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Diagnosis and Management of Growth Hormone Deficiency in Adults – Consultant360

Posted: July 16, 2022 at 2:00 am

AUTHORS:Alexandra Martirossian, MD1 Julie Silverstein, MD2

AFFILIATIONS:1Fellow, Division of Endocrinology, Metabolism, & Lipid Research, Washington University School of Medicine in St. Louis, St. Louis, Missouri

2Associate Professor of Medicine and Neurological Surgery, Division of Endocrinology, Metabolism, & Lipid Research, Washington University School of Medicine in St. Louis, St. Louis, Missouri

CITATION:Martirossian A, Silverstein J. Diagnosis and management of growth hormone deficiency in adults. Consultant.2022;62(6);e20-e27.doi:10.25270/con.2021.10.00004

Received July 25, 2021. Accepted August 27, 2021.Published online October 14, 2021.

DISCLOSURES:The authors report no relevant financial relationships.

CORRESPONDENCE:Julie Silverstein, MD, Washington University School of Medicine in St. Louis, 660 South Euclid Avenue, St. Louis, MO 63110 (jsilverstein@wustl.edu)

Growth hormone deficiency (GHD) is a clinical syndrome caused by decreased production of or decreased tissue responsiveness to growth hormone. The most common cause of GHD in adults is pituitary tumors and their associated treatments of surgery or radiotherapy. Clinical manifestations of adult-onset GHD are nonspecific and include central obesity, loss of lean muscle mass, decreased bone density, insulin resistance, cardiovascular disease, hyperlipidemia, decreased exercise tolerance, and decreased quality of life. Diagnosis of GHD is confirmed by stimulatory testing or a low insulin-like growth factor 1 (IGF-1) level in the setting of multiple pituitary hormone deficiencies and organic pituitary disease. Treatment involves replacement with recombinant human growth hormone, and goals of therapy include clinical improvement, avoidance of adverse effects, and normalization of IGF-1 levels. Recombinant human growth hormone should only be prescribed for its approved clinical uses by an endocrinologist, and the risks and benefits of therapy should be weighed on a case-by-case basis.1,2

Physiology

Growth hormone (GH) is a polypeptide hormone secreted by somatotroph cells in the anterior pituitary that exerts several anabolic effects throughout the body. The GH receptor is expressed in multiple tissues including the liver, cartilage, muscle, fat, and kidneys.1 Activation of the GH receptor in the liver leads to hepatic production of insulin-like growth factor 1 (IGF-1), a peptide important for mediating many of GHs effects. In children, GH and IGF-1 are required for chondrocyte proliferation and linear growth. In adults, GH promotes several primarily anabolic effects including breakdown of fat, muscle growth, hepatic glucose production, and bone formation.1,3 Growth hormone secretion is regulated by a complex mixture of signals from the hypothalamus, gut, liver, and gonads, with production stimulated by growth hormone-releasing hormone (GHRH) from the hypothalamus and inhibited by somatostatin, which is primarily secreted in the brain and gastrointestinal tract. Factors that stimulate GH secretion include deep sleep, fasting, hypoglycemia, -adrenergic pathways, ghrelin, sex steroids, stress, and amino acids (eg, arginine, leucine).3 Factors that suppress GH secretion include obesity, glucocorticoids, glucose, hypothyroidism, IGF-1 (negative feedback), -adrenergic pathways, and free fatty acids. GH secretion is episodic and exhibits a diurnal rhythm with approximately two-thirds of the total daily GH secretion produced at night triggered by the onset of slow-wave sleep.3 GH levels reach a nadir during the day and may be undetectable, especially in obese or elderly persons. Over the course of a lifetime, GH secretion gradually rises during childhood, peaks during puberty, then gradually declines through adulthood. The phenomenon of age-related decline in GH levels is sometimes referred to as somatopause.4

Causes of Growth Hormone Deficiency

GHD can occur at any age and results from both congenital and acquired disorders (Table 1). Congenital causes include gene mutations and structural defects. Mutations in the genes encoding GH, GH receptor, GHRH receptor, and various transcription factors can cause GHD. Structural defects include empty sella syndrome, septo optic dysplasia, hydrocele, and pituitary hypoplasia.2 Acquired causes include intracranial tumors (eg, pituitary adenoma, craniopharyngioma, Rathke cleft cyst, glioma/astrocytoma, metastasis), head trauma, central nervous system infection, infarction (Sheehan syndrome), and infiltrative/granulomatous disease (eg, sarcoidosis, Langerhans cell histiocytosis, tuberculosis). GHD can also result from treatments for some of the aforementioned conditions, particularly cranial surgery or irradiation. In adults, the most common cause of GHD is a pituitary adenoma or treatment of the adenoma with pituitary surgery and/or radiotherapy, with the risk of deficiency proportional to the size of the tumor and extent of treatment.2

Manifestations of GHD in adults may include central obesity, loss of lean muscle mass, decreased bone mass, insulin resistance, cardiovascular disease, hyperlipidemia, and decreased quality of life.1 Data supporting the benefits of GH replacement are mixed, with much of the data showing benefit coming from retrospective and open-label observational studies. Some, but not all, studies show that GH replacement is associated with an increase in strength and exercise capacity2 and is associated with an increase in bone mineral density5,6 and decreased fracture risk.7 In terms of cardiovascular disease, a metanalysis of randomized, blinded, placebo-controlled trials suggests that GH replacement increases lean body mass and decreases fat mass, has a beneficial effect on low-density lipoprotein cholesterol, and lowers diastolic blood pressure8, but there is no evidence that these changes are associated with measurable changes in cardiovascular function.9

Benefits of Growth Hormone Deficiency

The effect of GH replacement on glucose metabolism is complex. GH antagonizes the action of insulin, and evidence suggests that GH replacement may lead to a transient increase in fasting glucose10 but not necessarily an increased incidence of diabetes.11 Long-term observational studies of patients with adult GHD also suggest that GH replacement is associated with an improvement in quality of life when assessing parameters such as memory and concentration, fatigue, tenseness, socializing, and self-confidence.12,13

Diagnosing Growth Hormone Deficiency

Making the diagnosis of GHD is generally easier in children because the outcome of short stature is readily apparent. The task is more difficult in those with adult-onset deficiency because the symptoms are generally nonspecific, so a higher index of suspicion is required.

Because of the high financial cost of recombinant human growth hormone (rhGH) and possibility of adverse effects, it is crucial that the correct diagnosis is made and that treatment is only pursued in those adults who are truly GH deficient. This shrewdness is important for prevention of inappropriate treatment that is sometimes seen in nonmedical conditions such as aging and sports. In deciding who to screen, a clinical history guides the extent of required testing (Figure).

