucose SA, plasma was deproteinized with Ba(OH)2 and ZnSO4 and evaporated as described (35). Glucose Ra and Rd were calculated using the Steele equation, assuming a pool fraction of 0.65 for glucose and distribution volume of 200 ml/kg for glucose. Endogenous glucose Ra was calculated by subtracting the exogenous glucose infusion rate required to maintain euglycemia during hyperinsulinemia (0–360 min) from the rate of total glucose Ra. The percent suppression of basal endogenous glucose Ra during the last 2 h (240–360 min) by insulin was used as a measure of hepatic insulin sensitivity, i.e. the sensitivity of endogenous glucose production to insulin (percent suppression of endogenous Ra).

Liver fat content (proton spectroscopy)

Localized single voxel (2 x 2 x 2 cm3) proton spectra were acquired using a 1.5-T whole-body system (Magnetom Vision; Siemens, Erlangen, Germany), which consisted of a combination of whole-body and loop surface coils for radiofrequency transmitting and signal receiving, as previously described (3). T1-weighted high-resolution magnetic resonance imaging (MRI) scans were used for localization of the voxel of interest within the right lobe of the liver. Magnetic resonance spectroscopy measurements of the liver fat were performed in the middle of the right lobe of the liver at a location that was individually determined for each subject; vascular structures and sc fat tissue were avoided when selecting the voxel. Subjects lay on their stomachs on the surface coil, which was embedded in a mattress to minimize abdominal movement due to breathing. In one patient, the spectroscopic recording after therapy was technically unsuccessful. Spectroscopic intracellular triglyceride content (liver fat) was expressed as a ratio of the area under the methylene peak to that under the methylene and water peaks (x 100 = liver fat percent). This measurement has been validated against histologically determined lipid content in our laboratory (36) and against estimates of fatty degeneration or infiltration by x-ray computer-assisted tomography (3). All spectra were analyzed by physicists who were unaware of any of the clinical data. The reproducibility of repeated measurements of liver fat in nondiabetic subjects studied on two occasions in our laboratory is 11% (37).

Intraabdominal fat and sc fat (MRI)

A series of 16 T1-weighted transaxial scans were acquired from a region extending from 8 cm above to 8 cm below the fourth and fifth lumbar interspace (16 slices, field of view 375 x 500 mm2, slice thickness 10 mm, breath-hold repetition time 138.9 msec, echo time 4.1 msec). Intraabdominal and sc fat areas were measured using an image analysis program (Alice 3.0; Parexel, Waltham, MA). A histogram of pixel intensity in the intraabdominal region was displayed, and the intensity corresponding to the nadir between the lean and fat peaks was used as a cutoff point. Intraabdominal adipose tissue was defined as the area of pixels in the intraabdominal region above this cutoff point. For calculation of sc adipose tissue area, a region of interest was first manually drawn at the demarcation of sc adipose tissue and intraabdominal adipose tissue, as previously described (3).

Substrate oxidation rates

Glucose and lipid oxidation rates were measured with indirect calorimetry using the Deltatrac metabolic monitor (Datex, Helsinki, Finland) as previously described (38, 39). The measurements were performed for 40 min during the basal period and the last hour of insulin clamp. Samples of inspired and expired air, which were suctioned at 40 liters/min, were analyzed for O2 and CO2 concentration differences using paramagnetic O2 and CO2 analyzers, respectively. The hood was placed on the subject’s head 10 min before the measurement was started. Urine was collected during the study, and the protein oxidation rate was estimated from urea nitrogen excretion (1 g nitrogen = 6.25 g protein). The following constants were used for calculation of glucose and lipid oxidation rates from gas exchange data: oxidation of 1 g of protein requires 966 ml O2 and produces 782 ml CO2, oxidation of 1 g of glucose requires 746 ml O2 and produces 746 ml CO2, and oxidation of 1 g of lipid requires 2029 ml O2 and produces 1430 ml CO2. Energy production rates (joules per kilogram FFM per minute) were calculated assuming oxidation of 1 mg carbohydrate produces 15.65 J; 1 mg lipid, 39.75 J; and 1 mg protein, 17.15 J (38).

