Caloric restriction and diabetes prevention -
The impact of the intervention can be seen in Table 1 by comparing results at month 6 versus baseline. The changes in body composition and abdominal fat were not dependent on whether the caloric deficit was achieved by exercise and diet CREX or diet alone CR and LCD.
The improvement in S i was not different among the three intervention groups. The changes in IMCL, IHL, FCS, and the other abdominal fat depots were not additional independent determinants. These correlation analyses were repeated with the control group removed. The significance of the relationship between the changes in FCS and VAT and the changes in IHL and percent fat was lost, but no other relationships were affected.
In this study we examined the relationships between S i and various indexes of body fat in overweight, glucose-tolerant subjects before and after calorie restriction.
At baseline, we found that 1 fat deposition in liver was related to the accumulation of fat in the abdominal visceral area and to enlarged subcutaneous abdominal adipocytes and 2 increased FCS but not ectopic fat deposition in muscle and liver was independently associated with reduced insulin sensitivity.
In response to 6 months of calorie restriction, we found that 1 weight, visceral fat, and FCS are reduced with improvements in S i and reduced AIR g and 2 fat deposition in liver but not muscle was reduced by the intervention, but the changes were not associated with improvements in S i.
Several studies have suggested that ectopic fat accumulation is independent of whole-body adiposity 16 , 24 — However, other studies have noted that lipid accumulation in both muscle 27 , 31 — 33 and liver 34 — 37 increases as a function of obesity, providing that subjects with a wide range of adiposity are studied.
In this study, we observed that lipid deposition in liver but not muscle was related to both total and abdominal adiposity.
Specifically, our findings indicate that ectopic fat in the liver may be related to visceral fat stores. This relationship between liver lipid and visceral adiposity has been noted in some 34 , 38 but not all 29 , 30 studies. Most interestingly, we observed that liver lipid infiltration tended to be greater in overweight individuals who had enlarged adipocytes and increased visceral abdominal adiposity.
Furthermore, visceral fat was related to FCS. These findings support the hypothesis that inadequate subcutaneous adipose stores result in lipid overflow into visceral fat and other nonadipose tissues In this regard, visceral fat could be considered as a marker of ectopic fat.
At baseline and at month 6, large fat cells were also the strongest determinant of insulin resistance in these nondiabetic subjects. This finding prompts speculation that impaired adipogenesis may be the primary defect in insulin resistance, and the hypothesis is supported by findings that humans with partial or complete loss of adipose tissue are extremely insulin resistant 40 , that surgical replacement of adipose stores in the fatless mouse restores insulin sensitivity 41 , and that expression of Wnt signaling genes and adipogenic transcription factors are reduced in nondiabetic subjects with a family history of type 2 diabetes Large fat cells have also been shown to have a different pattern of adipocytokine secretion than smaller fat cells 43 , which may contribute to the strong association between large FCS and insulin sensitivity.
In contrast to previous studies 24 , 26 — 28 , 31 , 44 , 45 , we observed that IMCL was not related to insulin sensitivity. Furthermore, IMCL was not related to adipocyte size. Our results are consistent with the hypothesis that IMCL stores alone are not sufficient to account for impaired insulin action 46 — Liver lipid, on the other hand, was inversely related to insulin sensitivity.
Liver lipid content has previously been reported to correlate with measures of whole-body insulin sensitivity in individuals with and without diabetes 30 , 34 , 35 , 38 , 49 , but this relationship is difficult to explain mechanistically because most ingested or infused glucose is taken up by muscle.
Theoretically, IHL is expected to correlate with reduced hepatic insulin sensitivity impaired insulin suppression of glucose rate of appearance and not necessarily with whole-body insulin action.
However, the accumulation of hepatic triglyceride has been hypothesized to reduce insulin clearance and lead to peripheral insulin resistance via a downregulation of insulin receptors 34 , Clearly, prospective human studies that define whether lipid accumulation in liver precedes insulin resistance would be of interest.
Contrary to some previous studies 51 , 52 , we observed that diet alone or with exercise produced identical reductions in weight, fat mass, and abdominal fat mass.