In adults with a history of organic hypothalamic-pituitary disease (eg, pituitary mass with previous surgery and cranial irradiation) with at least 3 hormone deficiencies (eg, hypothyroidism, adrenal insufficiency, and hypogonadism) and a low serum IGF-1 level (< 2.0 standard deviation score, also reported as a Z-score), no further testing is required, and treatment can be initiated.14 This also applies to adults who have congenital structural defects or genetic mutations affecting the hypothalamic-pituitary axes who have at least 3 other hormone deficiencies and low serum IGF-1 level. In adults who have a history of organic hypothalamic-pituitary disease with 2 or fewer hormone deficiencies, high clinical suspicion, and a low IGF-1 level (< 0 standard deviation score), provocative testing for GHD is indicated.14

In the absence of any of these risk factors, testing is not advised. It should be noted that 30% to 40% of patients with adult-onset GHD may have normal IGF-1 levels, so if clinical suspicion remains high, diagnostic testing should be pursued.15 In adults with idiopathic GHD in childhood, retesting should be performed because a significant proportion of this population may have normal GH secretion as adults.16-19

Figure. Algorithm for Stimulation Testing and Treatment in Adults With Suspected Growth Hormone Deficiency14

Measurement of random GH levels for the purpose of diagnosing GHD is not reliable for multiple reasons. First, GH has a short circulating half-life of only 10 to 20 minutes, and the pulsatility of GH secretion makes interpretation of single measurements difficult.20 Second, GH secretion is suppressed in the postprandial state, so timing of food consumption is important to know. Other factors associated with decreased IGF-1 levels that should be taken into consideration when interpreting laboratory test results include advanced age, obesity, poorly controlled diabetes, liver disease, renal failure, oral estrogen use, hypothyroidism, and critical illness.21 Additionally, assays for GH and IGF-1 have not been rigorously standardized, and normal baseline values for adults are often inadequate. To circumvent these diagnostic issues, GH stimulation tests are used. There are several GH provocative tests available in clinical practice (Table 2), each with its own advantages and disadvantages.

The insulin tolerance test (ITT), although not commonly used in the United States, is considered the gold standard for diagnosis of GHD.4,14,22 Insulin-induced hypoglycemia stimulates the release of GH. The ITT is performed by having the patient fast for at least 8 hours and then intravenous insulin is administered at a dose of 0.05 to 0.15 U/kg. Blood is drawn fasting and then 20, 30, 40, and 60 minutes after adequate hypoglycemia is achieved (blood glucose, < 40 mg/dL).22,23 The diagnostic cutoff for GHD is a GH level 5 g/L or lower after hypoglycemia is achieved. The positive predictive value is 93%, sensitivity is 96%, and specificity is 92%.22 Several drawbacks of the ITTincluding the requirement for close medical supervision by a physician throughout the test, the possibility of inducing severe life-threatening hypoglycemia, and the risk of causing seizures and altered consciousness in certain susceptible populationslimit its use. The ITT is contraindicated in individuals aged older than 65 years, those who are pregnant, and those who have a history of or are at risk for seizures and cardiovascular disease. Moreover, normoglycemic or hyperglycemic patients with obesity and insulin resistance may require higher doses of insulin (0.15-0.2 U/kg) to achieve target hypoglycemia, thus increasing their risk for delayed hypoglycemia.

Finding an alternative to the ITT for the diagnosis of GHD has been challenging. The GHRH-arginine stimulation test showed favor for some time because of its convenience, reproducibility, and discriminatory power. However, in 2008, the recombinant GHRH (ie, injectable sermorelin) was removed from the market, so the test could no longer be performed in the United States.14,22 Since then, the glucagon stimulation test (GST) has become a preferred alternative diagnostic test for GHD in the United States. The exact mechanism for how glucagon stimulates GH secretion is poorly understood, but it has been shown to be a more-potent stimulator of GH secretion than other agents, including arginine and clonidine.24,25 Glucagon is more effective at stimulating GH secretion when administered intramuscularly compared with intravenously.26 The GST is performed by first having the patient fast for 8 to 10 hours, and then intramuscular glucagon is administered (1 mg if weight is 90 kg, 1.5 mg if weight is > 90 kg). Serum GH and blood glucose levels are measured at 0, 30, 60, 90, 120, 150, 180, 210, and 240 minutes after glucagon is administered. A GH cutoff of 3 g/L has been shown to have sensitivity and specificity of up to 100% in lean subjects (body mass index, 25 kg/m2).22 However, because obesity blunts the GH secretion response to glucagon, a lower cutoff of 1 g/L is recommended in individuals who are overweight or obese (body mass index, > 25 kg/m2).22 Advantages of the GST include its availability, reproducibility, safety, lack of influence by gender and hypothalamic cause of GHD, and relatively few contraindications. Disadvantages include its long duration, the need for intramuscular administration and multiple blood draws, and gastrointestinal adverse effects. The test is contraindicated in malnourished individuals or individuals who have not eaten for more than 48 hours, as well as those with severe fasting hyperglycemia (> 180 mg/dL).22,23 Because late hypoglycemia may occur, individuals should be advised to eat small and frequent meals after completion of the test.

In 2017, the US Food and Drug Administration (FDA) granted approval for the use of macimorelin for diagnosing adult GHD.27 Macimorelin acetate is an oral ghrelin receptor agonist with GH secretagogue activity that is readily absorbed and effectively stimulates endogenous GH secretion in healthy volunteers with good tolerability.28 To validate the efficacy and safety of macimorelin in the diagnosis of adult GHD, Garcia and colleagues performed an open-label, randomized, multicenter, 2-way crossover study of the macimorelin test vs the ITT.29 Participants with high (n = 38), intermediate (n = 37), and low (n = 39) likelihood for adult GHD and healthy, matched controls (n = 25) were included in the efficacy analysis. The macimorelin oral solution was prepared at a dose of 0.5 mg/kg of body weight. Blood samples for GH serum levels were collected before and at 30, 45, 60, and 90 minutes after administration of macimorelin. Using a GH cutoff of 2.8 ng/mL for the macimorelin test and 5.1 ng/mL for the ITT, the sensitivity was 87% and specificity was 96%. In post-hoc analyses, increasing the GH cutoff for the macimorelin test to 5.1 ng/mL while maintaining the GH cutoff of 5.1 ng/mL for the ITT resulted in a sensitivity of 92% and specificity of 96%. A greater peak GH level was seen in all groups with the macimorelin test compared with the ITT. Reproducibility for macimorelin was high at 97%. The macimorelin test was well tolerated with no serious or frequent adverse effects reported. The most common adverse effect was mild and transient dysgeusia. Garcia and colleagues later performed post-hoc analyses to determine whether macimorelin performance was affected by age, body mass index, or sex and evaluated its performance vs ITT over a range of GH cutoffs.30 They found that macimorelin performance was not meaningfully affected by age, body mass index, or sex. Caution should be used in generalizing these results in pediatric, elderly, and severely obese patients, since the study population age range was 18 to 66, and the highest recorded baseline body mass index was 36.6 kg/m2, with most participants having a body mass index of less than 30 kg/m2. Of the 4 GH cutoffs evaluated (2.8 ng/mL, 4.0 ng/mL, 5.1 ng/mL, and 6.5 ng/mL), the cutoff of 5.1 ng/mL provided maximal specificity (96%) and high sensitivity (92%) and was in good overall agreement with the ITT at the same cutoff (87%). At present, the approved FDA cutoff is the lower value of 2.8 ng/mL.29 Compared with the ITT and GST, the macimorelin stimulation test has the advantages of being safer, well tolerated, easier to perform, and is less influenced by body weight, so its use in clinical practice may increase in coming years. A major factor currently limiting its widespread use is high financial cost.14

Treatment of Growth Hormone Deficiency

Once the diagnosis of GHD has been made, treatment is initiated with rhGH, which contains the identical sequence of amino acids found in HGH. For many years, the only rhGH product on the US market was somatropin, a once-daily injection. In September 2020, the FDA approved once-weekly somapacitan for the treatment of adult GHD, but it is not yet available on the market.31,32 It is hoped that the decreased frequency of injections should lower the burden of treatment and improve treatment adherence. Multiple brands of somatropin are available, and there is no evidence that one commercial product is different or more advantageous than another, apart from differences in pen devices, electronic autoinjector devices that are user-friendly, dose per milligram adjustments, and whether the product requires refrigeration.14