Analytical procedures, calculations, and other measurements

Plasma glucose concentrations were measured in duplicate with the glucose oxidase method using Glucose Analyzer II (Beckman Instruments, Fullerton, CA) (40). Serum-free insulin concentrations were measured with the Auto-DELFIA kit (Wallac, Turku, Finland), and C-peptide concentrations by RIA (41). Fasting serum (fS)-HDL cholesterol and fS-triglyceride concentrations were measured with the enzymatic kits from Roche Diagnostics using an autoanalyzer (Roche Diagnostics Hitachi, Hitachi Ltd., Tokyo, Japan). The concentrations of LDL cholesterol were calculated using the Friedewald formula (42). Serum (S)-alanine aminotransferase (ALT) and S-aspartate aminotransferase (AST) activities were determined as recommended by the European Committee for Clinical Laboratory Standards.

The percent body fat was determined using bioelectrical impedance analysis (BioElectrical Impedance Analyzer System, model BIA-101A; RJL Systems, Detroit, MI) (43). Waist circumference was measured midway between spina iliaca superior and the lower rib margin and hip circumference at the level of the greater trochanters (44).

Statistical analyses

The paired t test was used to compare changes before and after additional rosiglitazone treatment. Logarithmic transformation was performed if necessary. Correlation analyses were performed using the Spearman nonparametric correlation coefficient. All data are shown as mean ± SEM. Calculations were made using GraphPad Prism version 4.00 for Windows (GraphPad Software, San Diego, CA) and SPSS 14.0 for Windows (SPSS, Chicago, IL). P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Glycemic control, insulin requirements, and body composition

HbA1c decreased by 1.1 ± 0.3%, from 8.9 ± 0.4 to 7.8 ± 0.3% (P = 0.007) during 8 months of rosiglitazone therapy. Insulin dose decreased by 89 ± 24 IU/d (40 ± 8%) from 218 ± 22 to 129 ± 20 IU/d (P = 0.002, Fig. 1Go). Body weight increased by 3.2 ± 0.9 kg, which was due to an increase in FFM (1.7 ± 0.7 kg) and fat mass (1.6 ± 0.7 kg). Subcutaneous but not intraabdominal fat increased significantly when measured with MRI (Table 1Go). Insulin regimens at the end of the study remained unchanged.


Figure 1
View larger version (7K):
[in this window]
[in a new window]

  		FIG. 1. Effects of addition of rosiglitazone on liver fat content (A), HbA1c (B), insulin dose (C), and S-ALT (D). *, P ≤ 0.05; **, P < 0.001; ***, P < 0.0001. White bars, before; black bars, after the rosiglitazone-insulin combination therapy.

 

View this table:
[in this window]
[in a new window]

  		TABLE 1. Clinical and biochemical characteristics of the patients before and after 8 months of rosiglitazone-insulin combination therapy

 
Liver fat content and serum liver enzyme concentrations

Liver fat content decreased by 46 ± 9% from 20 ± 3 to 11 ± 3% (P = 0.0002, Fig. 1Go). Serum ALT, AST, {gamma}-glutamyl transpeptidase ({gamma}GT), and alkaline phosphatase concentrations also decreased significantly (Table 1Go). The percent change in liver fat correlated with the percent changes in serum ALT (r = 0.50, P = 0.08), AST (0.63, P = 0.02), and serum {gamma}GT concentrations (r = 0.72, P = 0.01).

Associations between liver fat content and glycemic parameters

The percent change in liver fat content was positively correlated with percent change in insulin dose (r = 0.66, P = 0.014) and almost significantly with that in HbA1c (r = 0.53, P = 0.06, Fig. 2Go).


Figure 2
View larger version (10K):
[in this window]
[in a new window]

  		FIG. 2. The relationship between the percent change in liver fat content and the percent change in the suppression of endogenous glucose production (A), the percent change in HbA1c (B), and the percent change in insulin dose (C) by 8 months of rosiglitazone-insulin combination therapy.

