Insulin Resistance and Obesity

Insulin is a major hormone controlling systemic metabolism. Insulin-related defects are associated with diabetes.

In type I diabetes, there is no insulin production by beta-cells in the pancreas. In type II diabetes, not only do beta-cells not function well, but various organs of the body become resistant to insulin action.

The major cause of insulin resistance is obesity,¹ either because of excess fat interfering with insulin action,² or because of interference of insulin action by inflammation resulting from obesity³ or both. Obesity can shorten lifespan by many years.⁴

Elevated blood insulin due to insulin resistance or other causes increases obesity, whereas a reduction in blood insulin can enable weight loss.⁵ It’s a vicious circle of obesity increasing insulin resistance and insulin resistance increasing obesity.

A major function of insulin is to cause glucose to enter cells. Muscle absorbs more glucose with the help of insulin than any other body tissue, so insulin resistance of muscle results in the greatest elevation of blood glucose and insulin.¹

Glucose entering fat cells is converted to fat for energy storage. When fat cells become insulin resistant, they dump fats into the bloodstream which become abnormally deposited in other tissues, causing those tissues to become insulin resistant.⁶

Insulin action on the liver is more complex. Normally the liver releases glucose into the bloodstream, but when insulin rises after a meal, the insulin should suppress liver glucose release while stimulating the liver’s conversion of glucose to fat. For an insulin resistant liver, insulin does not suppress liver-glucose release and increases the conversion of glucose to fat (more fat production).¹

Insulin resistance most often originates in fat tissue (due to obesity), skeletal muscle, or the liver (due to excess fructose or alcohol consumption), but will eventually cause some insulin resistance in all of the insulin-responsive organs and tissues.⁶

Chronic high blood-glucose due to insulin resistance damages many tissues, which is why so many diabetics suffer from neuropathy, kidney damage, blood-vessel damage, and damage to the pancreas beta-cells such that insulin can no longer be secreted.⁷

The presentations below are mostly taken from the December 2016 World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease, or the January 2017 Keystone Symposium on Obesity and Adipose Tissue Biology.

Macrophages Causing Insulin Resistance

Anthony Ferrante, MD, PhD (professor of medicine, Columbia University, New York City), has studied the relationship between obesity, macrophages, and insulin resistance.

Macrophages are white blood cells of the immune system that can promote wound-healing during acute inflammation by “eating” pathogens and debris.

In obesity, expansion of fat cell mass can lead to reduced blood flow⁸ and increased fat-cell death, which attracts macrophages to clean-up the dead-cell debris.⁹

Dr. Ferrante has shown that macrophages accumulate in fat tissue in proportion to the amount of obesity.¹⁰ He estimates that fat tissue in lean humans consists of less than 10% macrophages, but that there are nearly 40% macrophages in the fat tissue in very obese humans.¹⁰

The macrophages in fat tissue become engulfed with ingested fat, developing a “foamy” appearance similar to the fat-filled macrophages in blood-vessel walls that contribute to atherosclerosis.¹

The chronic inflammatory factors produced by persistent resident macrophages in fat causes insulin resistance.¹¹

These macrophages become incapable of many cellular functions, including the autophagy that could remove malfunctioning mitochondria. The result is mitochondria that produce large quantities of free radicals.¹² It is thus understandable that approximately 85% of type II diabetic patients are insulin resistant and obese.¹²

Brown Fat May Reduce Obesity

Aaron Cypess, MD, PhD (acting section chief, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland), is interested in the possible use of brown fat to treat obesity and obesity-associated problems.