In adults, the typical dose of somatropin ranges from 0.1 to 0.4 mg/d and is influenced by age, sex, comorbidities, and concomitant medications. Per the 2019 guidelines published by the American Association of Clinical Endocrinologists (AACE), the recommended starting dose for patients aged younger than 30 years is 0.4 to 0.5 mg/d, aged between 30 to 60 years is 0.2 to 0.3 mg/d, and aged older than 60 years is 0.1 to 0.2 mg/d. In patients transitioning from pediatric to adult care, rhGH should be continued at 50% of the dose used in childhood and then gradually adjusted. In patients with concurrent type 2 diabetes, previous gestational diabetes, and obesity, lower doses of 0.1 to 0.2 mg/d are recommended. Women tend to require higher doses than men to achieve the same IGF-1 level, especially if they are taking oral estrogen.33,34 Approximately 85% of circulating IGF-I is liver derived, and oral estrogen, which undergoes first pass metabolism, suppresses hepatic production of IGF-1. rhGH dose reduction is often necessary when oral estrogen is stopped or switched to transdermal. Most adverse effects of treatment are dose related. The most common adverse effects are related to insulin resistance and fluid retention and include hyperglycemia, paresthesias, joint stiffness, peripheral edema, arthralgias, myalgias, and carpal tunnel syndrome.2 Contraindications to treatment include active malignancy and active proliferative or severe nonproliferative diabetic retinopathy.

After GH replacement therapy is initiated, it is recommended that patients follow-up in 1- or 2-month intervals at first, which can later be spaced out to 6- or 12-month intervals once a stable dose has been reached.14 Determination of the appropriate dose is influenced by multiple factors, including clinical improvement in symptoms, avoidance of adverse effects, and IGF-1 level. Assessment of fasting glucose, hemoglobin A1c, fasting lipids, body mass index, waist circumference, waist-to-hip ratio, and quality of life should be performed at least once per year. Assessment of other pituitary hormone deficiencies and structural pituitary lesions with laboratory and imaging studies, respectively, should be performed as clinically indicated. If the initial bone density scan is abnormal, repeat evaluations at 2- to 3-year intervals are recommended. IGF-1 levels are commonly used to guide the adequacy of rhGH dosing, and the general recommendation is to target a level within age-adjusted reference ranges (standard deviation score, 2 and +2). However, studies have shown varying benefits and drawbacks to targeting IGF-1 levels in the upper or lower half of this range. Targeting IGF-1 levels in the upper range of normal (standard deviation score, 1-2) has shown benefits in body fat composition, waist circumference, and microcirculatory function but at the expense of increased insulin resistance and myalgias.35,36 Targeting IGF-1 levels in the lower range of normal (standard deviation score, 2 to 1) is more often associated with fatigue. Women may have a narrower therapeutic dose window than men. In a study by van Bunderen and colleagues, a high-normal IGF-1 target level in female study participants was associated with impaired prefrontal cognitive functioning, whereas a low-normal target IGF-1 level was associated with decreased vigor.37

The question of how long to continue GH replacement therapy is frequently debated. If clinical benefits have resulted from treatment (eg, improved quality of life, body composition, cardiovascular health, bone density), rhGH can be continued indefinitely presuming there are no contraindications. If there are neither subjective nor objective benefits after at least 12 to 18 months of treatment, the option of discontinuing GH replacement should be discussed with the patient.2,14 Since GH promotes cellular proliferation and tissue growth, there has been a longstanding theoretical concern that rhGH leads to increased risk of malignancy. Although studies show no increased risk of malignancy in hypopituitary patients on long-term growth hormone treatment, an abundance of caution should be exercised when deciding whether to start rhGH in patients with GHD and a history of or genetic predisposition to malignancy.38 It has been suggested that in adult patients with a history of cancer, low-dose rhGH should only be initiated 5 years after cancer remission is achieved.14,39 The patients oncologist should be in agreement and closely involved in follow-up care while the patient is taking therapy. In all patients, regardless of cancer risk, cancer screening guidelines should be followed.

A topic that has gained much attention in our culture is the use of GH for antiaging, with some citing it as a fountain of youth.40 Despite the popularity of this idea, no studies have assessed long-term (> 6 months) efficacy or safety of rhGH administration for this purpose in humans.14 Paradoxically, studies performed in mice have shown that mice with isolated GHD caused by GHRH or GHRH receptor mutations, combined deficiency of GH, prolactin, and thyroid-stimulating hormone, or global deletion of GH receptors live longer than their normal siblings and exhibit multiple features of delayed and/or slower aging.41-43 Liu and colleagues performed a meta-analysis of 31 studies describing the use of GH in healthy elderly adults and found that GH use was associated with small changes in body composition but increased rates of adverse events.44 In the United States, off-label distribution or marketing of rhGH to treat aging or aging-related conditions and for the enhancement of athletic performance is illegal. Given the clinical concerns and legal issues involved, it is strongly recommended that rhGH only be prescribed for the well-defined approved uses of the medication, which are GHD and HIV-associated lipodystrophy.14,45,46

Conclusions

Growth hormone replacement therapy in adults with confirmed GHD has been shown to be associated with improvement in multiple aspects of health, including body composition, muscle mass, cardiovascular health, bone density, and quality of life. The clinical manifestations of GHD in adults are often nonspecific, so diligence to confirm an accurate diagnosis is essential for avoiding the costs and ethical dilemmas of inappropriate treatment. There are multiple GH stimulatory tests available, each with its own benefits and caveats. Once the diagnosis of adult GHD is established, rhGH should be initiated at low doses and uptitrated based on IGF-1 levels and symptoms, while avoiding adverse effects. Research into longer-acting rhGH formulations and enhanced diagnostic testing is ongoing and will be essential for guiding the management of adult GHD.

References

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27. Macrilen (macimorelin) for Oral Solution. US Food & Drug Administration. Published January 31, 2018. Accessed March 14, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/205598Orig1s000TOC.cfm

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30. Garcia JM, Biller BMK, Korbonits M, et al. Sensitivity and specificity of the macimorelin test for diagnosis of AGHD. Endocr Connect. 2021;10(1):76-83. https://doi.org/10.1530/ec-20-0491

31. FDA approves weekly therapy for adult growth hormone deficiency. News Release. US Food & Drug Administration. Published September 1, 2020. Accessed March 27, 2021. https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-weekly-therapy-adult-growth-hormone-deficiency

32. Johannsson G, Gordon MB, Hjby Rasmussen M, et al. Once-weekly somapacitan is effective and well tolerated in adults with GH deficiency: a randomized phase 3 trial. J Clin Endocrinol Metab. 2020;105(4):e1358-e1376. https://doi.org/10.1210/clinem/dgaa049

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34. Cook DM, Ludlam WH, Cook MB. Route of estrogen administration helps to determine growth hormone (GH) replacement dose in GH-deficient adults. J Clin Endocrinol Metab. 1999;84(11):3956-3960. https://doi.org/10.1210/jcem.84.11.6113