 
Insulin sensitivity

Steady-state plasma glucose concentrations during euglycemia (240–360 min) averaged 8.1 ± 0.05 and 8.2 ± 0.04 mmol/liter before and after rosiglitazone (P = NS). Fasting serum-free insulin decreased by 48% (Table 1Go). Serum-free insulin concentrations (60–360 min) averaged 77 mU/liter (47–106 mU/liter, median, interquartile range) vs. 59 mU/liter (39–93 mU/liter), respectively (P = 0.07). The increment in serum-free insulin concentrations was similar before [28 mU/liter (15–34 mU/liter)] and after [25 mU/liter (13–36 mU/liter), P = NS] rosiglitazone therapy, implying that insulin clearance remained unchanged [17 ml/kg FFM per minute (13–29 ml/kg FFM per minute) vs. 16 ml/kg FFM per minute (13–26 ml/kg FFM per minute), P = NS].

Rates of basal endogenous glucose production were similar before (2.82 ± 0.25 mg/kg FFM per minute) and after (2.33 ± 0.33 mg/kg FFM per minute, P = NS) rosiglitazone treatment. During the insulin infusion, the rate of endogenous glucose production decreased (1.69 ± 0.25 vs. 0.61 ± 0.24 mg/kg FFM per minute, P = 0.007), and the percent suppression by insulin increased from –40 ± 7 to –89 ± 12% (P = 0.001) by rosiglitazone. The change in the percent suppression of endogenous glucose production correlated positively with the percent change in liver fat content (r = 0.76, P = 0.003). The rate of basal glucose disposal decreased from 2.90 ± 0.24 to 2.06 ± 0.27 mg/kg FFM per minute (P = 0.028), whereas the rate of insulin-stimulated glucose disposal remained unchanged (2.87 ± 0.16 vs. 2.48 ± 0.18 mg/kg FFM per minute, P = NS).

Energy expenditure and substrate oxidation rates

During insulin therapy, energy expenditure in the basal (83.2 ± 3.2 vs. 78.2 ± 2.1 J/kg FFM per minute, P = 0.05) and insulin-stimulated (80.1 ± 3.0 vs. 75.1 ± 1.9 J/kg FFM per minute, P = 0.017) states decreased significantly by rosiglitazone. The rate of lipid oxidation during insulin stimulation decreased significantly (1.81 ± 0.12 vs. 1.51 ± 0.12 mg/kg FFM per minute, P = 0.04). Rates of carbohydrate and protein oxidation remained unchanged (Fig. 3Go).


Figure 3
View larger version (12K):
[in this window]
[in a new window]

  		FIG. 3. Effects of 8 months of the addition of rosiglitazone on rates of energy expenditure in the basal state (A) and during hyperinsulinemia (B). Black bars, protein oxidation; gray bars, carbohydrate oxidation; white bars, lipid oxidation. Symbols as in Fig. 1Go.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In the present study, we hypothesized that patients requiring exceptionally high insulin doses might respond particularly well to PPAR{gamma} agonist treatment. During 8 months of rosiglitazone therapy, HbA1c decreased significantly despite a 40% reduction in the insulin dose. Liver fat content decreased by 50%, and hepatic insulin sensitivity increased significantly. The changes in liver fat content correlated with both decreases in insulin requirements and increase in hepatic insulin sensitivity.

Due to the invasive measurements performed, it was not ethically possible to study a time-control group. A study effect could thus have contributed to the results, which is a potential limitation. However, we have preciously shown that addition of metformin alone for 4 months has no effect on liver fat content (15), whereas rosiglitazone alone decreases liver fat by 50% (15). Given that insulin requirements correlate closely and linearly with hepatic fat content (3, 10), and S-ALT predicts insulin requirements independent of body mass index (11), one could predict insulin requirements to decrease by 50% if liver fat decreases by 50%. This indeed happened after patients had been treated with stable insulin doses for 2 yr. These considerations make it likely that the changes were due to rosiglitazone rather than time, metformin, or continued insulin therapy.

