Metabolic Flexibility in Response to Glucose Is Not Impaired in People With Type 2 Diabetes After Controlling for Glucose Disposal Rate

Galgani, José E.; Heilbronn, Leonie K.; Azuma, Koichiro; Kelley, David E.; Albu, Jeanine; Pi‐Sunyer, Xavier; Smith, Steven R.; Ravussin, Éric

doi:10.2337/db08-0043

Cited by 107 publications

(149 citation statements)

References 23 publications

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“…Peripheral insulin sensitivity increased at 3 months and 1 year in both groups, probably because of weight loss (45,46), as indicated by the positive correlation between changes in glucose disposal and weight loss 1 year after surgery.…”

Section: Discussionmentioning

confidence: 86%

Early Enhancements of Hepatic and Later of Peripheral Insulin Sensitivity Combined With Increased Postprandial Insulin Secretion Contribute to Improved Glycemic Control After Roux-en-Y Gastric Bypass

et al. 2014

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Roux-en-Y gastric bypass (RYGB) improves glycemic control within days after surgery, and changes in insulin sensitivity and β-cell function are likely to be involved. We studied 10 obese patients with type 2 diabetes (T2D) and 10 obese glucose-tolerant subjects before and 1 week, 3 months, and 1 year after RYGB. Participants were included after a preoperative diet-induced total weight loss of −9.2 ± 1.2%. Hepatic and peripheral insulin sensitivity were assessed using the hyperinsulinemic- euglycemic clamp combined with the glucose tracer technique, and β-cell function was evaluated in response to an intravenous glucose-glucagon challenge as well as an oral glucose load. Within 1 week, RYGB reduced basal glucose production, improved basal hepatic insulin sensitivity, and increased insulin clearance, highlighting the liver as an important organ responsible for early effects on glucose metabolism after surgery. Insulin-mediated glucose disposal and suppression of fatty acids did not improve immediately after surgery but increased at 3 months and 1 year; this increase likely was related to the reduction in body weight. Insulin secretion increased after RYGB only in patients with T2D and only in response to oral glucose, underscoring the importance of the changed gut anatomy.

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Section: Discussionmentioning

confidence: 86%

Early Enhancements of Hepatic and Later of Peripheral Insulin Sensitivity Combined With Increased Postprandial Insulin Secretion Contribute to Improved Glycemic Control After Roux-en-Y Gastric Bypass

et al. 2014

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“…The concept arose from the recognition by Kelley and Mandarino (21) that the shift from fat to carbohydrate utilization was impaired by insulin resistance. The impairment is recognized as a diminution of the normal increase in RQ that occurs upon refeeding and has been attributed to compromised insulin-dependent glucose uptake in peripheral tissues (11)(12). The commensurate increase in glucose utilization associated with improved insulin sensitivity is reflected by a concomitant increase of RQ in the fed state.…”

Section: Discussionmentioning

confidence: 99%

Dietary methionine restriction enhances metabolic flexibility and increases uncoupled respiration in both fed and fasted states

Hasek

Stewart

Henagan

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

190

331

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(DR) in the sense that MR increases rodent longevity, but without food restriction. We report here that MR also persistently increases total energy expenditure (EE) and limits fat deposition despite increasing weightspecific food consumption. In Fischer 344 (F344) rats consuming control or MR diets for 3, 9, and 20 mo, mean EE was 1.5-fold higher in MR vs. control rats, primarily due to higher EE during the night at all ages. The day-to-night transition produced a twofold higher heat increment of feeding (3.0°C vs. 1.5°C) in MR vs. controls and an exaggerated increase in respiratory quotient (RQ) to values greater than 1, indicative of the interconversion of glucose to lipid by de novo lipogenesis. The simultaneous inhibition of glucose utilization and shift to fat oxidation during the day was also more complete in MR (RQ ϳ0.75) vs. controls (RQ ϳ0.85). Dietary MR produced a rapid and persistent increase in uncoupling protein 1 expression in brown (BAT) and white adipose tissue (WAT) in conjunction with decreased leptin and increased adiponectin levels in serum, suggesting that remodeling of the metabolic and endocrine function of adipose tissue may have an important role in the overall increase in EE. We conclude that the hyperphagic response to dietary MR is matched to a coordinated increase in uncoupled respiration, suggesting the engagement of a nutrient-sensing mechanism, which compensates for limited methionine through integrated effects on energy homeostasis. energy expenditure; metabolic efficiency; oxidative metabolism; futile cycles; adipose tissue; dietary restriction DIETARY METHIONINE RESTRICTION (MR) extends lifespan by 30 -35% in rats (28, 31) and mice (27) by delaying all causes of death. The increase in lifespan is accompanied by a reduction in adiposity that occurs despite a paradoxical increase in weight-specific food consumption (25,28,46). Pair-feeding studies comparing rats fed the control diet to the amount of MR diet consumed by the MR group clearly show that dietary MR decreases metabolic efficiency (25, 46), but the underlying basis for the metabolic responses to dietary MR remains poorly understood. Short-(12 wk) and long-term (80 wk) consumption of the MR diet after weaning also reduced circulating triglyceride, insulin, and leptin while increasing plasma adiponectin (25, 29). Collectively, work to date makes a compelling case that limitation of fat deposition by dietary MR is associated with preservation of insulin sensitivity and significant improvements in metabolic markers of lipid metabolism. Using the tools of metabolic phenotyping to examine energy homeostasis and peripheral substrate utilization, we found that dietary MR produced a significant long-term increase in EE that was temporally linked to exaggerated thermogenic responses to feeding and modest increases in resting EE. These physiological responses to MR limited fat deposition and were associated with significant changes in the metabolic and endocrine function of brown and white adipose tissue. MR effectively increas...