35. van Bunderen CC, Lips P, Kramer MH, Drent ML. Comparison of low-normal and high-normal IGF-1 target levels during growth hormone replacement therapy: a randomized clinical trial in adult growth hormone deficiency. Eur J Intern Med. 2016;31:88-93. https://doi.org/10.1016/j.ejim.2016.03.026

36. van Bunderen CC, Meijer RI, Lips P, Kramer MH, Sern EH, Drent ML. Titrating growth hormone dose to high-normal IGF-1 levels has beneficial effects on body fat distribution and microcirculatory function despite causing insulin resistance. Front Endocrinol (Lausanne). 2021;11:619173. https://doi.org/10.3389/fendo.2020.619173

37. van Bunderen CC, Deijen JB, Drent ML. Effect of low-normal and high-normal IGF-1 levels on memory and wellbeing during growth hormone replacement therapy: a randomized clinical trial in adult growth hormone deficiency. Health Qual Life Outcomes. 2018;16(1):135. https://doi.org/10.1186/s12955-018-0963-2

38. Child CJ, Conroy D, Zimmermann AG, Woodmansee WW, Erfurth EM, Robison LL. Incidence of primary cancers and intracranial tumour recurrences in GH-treated and untreated adult hypopituitary patients: analyses from the Hypopituitary Control and Complications Study. Eur J Endocrinol. 2015;172(6):779-790. https://doi.org/10.1530/eje-14-1123

39. Yuen KC, Heaney AP, Popovic V. Considering GH replacement for GH-deficient adults with a previous history of cancer: a conundrum for the clinician. Endocrine. 2016;52(2):194-205. https://doi.org/10.1007/s12020-015-0840-2

40. DiGiorgio L, Sadeghi-Nejad H. Growth hormone and the fountain of youth. J Sex Med. 2018;15(9):1208-1211. https://doi.org/10.1016/j.jsxm.2018.04.647

41. Bartke A, Darcy J. GH and ageing: pitfalls and new insights. Best Pract Res Clin Endocrinol Metab. 2017;31(1):113-125. https://doi.org/10.1016/j.beem.2017.02.005

42. Aguiar-Oliveira MH, Bartke A. Growth hormone deficiency: health and longevity. Endocr Rev. 2019;40(2):575-601. https://doi.org/10.1210/er.2018-00216

43. Flurkey K, Papaconstantinou J, Miller RA, Harrison DE. Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc Natl Acad Sci U S A. 2001;98(12):6736-6741. https://doi.org/10.1073/pnas.111158898

44. Liu H, Bravata DM, Olkin I, et al. Systematic review: the safety and efficacy of growth hormone in the healthy elderly. Ann Intern Med. 2007;146(2):104-115. https://doi.org/10.7326/0003-4819-146-2-200701160-00005

45. Clemmons DR, Molitch M, Hoffman AR, et al. Growth hormone should be used only for approved indications. J Clin Endocrinol Metab. 2014;99(2):409-411. https://doi.org/10.1210/jc.2013-4187

46. Burgess E, Wanke C. Use of recombinant human growth hormone in HIV-associated lipodystrophy. Curr Opin Infect Dis. 2005;18(1):17-24. https://doi.org/10.1097/00001432-200502000-00004

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Low-carbohydrate diet – Wikipedia

Posted: December 7, 2016 at 11:43 am

Low-carbohydrate diets or low-carb diets are dietary programs that restrict carbohydrate consumption, often for the treatment of obesity or diabetes. Foods high in easily digestible carbohydrates (e.g., sugar, bread, pasta) are limited or replaced with foods containing a higher percentage of fats and moderate protein (e.g., meat, poultry, fish, shellfish, eggs, cheese, nuts, and seeds) and other foods low in carbohydrates (e.g., most salad vegetables such as spinach, kale, chard and collards), although other vegetables and fruits (especially berries) are often allowed. The amount of carbohydrate allowed varies with different low-carbohydrate diets.

Such diets are sometimes 'ketogenic' (i.e., they restrict carbohydrate intake sufficiently to cause ketosis). The induction phase of the Atkins diet[1][2][3] is ketogenic.

The term "low-carbohydrate diet" is generally applied to diets that restrict carbohydrates to less than 20% of caloric intake, but can also refer to diets that simply restrict or limit carbohydrates to less than recommended proportions (generally less than 45% of total energy coming from carbohydrates).[4][5]

Low-carbohydrate diets are used to treat or prevent some chronic diseases and conditions, including cardiovascular disease, metabolic syndrome, auto-brewery syndrome, high blood pressure, and diabetes.[6][7]

Gary Taubes has argued that low-carbohydrate diets are closer to the ancestral diet of humans before the origin of agriculture, and humans are genetically adapted to diets low in carbohydrate.[8] Direct archaeological or fossil evidence on nutrition during the Paleolithic, when all humans subsisted by hunting and gathering, is limited, but suggests humans evolved from the vegetarian diets common to other great apes to one with a greater level of meat-eating.[9] Some close relatives of modern Homo sapiens, such as the Neanderthals, appear to have been almost exclusively carnivorous.[10]

A more detailed picture of early human diets before the origin of agriculture may be obtained by analogy to contemporary hunter-gatherers. According to one survey of these societies, a relatively low carbohydrate (2240% of total energy), animal food-centered diet is preferred "whenever and wherever it [is] ecologically possible", and where plant foods do predominate, carbohydrate consumption remains low because wild plants are much lower in carbohydrate and higher in fiber than modern domesticated crops.[11] Primatologist Katherine Milton, however, has argued that the survey data on which this conclusion is based inflate the animal content of typical hunter-gatherer diets; much of it was based on early ethnography, which may have overlooked the role of women in gathering plant foods.[12] She has also highlighted the diversity of both ancestral and contemporary foraging diets, arguing no evidence indicates humans are especially adapted to a single paleolithic diet over and above the vegetarian diets characteristic of the last 30 million years of primate evolution.[13]

The origin of agriculture brought about a rise in carbohydrate levels in human diets.[14] The industrial age has seen a particularly steep rise in refined carbohydrate levels in Western societies, as well as urban societies in Asian countries, such as India, China, and Japan.

In 1797, John Rollo reported on the results of treating two diabetic Army officers with a low-carbohydrate diet and medications. A very low-carbohydrate, ketogenic diet was the standard treatment for diabetes throughout the 19th century.[15][16]

In 1863, William Banting, a formerly obese English undertaker and coffin maker, published "Letter on Corpulence Addressed to the Public", in which he described a diet for weight control giving up bread, butter, milk, sugar, beer, and potatoes.[17] His booklet was widely read, so much so that some people used the term "Banting" for the activity usually called "dieting".[18]

In 1888, James Salisbury introduced the Salisbury steak as part of his high-meat diet, which limited vegetables, fruit, starches, and fats to one-third of the diet.[original research?]

In the early 1900s Frederick Madison Allen developed a highly restrictive short term regime which was described by Walter R. Steiner at the 1916 annual convention of the Connecticut State Medical Society as The Starvation Treatment of Diabetes Mellitus.[19]:176177[20][21][22] People showing very high urine glucose levels were confined to bed and restricted to an unlimited supply of water, coffee, tea, and clear meat broth until their urine was "sugar free"; this took two to four days but sometimes up to eight.[19]:177 After the person's urine was sugar-free food was re-introduced; first only vegetables with less than 5g of carbohydate per day, eventually adding fruits and grains to build up to 3g of carbohydrate per kilogram of body weight. Then eggs and meat were added, building up to 1g of protein/kg of body weight per day, then fat was added to the point where the person stopped losing weight or a maximum of 40 calories of fat per kilogram per day was reached. The process was halted if sugar appeared in the person's urine.[19]:177178 This diet was often administered in a hospital in order to better ensure compliance and safety.[19]:179

In 1958, Richard Mackarness M.D. published Eat Fat and Grow Slim, a low-carbohydrate diet with much of the same advice and based on the same theories as those promulgated by Robert Atkins more than a decade later. Mackarness also challenged the "calorie theory" and referenced primitive diets such as the Inuit as examples of healthy diets with a low-carbohydrate and high-fat composition.