In the present study, liver fat content was increased in each patient because it exceeded its upper limit of normal [5.6% measured by 1H-magnetic resonance spectroscopy (45)]. In the previous PPAR{gamma} agonist insulin combination studies, the decrease in insulin doses averaged 13 IU/d (20, 21, 22, 23, 24, 25, 26, 27), which is much less than the 90 IU/d in the present patients. In keeping with the present results, in previous studies, which had the highest baseline insulin doses, the percent reduction was also the greatest (27, 28). In these clinical studies, liver fat content was not measured. Heterogeneity analyses from the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication trial (DREAM) (29) and A Diabetes Outcome Progression trial (ADOPT) (30) suggested that patients with a large waist circumference respond best to PPAR{gamma} agonist treatment. Waist circumference is tightly correlated with liver fat content (46). These data support the idea that patients with a fatty liver respond particularly well to PPAR{gamma} agonists.

In the present study, no improvement in peripheral insulin sensitivity, as determined from glucose rate of disappearance, was observed. However, given that low physiological insulin infusion rates are optimal for assessment of hepatic rather than peripheral insulin sensitivity (8, 34, 47, 48), the lack of improvement in insulin-stimulated glucose disposal was not unexpected.

When glycemic control is improved, the energy need for glucose production in the liver decreases (49). The improvement in glycemic control is likely to be at least one reason for the decrease in energy expenditure found in the present study. When calculated from our previous data (49), the predicted change in the basal metabolic rate due to changes in fasting glucose and body weight in the present study corresponds to 6.3 ± 19 J/kg FFM per minute, which is not different from the observed change (5.2 ± 2.3 J/kg FFM per minute). The increase in body weight, which accompanies reduction in glucosuria, tends to increase energy expenditure but is not sufficient to keep net energy expenditure unchanged (49). Consistent with previous data regarding PPAR{gamma} agonists (50), weight gain (3.2 kg) was greater than would be expected from improvement in glycemic control [1.5–2.0 kg per 1% decrease in HbA1c (49)]. Weight gain was due to a roughly similar increase in FFM and fat mass, in keeping the data showing improved glycemia to increase predominantly FFM (10) and PPAR{gamma} agonists mainly fat mass (50).

Adverse effects of thiazolidinediones include fluid retention and the risk of heart failure (30, 31). A recent metaanalysis suggested rosiglitazone use to significantly increase the risk of myocardial infarction (32), although there is no randomized, adequately powered clinical trial to support this finding (51). In Europe, combination therapy with insulin and PPAR{gamma} agonists is contraindicated because of an increased risk of heart failure (http://www.emea.europa.eu/). In the Prospective Pioglitazone Clinical Trial in Macrovascular Events, a controlled study of 5238 type 2 diabetic patients at high risk of cardiovascular events randomized to receive either pioglitazone or placebo, 31% of patients were treated with insulin, but it is unknown whether the rate of cardiovascular events differed between insulin-treated and insulin-naive patients using pioglitazone (31). Because of the increased risk of heart failure, we performed echocardiographies in all patients before their participation to exclude heart failure at baseline.

In conclusion, we have shown that type 2 diabetic patients who are poorly controlled despite using unusually high doses of insulin do respond to rosiglitazone. We suggest the main mechanism underlying improved glycemic control despite reduced insulin requirements is enhanced hepatic insulin sensitivity. At least in monotherapy studies, pioglitazone is as effective as rosiglitazone (52) and may be associated with a better cardiovascular outcome during long-term treatment than rosiglitazone (30, 31).


   Acknowledgments
 
We gratefully acknowledge Katja Tuominen, Mia Urjansson, Pentti Pölönen, and Maarit Toivonen for excellent technical assistance; Mirja Tiikkainen, Leena Ryysy, Jukka Westerbacka, Anna-Maija Häkkinen, Helena Levänen, and Juha Saltevo for their contributions; and the volunteers for their help.