Unlike white fat, brown fat generates heat by containing large amounts of mitochondria¹³ (which creates the brown color). Brown fat is plentiful and active in newborn babies, which protects them from cold. Most fat in adults is white fat. It was only recently learned that brown fat exists at all in adults. Brown fat declines with age, and especially declines with the increased white fat due to obesity.¹³

In contrast to the inflammatory cytokines produced by white fat, brown fat produces more anti-inflammatory factors.¹⁴ Brown fat can consume large amounts of glucose and fat from the bloodstream.¹⁵

Brown fat transplanted from one age-matched mouse to another decreased body weight, fat mass, and insulin resistance.¹⁶ Cold exposure stimulates brown fat development. Lean, healthy human volunteers subjected to 50°F for two hours daily for four weeks showed a 45% increase in brown fat volume and a 2.2 times increase in brown fat activity.¹⁷

To investigate the possible use of brown fat to treat obesity, Dr. Cypess administered the adrenalin-like drug mirabegron to healthy human volunteers. The volunteers experienced increased basal metabolic rate, much of which was due to increased brown fat activity. But heart rate increased by about 14 beats per minute, and systolic blood pressure increased by about 11 mmHg.¹⁸ These effects are not good for health. Dr. Cypess would like to increase brown fat activity without negative side effects.

Endothelial Cell Insulin Resistance

Zachary Bloomgarden, MD (clinical professor of Medicine, Mount Sinai School of Medicine, New York City) spoke of the role of blood-vessel insulin resistance in cardiovascular disease.

Endothelial cells lining the walls of blood vessels mediate insulin action by transporting insulin to muscle, heart, fat, and brain. When the endothelial cells become insulin resistant, insulin transport is reduced and blood-vessel dilation is impeded (endothelial dysfunction).¹⁹

Free radicals due to obesity cause endothelial cell dysfunction leading to insulin resistance.²⁰ Endothelial-cell insulin resistance is associated with fat tissue surrounding blood vessels becoming inflamed, thereby increasing blood-vessel stiffness.²¹ Sustained high blood-glucose is also associated with increased arterial stiffness.²²

Blood vessel stiffness increases systolic blood pressure and decreases diastolic blood pressure, resulting in failure of the heart to function properly.²³ Endothelial-cell insulin resistance leads to high blood pressure and atherosclerosis.²⁴

Obesity in Children and Adolescents

Sonia Caprio, MD (professor of pediatric endocrinology, Yale School of Medicine, New Haven Connecticut), studies obesity and diabetes in children and adolescents.

She showed that about 10% of obese children between ages 4 and 18 who had not been glucose intolerant developed glucose intolerance within two years. Of those who had initially been glucose intolerant, 24% developed type II diabetes within two years.²⁵ This rate of metabolic deterioration is much faster than what is seen in obese adults.²⁶

Most women show some increase in insulin resistance during pregnancy, which is of benefit to the fetus by facilitating glucose²⁷ and fat²⁸ transport across the placenta. But insulin resistance is greater in pregnant women who are obese. Such women have a greater risk of miscarriage or of congenital abnormalities in the infant.²⁹

The question of whether women who develop diabetes during pregnancy (gestational diabetes) cause their children to develop diabetes has been hard to establish because of shared genes and lifestyle between mother and child.³⁰

Dr. Caprio showed that nearly a third of obese children between ages 4 and 20 born from mothers who had gestational diabetes developed type II diabetes or impaired glucose tolerance within the three year period of being studied.³¹ A plant-based Mediterranean-style diet may benefit both mother and child during gestational diabetes.³²

Incretins: GLP-1 and GIP

Jens Holst, MD (professor of medical physiology, University of Copenhagen, Copenhagen, Denmark), studies the effects of incretins in type II diabetes.

Incretins are hormones secreted by the small intestine in response to glucose from a meal. More than half of the insulin released by the pancreas from a meal is due to the two incretins GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic peptide).³³

Small meals mostly activate GIP, which is from the upper small intestine, whereas GLP-1 in the lower part is also activated when a meal is large.³³ GLP-1 enhances insulin synthesis and reduces appetite.³³ GLP-1 also makes liver and muscle cells more sensitive to insulin.³⁴

In type II diabetes GLP-1 secretion is reduced, whereas GIP secretion is not.^34,35 But GIP ceases to cause insulin secretion in diabetes, whereas GLP-1 retains its capacity to stimulate insulin secretion.³⁵

The antidiabetic drug metformin enhances GLP-1 secretion,³⁶ among its other effects.