In 1967, Irwin Stillman published The Doctor's Quick Weight Loss Diet. The "Stillman diet" is a high-protein, low-carbohydrate, and low-fat diet. It is regarded as one of the first low-carbohydrate diets to become popular in the United States.[23] Other low-carbohydrate diets in the 1960s included the Air Force diet[24] and the drinking man's diet.[25]Austrian physician Wolfgang Lutz published his book Leben Ohne Brot (Life Without Bread) in 1967.[26] However, it was not well known in the English-speaking world.

In 1972, Robert Atkins published Dr. Atkins Diet Revolution, which advocated the low-carbohydrate diet he had successfully used in treating patients in the 1960s (having developed the diet from a 1963 article published in JAMA).[27] The book met with some success, but, because of research at that time suggesting risk factors associated with excess fat and protein, it was widely criticized by the mainstream medical community as being dangerous and misleading, thereby limiting its appeal at the time.[28] Among other things, critics pointed out that Atkins had done little real research into his theories and based them mostly on his clinical work. Later that decade, Walter Voegtlin and Herman Tarnower published books advocating the Paleolithic diet and Scarsdale diet, respectively, each meeting with moderate success.[29][not in citation given]

The concept of the glycemic index was developed in 1981 by David Jenkins to account for variances in speed of digestion of different types of carbohydrates. This concept classifies foods according to the rapidity of their effect on blood sugar levels with fast-digesting simple carbohydrates causing a sharper increase and slower-digesting complex carbohydrates, such as whole grains, a slower one.[30] The concept has been extended to include the amount of carbohydrate actually absorbed, as well, as a tablespoonful of cooked carrots is less significant overall than a large baked potato (effectively pure starch, which is efficiently absorbed as glucose), despite differences in glycemic indices.

In the 1990s, Atkins published an update from his 1972 book, Dr. Atkins New Diet Revolution, and other doctors began to publish books based on the same principles. This has been said to be the beginning of what the mass media call the "low carb craze" in the United States.[31] During the late 1990s and early 2000s, low-carbohydrate diets became some of the most popular diets in the US. By some accounts, up to 18% of the population was using one type of low-carbohydrate diet or another at the peak of their popularity,[32] and this use spread to many countries.[citation needed]Food manufacturers and restaurant chains like Krispy Kreme noted the trend, as it affected their businesses.[33] Parts of the mainstream medical community has denounced low-carbohydrate diets as being dangerous to health, such as the AHA in 2001,[34] the American Kidney Fund in 2002,[35] Low-carbohydrate advocates did some adjustments of their own, increasingly advocating controlling fat and eliminating trans fat.[36][37]

Proponents who appeared with new diet guides at that time like the Zone diet intentionally distanced themselves from Atkins and the term 'low carb' because of the controversies, though their recommendations were based on largely the same principles .[38][39] It can be controversial which diets are low-carbohydrate and which are not.[citation needed] The 1990s and 2000s saw the publication of an increased number of clinical studies regarding the effectiveness and safety (pro and con) of low-carbohydrate diets (see low-carbohydrate diet medical research).

In the United States, the diet has continued to garner attention in the medical and nutritional science communities, and also inspired a number of hybrid diets that include traditional calorie-counting and exercise regimens.[7][40][41][42] Other low-carb diets, such as the Paleo Diet, focus on the removal of certain foods from the diet, such as sugar and grain.[43] On September 2, 2014 a small randomized trial by the NIH of 148 men and women comparing a low-carbohydrate diet with a low fat diet without calorie restrictions over one year showed that participants in the low-carbohydrate diet had greater weight loss than those on the low-fat diet.[44] The low-fat group lost weight, but appeared to lose more muscle than fat.[45]

No consensus definition exists of what precisely constitutes a low-carbohydrate diet.[46] Medical researchers and diet advocates may define different levels of carbohydrate intake when specifying low-carbohydrate diets.[46][not in citation given]

The American Academy of Family Physicians defines low-carbohydrate diets as diets that restrict carbohydrate intake to 20 to 60 grams per day, typically less than 20% of caloric intake.[47]

The body of research underpinning low-carbohydrate diets has grown significantly in the decades of the 1990s and 2000s.[48][49] Most research centers on the relationship between carbohydrate intake and blood sugar levels (i.e., blood glucose), as well as the two primary hormones produced in the pancreas, that regulate the blood sugar level, insulin, which lowers it, and glucagon, which raises it.[50]

Low-carbohydrate diets in general recommend reducing nutritive carbohydrates, commonly referred to as "net carbs", i.e., grams of total carbohydrates reduced by the non-nutritive carbohydrates[51][52] to very low levels. This means sharply reducing consumption of desserts, breads, pastas, potatoes, rice, and other sweet or starchy foods. Some recommend levels less than 20g of "net carbs" per day, at least in the early stages of dieting[53] (for comparison, a single slice of white bread typically contains 15g of carbohydrate, almost entirely starch). By contrast, the U.S. Institute of Medicine recommends a minimum intake of 130g of carbohydrate per day.[54] The FAO and WHO similarly recommend that the majority of dietary energy come from carbohydrates.[55][56]

Although low-carbohydrate diets are most commonly discussed as a weight-loss approach, some experts have proposed using low-carbohydrate diets to mitigate or prevent diseases, including diabetes, metabolic disease, and epilepsy.[57][58] Some low-carbohydrate proponents and others argue that the rise in carbohydrate consumption, especially refined carbohydrates, caused the epidemic levels of many diseases in modern society, including metabolic disease and type 2 diabetes.[59][60][61][62]

A category of diets is known as low-glycemic-index diets (low-GI diets) or low-glycemic-load diets (low-GL diets), in particular the Low GI Diet.[63] In reality, low-carbohydrate diets can also be low-GL diets (and vice versa) depending on the carbohydrates in a particular diet. In practice, though, "low-GI"/"low-GL" diets differ from "low-carb" diets in the following ways: First, low-carbohydrate diets treat all nutritive carbohydrates as having the same effect on metabolism, and generally assume their effect is predictable. Low-GI/low-GL diets are based on the measured change in blood glucose levels in various carbohydrates these vary markedly in laboratory studies. The differences are due to poorly understood digestive differences between foods. However, as foods influence digestion in complex ways (e.g., both protein and fat delay absorption of glucose from carbohydrates eaten at the same time) it is difficult to even approximate the glycemic effect (e.g., over time or even in total in some cases) of a particular meal.[64]

The low-insulin-index diet, is similar, except it is based on measurements of direct insulemic responses i.e., the amount of insulin in the bloodstream to food rather than glycemic response the amount of glucose in the bloodstream. Although such diet recommendations mostly involve lowering nutritive carbohydrates, some low-carbohydrate foods are discouraged, as well (e.g., beef).[65] Insulin secretion is stimulated (though less strongly) by other dietary intake. Like glycemic-index diets, predicting the insulin secretion from any particular meal is difficult, due to assorted digestive interactions and so differing effects on insulin release.[citation needed]

At the heart of the debate about most low-carbohydrate diets are fundamental questions about what is a 'normal' diet and how the human body is supposed to operate. These questions can be outlined as follows.