   Footnotes
 
This work was supported by research grants from the Academy of Finland, the Sigrid Juselius Foundation, and Novo Nordisk Foundation. This work is part of the project "Hepatic and adipose tissue and functions in the metabolic syndrome" (www.hepadip.org), which is supported by the European Commission as an Integrated Project under the 6th Framework Programe (Contract LSHM-CT-2005-018734).

Disclosure Statement: The authors have nothing to disclose.

First Published Online October 23, 2007

Abbreviations: ALT, Alanine aminotransferase; AST, aspartate aminotransferase; {gamma}GT, {gamma}-glutamyl transpeptidase; FFM, fat-free mass; fS, fasting S; HbA1c, glycosylated hemoglobin A1c; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MRI, magnetic resonance imaging; PPAR, peroxisome proliferator-activated receptor; Ra, rate of appearance; Rd, rate of disappearance; S, serum; SA, specific activity.

Received August 14, 2007.

Accepted October 17, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Yki-Jarvinen H 1993 Action of insulin on glucose metabolism in vivo. Baillieres Clin Endocrinol Metab 7:903–927[CrossRef][Medline]
  2. Seppala-Lindroos A, Vehkavaara S, Hakkinen AM, Goto T, Westerbacka J, Sovijarvi A, Halavaara J, Yki-Jarvinen H 2002 Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab 87:3023–3028[Abstract/Free Full Text]
  3. Ryysy L, Hakkinen AM, Goto T, Vehkavaara S, Westerbacka J, Halavaara J, Yki-Jarvinen H 2000 Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes 49:749–758[Abstract]
  4. Utriainen T, Takala T, Luotolahti M, Ronnemaa T, Laine H, Ruotsalainen U, Haaparanta M, Nuutila P, Yki-Jarvinen H 1998 Insulin resistance characterizes glucose uptake in skeletal muscle but not in the heart in NIDDM. Diabetologia 41:555–559[CrossRef][Medline]
  5. DeFronzo RA, Gunnarsson R, Bjorkman O, Olsson M, Wahren J 1985 Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. J Clin Invest 76:149–155[Medline]
  6. Baron AD, Laakso M, Brechtel G, Edelman SV 1991 Reduced capacity and affinity of skeletal muscle for insulin-mediated glucose uptake in noninsulin-dependent diabetic subjects. effects of insulin therapy. J Clin Invest 87:1186–1194[Medline]
  7. Mitrakou A, Kelley D, Veneman T, Jenssen T, Pangburn T, Reilly J, Gerich J 1990 Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in NIDDM. Diabetes 39:1381–1390[Abstract]
  8. Yki-Jarvinen H, Young AA, Lamkin C, Foley JE 1987 Kinetics of glucose disposal in whole body and across the forearm in man. J Clin Invest 79:1713–1719[Medline]
  9. Yki-Jarvinen H 1994 The liver as a target for therapy in non-insulin dependent diabetes mellitus. Diab Nutr Metab 7:1–10
  10. Juurinen L, Tiikkainen M, Hakkinen AM, Hakkarainen A, Yki-Jarvinen H 2007 Effects of insulin therapy on liver fat content and hepatic insulin sensitivity in patients with type 2 diabetes. Am J Physiol Endocrinol Metab 292:E829–E835
  11. Yki-Jarvinen H, Kauppinen-Makelin R, Tiikkainen M, Vahatalo M, Virtamo H, Nikkila K, Tulokas T, Hulme S, Hardy K, McNulty S, Hanninen J, Levanen H, Lahdenpera S, Lehtonen R, Ryysy L 2006 Insulin glargine or NPH combined with metformin in type 2 diabetes: the LANMET study. Diabetologia 49:442–451[CrossRef][Medline]
  12. Yki-Jarvinen H, Kauppila M, Kujansuu E, Lahti J, Marjanen T, Niskanen L, Rajala S, Ryysy L, Salo S, Seppala P 1992 Comparison of insulin regimens in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 327:1426–1433[Abstract]
  13. Yki-Jarvinen H, Juurinen L, Alvarsson M, Bystedt T, Caldwell I, Davies M, Lahdenpera S, Nijpels G, Vahatalo M 2007 Initiate Insulin by Aggressive Titration and Education (INITIATE): a randomized study to compare initiation of insulin combination therapy in type 2 diabetic patients individually and in groups. Diabetes Care 30:1364–1369[Abstract/Free Full Text]
  14. Yki-Jarvinen H, Ryysy L, Nikkila K, Tulokas T, Vanamo R, Heikkila M 1999 Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus. A randomized, controlled trial. Ann Intern Med 130:389–396[Abstract/Free Full Text]
  15. Tiikkainen M, Hakkinen AM, Korsheninnikova E, Nyman T, Makimattila S, Yki-Jarvinen H 2004 Effects of rosiglitazone and metformin on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type 2 diabetes. Diabetes 53:2169–2176[Abstract/Free Full Text]
