Intermittent Fasting: Can It Reduce Insulin Resistance, Improve Insulin Sensitivity, Prevent Diabetes and Metabolic Health Problems

AbstractAnimal studies indicate that the composition of gut microbiota may be involved in the progression of insulin resistance to type 2 diabetes. Probiotics and/or prebiotics could be a promising approach to improve insulin sensitivity by favourably modifying the composition of the gut microbial community, reducing intestinal endotoxin concentrations and decreasing energy harvest. The aim of the present review was to investigate the effects of probiotics, prebiotics and synbiotics (a combination of probiotics and prebiotics) on insulin resistance in human clinical trials and to discuss the potential mechanisms whereby probiotics and prebiotics improve glucose metabolism. The anti-diabetic effects of probiotics include reducing pro-inflammatory cytokines via a NF-κB pathway, reduced intestinal permeability, and lowered oxidative stress. SCFA play a key role in glucose homeostasis through multiple potential mechanisms of action. Activation of G-protein-coupled receptors on L-cells by SCFA promotes the release of glucagon-like peptide-1 and peptide YY resulting in increased insulin and decreased glucagon secretion, and suppressed appetite. SCFA can decrease intestinal permeability and decrease circulating endotoxins, lowering inflammation and oxidative stress. SCFA may also have anti-lipolytic activities in adipocytes and improve insulin sensitivity via GLUT4 through the up-regulation of 5'-AMP-activated protein kinase signalling in muscle and liver tissues. Resistant starch and synbiotics appear to have favourable anti-diabetic effects. However, there are few human interventions. Further well-designed human clinical studies are required to develop recommendations for the prevention of type 2 diabetes with pro- and prebiotics.

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The ERα-PI3K Cascade in Proopiomelanocortin Progenitor Neurons Regulates Feeding and Glucose Balance in Female Mice

Endocrinology ◽

10.1210/en.2015-1660 ◽

2015 ◽

Vol 156 (12) ◽

pp. 4474-4491 ◽

Cited By ~ 22

Author(s):

Liangru Zhu ◽

Pingwen Xu ◽

Xuehong Cao ◽

Yongjie Yang ◽

Antentor Othrell Hinton ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Food Intake ◽

Phosphatidyl Inositol ◽

Pi3k Pathway ◽

Improve Insulin Sensitivity ◽

Female Mice ◽

Intracellular Signals ◽

Inhibit Food Intake ◽

Regulatory Effects

Estrogens act upon estrogen receptor (ER)α to inhibit feeding and improve glucose homeostasis in female animals. However, the intracellular signals that mediate these estrogenic actions remain unknown. Here, we report that anorexigenic effects of estrogens are blunted in female mice that lack ERα specifically in proopiomelanocortin (POMC) progenitor neurons. These mutant mice also develop insulin resistance and are insensitive to the glucose-regulatory effects of estrogens. Moreover, we showed that propyl pyrazole triol (an ERα agonist) stimulates the phosphatidyl inositol 3-kinase (PI3K) pathway specifically in POMC progenitor neurons, and that blockade of PI3K attenuates propyl pyrazole triol-induced activation of POMC neurons. Finally, we show that effects of estrogens to inhibit food intake and to improve insulin sensitivity are significantly attenuated in female mice with PI3K genetically inhibited in POMC progenitor neurons. Together, our results indicate that an ERα-PI3K cascade in POMC progenitor neurons mediates estrogenic actions to suppress food intake and improve insulin sensitivity.

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Knockdown of angiopoietin-like 2 mimics the benefits of intermittent fasting on insulin responsiveness and weight loss

Experimental Biology and Medicine ◽

10.1177/1535370217745505 ◽

2017 ◽

Vol 243 (1) ◽

pp. 45-49 ◽

Cited By ~ 1

Author(s):

Cécile Martel ◽

Anthony Pinçon ◽

Alexandre Maxime Bélanger ◽

Xiaoyan Luo ◽

Marc-Antoine Gillis ◽

...