The diets of most people in modern Western nations, especially the United States, contain large amounts of starches, including refined flours, and substantial amounts of sugars, including fructose. Most Westerners seldom exhaust stored glycogen supplies and rarely go into ketosis. This has been regarded by the majority of the medical community in the last century as normal for humans.[citation needed] Ketosis should not be confused with ketoacidosis, a dangerous and extreme ketotic condition associated with type I diabetes. Some in the medical community have regarded ketosis as harmful and potentially life-threatening, believing it unnecessarily stresses the liver and causes destruction of muscle tissues.[citation needed] A perception developed that getting energy chiefly from dietary protein rather than carbohydrates causes liver damage and that getting energy chiefly from dietary fats rather than carbohydrates causes heart disease and other health problems. This view is still held by the majority of those in the medical and nutritional science communities.[66][67][68] However, it is now widely recognized that periodic ketosis is normal, and that ketosis provides a number of benefits, including neuroprotection against diverse types of cellular injury.[69]

People critical of low-carbohydrate diets cite hypoglycemia and ketoacidosis as risk factors. While mild acidosis may be a side effect when beginning a ketogenic diet,[70][71] no known health emergencies have been recorded. It should not be conflated with diabetic ketoacidosis, which can be life-threatening.

A diet very low in starches and sugars induces several adaptive responses. Low blood glucose causes the pancreas to produce glucagon,[72] which stimulates the liver to convert stored glycogen into glucose and release it into the blood. When liver glycogen stores are exhausted, the body starts using fatty acids instead of glucose. The brain cannot use fatty acids for energy, and instead uses ketones produced from fatty acids by the liver. By using fatty acids and ketones as energy sources, supplemented by conversion of proteins to glucose (gluconeogenesis), the body can maintain normal levels of blood glucose without dietary carbohydrates.

Most advocates of low-carbohydrate diets, such as the Atkins diet, argue that the human body is adapted to function primarily in ketosis.[73][74] They argue that high insulin levels can cause many health problems, most significantly fat storage and weight gain. They argue that the purported dangers of ketosis are unsubstantiated (some of the arguments against ketosis result from confusion between ketosis and ketoacidosis, which is a mostly diabetic condition unrelated to dieting or low-carbohydrate intake).[75] They also argue that fat in the diet only contributes to heart disease in the presence of high insulin levels and that if the diet is instead adjusted to induce ketosis, fat and cholesterol in the diet are beneficial. Most low-carb diet plans discourage consumption of trans fat.

On a high-carbohydrate diet, glucose is used by cells in the body for the energy needed for their basic functions, and about two-thirds of body cells require insulin to use glucose. Excessive amounts of blood glucose are thought to be a primary cause of the complications of diabetes, when glucose reacts with body proteins (resulting in glycosolated proteins) and change their behavior. Perhaps for this reason, the amount of glucose tightly maintained in the blood is quite low. Unless a meal is very low in starches and sugars, blood glucose will rise for a period of an hour or two after a meal. When this occurs, beta cells in the pancreas release insulin to cause uptake of glucose into cells. In liver and muscle cells, more glucose is taken in than is needed and stored as glycogen (once called 'animal starch').[76] Diets with a high starch/sugar content, therefore, cause release of more insulin, and so more cell absorption. In diabetics, glucose levels vary in time with meals and vary a little more as a result of high-carbohydrate meals. In nondiabetics, blood-sugar levels are restored to normal levels within an hour or two, regardless of the content of a meal.

However, the ability of the body to store glycogen is finite. Once liver and muscular stores are full to the maximum, adipose tissue (subcutaneous and visceral fat stores) becomes the site of sugar storage in the form of fat.[citation needed] The body's ability to store fat is almost limitless, hence the modern dilemma of morbid obesity.

While any diet devoid of essential fatty acids (EFAs) and essential amino acids (EAAs) will result in eventual death, a diet completely without carbohydrates can be maintained indefinitely because triglycerides (which make up fat stored in the body and dietary fat) include a (glycerol) molecule which the body can easily convert to glucose.[77] It should be noted that the EFAs and all amino acids are structural building blocks, not inherent fuel for energy. However, a very-low-carbohydrate diet (less than 20 g per day) may negatively affect certain biomarkers[78] and produce detrimental effects in certain types of individuals (for instance, those with kidney problems). The opposite is also true; for instance, clinical experience suggests very-low-carbohydrate diets for patients with metabolic syndrome.[79]

Because of the substantial controversy regarding low-carbohydrate diets and even disagreements in interpreting the results of specific studies, it is difficult to objectively summarize the research in a way that reflects scientific consensus.[80] Although some research has been done throughout the 20th century,[81] most directly relevant scientific studies have occurred in the 1990s and early 2000s. Researchers and other experts have published articles and studies that run the gamut from promoting the safety and efficacy of these diets[82][83] to questioning their long-term validity[84][85] to outright condemning them as dangerous.[86][87] A significant criticism of the diet trend was that no studies evaluated the effects of the diets beyond a few months. However, studies emerged which evaluate these diets over much longer periods, controlled studies as long as two years and survey studies as long as two decades.[82][88][89][90][91]

A systematic review published in 2014 included 19 trials with a total of 3,209 overweight and obese participants, some with diabetes. The review included both extreme low carbohydrate diets high in both protein and fat, as well as less extreme low carbohydrate diets that are high in protein but with recommended intakes of fat. The authors found that when the amount of energy (kilojoules/calories) consumed by people following the low carbohydrate and balanced diets (45 to 65% of total energy from carbohydrates, 25 to 35% from fat, and 10 to 20% from protein) was similar, there was no difference in weight loss after 3 to 6 months and after 1 to 2 years in those with and without diabetes. For blood pressure, cholesterol levels and diabetes markers there was also no difference detected between the low carbohydrate and the balanced diets. The follow-up of these trials was no longer than two years, which is too short to provide an adequate picture of the long term risk of following a low carbohydrate diet.[5]

A 2003 meta-analysis that included randomized controlled trials found that "low-carbohydrate, non-energy-restricted diets appear to be at least as effective as low-fat, energy-restricted diets in inducing weight loss for up to one year."[92][93][94] A 2007 JAMA study comparing the effectiveness of the Atkins low-carb diet to several other popular diets concluded, "In this study, premenopausal overweight and obese women assigned to follow the Atkins diet, which had the lowest carbohydrate intake, lost more weight and experienced more favorable overall metabolic effects at 12 months than women assigned to follow the Zone, Ornish, or LEARN diets."[89] A July 2009 study of existing dietary habits associated a low-carbohydrate diet with obesity, although the study drew no explicit conclusion regarding the cause: whether the diet resulted in the obesity or the obesity motivated people to adopt the diet.[95] A 2013 meta-analysis that included only randomized controlled trials with one year or more of follow-up found, "Individuals assigned to a very low carbohydrate ketogenic diet achieve a greater weight loss than those assigned to a low fat diet in the long term."[96] In 2013, after reviewing 16,000 studies, Sweden's Council on Health Technology Assessment concluded low-carbohydrate diets are more effective as a means to reduce weight than low-fat diets, over a short period of time (six months or less). However, the agency also concluded, over a longer span (1224 months), no differences occur in effects on weight between strict or moderate low-carb diets, low-fat diets, diets high in protein, Mediterranean diet, or diets aiming at low glycemic indices.[97]