Natural GLP-1 or synthetic GLP-1 analogs have been shown to result in significant weight loss when administered to obese humans.³⁷ Dr. Holst conducted a study administering GIP to persons at risk for type II diabetes in hope of benefit, but found an increase in visceral fat among men.³⁸

Treating Obesity With Bacteria

Patrice D. Cani, PhD (professor, Universite catholique de Louvain, Brussels, Belgium). Obesity has often been associated with reduced levels of gut bacteria in the phylum Bacteroides, and increased levels of bacteria in the phylum Firmicutes.³⁹ But phylum is a classification rank that includes too many species, and can be misleading. In particular, Firmicutes includes both harmfully infectious Clostridia (including tetanus and botulism), and beneficial Lactobacillus (found in yogurt).

Dr. Cani has shown that mice treated with prebiotics (oligofructose) show increased release of GLP-1 and reduced insulin resistance.⁴⁰ He has also shown that mice fed lard show reduced levels of the bacterial species Akkermansia muciniphila and increased inflammation, whereas mice fed fish oil showed increased levels of A. muciniphila and better intestinal function.⁴¹

By administering A. muciniphila to obese mice, Dr. Cani reduced fat mass and insulin resistance in the mice.⁴² A. muciniphila gut levels decline with age in humans.⁴³ Dr. Cani found that obese and overweight human subjects with higher levels of intestinal A. muciniphila were less insulin resistant and more metabolically healthy.⁴⁴

Dr. Cani is recruiting for a clinical trial to show that administration of A. muciniphila to obese humans can improve metabolic health.

Treating Obesity With Balloons

Shelby Sullivan, MD (director of Gastroenterology Metabolic and Bariatric Program, University of Colorado School of Medicine, Denver, Colorado), has investigated alternatives to drugs and bariatric surgery for treatment of obesity.

Although bariatric surgery can be very effective, it is expensive, and there is often a long waiting list.

A fluid-filled balloon that can occupy nearly 80% of stomach volume has been shown to result in about 15% weight loss in a period of one year (more than twice what is usually seen with drug therapy).⁴⁵ Dr. Sullivan showed a stomach balloon plus diet and exercise to be significantly more effective than diet and exercise alone to achieve weight loss.⁴⁶

Dr. Sullivan has also shown that partial removal of stomach contents 20 minutes after every meal enabled test subjects to maintain a 20% weight loss for two years.⁴⁷ She attributed some of this loss to disgust subjects felt when looking at their stomach contents.

Testosterone for Obese Male Diabetics

Paresh Dandona, MD, PhD (distinguished professor of Medicine, State University of New York, Buffalo, New York) has shown that low levels of testosterone are common in adults with type II diabetes.⁴⁸ He has also found that obese males between ages 14 to 20 have 40%-50% lower testosterone than normal-weight males the same age.⁴⁹

By treating male type II diabetics with testosterone, Dr. Dandona has been able to reduce insulin resistance and decrease fat⁵⁰ as well as decrease signs of anemia.⁵¹

Dietary Fasting

Jason Fung, MD (nephrologist, Scarborough General Hospital, Ontario, Canada) is a foremost authority on the health benefits of dietary fasting. Dr. Fung has written a book entitled The Complete Guide to Fasting.