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“…The inflexible state of metabolism results from a discordant attempt of numerous peripheral tissues to respond to changing fuel needs and nutrient availability, yielding little or no discernable response. Metabolic inflexibility is a common characteristic of obesity (119,220), and energy-restricted weight loss reverses many of its associated impairments in metabolic regulation (48,81,158,188,219). Because enhanced metabolic flexibility improves the metabolic response to ingested energy, it alters the peripheral signals of nutrient status that are sent to the brain during weight maintenance and during weight regain (Fig.…”

Section: Enhanced Metabolic Flexibility: Improved Nutrient Clearancementioning

confidence: 99%

“…Its regulation by leptin, insulin, and sympathetic neural efferents is impaired in DIO models of obesity (154), and some aspects of AMPK regulation appear to resolve after energy-restricted weight loss (81,108). This fuel preference may be exacerbated by an inherent impairment in the capacity to oxidize fat, which underlies the genetic predisposition for obesity (106,107).…”

Section: Skeletal Muscle: Reduced Energy Requirements and A Preferencmentioning

confidence: 99%

Biology's response to dieting: the impetus for weight regain

MacLean

Bergouignan

Cornier

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

374

326

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Dieting is the most common approach to losing weight for the majority of obese and overweight individuals. Restricting intake leads to weight loss in the short term, but, by itself, dieting has a relatively poor success rate for long-term weight reduction. Most obese people eventually regain the weight they have worked so hard to lose. Weight regain has emerged as one of the most significant obstacles for obesity therapeutics, undoubtedly perpetuating the epidemic of excess weight that now affects more than 60% of U.S. adults. In this review, we summarize the evidence of biology's role in the problem of weight regain. Biology's impact is first placed in context with other pressures known to affect body weight. Then, the biological adaptations to an energy-restricted, low-fat diet that are known to occur in the overweight and obese are reviewed, and an integrative picture of energy homeostasis after long-term weight reduction and during weight regain is presented. Finally, a novel model is proposed to explain the persistence of the "energy depletion" signal during the dynamic metabolic state of weight regain, when traditional adiposity signals no longer reflect stored energy in the periphery. The preponderance of evidence would suggest that the biological response to weight loss involves comprehensive, persistent, and redundant adaptations in energy homeostasis and that these adaptations underlie the high recidivism rate in obesity therapeutics. To be successful in the long term, our strategies for preventing weight regain may need to be just as comprehensive, persistent, and redundant, as the biological adaptations they are attempting to counter. energy restriction; diet-induced obesity; obesity prone; weight loss; energy balance IN THE UNITED STATES, OVER 60% of adults and close to 20% of children are overweight or obese (35,174). A number of effective weight loss strategies are available, but most are only transiently effective over a period of 3 to 6 mo. Less than 20% of individuals that have attempted to lose weight are able to achieve and maintain a 10% reduction over a year (128). Over one-third of lost weight tends to return within the first year, and the majority is gained back within 3 to 5 years (3,246). A number of reasons have been proposed for the high incidence of weight regain (69,246), and several point to the biological response to weight loss.The objective of this review is to examine the role of this biological response in the process of weight regain. Biological regulation is first discussed in relation to other nonbiological pressures that affect body weight as weight is gained, lost, and regained. The specific biological adaptations to the most common form of dieting, an energy-restricted low-fat diet, are then discussed in more detail. Previous reviews provide extensive descriptions of the normal adaptive response to energy restriction. We do not attempt to recapitulate those efforts here. Rather, the unique perspective of this review summarizes those adaptations that have been confirmed o...

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Metabolic Flexibility in Response to Glucose Is Not Impaired in People With Type 2 Diabetes After Controlling for Glucose Disposal Rate

Cited by 107 publications

References 23 publications

Early Enhancements of Hepatic and Later of Peripheral Insulin Sensitivity Combined With Increased Postprandial Insulin Secretion Contribute to Improved Glycemic Control After Roux-en-Y Gastric Bypass

Early Enhancements of Hepatic and Later of Peripheral Insulin Sensitivity Combined With Increased Postprandial Insulin Secretion Contribute to Improved Glycemic Control After Roux-en-Y Gastric Bypass

Dietary methionine restriction enhances metabolic flexibility and increases uncoupled respiration in both fed and fasted states

Biology's response to dieting: the impetus for weight regain

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