In one theory, one of the reasons people lose weight on low-carbohydrate diets is related to the phenomenon of spontaneous reduction in food intake.[98]

Carbohydrate restriction may help prevent obesity and type 2 diabetes,[99][100] as well as atherosclerosis.[101]

Potential favorable changes in triglyceride and high-density lipoprotein cholesterol values should be weighed against potential unfavorable changes in low-density lipoprotein cholesterol and total cholesterol values when low-carbohydrate diets to induce weight loss are considered.[102] However, the type of LDL cholesterol should also be taken into account here, as it could be that small, dense LDL is decreased and larger LDL molecules are increased with low-carb diets.[citation needed] The health effects of the different molecules are still being elucidated, and many cholesterol tests do not account for such details, but small, dense LDL is thought to be problematic and large LDL is not. A 2008 systematic review of randomized controlled studies that compared low-carbohydrate diets to low-fat/low-calorie diets found the measurements of weight, HDL cholesterol, triglyceride levels, and systolic blood pressure were significantly better in groups that followed low-carbohydrate diets. The authors of this review also found a higher rate of attrition in groups with low-fat diets, and concluded, "evidence from this systematic review demonstrates that low-carbohydrate/high-protein diets are more effective at six months and are as effective, if not more, as low-fat diets in reducing weight and cardiovascular disease risk up to one year", but they also called for more long-term studies.[103]

A study of more than 100,000 people over more than 20 years within the Nurses' Health Study observationally concluded a low-carbohydrate diet high in vegetables, with a large proportion of proteins and oils coming from plant sources, decreases mortality with a hazard ratio of 0.8.[104] In contrast, a low-carbohydrate diet with largely animal sources of protein and fat increases mortality, with a hazard ratio of 1.1.[104] This study, however, has been met with criticism, due to the unreliability of the self-administered food frequency questionnaire, as compared to food journaling,[105] as well as classifying "low-carbohydrate" diets based on comparisons to the group as a whole (decile method) rather than surveying dieters following established low-carb dietary guidelines like the Atkins or Paleo diets.[106]

Opinions regarding low-carbohydrate diets vary throughout the medical and nutritional science communities, yet government bodies, and medical and nutritional associations, have generally opposed this nutritional regimen.[citation needed] Since 2003, some organizations have gradually begun to relax their opposition to the point of cautious support for low-carbohydrate diets. Some of these organizations receive funding from the food industry.[citation needed] Official statements from some organizations:

The AAFP released a 'discussion paper' on the Atkins diet in 2006. The paper expresses reservations about the Atkins plan, but acknowledges it as a legitimate weight-loss approach.[107]

The ADA revised its Nutrition Recommendations and Interventions for Diabetes in 2008 to acknowledge low-carbohydrate diets as a legitimate weight-loss plan.[108][109] The recommendations fall short of endorsing low-carbohydrate diets as a long-term health plan, and do not give any preference to these diets. Nevertheless, this is perhaps the first statement of support, albeit for the short term, by a medical organization.[110][111] In its 2009 publication of Clinical Practice Recommendations, the ADA again reaffirmed its acceptance of carbohydrate-controlled diets as an effective treatment for short-term (up to one year) weight loss among obese people suffering from type two diabetes.[112]

As of 2003 in commenting on a study in the Journal of the American Medical Association, a spokesperson for the American Dietetic Association reiterated the association's belief that "there is no magic bullet to safe and healthful weight loss."[113] The Association specifically endorses the high-carbohydrate diet recommended by the National Academy of Sciences. They have stated "Calories cause weight gain. Excess calories from carbohydrates are not any more fattening than calories from other sources. Despite the claims of low-carb diets, a high-carbohydrate diet does not promote fat storage by enhancing insulin resistance."[114][bettersourceneeded]

As of 2008[update] the AHA states categorically that it "doesn't recommend high-protein diets."[115] A science advisory from the association further states the association's belief that these diets "may be associated with increased risk for coronary heart disease."[34] The AHA has been one of the most adamant opponents of low-carbohydrate diets.[citation needed] Dr. Robert Eckel, past president, noted that a low-carbohydrate diet could potentially meet AHA guidelines if it conformed to the AHA guidelines for low fat content.[116]

The position statement by the Heart Foundation regarding low-carbohydrate diets states, "the Heart Foundation does not support the adoption of VLCARB diets for weight loss."[46] Although the statement recommends against use of low-carbohydrate diets, it explains their major concern is saturated fats as opposed to carbohydrate restriction and protein. Moreover, other statements suggest their position might be re-evaluated in the event of more evidence from longer-term studies.

The consumer advice statements of the NHS regarding low-carbohydrate diets state that "eating a high-fat diet could increase your risk of heart disease" and "try to ensure starchy foods make up about a third of your diet"[117]

In 2008, the Socialstyrelsen in Sweden altered its standing regarding low-carbohydrate diets.[118] Although formal endorsement of this regimen has not yet appeared, the government has given its formal approval for using carbohydrate-controlled diets for medically supervised weight loss.

In a recommendation for diets suitable for diabetes patients published in 2011 a moderate low-carb option (3040%) is suggested.[119]

The HHS issues consumer guidelines for maintaining heart health which state regarding low-carbohydrate diets that "they're not the route to healthy, long-term weight management."[120]

Low-carbohydrate diets became a major weight loss and health maintenance trend during the late 1990s and early 2000s.[121][122][123] While their popularity has waned recently from its peak, they remain popular.[124][125] This diet trend has stirred major controversies in the medical and nutritional sciences communities and, as yet, there is not a general consensus on their efficacy or safety.[126][127] Many in the medical community remain generally opposed to these diets for long term health[128] although there has been a recent softening of this opposition by some organizations.[129][130]

Because of the substantial controversy regarding low-carbohydrate diets, and even disagreements in interpreting the results of specific studies, it is difficult to objectively summarize the research in a way that reflects scientific consensus.[131][132][133]

Although there has been some research done throughout the twentieth century, most directly relevant scientific studies have occurred in the 1990s and early 2000s and, as such, are relatively new and the results are still debated in the medical community.[132] Supporters and opponents of low-carbohydrate diets frequently cite many articles (sometimes the same articles) as supporting their positions.[134][135][136] One of the fundamental criticisms of those who advocate the low-carbohydrate diets has been the lack of long-term studies evaluating their health risks.[137][138] This has begun to change as longer term studies are emerging.[82]

A 2012 systematic review studying the effects of low-carbohydrate diet on weight loss and cardiovascular risk factors showed the LCD to be associated with significant decreases in body weight, body mass index, abdominal circumference, blood pressure, triglycerides, fasting blood sugar, blood insulin and plasma C-reactive protein, as well as an increase in high-density lipoprotein cholesterol (HDL). Low-density lipoprotein cholesterol (LDL) and creatinine did not change significantly. The study found the LCD was shown to have favorable effects on body weight and major cardiovascular risk factors (but concluded the effects on long-term health are unknown). The study did not compare health benefits of LCD to low-fat diets.[139]

A meta-analysis published in the American Journal of Clinical Nutrition in 2013 compared low-carbohydrate, Mediterranean, vegan, vegetarian, low-glycemic index, high-fiber, and high-protein diets with control diets. The researchers concluded that low-carbohydrate, Mediterranean, low-glycemic index, and high-protein diets are effective in improving markers of risk for cardiovascular disease and diabetes.[140]