Insulin causes weight gain, and any food causes some insulin release, so fasting is a way to reduce weight. Fasting reduces fat mass, blood pressure, and insulin resistance.⁵²

With extended fasting, ketones rather than glucose become the primary energy source.⁵³ Ketones generate fewer free radicals, and inhibit cancer-cell growth (in contrast to glucose, which promotes cancer).^54,55 Fasting activates autophagy, a process that cleanses cells of damaged molecules and organelles.⁵⁶ Fasting improves cognitive function, and reduces the likelihood of neurodegenerative diseases (like Alzheimer’s disease).³⁴

A 250-pound obese person has enough stored energy in fat to survive about 150 days of complete fasting.⁵⁷ The longest recorded fast was 382 days by a very obese man who used only calorie-free fluids and vitamin supplements.⁵⁸ Forty-four of forty-six obese patients completed a two-week fast without ill effects, in many cases reporting feelings of euphoria.⁵⁹

The hunger hormone ghrelin peaks within two days and declines thereafter.⁶⁰ After the first few days of fasting, hunger becomes less of a concern. Even when hunger occurs, it rarely persists very long. Oddly, many people find even the slightest amount of hunger intolerable, but will strenuously exercise in an attempt to lose weight.

In the 1970s, when most Americans ate only three meals per day, a 12-hour fast between dinner and breakfast was normal. By 2006 Americans were eating more snacks with less time between eating and nearly 500 additional calories consumed per day.⁶¹ Skipping breakfast and eating only two meals per day could reduce daily calorie consumption by more than 500 Calories.⁶²

Some fasting experts recommend against fasting more than a day without medical supervision.⁵² This is especially important for people with health problems, or who are on medications.

Concluding Remarks

Location of fat can be a more important determinant of metabolic health than the amount of fat.

Fat attached to visceral organs like the liver, pancreas, and intestine (visceral fat) produces more inflammation and insulin resistance than fat under the skin (subcutaneous fat).⁶³

Japanese Sumo wrestlers, for example, are metabolically healthy because they have large amounts of subcutaneous fat, but not much visceral fat.⁶⁴ By contrast, non-obese persons with large amounts of visceral fat tend to be insulin resistant.⁶⁵

Persons subject to chronic stress secrete large amounts of the stress hormone cortisol, which results in increased visceral fat and insulin resistance.^66,67 Inadequate sleep increases cortisol, which increases insulin resistance in muscle and fat (but not liver) and causes weight gain.⁶⁸ Cigarette smoking increases visceral fat and insulin resistance.⁶⁹ Surgical removal of visceral fat from rats substantially reduces insulin resistance and increases lifespan.⁷⁰

Table sugar (sucrose) is composed of both glucose, which spikes blood-glucose levels, and fructose. Excessive blood glucose raises blood insulin and can cause insulin resistance, but fructose does not have this effect in small amounts. When fructose is consumed in limited quantities, as in fruit, it is far less harmful.⁷¹ But when fructose is consumed in large amounts, such as in soft drinks sweetened with high-fructose corn syrup, the fructose increases visceral fat, insulin resistance and fatty liver disease.^72,73

About 30% of the general population (and about 70% of the obese) suffer from nonalcoholic fatty liver disease (NAFLD), which causes insulin resistance of the liver.⁷⁴ Besides fructose, cigarette smoking increases the likelihood of NAFLD.⁷⁵ Excess alcohol consumption causes both fatty liver disease and insulin resistance of the liver.⁷⁶

When insulin resistance develops in the hypothalamus, mental function becomes impaired.⁷⁷ Inflammatory factors in the blood circulation from insulin resistant fat or liver cells can result in insulin resistance of the brain.⁷⁸ High fructose consumption can lead to brain insulin resistance and increased appetite, as well as impaired learning and memory.⁷⁹

Some Dietary Advice to Reduce or Avoid Obesity

All calories do not have the same effect on obesity. The glycemic index of foods measures the amount by which a food increases blood glucose, and thus increases blood insulin. Pure glucose is the standard, but refined carbohydrates such as white bread and pasta have a high glycemic index. Rodents fed a high glycemic index diet gained 70% more fat than rodents on a low glycemic index diet.⁸⁰

Fructose has a low glycemic index, but fructose causes obesity by causing insulin resistance in the liver and brain. Elevated blood insulin due to insulin resistance causes obesity. Sucrose, fruit juices, and foods such as soft drinks sweetened with high-fructose corn syrup should be avoided.