  16. Bajaj M, Suraamornkul S, Pratipanawatr T, Hardies LJ, Pratipanawatr W, Glass L, Cersosimo E, Miyazaki Y, DeFronzo RA 2003 Pioglitazone reduces hepatic fat content and augments splanchnic glucose uptake in patients with type 2 diabetes. Diabetes 52:1364–1370[Abstract/Free Full Text]
  17. Mayerson AB, Hundal RS, Dufour S, Lebon V, Befroy D, Cline GW, Enocksson S, Inzucchi SE, Shulman GI, Petersen KF 2002 The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes 51:797–802[Abstract/Free Full Text]
  18. Carey DG, Cowin GJ, Galloway GJ, Jones NP, Richards JC, Biswas N, Doddrell DM 2002 Effect of rosiglitazone on insulin sensitivity and body composition in type 2 diabetic patients. Obes Res 10:1008–1015[Medline]
  19. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, Balas B, Gastaldelli A, Tio F, Pulcini J, Berria R, Ma JZ, Dwivedi S, Havranek R, Fincke C, DeFronzo R, Bannayan GA, Schenker S, Cusi K 2006 A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 355:2297–2307[Abstract/Free Full Text]
  20. Mattoo V, Eckland D, Widel M, Duran S, Fajardo C, Strand J, Knight D, Grossman L, Oakley D, Tan M, H6E-MC-GLAT Study Group 2005 Metabolic effects of pioglitazone in combination with insulin in patients with type 2 diabetes mellitus whose disease is not adequately controlled with insulin therapy: results of a six-month, randomized, double-blind, prospective, multicenter, parallel-group study. Clin Ther 27:554–567[CrossRef][Medline]
  21. Davidson JA, Perez A, Zhang J, The Pioglitazone 343 Study Group 2006 Addition of pioglitazone to stable insulin therapy in patients with poorly controlled type 2 diabetes: Results of a double-blind, multicentre, randomized study. Diabetes Obes Metab 8:164–174[CrossRef][Medline]
  22. Berhanu P, Perez A, Yu S 2007 Effect of pioglitazone in combination with insulin therapy on glycaemic control, insulin dose requirement and lipid profile in patients with type 2 diabetes previously poorly controlled with combination therapy. Diabetes Obes Metab 9:512–520[CrossRef][Medline]
  23. Raskin P, Rendell M, Riddle MC, Dole JF, Freed MI, Rosenstock J, Rosiglitazone Clinical Trials Study Group 2001 A randomized trial of rosiglitazone therapy in patients with inadequately controlled insulin-treated type 2 diabetes. Diabetes Care 2:1226–1232
  24. Poulsen MK, Henriksen JE, Hother-Nielsen O, Beck-Nielsen H 2003 The combined effect of triple therapy with rosiglitazone, metformin, and insulin aspart in type 2 diabetic patients. Diabetes Care 26:3273–3279[Abstract/Free Full Text]
  25. Garg R, Gopal J, Jones GR 2007 Rosiglitazone: safety and efficacy in combination with insulin in poorly controlled type 2 diabetes mellitus patients treated with insulin alone. J Diabetes Complications 21:1–6[CrossRef][Medline]
  26. Hollander P, Yu D, Chou HS 2007 Low-dose rosiglitazone in patients with insulin-requiring type 2 diabetes. Arch Intern Med 167:1284–1290[Abstract/Free Full Text]
  27. Buch HN, Baskar V, Barton DM, Kamalakannan D, Akarca C, Singh BM 2002 Combination of insulin and thiazolidinedione therapy in massively obese patients with type 2 diabetes. Diabet Med 19:572–574[CrossRef][Medline]
  28. Yu JG, Kruszynska YT, Mulford MI, Olefsky JM 1999 A comparison of troglitazone and metformin on insulin requirements in euglycemic intensively insulin-treated type 2 diabetic patients. Diabetes 48:2414–2421[Abstract]
  29. DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators, Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, Hanefeld M, Hoogwerf B, Laakso M, Mohan V, Shaw J, Zinman B, Holman RR 2006 Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 368:1096–1105[CrossRef][Medline]
  30. Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O’Neill MC, Zinman B, Viberti G, ADOPT Study Group 2006 Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 355:2427–2443[Abstract/Free Full Text]