These conflicting results may be due to inaccurate calculations of the energy costs of the prescribed activity in those studies, which would lead to differences in energy deficits among groups. We also observed that FCS was reduced in response to an energy deficit, but we could not detect an additional effect of exercise.
Our study was underpowered to detect differences in FCS among groups and our results contrast with the reports of You et al. The current study is also the first to simultaneously measure ectopic fat stores in both muscle and liver in response to a calorie restriction intervention.
We found that the calorie restriction alone or with exercise did not affect IMCL in the soleus. These results are consistent with previous studies 6 , 14 , 15 and together with the findings that IMCL was not independently related to S i suggest that IMCL accumulation alone is not likely to be a causal factor leading to acquired insulin-signaling defects in muscle.
Many other factors, including lipid droplet size, location of lipid droplets relative to mitochondria, and muscle oxidative capacity, are all potential determinants of insulin resistance 15 , 48 , An alternate hypothesis is that the capacity for lipid metabolism is an important mediator in the association between IMCL and insulin resistance.
Caution must be exercised when interpreting these results because the study may have been underpowered to detect small differences in IHL among groups. The reduction in liver lipid levels is consistent with results of Tiikkainen et al.
In addition, we also observed parallel reductions in IHL and abdominal visceral fat. In summary, calorie restriction by diet alone or in conjunction with exercise leads to similar improvements in insulin sensitivity and reductions in β-cell sensitivity in overweight, glucose-tolerant subjects.
The study also provides support for the hypothesis that the underlying pathologic cause of insulin resistance is related to abnormal partitioning of fat among adipose, hepatic, muscle, and pancreatic tissues, probably as a result of an inability to make new fat cells. However, the finding that IMCL was not responsive to weight loss despite improvements in insulin sensitivity suggests that intracellular fat accumulation is not a causal factor in insulin resistance in muscle.
Overall, this study provides new evidence to suggest that impaired adipogenesis and increased liver lipid infiltration occur early in the pathogenesis of insulin resistance. In healthy overweight men and women at baseline, there was a strong positive correlation between abdominal subcutaneous FCS and VAT A and abdominal subcutaneous FCS and IHL B.
Groups were pooled for analysis. The improvement in insulin sensitivity with 6 months of calorie restriction was significantly associated with the loss of fat mass A and abdominal VAT depots B but not to the change in subcutaneous abdominal FCS C and IHL D.
Analyses are reported with and without the control group included. Physical characteristics of the subject groups at baseline and following 6 months of calorie restriction. Differences between treatment groups for the change scores using an ANCOVA with the absolute change as the dependent variable and the baseline score as a covariate.
This work was supported by grants U01 AG to E. and K01 DK to D. is supported by a Neil Hamilton-Fairley Training Fellowship awarded by the National Health and Medical Research Council of Australia ID The authors thank the remaining members of the Pennington CALERIE Research Team: James DeLany, Corby Martin, Julia Volaufova, Marlene Most, Lilian de Jonge, Tuong Nguyen, Frank Greenway, Emily York-Crow, Catherine Champagne, Brenda Dahmer, Andy Deutsch, Paula Geiselman, Jennifer Howard, Jana Ihrig, Michael Lefevre, Darlene Marquis, Connie Murla, Sabrina Yang, Robbie Durand, Sean Owens, Aimee Stewart, and Vanessa Tarver.
Our gratitude is extended to the excellent staffs of the Inpatient Clinic and Metabolic Kitchen. Our thanks also go to Health and Nutrition Technology Carmel, CA for providing us with all of the HealthOne formula used in the study and to Edward J. Robarge for technical assistance with collection of the magnetic resonance spectroscopy data.
Finally, our profound gratitude goes to all the volunteers who spent so much time participating in this very demanding research study. is currently affiliated with the Department of Family and Consumer Sciences, University of Wyoming, Laramie, Wyoming.
is currently affiliated with the Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia. A table elsewhere in this issue shows conventional and Système International SI units and conversion factors for many substances.
The costs of publication of this article were defrayed in part by the payment of page charges. Section solely to indicate this fact.