Carbohydrates high in fiber such as whole grains are not believed to cause insulin resistance.⁸¹ A Mediterranean diet high in vegetables, whole grains, fish, and nuts is associated with reduced obesity.⁸² Not only is olive oil an important component of the Mediterranean diet, but olive oil has been shown to prevent accumulation of visceral fat even if body weight is not affected.⁸³

If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.

References

1. Osborn O, Olefsky JM. The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med. 2012;18(3):363-74.
2. Chavez JA, Summers SA. Lipid oversupply, selective insulin resistance, and lipotoxicity: molecular mechanisms. Biochim Biophys Acta. 2010;1801(3):252-65.
3. Choe SS, Huh JY, Hwang IJ, et al. Adipose Tissue Remodeling: Its Role in Energy Metabolism and Metabolic Disorders. Front Endocrinol (Lausanne). 2016;7:30.
4. Fontaine KR, Redden DT, Wang C, et al. Years of life lost due to obesity. JAMA. 2003;289(2):187-93.
5. Templeman NM, Skovso S, Page MM, et al. A causal role for hyperinsulinemia in obesity. J Endocrinol. 2017;232(3):R173-R83.
6. Hardy OT, Czech MP, Corvera S. What causes the insulin resistance underlying obesity? Curr Opin Endocrinol Diabetes Obes. 2012;19(2):81-7.
7. Robertson RP. Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes. J Biol Chem. 2004;279(41):42351-4.
8. Ye J, Gao Z, Yin J, et al. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab. 2007;293(4):E1118-28.
9. Lin, Chun TH, Kang L. Adipose extracellular matrix remodelling in obesity and insulin resistance. Biochem Pharmacol. 2016;119:8-16.
10. Weisberg SP, McCann D, Desai M, et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112(12):1796-808.
11. Lee BC, Lee J. Cellular and molecular players in adipose tissue inflammation in the development of obesity-induced insulin resistance. Biochim Biophys Acta. 2014;1842(3):446-62.
12. Kang YH, Cho MH, Kim JY, et al. Impaired macrophage autophagy induces systemic insulin resistance in obesity. Oncotarget. 2016;7(24):35577-91.
13. Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev. 2004;84(1):277-359.
14. Villarroya F, Cereijo R, Villarroya J, et al. Brown adipose tissue as a secretory organ. Nat Rev Endocrinol. 2017;13(1):26-35.
15. Nedergaard J, Bengtsson T, Cannon B. New powers of brown fat: fighting the metabolic syndrome. Cell Metab. 2011;13(3):238-40.
16. Stanford KI, Middelbeek RJ, Townsend KL, et al. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J Clin Invest. 2013;123(1):215-23.
17. Blondin DP, Labbe SM, Tingelstad HC, et al. Increased brown adipose tissue oxidative capacity in cold-acclimated humans. J Clin Endocrinol Metab. 2014;99(3):E438-46.
18. Cypess AM, Weiner LS, Roberts-Toler C, et al. Activation of human brown adipose tissue by a beta3-adrenergic receptor agonist. Cell Metab. 2015;21(1):33-8.
19. King GL, Park K, Li Q. Selective Insulin Resistance and the Development of Cardiovascular Diseases in Diabetes: The 2015 Edwin Bierman Award Lecture. Diabetes. 2016;65(6):1462-71.
20. Prieto D, Contreras C, Sanchez A. Endothelial dysfunction, obesity and insulin resistance. Curr Vasc Pharmacol. 2014;12(3):412-26.
21. Lastra G, Manrique C. Perivascular adipose tissue, inflammation and insulin resistance: link to vascular dysfunction and cardiovascular disease. Horm Mol Biol Clin Investig. 2015;22(1):19-26.