In the first week or two of a low-carbohydrate diet, much of the weight loss comes from eliminating water retained in the body.[141] The presence of insulin in the blood fosters the formation of glycogen stores in the body, and glycogen is bound with water, which is released when insulin and blood sugar drop.[citation needed][142] A ketogenic diet is known to cause dehydration as an early, temporary side-effect.[143]

Advocates of low-carbohydrate diets generally dispute any suggestion that such diets cause weakness or exhaustion (except in the first few weeks as the body adjusts), and indeed most highly recommend exercise as part of a healthy lifestyle.[142][144] A large body of evidence stretching back to the 1880s shows that physical performance is not negatively affected by ketogenic diets once a person has been accustomed to such a diet.[145]

Arctic cultures, such as the Inuit, were found to lead physically demanding lives consuming a diet of about 1520% of their calories from carbohydrates, largely in the form of glycogen from the raw meat they consumed.[145][146][147][148] However, studies also indicate that while low-carb diets will not reduce endurance performance after adapting, they will probably deteriorate anaerobic performance such as strength-training or sprint-running because these processes rely on glycogen for fuel.[144]

Many critics argue that low-carbohydrate diets inherently require minimizing vegetable and fruit consumption, which in turn robs the body of important nutrients.[149] Some critics imply or explicitly argue that vegetables and fruits are inherently all heavily concentrated sources of carbohydrates (so much so that some sources treat the words 'vegetable' and 'carbohydrate' as synonymous).[150] While some fruits may contain relatively high concentrations of sugar, most are largely water and not particularly calorie-dense. Thus, in absolute terms, even sweet fruits and berries do not represent a significant source of carbohydrates in their natural form, and also typically contain a good deal of fiber which attenuates the absorption of sugar in the gut.[151] Lastly, most of the sugar in fruit is fructose, which has a reported negligible effect on insulin levels in obese subjects.[152]

Most vegetables are low- or moderate-carbohydrate foods (in the context of these diets, fiber is excluded because it is not a nutritive carbohydrate). Some vegetables, such as potatoes and carrots, have high concentrations of starch, as do corn and rice. Most low-carbohydrate diet plans accommodate vegetables such as broccoli, spinach, cauliflower, and peppers.[153] The Atkins diet recommends that most dietary carbs come from vegetables. Nevertheless, debate remains as to whether restricting even just high-carbohydrate fruits, vegetables, and grains is truly healthy.[154]

Contrary to the recommendations of most low-carbohydrate diet guides, some individuals may choose to avoid vegetables altogether to minimize carbohydrate intake. Low-carbohydrate vegetarianism is also practiced.

Raw fruits and vegetables are packed with an array of other protective chemicals, such as vitamins, flavonoids, and sugar alcohols. Some of those molecules help safeguard against the over-absorption of sugars in the human digestive system.[155][156] Industrial food raffination depletes some of those beneficial molecules to various degrees, including almost total removal in many cases.[157]

The major low-carbohydrate diet guides generally recommend multivitamin and mineral supplements as part of the diet regimen, which may lead some to believe these diets are nutritionally deficient. The primary reason for this recommendation is that if the switch from a high-carbohydrate to a low-carbohydrate, ketogenic diet is rapid, the body can temporarily go through a period of adjustment during which it may require extra vitamins and minerals. This is because the body releases excess fluids stored during high-carbohydrate eating. In other words, the body goes through a temporary "shock" if the diet is changed to low-carbohydrate quickly, just as it would changing to a high-carbohydrate diet quickly. This does not, in and of itself, indicate that either type of diet is nutritionally deficient. While many foods rich in carbohydrates are also rich in vitamins and minerals, many low-carbohydrate foods are similarly rich in vitamins and minerals.[158]

A common argument in favor of high-carbohydrate diets is that most carbohydrates break down readily into glucose in the bloodstream, and therefore the body does not have to work as hard to get its energy in a high-carbohydrate diet as a low-carbohydrate diet. This argument, by itself, is incomplete. Although many dietary carbohydrates do break down into glucose, most of that glucose does not remain in the bloodstream for long. Its presence stimulates the beta cells in the pancreas to release insulin, which has the effect of causing about two-thirds of body cells to take in glucose, and causing fat cells to take in fatty acids and store them. As the blood-glucose level falls, the amount of insulin released is reduced; the entire process is completed in non-diabetics in an hour or two after eating.[citation needed] High-carbohydrate diets require more insulin production and release than low-carbohydrate diets,[citation needed] and some evidence indicates the increasingly large percentage of calories consumed as refined carbohydrates is positively correlated with the increased incidence of metabolic disorders such as type 2 diabetes.[159]

In addition, this claim neglects the nature of the carbohydrates ingested. Some are indigestible in humans (e.g., cellulose), some are poorly digested in humans (e.g., the amylose starch variant), and some require considerable processing to be converted to absorbable forms. In general, uncooked or unprocessed (e.g., milling, crushing, etc.) foods are harder (typically much harder) to absorb, so do not raise glucose levels as much as might be expected from the proportion of carbohydrate present. Cooking (especially moist cooking above the temperature necessary to expand starch granules) and mechanical processing both considerably raise the amount of absorbable carbohydrate and reduce the digestive effort required.

Analyses which neglect these factors are misleading and will not result in a working diet, or at least one which works as intended. In fact, some evidence indicates the human brain the largest consumer of glucose in the body can operate more efficiently on ketones (as efficiency of source of energy per unit oxygen).[160]

The restriction of starchy plants, by definition, severely limits the dietary intake of microbiota accessible carbohydrates (MACs) and may negatively affect the microbiome in ways that contribute to disease.[161] Starchy plants, in particular, are a main source of resistant starch an important dietary fiber with strong prebiotic properties.[162][163][164] Resistant starches are not digestible by mammals and are fermented and metabolized by gut flora into short chain fatty acids, which are well known to offer a wide range of health benefits.[163][165][166][167][168][169] Resistant starch consumption has been shown to improve intestinal/colonic health, blood sugar, glucose tolerance, insulin-sensitivity and satiety.[170][171][172] Public health authorities and food organizations such as the Food and Agricultural Organization, the World Health Organization,[173] the British Nutrition Foundation[174] and the U.S. National Academy of Sciences[175] recognize resistant starch as a beneficial carbohydrate. The Joint Food and Agricultural Organization of the United Nations/World Health Organization Expert Consultation on Human Nutrition stated, "One of the major developments in our understanding of the importance of carbohydrates for health in the past twenty years has been the discovery of resistant starch."[173]

In 2004, the Canadian government ruled that foods sold in Canada could not be marketed with reduced or eliminated carbohydrate content as a selling point, because reduced carbohydrate content was not determined to be a health benefit. The government ruled that existing "low carb" and "no carb" packaging would have to be phased out by 2006.[176]

Some variants of low-carbohydrate diets involve substantially lowered intake of dietary fiber, which can result in constipation if not supplemented.[citation needed] For example, this has been a criticism of the induction phase of the Atkins diet (the Atkins diet is now clearer about recommending a fiber supplement during induction). Most advocates[who?][dubious discuss] today argue that fiber is a "good" carbohydrate and encourage a high-fiber diet.[citation needed]

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Low-carbohydrate diet - Wikipedia

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