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RESEARCH DESIGN AND METHODS. Article Information. Article Navigation. Effect of Calorie Restriction With or Without Exercise on Insulin Sensitivity, β-Cell Function, Fat Cell Size, and Ectopic Lipid in Overweight Subjects D. Enette Larson-Meyer, PHD ; D.
Enette Larson-Meyer, PHD. This Site. Google Scholar. Leonie K. Heilbronn, PHD ; Leonie K. Heilbronn, PHD. Leanne M. Redman, PHD ; Leanne M. Redman, PHD. Bradley R. Newcomer, PHD ; Bradley R. Newcomer, PHD. Madlyn I. Frisard, PHD ; Madlyn I. Frisard, PHD.
Steve Anton, PHD ; Steve Anton, PHD. Steven R. Smith, MD ; Steven R. Smith, MD. Anthony Alfonso, MAPLSTAT ; Anthony Alfonso, MAPLSTAT. Eric Ravussin, PHD ; Eric Ravussin, PHD. the Pennington CALERIE Team the Pennington CALERIE Team. Address correspondence and reprint requests to Eric Ravussin, PhD, Pennington Biomedical Research Center, Perkins Rd.
E-mail: ravusse pbrc. Diabetes Care ;29 6 — Article history Received:. Get Permissions. toolbar search Search Dropdown Menu. toolbar search search input Search input auto suggest. Figure 1—. View large Download slide.
Figure 2—. Table 1— Physical characteristics of the subject groups at baseline and following 6 months of calorie restriction. Month 6. View Large. Forsey RJ, Thompson JM, Ernerudh J, Hurst TL, Strindhall J, Johansson B, Nilsson BO, Wikby A: Plasma cytokine profiles in elderly humans.
Mech Ageing Dev. Matsumoto K, Sera Y, Abe Y, Ueki Y, Tominaga T, Miyake S: Inflammation and insulin resistance are independently related to all-cause of death and cardiovascular events in Japanese patients with type 2 diabetes mellitus. Utzschneider KM, Carr DB, Hull RL, Kodama K, Shofer JB, Retzlaff BM, Knopp RH, Kahn SE: Impact of intra-abdominal fat and age on insulin sensitivity and β-cell function.
Kelley DE, Thaete FL, Troost F, Huwe T, Goodpaster BH: Subdivisions of subcutaneous abdominal adipose tissue and insulin resistance. Am J Physiol. Weyer C, Foley JE, Bogardus C, Tataranni PA, Pratley RE: Enlarged subcutaneous abdominal adipocyte size, but not obesity itself, predicts type II diabetes independent of insulin resistance.
Goodpaster BH, Katsiaras A, Kelley DE: Enhanced fat oxidation through physical activity is associated with improvements in insulin sensitivity in obesity. Goodpaster BH, Kelley DE, Wing RR, Meier A, Thaete FL: Effects of weight loss on regional fat distribution and insulin sensitivity in obesity.
Niskanen L, Uusitupa M, Sarlund H, Siitonen O, Paljarvi L, Laakso M: The effects of weight loss on insulin sensitivity, skeletal muscle composition and capillary density in obese non-diabetic subjects. Int J Obes Relat Metab Disord. Dengel DR, Pratley RE, Hagberg JM, Rogus EM, Goldberg AP: Distinct effects of aerobic exercise training and weight loss on glucose homeostasis in obese sedentary men.
J Appl Physiol. The researchers noted that the American Diabetes Association recently recommended that most people with overweight, obesity or type 2 diabetes adopt a lifestyle intervention program that includes weight loss by a to kcal per day energy deficit — about 1, to 1, kcal per day for men and 1, to 1, kcal per day for women.
Jayedi and colleagues found, at 6 months, each kcal per day decrease in energy intake resulted in clinically meaningful reductions in HbA1c mean difference, and body weight decreased linearly along with the decrease in energy intake.
Jayedi A, et al. Am J Clin Nutr. Healio News Primary Care Diabetes. By Emma Bascom. Fact checked by Shenaz Bagha. Read more. April 06, Add topic to email alerts. Receive an email when new articles are posted on. Please provide your email address to receive an email when new articles are posted on.
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