22. Strazhesko I, Tkacheva O, Boytsov S, et al. Association of Insulin Resistance, Arterial Stiffness and Telomere Length in Adults Free of Cardiovascular Diseases. PLoS One. 2015;10(8):e0136676.
23. Jia G, Aroor AR, DeMarco VG, et al. Vascular stiffness in insulin resistance and obesity. Front Physiol. 2015;6:231.
24. Muniyappa R, Sowers JR. Role of insulin resistance in endothelial dysfunction. Rev Endocr Metab Disord. 2013;14(1):5-12.
25. Weiss R, Taksali SE, Tamborlane WV, et al. Predictors of changes in glucose tolerance status in obese youth. Diabetes Care. 2005;28(4):902-9.
26. Meigs JB, Muller DC, Nathan DM, et al. The natural history of progression from normal glucose tolerance to type 2 diabetes in the Baltimore Longitudinal Study of Aging. Diabetes. 2003;52(6):1475-84.
27. Farrar D. Hyperglycemia in pregnancy: prevalence, impact, and management challenges. Int J Womens Health. 2016;8:519-27.
28. Herrera E, Amusquivar E, Lopez-Soldado I, et al. Maternal lipid metabolism and placental lipid transfer. Horm Res. 2006;65 Suppl 3:59-64.
29. Catalano PM, Shankar K. Obesity and pregnancy: mechanisms of short term and long term adverse consequences for mother and child. BMJ. 2017;356:j1.
30. Finer S. Fetal programming via maternal diabetes: the controversy continues. Diabet Med. 2015;32(3):291-4.
31. Holder T, Giannini C, Santoro N, et al. A low disposition index in adolescent offspring of mothers with gestational diabetes: a risk marker for the development of impaired glucose tolerance in youth. Diabetologia. 2014;57(11):2413-20.
32. Santangelo C, Zicari A, Mandosi E, et al. Could gestational diabetes mellitus be managed through dietary bioactive compounds? Current knowledge and future perspectives. Br J Nutr. 2016;115(7):1129-44.
33. Vilsboll T, Holst JJ. Incretins, insulin secretion and Type 2 diabetes mellitus. Diabetologia. 2004;47(3):357-66.
34. Mattson MP. Energy intake and exercise as determinants of brain health and vulnerability to injury and disease. Cell Metab. 2012;16(6):706-22.
35. Kim W, Egan JM. The role of incretins in glucose homeostasis and diabetes treatment. Pharmacol Rev. 2008;60(4):470-512.
36. Holst JJ, Knop FK, Vilsboll T, et al. Loss of incretin effect is a specific, important, and early characteristic of type 2 diabetes. Diabetes Care. 2011;34 Suppl 2:S251-7.
37. Punjabi M, Arnold M, Geary N, et al. Peripheral glucagon-like peptide-1 (GLP-1) and satiation. Physiol Behav. 2011;105(1):71-6.
38. Moller CL, Vistisen D, Faerch K, et al. Glucose-Dependent Insulinotropic Polypeptide Is Associated With Lower Low-Density Lipoprotein But Unhealthy Fat Distribution, Independent of Insulin: The ADDITION-PRO Study. J Clin Endocrinol Metab. 2016;101(2):485-93.
39. Tilg H, Kaser A. Gut microbiome, obesity, and metabolic dysfunction. J Clin Invest. 2011;121(6):2126-32.
40. Everard A, Lazarevic V, Derrien M, et al. Responses of gut microbiota and glucose and lipid metabolism to prebiotics in genetic obese and diet-induced leptin-resistant mice. Diabetes. 2011;60(11):2775-86.
41. Schneeberger M, Everard A, Gomez-Valades AG, et al. Akkermansia muciniphila inversely correlates with the onset of inflammation, altered adipose tissue metabolism and metabolic disorders during obesity in mice. Sci Rep. 2015;5:16643.
42. Plovier H, Everard A, Druart C, et al. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat Med. 2017;23(1):107-13.