Keyword(s):

Insulin Resistance ◽

Weight Gain ◽

Insulin Sensitivity ◽

Energy Intake ◽

Intermittent Fasting ◽

Wild Type ◽

Beneficial Effects ◽

Obesity And Diabetes ◽

Ad Libitum ◽

Insulin Responsiveness

Angiopoietin-like 2 (ANGPTL2) is an inflammatory adipokine linking obesity to insulin resistance. Intermittent fasting, on the other hand, is a lifestyle intervention able to prevent obesity and diabetes but difficult to implement and maintain. Our objectives were to characterize a link between ANGPTL2 and intermittent fasting and to investigate whether the knockdown of ANGPTL2 reproduces the benefits of intermittent fasting on weight gain and insulin responsiveness in knockdown and wild-type littermates mice. Intermittent fasting, access to food ad libitum once every other day, was initiated at the age of three months and maintained for four months. Intermittent fasting decreased by 63% (p < 0.05) gene expression of angptl2 in adipose tissue of wild-type mice. As expected, intermittent fasting improved insulin sensitivity (p < 0.05) and limited weight gain (p < 0.05) in wild-type mice. Knockdown mice fed ad libitum, however, were comparable to wild-type mice following the intermittent fasting regimen: insulin sensitivity and weight gain were identical, while intermittent fasting had no additional impact on these parameters in knockdown mice. Energy intake was similar between both wild-type fed intermittent fasting and ANGPTL2 knockdown mice fed ad libitum, suggesting that intermittent fasting and knockdown of ANGPTL2 equally lower feeding efficiency. These results suggest that the reduction of ANGPTL2 could be a useful and promising strategy to prevent obesity and insulin resistance, although further investigation of the mechanisms linking ANGPTL2 and intermittent fasting is warranted. Impact statement Intermittent fasting is an efficient diet pattern to prevent weight gain and improve insulin sensitivity. It is, however, a difficult regimen to follow and compliance is expected to be very low. In this work, we demonstrate that knockdown of ANGPTL2 in mice fed ad libitum mimics the beneficial effects of intermittent fasting on weight gain and insulin sensitivity in wild-type mice. ANGPTL2 is a cytokine positively associated with fat mass in humans, which inactivation in mice improves resistance to a high-fat metabolic challenge. This study provides a novel pathway by which IF acts to limit obesity despite equivalent energy intake. The development of a pharmacological ANGPTL2 antagonist could provide an efficient tool to reduce the burden of obesity.

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Obesity-linked PPARγ S273 phosphorylation promotes insulin resistance through Growth Differentiation Factor 3

10.1101/2020.01.13.904953 ◽

2020 ◽

Author(s):

Jessica A. Hall ◽

Deepti Ramachandran ◽

Hyun C. Roh ◽

Joanna R. DiSpirito ◽

Thiago Belchior ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Side Effects ◽

Ectopic Expression ◽

Bmp Signaling ◽

Whole Body ◽

Improve Insulin Sensitivity ◽

Induce Insulin Resistance ◽

Systemic Insulin Resistance

AbstractOvernutrition and obesity promote adipose tissue dysfunction, often leading to systemic insulin resistance. The thiazolidinediones (TZDs) are a potent class of insulin-sensitizing drugs and ligands of PPARγ that improve insulin sensitivity, but their use is limited due to significant side effects. Recently, we demonstrated a mechanism by which TZDs improve insulin sensitivity distinct from receptor agonism and adipogenesis: reversal of obesity-linked phosphorylation of PPARγ at Serine 273. However, the role of this modification has not been tested genetically. Here we demonstrate that mice encoding an allele of PPARγ which cannot be phosphorylated at S273 are protected from insulin resistance, without exhibiting differences in body weight or TZD-associated side effects. Indeed, hyperinsulinemic-euglycemic clamp experiments confirm improved insulin sensitivity, as evidenced by increased whole-body glucose uptake. RNA-seq experiments reveal PPARγ S273 phosphorylation specifically enhances transcription of Gdf3, a BMP family member. Ectopic expression of Gdf3 is sufficient to induce insulin resistance in lean, healthy mice. We find that Gdf3 can impact metabolism by inhibition of BMP signaling. Together, these results highlight the diabetogenic role of PPARγ S273 phosphorylation and focuses attention on a putative target, Gdf3.

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Impaired Skeletal Muscle β-Adrenergic Activation and Lipolysis Are Associated with Whole-Body Insulin Resistance in Rats Bred for Low Intrinsic Exercise Capacity

Endocrinology ◽

10.1210/en.2009-0158 ◽

2009 ◽

Vol 150 (11) ◽

pp. 4883-4891 ◽

Cited By ~ 38

Author(s):

Sarah J. Lessard ◽

Donato A. Rivas ◽

Zhi-Ping Chen ◽

Bryce J. van Denderen ◽

Matthew J. Watt ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Protein Content ◽