  31. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, Skene AM, Tan MH, Lefebvre PJ, Murray GD, Standl E, Wilcox RG, Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine RJ, Koranyi L, Laakso M, Mokan M, Norkus A, Pirags V, Podar T, Scheen A, Scherbaum W, Schernthaner G, Schmitz O, Skrha J, Smith U, Taton J, PROactive investigators 2005 Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study (PROspective pioglitAzone clinical trial in macroVascular events): a randomised controlled trial. Lancet 366:1279–1289[CrossRef][Medline]
  32. Nissen SE, Wolski K 2007 Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 356:2457–2471[Abstract/Free Full Text]
  33. DeFronzo RA, Tobin JD, Andres R 1979 Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237:E214–E223
  34. Rizza RA, Mandarino LJ, Gerich JE 1981 Dose-response characteristics for effects of insulin on production and utilization of glucose in man. Am J Physiol 24:E630–E639
  35. Puhakainen I, Koivisto VA, Yki-Jarvinen H 1991 No reduction in total hepatic glucose output by inhibition of gluconeogenesis with ethanol in NIDDM patients. Diabetes 40:1319–1327[Abstract]
  36. Kotronen A, Vehkavaara S, Seppala-Lindroos A, Bergholm R, Yki-Jarvinen H 2007 Effect of liver fat on insulin clearance. Am J Physiol Endocrinol Metab Sep 25 [Epub ahead of print]
  37. Sutinen J, Hakkinen AM, Westerbacka J, Seppala-Lindroos A, Vehkavaara S, Halavaara J, Jarvinen A, Ristola M, Yki-Jarvinen H 2002 Increased fat accumulation in the liver in HIV-infected patients with antiretroviral therapy-associated lipodystrophy. AIDS 16:2183–2193[CrossRef][Medline]
  38. Ferrannini E 1988 The theoretical bases of indirect calorimetry: a review. Metabolism 37:287–301[CrossRef][Medline]
  39. Yki-Jarvinen H, Puhakainen I, Saloranta C, Groop L, Taskinen MR 1991 Demonstration of a novel feedback mechanism between FFA oxidation from intracellular and intravascular sources. Am J Physiol 260(5 Pt 1):E680–E689
  40. Kadish AH, Little RL, Sternberg JC 1968 A new and rapid method for the determination of glucose by measurement of rate of oxygen consumption. Clin Chem 14:116–131[Abstract]
  41. Kuzuya H, Blix PM, Horwitz DL, Steiner DF, Rubenstein AH 1977 Determination of free and total insulin and C-peptide in insulin-treated diabetics. Diabetes 26:22–29[Abstract]
  42. Friedewald WT, Levy RI, Fredrickson DS 1972 Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18:499–502[Abstract]
  43. Lukaski HC, Johnson PE, Bolonchuk WW, Lykken GI 1985 Assessment of fat-free mass using bioelectrical impedance measurements of the human body. Am J Clin Nutr 41:810–817[Abstract/Free Full Text]
  44. Marti B, Tuomilehto J, Salomaa V, Kartovaara L, Korhonen HJ, Pietinen P 1991 Body fat distribution in the Finnish population: environmental determinants and predictive power for cardiovascular risk factor levels. J Epidemiol Community Health 45:131–137[Abstract/Free Full Text]
  45. Szczepaniak LS, Nurenberg P, Leonard D, Browning JD, Reingold JS, Grundy S, Hobbs HH, Dobbins RL 2005 Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 288:E462–E468
  46. Kotronen A, Westerbacka J, Bergholm R, Pietilainen KH, Yki-Jarvinen H 2007 Liver fat in the metabolic syndrome. J Clin Endocrinol Metab 92:3490–3497[Abstract/Free Full Text]
  47. Ferrannini E, Mari A 1998 How to measure insulin sensitivity. J Hypertens 16:895–906[CrossRef][Medline]
  48. DeFronzo RA, Ferrannini E, Hendler R, Felig P, Wahren J 1983 Regulation of splanchnic and peripheral glucose uptake by insulin and hyperglycemia in man. Diabetes 32:35–45[Medline]
  49. Makimattila S, Nikkila K, Yki-Jarvinen H 1999 Causes of weight gain during insulin therapy with and without metformin in patients with type II diabetes mellitus. Diabetologia 42:406–412[CrossRef][Medline]
  50. Balas B, Belfort R, Harrison SA, Darland C, Finch J, Schenker S, Gastaldelli A, Cusi K 2007 Pioglitazone treatment increases whole body fat but not total body water in patients with non-alcoholic steatohepatitis. J Hepatol 47:565–570[CrossRef][Medline]
  51. Home PD, Pocock SJ, Beck-Nielsen H, Gomis R, Hanefeld M, Jones NP, Komajda M, McMurray JJ 2007 Rosiglitazone evaluated for cardiovascular outcomes—an interim analysis. N Engl J Med 357:28–38[Abstract/Free Full Text]
  52. Yki-Jarvinen H 2004 Thiazolidinediones. N Engl J Med 351:1106–1118[Free Full Text]