43. Collado MC, Derrien M, Isolauri E, et al. Intestinal integrity and Akkermansia muciniphila, a mucin-degrading member of the intestinal microbiota present in infants, adults, and the elderly. Appl Environ Microbiol. 2007;73(23):7767-70.
44. Dao MC, Everard A, Aron-Wisnewsky J, et al. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut. 2016;65(3):426-36.
45. Farina MG, Baratta R, Nigro A, et al. Intragastric balloon in association with lifestyle and/or pharmacotherapy in the long-term management of obesity. Obes Surg. 2012;22(4):565-71.
46. Ponce J, Woodman G, Swain J, et al. The REDUCE pivotal trial: a prospective, randomized controlled pivotal trial of a dual intragastric balloon for the treatment of obesity. Surg Obes Relat Dis. 2015;11(4):874-81.
47. Sullivan S, Stein R, Jonnalagadda S, et al. Aspiration therapy leads to weight loss in obese subjects: a pilot study. Gastroenterology. 2013;145(6):1245-52 e1-5.
48. Dhindsa S, Prabhakar S, Sethi M, et al. Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J Clin Endocrinol Metab. 2004;89(11):5462-8.
49. Mogri M, Dhindsa S, Quattrin T, et al. Testosterone concentrations in young pubertal and post-pubertal obese males. Clin Endocrinol (Oxf). 2013;78(4):593-9.
50. Dhindsa S, Ghanim H, Batra M, et al. Insulin Resistance and Inflammation in Hypogonadotropic Hypogonadism and Their Reduction After Testosterone Replacement in Men With Type 2 Diabetes. Diabetes Care. 2016;39(1):82-91.
51. Dhindsa S, Ghanim H, Batra M, et al. Effect of testosterone on hepcidin, ferroportin, ferritin and iron binding capacity in patients with hypogonadotropic hypogonadism and type 2 diabetes. Clin Endocrinol (Oxf). 2016;85(5):772-80.
52. Longo VD, Mattson MP. Fasting: molecular mechanisms and clinical applications. Cell Metab. 2014;19(2):181-92.
53. Cahill GF, Jr. Fuel metabolism in starvation. Annu Rev Nutr. 2006;26:1-22.
54. Bozzetti F, Gavazzi C, Mariani L, et al. Glucose-based total parenteral nutrition does not stimulate glucose uptake by humans tumours. Clin Nutr. 2004;23(3):417-21.
55. Veech RL. The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins Leukot Essent Fatty Acids. 2004;70(3):309-19.
56. Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms. J Pathol. 2010;221(1):3-12.
57. Spiegelman BM, Flier JS. Obesity and the regulation of energy balance. Cell. 2001;104(4):531-43.
58. Stewart WK, Fleming LW. Features of a successful therapeutic fast of 382 days’ duration. Postgrad Med J. 1973;49(569):203-9.
59. Gilliland IC. Total fasting in the treatment of obesity. Postgrad Med J. 1968;44(507):58-61.
60. Espelund U, Hansen TK, Hojlund K, et al. Fasting unmasks a strong inverse association between ghrelin and cortisol in serum: studies in obese and normal-weight subjects. J Clin Endocrinol Metab. 2005;90(2):741-6.
61. Popkin BM, Duffey KJ. Does hunger and satiety drive eating anymore? Increasing eating occasions and decreasing time between eating occasions in the United States. Am J Clin Nutr. 2010;91(5):1342-7.
62. Betts JA, Richardson JD, Chowdhury EA, et al. The causal role of breakfast in energy balance and health: a randomized controlled trial in lean adults. Am J Clin Nutr. 2014;100(2):539-47.
63. Hocking S, Samocha-Bonet D, Milner KL, et al. Adiposity and insulin resistance in humans: the role of the different tissue and cellular lipid depots. Endocr Rev. 2013;34(4):463-500.