Exercise Capacity ◽

Metabolic Health ◽

Whole Body ◽

Receptor Protein ◽

Endurance Capacity ◽

Triacylglycerol Lipase

Rats selectively bred for high endurance running capacity (HCR) have higher insulin sensitivity and improved metabolic health compared with those bred for low endurance capacity (LCR). We investigated several skeletal muscle characteristics, in vitro and in vivo, that could contribute to the metabolic phenotypes observed in sedentary LCR and HCR rats. After 16 generations of selective breeding, HCR had approximately 400% higher running capacity (P < 0.001), improved insulin sensitivity (P < 0.001), and lower fasting plasma glucose and triglycerides (P < 0.05) compared with LCR. Skeletal muscle ceramide and diacylglycerol content, basal AMP-activated protein kinase (AMPK) activity, and basal lipolysis were similar between LCR and HCR. However, the stimulation of lipolysis in response to 10 μm isoproterenol was 70% higher in HCR (P = 0.004). Impaired isoproterenol sensitivity in LCR was associated with lower basal triacylglycerol lipase activity, Ser660 phosphorylation of HSL, and β2-adrenergic receptor protein content in skeletal muscle. Expression of the orphan nuclear receptor Nur77, which is induced by β-adrenergic signaling and is associated with insulin sensitivity, was lower in LCR (P < 0.05). Muscle protein content of Nur77 target genes, including uncoupling protein 3, fatty acid translocase/CD36, and the AMPK γ3 subunit were also lower in LCR (P < 0.05). Our investigation associates whole-body insulin resistance with impaired β-adrenergic response and reduced expression of genes that are critical regulators of glucose and lipid metabolism in skeletal muscle. We identify impaired β-adrenergic signal transduction as a potential mechanism for impaired metabolic health after artificial selection for low intrinsic exercise capacity.

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Zinc 100 ppm Does not Improve Insulin Sensitivity of High Fructose Fed Rats Leading to Insulin Resistance

Trace Elements in Man and Animals 10 ◽

10.1007/0-306-47466-2_171 ◽

2002 ◽

pp. 538-538

Author(s):

E. Rossini ◽

S. Bouvard ◽

M. J. Richard ◽

S. Halimi ◽

A. Favier

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Improve Insulin Sensitivity ◽

High Fructose

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Long-term exposure to a high-fat diet results in the development of glucose intolerance and insulin resistance in interleukin-1 receptor I-deficient mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00297.2013 ◽

2013 ◽

Vol 305 (7) ◽

pp. E834-E844 ◽

Cited By ~ 18

Author(s):

Fiona C. McGillicuddy ◽

Clare M. Reynolds ◽

Orla Finucane ◽

Eilish Coleman ◽

Karen A. Harford ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Glucose Intolerance ◽

High Fat Diet ◽

Saturated Fatty Acids ◽

Interleukin 1 ◽

Stromal Vascular Fraction ◽

Metabolic Health ◽

High Fat

Emerging evidence has demonstrated that saturated fatty acids prime pro-IL-1β production and inflammasome-mediated IL-1β activation is critical in obesity-associated insulin resistance (IR). Nonetheless, IL-1 receptor I-deficient (IL-1RI−/−) mice develop mature-onset obesity despite consuming a low-fat diet (LFD). With this apparent contradiction, the present study evaluated whether IL-1RI−/− mice were protected against long-term (6 mo) high-fat diet (HFD)-induced IR. Male wild-type and IL-1RI−/− mice were fed LFD or HFD for 3 or 6 mo, and glucose and insulin tolerance tests were performed. Adipose insulin sensitivity, cytokine profiles, and adipocyte morphology were assessed. The adipogenic potential of stromal vascular fraction was determined. Hepatic lipid accumulation and insulin sensitivity were characterized. IL-1RI−/− mice developed glucose intolerance and IR after 6 mo HFD compared with 3 mo HFD, coincident with enhanced weight gain, hyperinsulinemia, and hyperleptinemia. The aggravated IR phenotype was associated with loss of adipose functionality, switch from adipocyte hyperplasia to hypertrophy and hepatosteatosis. Induction of adipogenic genes was reduced in IL-1RI−/− preadipocytes after 6 mo HFD compared with 3 mo HFD. Obese LFD-IL-1RI−/− mice exhibited preserved metabolic health. IL-1RI−/− mice develop glucose intolerance and IR after 6 mo HFD intervention. While mature-onset obesity is evident in LFD-IL-1RI−/− mice, the additional metabolic insult of HFD was required to drive adipose inflammation and systemic IR. These findings indicate an important interaction between dietary fat and IL-1, relevant to optimal metabolic health.