This article has been cited by other articles:


Home page
 EndocrinologyHome page
O. Nov, A. Kohl, E. C. Lewis, N. Bashan, I. Dvir, S. Ben-Shlomo, S. Fishman, S. Wueest, D. Konrad, and A. Rudich
Interleukin-1{beta} May Mediate Insulin Resistance in Liver-Derived Cells in Response to Adipocyte Inflammation
Endocrinology, September 1, 2010; 151(9): 4247 - 4256.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
B. Charbonnel, R. DeFronzo, J. Davidson, O. Schmitz, K. Birkeland, V. Pirags, A. Scheen, and on behalf of the PROactive investigators
Pioglitazone Use in Combination with Insulin in the Prospective Pioglitazone Clinical Trial in Macrovascular Events Study (PROactive19)
J. Clin. Endocrinol. Metab., May 1, 2010; 95(5): 2163 - 2171.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
L. C. Chao, K. Wroblewski, Z. Zhang, L. Pei, L. Vergnes, O. R. Ilkayeva, S. Y. Ding, K. Reue, M. J. Watt, C. B. Newgard, et al.
Insulin Resistance and Altered Systemic Glucose Metabolism in Mice Lacking Nur77
Diabetes, December 1, 2009; 58(12): 2788 - 2796.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
A. Fraser, N. Sattar, S. Ebrahim, and D.A. Lawlor
Is Serum-Glutamylatransferase a Biomarker of Xenobiotics Which Are Conjugated by Glutathione?
Arterioscler Thromb Vasc Biol, April 1, 2008; 28(4): e29 - e29.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints, Permissions and Rights
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Juurinen, L.
Right arrow Articles by Yki-Järvinen, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Juurinen, L.
Right arrow Articles by Yki-Järvinen, H.
Related Collections
Right arrow Diabetes and Insulin
Right arrow Metabolism

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals