Reversal of Nonalcoholic Hepatic Steatosis, Hepatic Insulin Resistance, and Hyperglycemia by Moderate Weight Reduction in Patients With Type 2 Diabetes

Kitt Falk Petersen Sylvie Dufour Douglas Befroy Michael Lehrke Rosa E. Hendler Gerald I. Shulman To examine the mechanism by which moderate weight reduction improves basal and insulin-stimulated rates of glucose metabolism in patients with type 2 diabetes, we used 1H magnetic resonance spectroscopy to assess intrahepatic lipid (IHL) and intramyocellular lipid (IMCL) content in conjunction with hyperinsulinemiceuglycemic clamps using [6,6-2H2]glucose to assess rates of glucose production and insulin-stimulated peripheral glucose uptake. Eight obese patients with type 2 diabetes were studied before and after weight stabilization on a moderately hypocaloric very-low-fat diet (3%). The diabetic patients were markedly insulin resistant in both liver and muscle compared with the lean control subjects. These changes were associated with marked increases in IHL (12.2 3.4 vs. 0.6 0.1%; P 0.02) and IMCL (2.0 0.3 vs. 1.2 0.1%; P 0.02) compared with the control subjects. A weight loss of only 8 kg resulted in normalization of fasting plasma glucose concentrations (8.8 0.5 vs. 6.4 0.3 mmol/l; P < 0.0005), rates of basal glucose production (193 7 vs. 153 10 mg/min; P < 0.0005), and the percentage suppression of hepatic glucose production during the clamp (29 22 vs. 99 3%; P 0.003). These improvements in basal and insulin-stimulated hepatic glucose metabolism were associated with an 81 4% reduction in IHL (P 0.0009) but no significant change in insulin-stimulated peripheral glucose uptake or IMCL (2.0 0.3 vs. 1.9 0.3%; P 0.21). In conclusion, these data support the hypothesis that moderate weight loss normalizes fasting hyperglycemia in patients with poorly controlled type 2 diabetes by mobilizing a relatively small pool of IHL, which reverses hepatic insulin resistance and normalizes rates of basal glucose production, independent of any changes in insulin-stimulated peripheral glucose metabolism. Diabetes 54:603- 608, 2005 - revious studies have demonstrated that relatively modest weight reduction in obese patients with poorly controlled type 2 diabetes can markedly reduce plasma glucose concentrations, but the mechanism responsible for this phenomenon is not known (1). Henry et al. (1) showed that a weight loss of 16.8 2.7 kg led to a reduction in fasting plasma glucose concentrations from 15.3 1.2 to 6.8 0.4 mmol/l and that the individual fasting glucose concentrations were highly correlated with rates of basal hepatic glucose production. We hypothesized that a relatively small pool of intrahepatic lipid (IHL) might be responsible for the hepatic insulin resistance and increased rates of glucose production in patients with poorly controlled type 2 diabetes and that hepatic steatosis and hepatic insulin resistance would reverse with modest weight reduction before any changes in peripheral insulin resistance and intramyocellular lipid (IMCL) content. To test these hypotheses, we used 1H magnetic resonance spectroscopy (MRS) to noninvasively assess IHL and IMCL content in eight obese type 2 diabetic patients before and after weight stabilization on a hypocaloric diet, which was maintained until they reached normal fasting plasma glucose concentrations. Hepatic glucose production and insulin sensitivity of liver and muscle were assessed with a hyperinsulinemic (480 pmol/l)-euglycemic ( 6.0 mmol/l) clamp, using [6,6-2H2]glucose. In addition, rates of net hepatic glycogenolysis and gluconeogenesis were assessed in a subgroup of patients before and after weight loss by 13C MRS as previously described (2). RESEARCH DESIGN AND METHODS Eight healthy, nonsmoking, obese type 2 diabetic patients (five men and three women; 47 3 years of age) were studied (Table 1). At the time of study enrollment, three patients diabetes was controlled with diet and the five others were taking sulfonylurea agents to control their diabetes. They did not take any other medications. The patients discontinued this antidiabetic diet/medication 10 days before the baseline study. The control group consisted of 10 lean, nonsmoking, healthy volunteers (5 men and 5 women; 30 2 years of age) who were studied once at baseline. The control subjects were not taking any medications. All of the study participants had a sedentary lifestyle, and none were engaged in any regular exercise regimens. For 3 days before each of the studies, the subjects were given an isocaloric diet (35 kcal/kg; 60% carbohydrate, 20% protein, 20% fat) that was prepared by the metabolic kitchen of the Yale/New Haven Hospital General Clinical Research Center (GCRC). The calories in this diet were divided evenly among the three daily meals. At 4 P.M. on the 3rd day, they were admitted to the GCRC, given TABLE 1 Body weight, BMI, and body composition in control subjects and patients with type 2 diabetes before and after weight loss Data are means dinner at 6 P.M., and then fasted until the end of the baseline study the following day. Body composition. On the day of admission, dual energy X-ray absorptiometry scan (Hologic QDR-4500 W, Bedford, MA) was performed with the subject lying in the supine position as previously described (3). MRS measurements of liver and muscle triglyceride content. After an overnight fast, the subjects were brought to the Yale-Magnetic Resonance Center and positioned in a 2.1T NMR Biospec system (Bruker Instruments, Billerica, MA) spectrometer for measurement of lipid content in the liver and the right soleus muscle. After percussion of the liver borders, a circular 1H observation coil (12 cm) was placed rigidly over the lateral aspect of the abdomen and localized 1H magnetic resonance spectra of the liver were obtained. Placement of the liver volume of interest (15 mm3) was confirmed by imaging the liver with a multislice gradient echo sequence. Before each measurement, the water signal was optimized during a shimming procedure and localized 1H spectra were collected using a PRESS sequence (repetition time of 3 s, echo time of 24.1 ms, 8,192 data points over 5,000-Hz spectral width and 64 scans) complemented by a spatially localized suppression pulse centered into the adipose tissue (4). A Lorentzian filter of 5 Hz was applied before Fourier transformation and manual phase correction. Hepatic triglyceride content was calculated from the area of intrahepatic CH2 resonance relative to the area of the water resonance, using the integration routine of Paravision software (Bruker Instruments) and then expressed as a percentage of water content. Localized 1H magnetic resonance spectra of the soleus muscle to assess IMCL content were obtained as previously described (4). Indirect calorimetry. Continuous indirect calorimetry was performed with a SensorMedics calorimeter (SensorMedics, Anaheim, CA) as previously described (5,6). Euglycemic-hyperinsulinemic clamp. On the morning of the study, after the overnight fast and the MRS measurements of lipid in liver and muscle, a catheter was placed in an antecubital vein for infusi (...truncated)