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Effects of Intermittent Fasting or Calorie Restriction on Markers of Lipid Metabolism in Human Skeletal Muscle

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa707 ◽

2020 ◽

Author(s):

Bo Liu ◽

Amy T Hutchison ◽

Campbell H Thompson ◽

Kylie Lange ◽

Gary A Wittert ◽

...

Keyword(s):

Insulin Resistance ◽

Antioxidant Enzymes ◽

Lipid Metabolism ◽

Insulin Sensitivity ◽

Controlled Trial ◽

Quantitative Polymerase Chain Reaction ◽

Energy Requirements ◽

Intermittent Fasting ◽

Mrna Levels ◽

Nonesterified Fatty Acids

Abstract Context Impaired lipid metabolism is linked with obesity-associated insulin resistance, which may be reversed by caloric restriction (CR). Objective In a secondary analysis of a randomized controlled trial, we compared the effects of intermittent fasting (IF) and CR on markers of lipid metabolism in muscle. Design Seventy-six women (body mass index, 25-40 kg/m2) were randomly assigned to 1 of 3 diets for 8 weeks and provided foods at 70% (CR70 and IF70) or 100% (IF100) of energy requirements. IF groups ate breakfast prior to a 24-hour fast on 3 nonconsecutive days per week. On nonfasting days, IF70 ate at 100% and IF100 ate at 145% of energy requirements to achieve the prescribed target. Weight, body composition, insulin sensitivity by clamp, nonesterified fatty acids (NEFAs), β-hydroxybutyrate (BHB), and markers of lipid metabolism and oxidative stress in muscle by quantitative polymerase chain reaction were measured at baseline and week 8 following a 12-hour overnight fast (all groups) and 24-hour fast (IF groups). Results IF70 resulted in greater weight and fat loss and reduced NEFAs vs CR70 and IF100 after an overnight fast. IF70 and IF100 induced a greater reduction only in mRNA levels of antioxidant enzymes glutathione peroxidase 1 (GPX1), superoxide dismutase 1, soluble (SOD1), and SOD2 vs CR70. Fasting for 24 hours increased NEFAs and BHB in IF groups, but impaired insulin sensitivity and increased PLIN5 mRNA levels. Conclusions In comparison to CR, IF did not increase markers of lipid metabolism in muscle, but reduced expression of antioxidant enzymes. However, fasting-induced insulin resistance was detected, alongside increased PLIN5 expression, potentially reflecting transient lipid storage.

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Adipocytokines and the Regulation of Lipid Metabolism in Growth Hormone Transgenic and Calorie-Restricted Mice

Endocrinology ◽

10.1210/en.2006-1313 ◽

2007 ◽

Vol 148 (6) ◽

pp. 2845-2853 ◽

Cited By ~ 69

Author(s):

Zhihui Wang ◽

Michal M. Masternak ◽

Khalid A. Al-Regaiey ◽

Andrzej Bartke

Keyword(s):

Insulin Resistance ◽

Lipid Metabolism ◽

Insulin Sensitivity ◽

Transgenic Mice ◽

Plasma Lipid ◽

Improve Insulin Sensitivity ◽

Plasma Adiponectin ◽

Protein Levels ◽

Cholesterol Levels ◽

Resistance To Insulin

Chronic elevation of GH induces resistance to insulin and hyperinsulinemia in both humans and animals, whereas calorie restriction (CR) improves peripheral insulin sensitivity in many species. To investigate the mechanisms that lead to insulin resistance in animals with high levels of GH as well as the mechanisms that might improve insulin sensitivity, we fed GH-overexpressing transgenic mice ad libitum or subjected them to 30% CR. We then assayed the plasma adipocytokines levels related to insulin sensitivity, plasma lipid levels, and tissue triglycerides accumulation and examined adipocyte morphology. Furthermore, we evaluated mRNA expression and protein levels of enzymes or regulators involved in regulating hepatic lipid metabolism. Our results suggest that decreased plasma adiponectin, increased plasma resistin and cholesterol, and elevated levels of TNF-α and IL-6 in adipocytes may all contribute to the insulin resistance observed in GH-Tg mice. Increased accumulation of triglycerides and impaired adipocytes differentiation in GH-transgenic mice provide plausible mechanisms for the alterations of adipocytokines. Hepatic and muscle insulin resistance in these mice is probably related to excessive accumulation of fatty acids and their metabolites. An increase in plasma adiponectin and decrease in plasma IL-6, triglycerides, and cholesterol levels in response to CR may improve insulin sensitivity.

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