64. Matsuzawa Y. The role of fat topology in the risk of disease. Int J Obes (Lond). 2008;32 Suppl 7:S83-92.
65. Masharani UB, Maddux BA, Li X, et al. Insulin resistance in non-obese subjects is associated with activation of the JNK pathway and impaired insulin signaling in skeletal muscle. PLoS One. 2011;6(5):e19878.
66. Lemmens SG, Born JM, Martens EA, et al. Influence of consumption of a high-protein vs. high-carbohydrate meal on the physiological cortisol and psychological mood response in men and women. PLoS One. 2011;6(2):e16826.
67. Lee MJ, Pramyothin P, Karastergiou K, et al. Deconstructing the roles of glucocorticoids in adipose tissue biology and the development of central obesity. Biochim Biophys Acta. 2014;1842(3):473-81.
68. Rao MN, Neylan TC, Grunfeld C, et al. Subchronic sleep restriction causes tissue-specific insulin resistance. J Clin Endocrinol Metab. 2015;100(4):1664-71.
69. Chiolero A, Faeh D, Paccaud F, et al. Consequences of smoking for body weight, body fat distribution, and insulin resistance. Am J Clin Nutr. 2008;87(4):801-9.
70. Huffman DM, Barzilai N. Role of visceral adipose tissue in aging. Biochim Biophys Acta. 2009;1790(10):1117-23.
71. Macdonald IA. A review of recent evidence relating to sugars, insulin resistance and diabetes. Eur J Nutr. 2016;55(Suppl 2):17-23.
72. Stanhope KL, Schwarz JM, Keim NL, et al. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J Clin Invest. 2009;119(5):1322-34.
73. Ouyang X, Cirillo P, Sautin Y, et al. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol. 2008;48(6):993-9.
74. Smith BK, Marcinko K, Desjardins EM, et al. Treatment of nonalcoholic fatty liver disease: role of AMPK. Am J Physiol Endocrinol Metab. 2016;311(4):E730-E40.
75. Hamabe A, Uto H, Imamura Y, et al. Impact of cigarette smoking on onset of nonalcoholic fatty liver disease over a 10-year period. J Gastroenterol. 2011;46(6):769-78.
76. Carr RM, Correnti J. Insulin resistance in clinical and experimental alcoholic liver disease. Ann N Y Acad Sci. 2015;1353:1-20.
77. Biessels GJ, Reagan LP. Hippocampal insulin resistance and cognitive dysfunction. Nat Rev Neurosci. 2015;16(11):660-71.
78. Blazquez E, Velazquez E, Hurtado-Carneiro V, et al. Insulin in the brain: its pathophysiological implications for States related with central insulin resistance, type 2 diabetes and Alzheimer’s disease. Front Endocrinol (Lausanne). 2014;5:161.
79. Lowette K, Roosen L, Tack J, et al. Effects of high-fructose diets on central appetite signaling and cognitive function. Front Nutr. 2015;2:5.
80. Pawlak DB, Kushner JA, Ludwig DS. Effects of dietary glycaemic index on adiposity, glucose homoeostasis, and plasma lipids in animals. Lancet. 2004;364(9436):778-85.
81. Bernstein AM, Titgemeier B, Kirkpatrick K, et al. Major cereal grain fibers and psyllium in relation to cardiovascular health. Nutrients. 2013;5(5):1471-87.
82. Perez-Martinez P, Garcia-Rios A, Delgado-Lista J, et al. Mediterranean diet rich in olive oil and obesity, metabolic syndrome and diabetes mellitus. Curr Pharm Des. 2011;17(8):769-77.
83. Paniagua JA, Gallego de la Sacristana A, Romero I, et al. Monounsaturated fat-rich diet prevents central body fat distribution and decreases postprandial adiponectin expression induced by a carbohydrate-rich diet in insulin-resistant subjects. Diabetes Care. 2007;30(7):1717-23.